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To order products in the Ross Metabolic Formula System, call:

1-800-551-5838

8:30 AM - 5:00 PM EST, Monday - Friday, except holidays.

For answers to questions about nutrition management of patients with


inherited metabolic disorders, call the Ross Metabolic Hotline:
1-800-986-8755.
The Ross Metabolic Formula System

Nutrition Support Protocols

4th Edition
The Ross Metabolic Formula System
Nutrition Support Protocols, 4th Edition
Authors:
Phyllis B. Acosta, Dr PH, RD, LD
Steven Yannicelli, PhD, RD, LD

Medical Director, Medical and Regulatory Affairs


Russell J. Merritt, MD, PhD

Vice President, Medical and Regulatory Affairs


William C. MacLean, MD

Manuscript Processor:
Christine K. Downs

Ross Products Division


Division of Abbott Laboratories
Columbus, Ohio 43216

Library of Congress, Catalog Card No 97-066096


© 2001 Abbott Laboratories
Price: $500

The product information contained here, although accurate at the time of publication, is subject to change.
The most current information may be obtained by referring to product labels.

A6224/(500)/June, 2001 LITHO IN USA


Acknowledgments

The shared experience of many clinicians has made possible the publication of the Ross Metabolic
Formula System Nutrition Support Protocols. We are particularly indebted, however, to three clinicians
listed below:
Vyoone Lewis, PhD, RD, Adjunct Professor, Pediatrics and Public Health and Tropical Medicine,
Tulane University, reviewed and made many excellent suggestions for improvement of Protocol 7,
"Nutrition Support of Infants, Children, and Adults with ß-Ketothiolase Deficiency."
Fran Rohr, MS, RD, in the Division of Clinical Genetics at The Children's Hospital, Boston, helped
prepare Protocol 9 "Nutrition Support of Infants, Children and Adults with Glutaric Aciduria Type I."
Sandy van Calcar, MS, RD, Nutritionist at the Metabolic Clinic, Biochemical Genetics Program,
University of Wisconsin helped prepare Protocol 20 for nutrition support of very long-chain-, long-chain-,
and long-chain-hydroxyacyl-CoA dehydrogenase deficiencies. She may be reached at 608/263-5981 if
you need to discuss these disorders further.
In addition, we thank the following physicians and nutritionists who reviewed and critiqued drafts of
protocols:

Karen Amorde-Spalding, MS, RD Reuben Matalon, MD, PhD


Children's Hospital Department of Pediatrics
Oakland, CA The University of Texas Medical Branch
Galveston, TX
Georgianne Arnold, MD Kimberlee Matalon, PhD, RD
Division of Genetics Department of Human Development
University of Rochester Medical Center University of Houston
Rochester, NY Houston, TX
Paul M Fernhoff, MD Shideh Mofidi, MS, RD
Division of Medical Genetics Westchester Institute for Human Development
Department of Pediatrics Valhalla, NY
Emory University School of Medicine
Atlanta, GA
Carol Greene, MD Maria Nardella, MA, RD
Children's National Medical Center Office of Children With Special Health Care Needs
Washington, DC Washington Department of Health
Olympia, WA
Harry Greene, MD Vivian Shih, MD
Medical Director, Slim Fast® Foods Company Massachusetts General Hospital
West Palm Beach, FL Boston, MA
L. Lyndon Key, Jr, MD, FAAP
Chief, Division of Pediatric Endocrinology
Department of Pediatrics
Medical University of South Carolina
Charleston, SC

Ross Products Division welcomes comments for additions or changes to this manual. Please address all
suggestions and inquiries to:
Phyllis B. Acosta, Dr PH, RD or Steven Yannicelli, PhD, RD
Director, Metabolic Diseases Clinical Research Scientist
614/624-7516; 800/986-8755 614/624-7648; 800/986-8755

Ross Products Division/Abbott Laboratories


P O Box 1317
Columbus, OH 43216-1317

© 2001 Ross Products Division iii


Contents
Page

Practical Aspects of Nutrition Support of Inborn Errors of Metabolism........................................vii

DISORDERS OF AMINO ACID METABOLISM


Aromatic Amino Acids
PROTOCOL 1 — Phenylketonuria (PKU) Nutrition Support of Infants, Children, and Adults With
PHENEX™-1 and PHENEX™-2 Amino Acid-Modified Medical Foods................... 1
PROTOCOL 2 — Maternal Phenylketonuria (MPKU) Nutrition Support of Pregnant Women With
Phenylketonuria (PKU) With PHENEX™-2 Amino Acid-Modified Medical Food .. 33
PROTOCOL 3 — Tyrosinemia Types Ia and Ib Nutrition Support of Infants, Children and Adults
With TYREX ®-1 and TYREX ®-2 Amino Acid-Modified Medical Foods.............. 49
PROTOCOL 4 — Tyrosinemia Types II and III Nutrition Support of Infants, Children, and Adults With
TYREX ®-1 and TYREX ®-2 Amino Acid-Modified Medical Foods ...................... 63

Branched-chain amino Acids


PROTOCOL 5 — Maple Syrup Urine Disease (MSUD) Nutrition Support of Infants, Children, and
Adults With KETONEX ®-1 and KETONEX ®-2 Amino Acid-Modified
Medical Foods..................................................................................................... 74
PROTOCOL 6 — Disorders of Leucine Catabolism Nutrition Support of Infants, Children, and Adults
With I-VALEX ®-1 and I-VALEX ®-2 Amino Acid-Modified Medical Foods ........ 103
PROTOCOL 7 — Mitochondrial Acetoacetyl-CoA Thiolase Deficiency (ß-Ketothiolase Deficiency)
Nutrition Support of Infants, Children, and Adults With KETONEX ®-1 and
KETONEX ®-2 Amino Acid-Modified Medical Foods......................................... 123

Sulfur Amino Acids


PROTOCOL 8 — Homocystinuria Nutrition Support of Infants, Children, and Adults With
HOMINEX ®-1 and HOMINEX ®-2 Amino Acid-Modified Medical Foods........... 137

Other Amino Acids


PROTOCOL 9 — Glutaric Aciduria Type I or 2-Ketoadipic Aciduria Nutrition Support of Infants,
Children, and Adults With GLUTAREX ®-1 and GLUTAREX ®-2 Amino Acid-
Modified Medical Foods .................................................................................... 166
PROTOCOL 10 — Glutaric Acidemia Type II (Multiple Acyl-CoA Dehydrogenase Deficiency)
Nutrition Support of Infants, Children, and Adults With PROVIMIN ® Protein-
Vitamin-Mineral Formula Component With Iron................................................. 196
PROTOCOL 11 — Lysinuric Protein Intolerance Nutrition Support of Infants, Children, and
Adults With PRO-PHREE ® Protein-Free Energy Module With Iron,
Vitamins & Minerals .......................................................................................... 209
PROTOCOL 12 — Nonketotic Hyperglycinemia Nutrition Support of Infants, Children, and
Adults With PRO-PHREE ® Protein-Free Energy Module With Iron,
Vitamins & Minerals .......................................................................................... 220
PROTOCOL 13 — Propionic or Methylmalonic Acidemia Nutrition Support of Infants, Children, and
Adults With PROPIMEX ®-1 and PROPIMEX ®-2 Amino Acid-Modified
Medical Foods................................................................................................... 230

DISORDERS OF CARBOHYDRATE METABOLISM


PROTOCOL 14 — Galactosemia Nutrition Support of Infants, Children, and Adults With ISOMIL ®
Soy Formula Powder With Iron ......................................................................... 262
PROTOCOL 15 — Glucose Transport Protein Defect, Pyruvate Dehydrogenase Complex Deficiency,
and Intractable Seizures Nutrition Support of Infants, Children, and Adults With
RCF ® Ross Carbohydrate-Free Soy Formula Base With Iron or ProViMin ®
Protein-Vitamin-Mineral Formula Component With Iron Powder........................ 279

iv © 2001 Ross Products Division


Page
PROTOCOL 16 — Glycogen Storage Disease Types Ia and Ib Nutrition Support of Infants,
Children, and Adults With RCF ® Ross Carbohydrate-Free Soy Formula Base
With Iron or ProViMin ® Protein-Vitamin-Mineral Formula Component With
Iron Powder ....................................................................................................... 296
PROTOCOL 17 — Hereditary Fructose Intolerance Nutrition Support of Infants,
Children, and Adults .......................................................................................... 313
PROTOCOL 18 — Pyruvate Carboxylase Deficiency Nutrition Support of Infants and Children With
PROVIMIN ® Protein-Vitamin-Mineral Formula Component With Iron ............... 325

DISORDERS OF LIPID METABOLISM


PROTOCOL 19 — Fasting Chylomicronemia Nutrition Support of Infants, Children, and Adults
With PROVIMIN ® Protein-Vitamin-Mineral Formula Component With Iron....... 338
PROTOCOL 20 — Mitochondrial Fatty Acid Oxidation Defects Nutrition Support of Infants, Children,
and Adults With PROVIMIN ® Protein-Vitamin-Mineral Formula Component
With Iron............................................................................................................ 350
DISORDERS OF MINERAL METABOLISM
PROTOCOL 21 — Hypercalcemia Nutrition Support of Infants, Children, and Adults With
CALCILO XD® Low-Calcium/Vitamin D-Free Infant Formula With Iron.............. 366
DISORDERS OF NITROGEN METABOLISM
PROTOCOL 22 — Gyrate Atrophy of the Choroid and Retina Nutrition Support of Infants, Children,
and Adults With CYCLINEX ®-1 and CYCLINEX ®-2 Amino Acid-Modified
Medical Foods ................................................................................................... 379
PROTOCOL 23 — Hyperornithinemia-Hyperammonemia-Homocitrullinuria Syndrome Nutrition
Support of Infants, Children, and Adults With CYCLINEX ®-1 and
CYCLINEX ®-2 Amino Acid-Modified Medical Foods......................................... 406
PROTOCOL 24 — Urea Cycle Disorders Nutrition Support of Infants, Children, and Adults With
CYCLINEX ®-1 and CYCLINEX ®-2 Amino Acid-Modified Medical Foods ......... 418

APPENDICES
Nutrient Composition Tables
APPENDIX 1. Fatty Acid Profile of Infant/Toddler Metabolic Medical Foods ..................................... A-2
APPENDIX 2. Fatty Acid Profile of Child/Adult Metabolic Medical Foods .......................................... A-2
APPENDIX 3. Density of Metabolic Medical Foods ........................................................................... A-3
APPENDIX 4. Nutrient Composition of Alimentum ® Protein Hydrolysate Formula With Iron............ A-4
APPENDIX 5. Nutrient Composition of Isomil ® Soy Formula With Iron............................................ A-5
APPENDIX 6. Nutrient Composition of Similac ® With Iron Infant Formula....................................... A-6
APPENDIX 7. Nutrient Composition of NeoSure® and Similac® Lactose Free ................................. A-7
APPENDIX 8. Nutrient Composition of Mature Human Milk, Skim Milk, Whole Cow's Milk, and
Whole Egg......................................................................................................... A-8
APPENDIX 9. Nutrient Composition of Polycose ® Glucose Polymers and Pedialyte ® Oral
Electrolyte Maintenance Solution....................................................................... A-9
APPENDIX 10. Nutrient Composition of Selected Vegetable Oils...................................................... A-9
APPENDIX 11. Nutrient Composition of Vi-Daylin ® Multivitamin + Iron Drops and
Pro-Phree ® Protein-Free Energy Module with Iron, Vitamins, and Minerals.... A-10
APPENDIX 12. Nutrient Composition of Very-Low-Protein Foods per 100 g.................................... A-11
Recommended Dietary Allowances (RDIs)
APPENDIX 13. Recommended Dietary Intakes (RDIs) for Minerals and Vitamins by Infants........... A-14
APPENDIX 14. Recommended Dietary Intakes (RDIs) for Minerals and Vitamins by Children,
Adolescents, and Adults................................................................................... A-15

© 2001 Ross Products Division v


Page

Technical Information
APPENDIX 15. Mathematical Formula for Interconversion of Plasma Amino Acids Between
µmol/L and mg/dL ............................................................................................ A-17
APPENDIX 16. Molecular Weights of Amino Acids.......................................................................... A-17
APPENDIX 17. Selected Laboratory Standards ............................................................................... A-18
APPENDIX 18. Estimating Osmolarity of a Medical Food Mixture ................................................... A-20
APPENDIX 19. Approximate Osmolarity of Selected Foods ............................................................ A-21
APPENDIX 20. Potential Renal Solute Load of Medical Food Mixture ............................................. A-22
APPENDIX 21. NDC Numbers for Metabolic Medical Foods............................................................ A-23

Clinical Forms
APPENDIX 22. Diet Guide .............................................................................................................. A-24
APPENDIX 23. Evaluation of Mineral/Vitamin Content of Medical Food Mixture ............................. A-25
APPENDIX 24. Diet Diary................................................................................................................ A-26
APPENDIX 25. Directions for Recording the Diet Diary ................................................................... A-27

Supplier Information
APPENDIX 26. Sources of Nutrients and Drugs............................................................................... A-28
APPENDIX 27. Low-Protein Food Suppliers .................................................................................... A-29
APPENDIX 28. Products for Prescription Diet Management ............................................................ A-29

INDEX ........................................................................................................................... I-1

vi © 2001 Ross Products Division


Practical Aspects of Nutrition Support of Inborn Errors of Metabolism
The problem of assuring adequate nutrition for infants, children, and adults with inherited metabolic
disorders may be decreased by the use of a protocol — a plan for treatment — because each patient
requires individualized nutrition care. The protocols in this manual are intended to serve as guides for
health care professionals who treat infants, children, adolescents, adults, and pregnant women with
inherited metabolic disorders. The protocols have been developed for use with the Ross Metabolic
Formula System (RMFS). They will be particularly useful to those who are relatively unfamiliar with
nutrition support of metabolic disorders, although specialists working in treatment centers where
protocols are already established should find them useful as well.

Overview
The protocols are organized according to disorder, with the Appendix containing information about
recommended nutrient intakes for various age groups, laboratory standards, and other technical
information. Also included in the Appendix are sample forms for a Diet Guide and Diet Diary, which may
be photocopied for individual use.
The newcomer to treatment of metabolic disorders will benefit from scanning the entire volume,
giving attention not only to the protocol relevant to the disorder of interest and the Appendices, but also
to the "Technical Information" section in the Appendices.
Recommended Dietary Intakes (RDIs)
Protein requirements are greater than Dietary Reference Intakes (DRIs) when L-amino acids are the
primary protein source (2). This increased need is because of rapid amino acid absorption and
subsequent oxidation (11, 16, 27), resulting in poor linear growth (7, 30), and lower than normal nitrogen
retention (27), body protein, and nitrogen content of patients fed primarily L-amino acids (3).
Recommended mineral and vitamin intakes suggested for patients with inherited metabolic
disorders are the greatest intakes suggested for each age in the 1980 and 1989 National Academy of
Sciences National Research Council (NAS-NRC) Recommended Dietary Allowances (RDAs) (10) and
the DRIs (22). Reasons for choosing the greatest intakes recommended include reports of inadequate
linear growth (7, 30) and poor bone mineralization (17) with Food and Agriculture Organization/World
Health Organization (FAO/WHO)-recommended protein intakes (9); greater than normal energy needs
when L-amino acids supply the bulk of protein equivalent (23); and depressed plasma concentrations of
ferritin (5, 25), selenium (12), and zinc (1) when RDAs were achieved with chemically defined diets.

Measuring Medical Foods


All measures for dry powders referred to in this manual are US standard, level household measures.
Cups and spoons intended for measuring liquids should not be used to measure powders. Many
measuring cups and spoons sold in food markets are grossly inaccurate. If scales that read in grams are
not available, US standard measuring equipment for dry materials, calibrated by the US Bureau of
Standards, should be obtained (8). Professionals, parents and patients should be aware that density of
medical foods varies because of settling during shipping and differences in packing. Because of this
variability, medical foods should be weighed on a scale that reads in grams. Weighing takes the
guesswork out of determining whether the amount of medical food ingested was the same as that
prescribed.

Supplying Restricted Amino Acids


For infants younger than 4 months of age, restricted amino acids are normally supplied by iron-fortified
® ®
proprietary infant formulas such as Similac With Iron Infant Formula or Isomil Soy Formula With Iron.
Use of iron-fortified products enhances iron status of infants who may absorb less than normal amounts
of iron from elemental medical foods. Similac and Isomil are available in Ready to Feed, Concentrated
Liquid, and Powder forms.
Baby foods (beikost) should be added slowly to the diet as the infant becomes developmentally
ready — sometime between 3 and 4 months of age for the developmentally normal. Prescribed amounts
of selected baby foods, and, later, table foods gradually displace infant formula as the source of
restricted amino acid(s).

© 2001 Ross Products Division vii


Meeting Water Needs
Water needs of infants should be supplied by the medical food mixture. Children and adults may have
additional free water when they are thirsty, if both the osmolarity and potential renal solute load of their
medical food mixtures are in safe ranges. Appendices 18, 19, and 20, pp A-20 through A-22, provide
help in estimating these.

Recognizing the Maillard Reaction


The Maillard reaction is a name given to a complex group of chemical reactions in foods in which
reacting amino acids, peptides, and proteins condense with sugars, forming bonds for which no digestive
enzymes are available. The Maillard reaction is accelerated by heat. It is characterized in its initial stage
by a light-brown color, followed by buff yellow and then dark brown in the intermediate and final stages.
Caramel-like and roasted aromas develop. Preparers of medical foods need to be able to recognize the
Maillard reaction because it causes loss of some sugars and amino acids. For this reason, medical foods
should not be heated beyond 100o F. For babies in the newborn nursery and at home, the aseptic
technique of mixing medical foods should be used (24).

Monitoring Amino Acid Concentrations


Successful management of inherited disorders of metabolism requires frequent monitoring of
appropriate analytes. The recommendations for plasma amino acid concentrations given here are close
to the normal range because 30 years of practice have suggested that values as close to normal as
possible are best. In the past, normal values were difficult to achieve because of inadequate knowledge
of requirements and food composition, infrequent monitoring, and failure to recognize the effects of
infection, trauma, and catabolism on plasma amino acid concentrations.
Frequent monitoring of plasma amino acid concentrations and other analytes gives the physician
and nutritionist data that verify the adequacy of the nutrition support prescription. These data are also
useful in motivating patient/parent compliance with the prescription. Patients with insulin-dependent
diabetes often monitor blood glucose three times daily, so frequent monitoring of plasma amino acids
should pose no major problem.
Some centers may wish to draw blood to monitor plasma amino acids at times other than those
listed in these protocols. We recognize the need to take a practical approach to nutrition support. If
blood cannot be drawn 2 to 4 hours after feeding, local normal standards should be developed for
plasma amino acid concentrations. However, prolonged fasting may cause spurious elevations of
plasma amino acid concentrations that could lead to unwarranted diet changes (13, 14), and blood
drawn 15 minutes to 1 hour after a meal may also yield spuriously high values (11).

Tuning the Prescription


Beikost should be introduced into the diet when infants are between 3 and 4 months of age or when
developmentally ready. Delay in introduction of beikost or table foods beyond this "critical period" often
leads to great difficulty in getting the infant to accept them at a later age. The protocols in this manual
for disorders of amino acid metabolism make use of a system of exchanges in which the primary
restricted amino acid is used as the basis for providing specific amounts of food in each serving list.
Serving Lists are Breads and Cereals, Fats, Fruits, Vegetables, Free Foods A, and Free Foods B. Some
centers with extensive experience have developed their own food lists for each disorder; the Ross
Metabolic Formula System products can be safely prescribed here as well.
Amino acid intakes recommended in these protocols are ranges within which requirements for most
patients will fall; however, the requirement of each patient will differ, with some patients tolerating
the lower end of the range and others requiring the upper end. The specific requirement for each
patient must be determined by frequent evaluation of plasma amino acid and transthyretin
concentrations, growth, and skin and hair. Patients who are growing well due to adequate protein intake
can normally tolerate more of the restricted amino acid(s) than can poorly growing infants and children
(2, 20).
When the restricted amino acid concentration(s) is (are) elevated in blood or plasma, detective work
is required to determine the reason(s) for the elevation. Some questions that should be asked are given
below:
Is the prescribed diet ingested daily?

viii © 2001 Ross Products Division


Does the child fail to ingest significant amounts of prescribed medical food? Beikost or table food?
Is measuring equipment accurate and are foods carefully weighed or measured?
Is the appropriate form of infant formula (concentrated liquid, powder, ready-to-feed) mixed with the
medical food?
Do siblings, relatives, neighbors, or baby sitters feed the patient? If "yes," do they give foods not
prescribed, or prescribed foods in greater than prescribed amounts?
If the patient is in daycare or school, are peers, teachers, etc, giving the child food, or is the child
"trading" foods?
Has the patient eaten any foods NOT on the servings lists?
Is the child "snitching" food?
Is the child ill?

Appropriate monitoring and disciplining of the child (18) on a special diet from an early age are essential
to diet compliance. For additional information about this topic, see references 21 and 28.

Changing Medical Foods


RMFS infant/toddler medical foods are designed to supply the nutrient needs of infants and young
children when they are supplemented with enough iron-fortified infant formula or foods to provide the
restricted amino acid(s) in amounts necessary for normal growth and development. When a toddler's
appetite is small, RMFS infant/toddler medical food should be replaced by RMFS child/adult medical
food. This change may be immediate only if the RMFS medical food is promptly accepted by the child.
Many children, however, are slow to accept new flavors.
As infants grow into children, they become more sensitive to changes in flavors of foods, a
phenomenon that often complicates ingestion of medical foods. Because nutrient requirements change
gradually over time, the medical food does not need to be changed abruptly. If acceptance is slow, the
amount of RMFS child/adult medical food is gradually increased as the infant/toddler medical
food is gradually decreased. The change from infant/toddler to child/adult medical food may require a
few days or several months.

Masking the Taste of Free Amino Acids


Foods with free amino acids containing sulfur and those with acidic or basic groups have a sulfurous,
bitter, unpleasant taste that may make diet compliance difficult (26). Products containing free amino
acids taste best when they are served very cold. Patients will accept these products containing free
amino acids more easily if they are served as "slushes," that is, chilled almost to freezing.

Selecting Nutrient Analysis Computer Software


A number of different software packages are available for computer evaluation of nutrient intake. Many
software packages appear impressive because their databases contain a large number of nutrients;
however, some packages with many nutrients have significant missing data (6). For calculating diets of
infants, children, and adults with inherited metabolic disorders, we recommend Amino Acid Analyzer (4)
available from Ross Products Division of Abbott Laboratories.

General Principles of Nutrition Support of Genetic Disease


Specific enzymes produced under the direction of individual genes catalyze specific reactions as noted
in the following genetic and metabolic sequences. A is converted to D through intermediates B and C
using enzymes AB, BC, and CD:

© 2001 Ross Products Division ix


If enzyme CD were genetically impaired, at least six pathophysiologic consequences could result:

G ene A B Gene BC G ene C D

Enzym e A B Enzym e B C Enzym e C D

A B C D

1. A deficiency of product D or some compound derived only from D. For example, in


phenylketonuria (PKU), phenylalanine (PHE) is not hydroxylated to form tyrosine (TYR). Not only is the
accumulated PHE toxic, but TYR becomes an essential nutrient. TYR must be supplemented to
maintain proper growth and plasma TYR concentrations in the nutrition support of patients with PKU.

2. A loss of feedback control. If product D normally functions in feedback control of enzyme AB,
overproduction of an intermediate product may occur because D is not present in amounts necessary to
regulate production of intermediates B and C.

3. An accumulation of C, the immediate precursor of the blocked reaction. In maple syrup urine
disease (MSUD), toxic branched-chain-α-ketoacids accumulate because they cannot be decarboxylated
and transacylated to their coenzyme A-acyl derivatives. The consequence in the neonate is severe
central nervous system depression with apnea, stupor, coma, and death. If the neonate survives, mental
retardation or death ensues if the child is not treated by diet restriction within 3 to 5 days of life.
4. An accumulation of A or B, remote precursors of the blocked reaction sequence CD. If the
preceding reactions are freely reversible, a precursor in addition to that proximal to the block will
accumulate. This process is illustrated in MSUD by increased leucine (LEU), isoleucine (ILE), and valine
(VAL), which are formed by reamination of the branched-chain-α-ketoacids — α-ketoisocaproic, α-keto-
β-methylvaleric, and α-ketoisovaleric acids, respectively.

5. Increased production of alternative product (eg, E, through little-used metabolic pathways.


When PHE accumulates because of impaired phenylalanine hydroxylase, phenylpyruvic, phenylacetic,
and phenyllactic acids are produced in greater than normal amounts through existing pathways that
normally do not function at physiologic concentrations of cellular PHE.

6. Inhibition of alternative pathways by accumulated substrate (eg, C in CD impairment). For


example, neurotransmitter synthesis may be depressed in PKU owing to increased blood PHE
concentrations that inhibit tyrosine hydroxylase and tryptophan hydroxylase in the central nervous
system. Another example is type Ia tyrosinemia. The accumulation of succinylacetone inhibits δ-
aminolevulinic acid (δ-ALA) dehydratase and results in secondary accumulation of δ-ALA, attacks of
acute porphyria with peripheral neuropathy, hypertension, and bizarre behavior.

Nine approaches to nutrition support of inborn errors of metabolism are discussed below. The
appropriate approach depends on the biochemistry and pathophysiology of disease expression —
several therapeutic approaches may be used simultaneously.

1. Enhancing anabolism and depressing catabolism. This involves the use of adequate amounts
of appropriate medical food and other foods to supply protein and energy, and administration of insulin,

x © 2001 Ross Products Division


if needed. Fasting should be prevented. This therapeutic measure should be used in all patients with an
inborn error involving catabolic pathways.

2. Correcting the primary imbalance in metabolic relationships. This correction involves reducing,
through diet restriction, the accumulation of substrate that is toxic. This approach is used in PKU where
PHE, and MSUD where LEU, ILE, and VAL are limited.

3. Providing alternative metabolic pathways to decrease accumulated toxic precursors in


blocked reaction sequences. In the treatment of isovaleric acidemia, innocuous isovalerylglycine is
formed from accumulating isovaleric acid if supplemental glycine is provided to drive glycine-N-
transacylase. Isovalerylglycine is excreted in the urine.

4. Supplying products of blocked primary pathways. As examples, arginine (ARG) is supplied in


most disorders of the urea cycle, cystine (CYS) is supplied in homocystinuria (HCU), TYR in PKU,
tetrahydrobiopterin in biopterin synthetic defects, and ether lipids in patients with some peroxisomal
disorders.

5. Supplementing "conditionally essential" nutrients. Carnitine, CYS, and TYR are supplemented
in secondary liver disease, and carnitine is supplemented in organic acidemias.

6. Stabilizing altered enzyme proteins. The rate of biologic synthesis and degradation of
holoenzymes depends on their structure. In some holoenzymes, saturation by coenzyme increases their
biologic half-life and, thus, overall enzyme activity at the new equilibrium. This therapeutic mechanism
is used in HCU and MSUD. Pharmacologic intakes of pyridoxine in HCU and thiamin in MSUD increase
intracellular pyridoxal phosphate and thiamin pyrophosphate and increase the specific activity of
cystathionine ß-synthase and branched-chain-α-ketoacid dehydrogenase complex.
7. Replacing deficient cofactors. Many vitamin-dependent disorders are caused by blocks in
coenzyme production and are "cured" by pharmacologic intake of a specific vitamin precursor. This
mechanism presumably involves overcoming a partially impaired enzyme reaction by mass action.
Impairment of reactions required to produce either methylcobalamin or adenosylcobalamin result in
HCU and/or methylmalonic aciduria (MMA). Daily intakes of appropriate forms of milligram quantities of
vitamin B12 may cure the disease.

8. Inducing enzyme product. If the structural gene or enzyme is intact, but suppressor, enhancer, or
promoter elements are not functional, abnormal amounts of enzyme may be produced. The structural
gene may be "turned on" or "turned off" to enable normal enzymatic production to occur. In the acute
porphyria of tyrosinemia type Ia, excessive δ-ALA production may be reduced by suppressing
transcription of the δ-ALA synthase gene with excess glucose.

9. Supplementing nutrients that are inadequately absorbed or not released from their
apoenzyme. Examples are zinc in acrodermatitis enteropathica and biotin in biotinidase deficiency.

The Table that follows provides information, by disorder, on appropriate Ross Products or other products
to use for nutrition support of a variety of inborn errors of metabolism.

© 2001 Ross Products Division xi


xii
TABLE A. Nutrition Support of Selected Inborn Errors of Metabolism

Inborn Error and Defect Nutrient(s) To Modify Vitamin-Responsive Ross Metabolic


Formula/Other
INBORN ERRORS OF AMINO ACID METABOLISM
Aromatic Amino Acids
Alcaptonuria (homogentisic acid oxidase) Restrict phenylalanine (PHE) and tyrosine (TYR). No Tyrex-2
Phenylketonuria (PKU) and Restrict PHE and increase TYR. Maintain protein No Phenex-1
Hyperphenylalaninemia (phenylalanine hydroxylase) intake above NAS-NRC RDAs for age. Phenex-2
Hyperphenylalaninemia (dihydropteridine reductase); Restrict PHE and increase TYR. Maintain protein Yes; tetrahydrobiopterin, Phenex-1
GTP cyclohydrolase I; pyruvolyltetrahydropterin intake above NAS-NRC RDAs for age. 2 mg/kg/day. Phenex-2
synthase)
Tyrosinemia type Ia (fumarylacetoacetate Restrict PHE and TYR. Maintain protein and energy No Tyrex-1
hydrolyase) intakes above NAS-NRC RDAs for age. Tyrex-2
Tyrosinemia type Ib (maleylacetoacetate isomerase) Restrict PHE and TYR. Maintain protein and energy No Tyrex-1
intakes above NAS-NRC RDAs for age. Tyrex-2
Tyrosinemia types II and III (tyrosine Restrict PHE and TYR. Maintain protein and energy No Tyrex-1
aminotransferase) intakes above NAS-NRC RDAs for age. Tyrex-2
Branched-chain amino Acids
ß-Ketothiolase deficiency Restrict ILE. Maintain protein and energy intakes No Ketonex-1
above NAS-NRC RDAs for age. Administer L- Ketonex-2
carnitine (both must be
supplemented with
LEU and VAL)
Maple syrup urine disease (MSUD) (branched-chain- Restrict ILE, LEU, and VAL. Maintain protein and Yes; thiamin-responsive if anyKetonex-1
ketoacid [BCKA] dehydrogenase complex) energy intakes above NAS-NRC RDAs for age. residual enzyme activity. Ketonex-2
Response to thiamin
inadequate to alleviate need
for restriction of branched-
chain amino acids. 100 to
300 mg of ORAL thiamin
daily.
3-Hydroxyisobutyric aciduria (3-Hydroxyisobutyric Restrict VAL. Administer L-carnitine. Maintain No Ketonex-1
acid dehydrogenase) protein and energy intakes above NAS-NRC Ketonex-2 (both must
© 2001 Ross Products Division

RDAs for age. be supplemented


with ILE and LEU)
Isovaleric acidemia (isovaleryl-CoA dehydrogenase); Restrict LEU. Administer L-carnitine and glycine No I-Valex-1
3-Methylcrotonylglycinuria (3-methylcrotonyl-CoA (GLY). Maintain protein and energy intakes I-Valex-2
carboxylase) above NAS-NRC RDAs for age.
3-Methylglutaconic aciduria (3-methylglutaconyl-CoA Restrict LEU. Administer L-carnitine and GLY Yes, pantothenic acid, 15- I-Valex-1
hydratase) Maintain protein and energy intakes above NAS- 150 mg/day I-Valex-2
NRC RDAs for age.
© 2001 Ross Products Division

Inborn Error and Defect Nutrient(s) To Modify Vitamin-Responsive Ross Metabolic


Formula/Other
3-Hydroxy-3-methylglutaric aciduria (3-hydroxy-3- Restrict LEU and fat. Maintain protein and energy No I-Valex-1
methylglutaryl-CoA lyase) intakes above NAS-NRC RDAs for age. I-Valex-2
Sulfur Amino Acids
Homocystinuria, pyridoxine nonresponsive Restrict MET; increase cystine (CYS); supplement No Hominex-1
(cystathionine ß-synthase) folate and betaine. Maintain protein intake above Hominex-2
NAS-NRC RDAs for age.
Homocystinuria, pyridoxine-responsive Pyridoxine. Yes; 25 to 1,000 mg of ORAL None indicated
(Cystathionine ß-synthase) pyridoxine daily. Use
smallest amount that results
in biochemical normalcy as
excess may cause
peripheral neuropathy.
Other Inborn Errors of Amino Acid Metabolism
Glutaric aciduria type I (glutaryl-CoA Restrict lysine (LYS) and tryptophan (TRP). Yes; some patients may have a Glutarex-1
dehydrogenase) Administer L-carnitine. Maintain protein intake partial response to ORAL Glutarex-2
above NAS-NRC RDAs for age. riboflavin, 100 to 300 mg
daily in small doses
administered with food.
Glutaric acidemia type II (multiple acyl-CoA Restrict protein and fat. Administer L-carnitine, and Yes? Prescribe 100 to 300 mg Pro-Phree
dehydrogenase) GLY. Maintain energy intake above NAS-NRC ORAL riboflavin daily in ProViMin
RDAs for age. small doses with food.
2-Ketoadipic aciduria (2-ketoadipic dehydrogenase) Restrict LYS and TRP. Administer L-carnitine. No Glutarex-1
Maintain protein intake above NAS-NRC RDAs Glutarex-2
for age.
Lysinuric protein intolerance (defect in renal, Restrict protein. Supplement with L-citrulline (CIT). No Pro-Phree
intestinal, and hepatic membrane transport of Maintain energy intake above NAS-NRC RDAs
dibasic amino acids) for age.
Methylmalonic acidemia (methylmalonyl-CoA Restrict ILE, MET, threonine (THR), VAL, odd- No Propimex-1
mutase º or —) chain-fatty acids, and long-chain-unsaturated Propimex-2
fatty acids. Maintain protein and energy intakes
above NAS-NRC RDAs for age.
Methylmalonic acidemia (cobalamin reductase; Minimum restriction of ILE, MET, THR, and VAL. Yes; 1 to 2 mg Propimex-1
adenosyltransferase) Administer L-carnitine. hydroxycobalamin daily. Propimex-2
Nonketotic hyperglycinemia (one of four protein Restrict protein. Maintain energy intake above NAS- No Pro-Phree
components [P, H, T, or L] of a multienzyme NRC RDAs for age. Similac
complex in the mitochondrial GLY cleavage Isomil
system) Alimentum
xiii
xiv

Inborn Error and Defect Nutrient(s) To Modify Vitamin-Responsive Ross Metabolic


Formula/Other
Propionic acidemia (propionyl-CoA carboxylase) Restrict ILE, MET, THR, VAL, odd-chain-fatty acids, Yes? Questionable; some Propimex-1
and long-chain-unsaturated fatty acids. clinicians supplement with Propimex-2
Administer L-carnitine. Maintain protein and 5 to 10 mg ORAL D-biotin
energy intakes above NAS-NRC RDAs for age. daily.
INBORN ERRORS OF CARBOHYDRATE METABOLISM
Galactosemias
Epimerase deficiency Delete galactose, add specific known amount of No Health Source
galactose if no epimerase activity. Maintain Isomil Powder
protein and energy intakes at NAS-NRC RDAs
for age.
Galactokinase deficiency Delete galactose. Maintain protein and energy No Health Source
intakes at NAS-NRC RDAs for age. Isomil Powder
Galactose-1-phosphate uridyl transferase deficiency Delete galactose. Maintain protein and energy No Health Source
intakes at NAS-NRC RDAs for age. Isomil Powder
Glucose transport protein deficiency (GLUT1) Restrict carbohydrate (CH2O). High-fat, ketogenic No ProViMin
diet. RCF
Glycogen Storage Diseases
GSD Type Ia (glucose-6-phosphatase); Avoid lactose, fructose and sucrose. Modify type of No ProViMin
GSD Type Ib (defective glucose-6-phosphate CH2O and frequency of feeds. Maintain protein Polycose
transport) and energy intakes at NAS-NRC RDAs for age. RCF
Raw cornstarch after 6
to 9 mos of age
GSD Type III (amylo-1, 6-glucosidase) Provide high protein. Avoid lactose, fructose and No Polycose
sucrose. Supplement with L-alanine (ALA). ProViMin
Modify type of CH2O and frequency of feeds. RCF
Maintain energy intake at NAS-NRC RDAs for Raw cornstarch after 6
age. to 9 mos of age
GSD Type IV (α-1, 4-Glucan α-1, 4-glucan 6- Provide high protein unless cirrhosis present. No ProViMin
glucosyltransferase) Modify type of CH2O and frequency of feeds. RCF
Maintain energy intakes at NAS-NRC RDAs for Polycose
age. Raw cornstarch after 6
to 9 mos of age
© 2001 Ross Products Division

GSD Type V (muscle phosphorylase) Provide high protein. Supplement L-ALA. Maintain No ProViMin
energy intake at NAS-NRC RDAs for age. RCF
Hereditary Fructose Intolerance
Hereditary fructose intolerance (aldolase B) Restrict fructose to < 10 mg/kg of body weight; No Pro-Phree
restrict protein if liver damage. Maintain energy Similac for infants
intake at NAS-NRC RDAs for age. Cow's milk for children
© 2001 Ross Products Division

Inborn Error and Defect Nutrient(s) To Modify Vitamin-Responsive Ross Metabolic


Formula/Other
Pyruvate Dehydrogenase Complex Deficiency Restrict CH2O. High-fat, ketogenic diet. Yes? Thiamin. ProViMin
(E1α or E1β) RCF
Pyruvate carboxylase deficiency Moderate protein, CH2O, fat. Administer thiamin, No ProViMin
citrate, and possibly L-ASP acid, L-asparagine,
L-glutamic acid, and L-glutamine.
Seizures Restrict CH2O. High-fat, ketogenic diet. No ProViMin
RCF
INBORN ERRORS OF CHOLESTEROL METABOLISM
Smith-Lemli-Opitz syndrome (microsomal 7- Supplement cholesterol, > 50 mg/kg body weight; increase No Any tolerated
energy intake to amount required for adequate weight gain
dehydrocholesterol reductase) (19)
INBORN ERRORS OF FATTY ACID OXIDATION
Disorders of Mitochondrial Fatty Acid Oxidation
Carnitine-acylcarnitine translocase deficiency (15) Restrict fat; limit MCT. Provide adequate essential No ProViMin
fatty acids. Administer L-carnitine; prevent fasting
Very-long-chain and long-chain-acyl-CoA Restrict long-chain-fatty acids (> 14 carbons) to 15% No ProViMin
dehydrogenase deficiencies; of energy. Avoid fasting. Provide adequate protein
Long-chain-hydroxyacyl-CoA dehydrogenase and energy. Supplement fractionated coconut oil
deficiency and L-carnitine. Supplement docosahexaenoic acid
(DHA) in patients with long-chain-hydroxyacyl-CoA
dehydrogenase deficiency.
Medium-chain-acyl-CoA dehydrogenase deficiency Restrict fat to 20% to 30% of energy. Avoid fasting. No ProViMin
Provide adequate protein and energy. Supplement
L-carnitine.
Short-chain and short-chain-hydroxyacyl-CoA Restrict fat to 20% to 30% of energy. Avoid fasting. No ProViMin
dehydrogenase deficiencies Provide adequate protein and energy. Supplement
L-carnitine
INBORN ERRORS OF LIPOPROTEIN METABOLISM
Abetalipoproteinemia and hypobetalipoproteinemia Restrict triglycerides with long-chain-fatty acids. No ProViMin
(Apo B, absence and decreased) Supplement with vitamins A, D, E and K and Polycose
linoleic and α-linolenic acids. Maintain protein and
energy intakes at NAS-NRC RDAs for age.
Lecithin:cholesterol acyltransferase deficiency Restrict fat. Maintain protein and energy intakes at No ProViMin
(LCAT) NAS-NRC RDAs for age. Polycose
Hyperlipoproteinemias
Type I (extrahepatic lipoprotein lipase; Apo C-II Restrict triglycerides with long-chain-fatty acids to 8% No ProViMin
absent or decreased; lipoprotein lipase inhibitors) to 15% of energy. Maintain protein and energy Polycose
intakes at NAS-NRC RDAs for age.
xv
xvi

Inborn Error and Defect Nutrient(s) To Modify Vitamin-Responsive Ross Metabolic


Formula/Other
Type IIa (LDL receptors absent or defective) Restrict cholesterol and saturated fat; increase No Isomil
polyunsaturated fatty acids (PUFAs). Maintain ProViMin
protein and energy intakes at NAS-NRC RDAs RCF
for age. Polycose
Type IIb Restrict cholesterol, saturated fat, mono- and No ProViMin
disaccharides, and alcohol. Increase PUFAs and RCF
fiber. Maintain protein and energy intakes at Polycose
NAS-NRC RDAs for age.
Type III (hepatic lipoprotein lipase; homozygous for Restrict cholesterol, saturated fat, mono- and No ProViMin
abnormal Apo E2; remnant receptor defect) disaccharides, and alcohol. Increase PUFAs and RCF
fiber. Restrict energy if patient is overweight. Polycose
Maintain protein intake at NAS-NRC RDAs for
age.
INBORN ERRORS OF MINERAL METABOLISM
Idiopathic hypercalcemia with supravalvular aortic Restrict calcium and vitamin D. No Calcilo XD
stenosis — Williams syndrome.
Osteopetrosis Restrict calcium and vitamin D. No Calcilo XD
Sulphite oxidase deficiency (29) Restrict cystine and methionine No Pro-Phree
INBORN ERRORS OF NITROGEN METABOLISM
Carbamylphosphate synthetase deficiency; Restrict protein. Supplement with essential amino No Cyclinex-1
Ornithine transcarbamylase deficiency acids (EAAs), L-carnitine, and L-CIT. Maintain Cyclinex-2
energy intake above NAS-NRC RDAs for age.
Citrullinemia (argininosuccinate synthetase); Restrict protein. Supplement with EAAs, L-carnitine, No Cyclinex-1
Argininosuccinic aciduria (argininosuccinate lyase) and L-ARG. Maintain energy intake above NAS- Cyclinex-2
NRC RDAs for age.
Argininemia (arginase) Restrict protein. Supplement with EAAs and No Cyclinex-1
L-carnitine. Maintain energy intake above NAS- Cyclinex-2
NRC RDAs for age.
Gyrate atrophy (ornithine-∆-aminotransferase) Restrict arginine (ARG) and protein. Supplement Yes; pyridoxine. Cyclinex-1
with EAAs and L-carnitine. Maintain energy Cyclinex-2
intake above NAS-NRC RDAs for age.
Hypernornithinemia - hyperammonemia - Restrict protein. Supplement with L-ARG, L-CIT, or No Cyclinex-1
© 2001 Ross Products Division

homocitrullinuria syndrome (HHH syndrome) L-ornithine (ORN). Maintain energy intake above Cyclinex-2
(defective ornithine transport across mitochondrial NAS-NRC RDAs for age.
membrane)
N-acetylglutamate synthetase deficiency Restrict protein. Supplement with EAAs, L-carnitine, No Cyclinex-1
and N-carbamylglutamate. Maintain energy Cyclinex-2
intake above NAS-NRC RDAs for age.
References

1. Acosta PB, Fernhoff PM, Warshaw HS, et al: Zinc status and growth of children undergoing treatment for
phenylketonuria. J Inher Metab Dis 1982;5:107-110.
2. Acosta PB, Yannicelli S: Protein intake affects phenylalanine requirements and growth of infants with
phenylketonuria. Acta Paediatr 1994; (Suppl):407:66-67.
3. Allen JR, Baur LA, Waters DL, et al: Body protein in prepubertal children with phenylketonuria. Eur J Clin Nutr
1996;50:178-186.
4. Amino Acid Analyzer© is available from Ross Products Division, Appendix 28, p A-29.
5. Bodley JL, Austin VJ, Hanley WB, et al: Low iron stores in infants and children with treated phenylketonuria: A
population at risk for iron-deficiency anaemia and associated cognitive deficits. Eur J Pediatr 1993;152:140-143.
6. Byrd-Bredbenner C: Computer nutrient analysis software packages: Considerations for selection. Nutr Today
1988; September-October:13.
7. Dhondt JL, Largilliere C, Moreno L, Farriaux JP: Physical growth in patients with phenylketonuria. J Inher Metab
Dis 1995;18:135-137.
8. Dietetic scales that weigh in grams are available from Pelouze Scales Co, PO Box 1058, Evanston, IL 60204. For
ordering information, see Appendix 28, p A-29.
9. FAO/WHO/UNU Expert Consultation: Energy and Protein Requirements. Geneva: World Health Organization,
1985.
10. Food and Nutrition Board, Committee on Dietary Allowances: Recommended Dietary Allowances, eds 9 and 10.
Washington, DC: National Academy of Sciences, 1980 and 1989.
11. Gropper S, Acosta PB: Effect of simultaneous ingestion of L-amino acids and whole protein on plasma amino
acids and urea nitrogen concentrations in humans. JPEN 1991;15:48-53.
12. Gropper S, Acosta PB, Clarke-Sheehan N, et al: Trace element status of children with PKU and normal children.
J Amer Diet Assoc 1988;88:459-464.
13. Gropper SS, Gropper DM, Acosta PB: Plasma amino acid response to ingestion of L-amino acids and whole
protein. J Pediatr Gastroenterol Nutr 1993;16:143-150.
14. Guttler F, Olseson ES, Wamberg E: Diurnal variations of serum phenylalanine in phenylketonuric children on low
phenylalanine diet. Am J Clin Nutr 1969;22:1568-1570.
15. Haworth JC, Demaugre F, Booth FA, et al: A typical features of the hepatic form of carnitine palmitoyltransferase
deficiency in a Hutterite family. J Pediatr 1992;121;553-557.
16. Herrmann ME, Broesicke HG, Keller M, et al: Dependence of the utilization of a phenylalanine free amino acid
mixture on different amounts of a single dose ingested. A case report. Eur J Pediatr 1994;153:501-503.
17. Hillman L, Schlotzhauer C, Lee D, et al: Decreased bone mineralization in children with phenylketonuria under
treatment. Eur J Pediatr 1996;155 (Suppl 1):S148-S152.
18. Howard BJ: Discipline in early childhood. Pediatr Clin North Am 1991;38:1351-1369.
19. Kelly RJ: Inborn errors of cholesterol biosynthesis. Adv Pediatr 2000;47:1-53.
20. Kindt E, Motzfeldt K, Halvorsen S, Lie S: Protein requirements in infants and children treated for phenylketonuria.
Am J Clin Nutr 1983;37:778-785.
21. Macht J: Poor Eaters: Helping Children Who Refuse to Eat. New York: Plenum Press, 1990.
22. Monsen ER: Dietary reference intakes for antioxidant nutrients: Vitamin C, vitamin E, selenium, and carotenoids.
J Amer Diet Assoc 2000;100:637-640.
23. Pratt EL, Snyderman SE, Cheung MW, et al: The threonine requirement of the normal infant. J Nutr
1955;56:231-251.
24. Preparation of Formula for Infants: Guidelines for Health Care Facilities. Chicago, IL: The American Dietetic
Association, 1991.
25. Scaglioni S, Zucotti G, Vedovello M, et al: Study of serum ferritin in 58 children with classic phenylketonuria and
persistent hyperphenylalaninemia. J Inher Metab Dis 1985;8:160.
26. Schiffman SS, et al: Increased taste thresholds of amino acids with age. Am J Clin Nutr 1979;32:1622.
27. Schoeffer A, Herrmann ME, Broesicke HG, Moench E: Effect of dosage and timing of amino acid mixtures on
nitrogen retention in patients with phenylketonuria. J Nutr Med 1994;4:415-418.
28. Taylor JF, Latta RS: Why Can't I Eat That? Saratoga, CA: R & E Publishers, 1993.
29. Touati G, Rusthoven E, Depondt E, et al: Dietary therapy in two patients with a mild form of sulphite oxidase
deficiency. Evidence for clinical and biological improvement. J Inher Metab Dis 2000;23:45-53.
30. Verkerk PH, van Spronsen FJ, Smit GPA, Sengers RCA: Impaired prenatal and postnatal growth in Dutch patients
with phenylketonuria. Arch Dis Child 1994;71:114-118.

© 2001 Ross Products Division xvii


PROTOCOL 1 — Phenylketonuria (PKU)

Nutrition Support of Infants, Children, and Adults With


PHENEX™-1 and PHENEX™-2 Amino Acid-Modified Medical Foods
I. Introduction
Phenylketonuria (PKU) and hyperphenylalaninemia result from a defect in the enzyme phenylalanine
(PHE) hydroxylase (PAH), which is responsible for changing PHE, an essential amino acid, to tyrosine
(TYR), normally a nonessential amino acid (Figure A) (19, 58). A defect in PAH activity results in
accumulation of PHE in blood and body tissues from which PHE metabolites are produced. Another
consequence is that blood and tissue concentrations of TYR may be deficient since TYR is an
essential amino acid for patients with PKU. Hyperphenylalaninemia may also result from deficiency of
tetrahydrobiopterin (H4 biopterin), a coenzyme for PAH, TYR hydroxylase, and tryptophan
hydroxylase. The latter two enzymes are required for neurotransmitter synthesis. Therapy of H4
biopterin deficiency requires L-DOPA, carbidopa, and H4 biopterin in addition to a PHE-restricted diet
(19, 58). Some patients with hyperphenylalaninemia may have a mutant PAH enzyme with decreased
affinity for the coenzyme H4 biopterin (treat with H4 biopterin, 5-10 mg/kg) (42, 66).

GTP
GTP cyclohydrolase

Dihydroneopterin triphosphate
+ +
NAD NADH + H

Dihydrobiopterin Dihydropteridine reductase


synthetase
(N)

Dietary protein

Dietary protein H4 biopterin H2 biopterin


Tissue protein

CO2 + H2O
Tissue Tyrosine (N)
Phenylalanine*
protein (N) Melanin
(N)
Epinephrine

Phenylalanine Thyroxine
O2 H2O
hydroxylase

Orthohydroxy- Phenylpyruvate* Phenylethylamine


phenylacetate
* Accumulates in untreated PKU

(N) = several steps


Phenyllactate* Phenylacetate*

Indicates sites of possible enzyme defects

Phenylacetylglutamine

Figure A. Phenylalanine metabolism in phenylketonuria

© 2001 Ross Products Division Phenylketonuria 1


II. Screening for PKU
Newborn screening for PKU started in the mid-1960s. An elevated blood PHE concentration found on a
newborn screen suggests the need for a diagnostic work-up. A positive newborn screen for elevated
blood PHE concentration is NOT a positive diagnosis (19, 58).
The incidence of PKU is approximately 1/10,000 to 1/25,000 live births. It is greater in people of Irish
descent than in many other ethnic groups, but PKU is found in all ethnic groups (19, 58).

III. Outcome of Nutrition Support


If untreated, persons with PKU may have irreversible mental retardation and one or more of the
following: neurologic abnormalities, abnormal electroencephalograms (EEGs), seizures, hyperactivity,
musty odor, and eczema. Newborn screening, retrieval, diagnosis, and early nutrition intervention
have resulted in children with normal intelligence. Many treated patients complete college (19, 58).
Until recently, children with PKU were removed from a PHE-restricted diet at school age or younger.
Because brain growth was believed to be complete, a PHE-restricted diet was thought to be no longer
necessary. But data have shown that children removed from a PHE-restricted diet have decreased IQ
and poorer school performance compared to the same age-matched children with PKU who remained
on diet (12). Neurologic deterioration, mental aberrations, physical changes in the brain, and
psychiatric problems have been reported in persons either removed from the PHE-restricted diet or in
poor metabolic control (56, 68, 70, 71). For these reasons, it is now recommended that persons with
PKU remain on diet for life and remain in good metabolic control.
Offspring of mothers with untreated PKU or hyperphenylalaninemia (increased blood PHE without
phenylketones in the urine) suffer from permanent mental retardation and may have microcephaly,
congenital heart defects, and other anomalies. Although these offspring usually do not have PKU, they
are exposed in utero to toxic concentrations of PHE (58).

IV. Establish Diagnosis


A. The Defect (19, 58)
1. PKU may result from defect in any of at least 3 enzymes:
a. Biopterin synthetase group of enzymes.
b. Dihydropteridine reductase.
c. PAH.
d. PAH with decreased affinity for H4 biopterin (42, 66)
B. Clinical Evaluation
1. Concentration of ≥ 2 mg PHE/dL by bacterial inhibition assay of dried blood spot if test is
administered before neonate is 24 hours old (18), or ≥ 4 mg/dL after 24 hours, requires
differential diagnosis.
C. Differential Diagnosis (19, 58)
1. Differential diagnosis will reveal false-positives and identify specific enzyme defect.
2. Therapy depends on enzyme defect present.
3. This protocol addresses nutrition support of patients with PAH deficiency.

V. Rationale for Nutrition Support


A. Correct Primary Imbalance in Metabolic Relationships
1. Restrict dietary PHE to amount tolerated by patient to maintain treatment plasma PHE
concentration.
B. Supply Product of Blocked Primary Pathway
1. Supplement dietary TYR as necessary to maintain normal plasma TYR concentration.

VI. Establish Goals of Nutrition Support (19, 58)


A. Plasma PHE Concentration
1. Maintain 2- to 4-hour postprandial plasma PHE concentration between 2 and 5 mg/dL when
measured by bacterial inhibition assay (120 and 300 µmol/L when measured by quantitative
methods) (19, 46, 47, 63, 64).
a. In patients >10 years of age until adulthood, plasma PHE concentration may range
between 2 and 8 mg/dL (120 - 485 µmol/L) (63, 64).
2 Phenylketonuria © 2001 Ross Products Division
b. For adults with PKU, maintain 2- to 4-hour postprandial plasma PHE concentration
between 2 and 10 mg/dL (120 - 605 µmol/L) (75), although normal concentration was
required in a patient to prevent complications (73).
2. In practice, obtaining blood 2 to 4 hours postprandially is not always possible. Acceptable local
standards should be developed if plasma amino acids are evaluated at other times (Practical
Aspects of Nutrition Support, p viii).
Warning: Blood/plasma PHE concentration must be evaluated once or twice weekly,
with concentrations maintained between 2 and 5 mg/dL. Otherwise, PHE
deficiency may occur. PHE deficiency may result in failure to thrive and
mental retardation (33, 37, 64).
B. Plasma TYR Concentration
1. Maintain 2- to 4-hour postprandial plasma TYR concentration between 50 and 100 µmol/L
(0.9-1.8 mg/dL), or within normal range for age established by laboratory used.
C. Growth, Development, and Nutrition Status
1. Support normal growth rate in infants and children and maintain appropriate weight for height
in adults (3, 5, 7).
2. Support normal development (12, 24, 25, 63, 64).
3. Maintain normal nutrition status (2, 6-8, 16, 23, 28, 29, 33, 51, 53, 54, 57).
4. Prevent catabolism.
D. Behavior, Mental Development, and Neurologic Status
1. Prevent behavioral abnormalities (10, 63, 64, 71).
2. Improve behavior of previously untreated adults with PKU (10, 73, 75).
3. Prevent EEG changes and neurologic deterioration in adults (20, 68, 70).
E. Physical Manifestations
1. Prevent osteopenia (17, 36), eczema and offensive body odor (56).

VII. Establish Prescription


A. PHE
1. Prescribe PHE intake that promotes goals of nutrition support (Table 1-1, p 12).
2. PHE requirements vary widely:
a. From patient to patient, depending on activity of PAH, which is dependent on genotype
(1, 3, 4, 30, 31, 69).
b. In same patient, depending on:
1) Age.
2) Growth rate (41).
3) Adequacy of energy and protein intakes (39).
4) State of health.
3. If diagnostic plasma PHE concentration is in following ranges, delete PHE from diet for hours
noted:
Diagnostic Plasma PHE Delete Dietary PHE For:
(µmol/L) (mg/dL) (Hours)
240 < 605 4 < 10 24
605 < 1,210 10 < 20 48
1,210 < 2,420 20 < 40 72
≥ 2,420 > 40 96
a. To prevent PHE deficiency, plasma PHE concentration must be analyzed daily when
all PHE is deleted from diet.
b. When plasma PHE concentration reaches upper limit of treatment range
(300 µmol/L), PHE must be added to diet.
4. Dietary PHE suggested for initiating therapy after 1 to 4 days of PHE-free medical food
mixture depends on maximum diagnostic quantitative plasma PHE concentration (not by
bacterial inhibition assay). See values noted below for amounts of dietary PHE to begin
therapy for specific plasma PHE concentrations:

© 2001 Ross Products Division Phenylketonuria 3


Plasma PHE Dietary PHE
(µmol/L) (mg/dL) (mg/kg)
≤ 605 ≤ 10 70
> 605 to ≤ 1210 > 10 to ≤ 20 55
> 1210 to ≤ 1815 > 20 to ≤ 30 45
> 1815 to ≤ 2420 > 30 to ≤ 40 35
> 2420 > 40 25
5. Frequent monitoring of plasma PHE concentration is essential to assess patient's changing
requirements.
a. The closer to normal range that plasma PHE concentration is maintained, the more
frequently plasma PHE concentration must be evaluated to prevent deficiency.
b. See Section X, Suggested Evaluation of Nutrition Support, p 7.
6. Between 3 and 5 months of age, PHE requirements per kg body weight may decrease
considerably.
Warning: PHE deficiency results in following adverse effects:
Low or elevated plasma PHE concentration, depending on stage of PHE
deficiency (19).
Bone changes and decreased growth rate in infants and children and weight
loss in adults (21, 36, 40, 60).
Changes in red blood cell precursors and anemia (53, 54).
Generalized aminoaciduria and hypoproteinemia (37).
Mental retardation (33, 64).
Hair loss.
Low plasma transthyretin (11).
B. TYR (46)
1. Prescribe TYR intake that maintains treatment plasma TYR concentration.
2. Lowest value for dietary TYR for each age group listed in Table 1-1, p 12, is suggested to start
therapy.
3. Changing requirements of patients are determined only by frequent monitoring of plasma TYR
concentration.
a. Prescribe TYR above amount supplied by Phenex and beikost or table foods only if
plasma TYR concentration is below normal.
C. Protein
1. Prescribe, initially, amount greater than Recommended Dietary Allowances (RDAs) (5, 22, 35,
41, 46, 55, 62) (Table 1-1, p 12). For neonates, use 3.50 g/kg/day.
2. Requirements are greater than RDAs when L-amino acids supply majority of protein
equivalent as result of:
a. Rapid amino acid absorption (26, 27).
b. Early and high peak of plasma amino acid concentrations after ingestion of meals where
large part of protein is supplied by L-amino acids (26, 27).
c. Rapid catabolism of amino acids (35, 38).
d. Possible decreased total amino acid absorption (48).
Warning: Long-term inadequate protein intake will result in failure to thrive in infants,
poor growth in children, weight loss in adults, low plasma transthyretin
concentrations, osteopenia, hair loss, and decreased PHE tolerance.
D. Energy (9)
1. Prescribe amount that should support normal weight gain in infants and children and maintain
appropriate weight for height in adults (Table 1-1, p 12).
2. Requirements vary widely and may be greater than normal when L-amino acids supply
majority of protein equivalent (50, 52)
3. Hyperactivity, if present, may significantly increase needs.

4 Phenylketonuria © 2001 Ross Products Division


Warning: Inadequate energy intake will result in failure to thrive in infants, poor growth
in children, weight loss in adults, and low plasma transthyretin concentration.
Weight loss will result in elevated plasma PHE concentration as result of
protein catabolism. Poor growth will result in lower than expected tolerance
of PHE.
E. Fluid
1. Prescribe amount that will supply water requirements (Table 1-1, p 12). Under normal
circumstances, offer minimum of 1.5 mL fluid to neonates and 1.0 mL to children and adults
for each kcal ingested.
2. Requirements may be higher than recommended secondary to increased fluid loss with fever.

VIII. Fill Prescription


A. PHE
1. Calculate amount of infant formula with iron, human milk, beikost, or table foods (Table 1-2,
p 12) required to fill PHE prescription.
a. Low-iron infant formula, whole cow's milk, and evaporated milk should not be used as
PHE source for infants because of low iron content.
2. Measure liquid infant formula, human milk, and whole cow's milk with disposable syringe.
Weigh powdered infant formula on scale that reads in grams.
a. For other approaches to using human milk, see reference 76.
3. Add beikost (table foods) (Table 1-2, p 12) to gradually displace PHE provided by infant
formula or human milk after infant is 3 to 4 months old or is developmentally ready.
4. Parents or patients may select any food in prescribed food lists (Table 1-3, p 13) in specified
amounts to fill diet prescription.
B. Protein
1. Calculate amount of infant formula with iron, human milk, beikost, whole cow's milk, or table
foods (Table 1-2, p 12) required to fill the PHE prescription.
2. Subtract amount determined above from total protein prescription.
3. Supply any remaining prescribed protein with Phenex (Table 1-4, p 27).
a. Phenex-1 is for infants and toddlers and Phenex-2 is for children, adolescents, and adults,
but may be used by toddlers if child's appetite is small.
b. Weigh Phenex powder on scale that reads in grams because of variability of household
measuring equipment (Practical Approaches to Nutrition Support, p vii) and changes in
density during shipping.
c. See Table 1-4 (p 27, footnote 3) for approximate packed weight of Phenex powder in
level, dry US standard household measures.
C. TYR
1. Calculate approximate amount of TYR provided by infant formula with iron, human milk,
beikost, whole cow's milk, or table foods (Table 1-2, p 12) required to fill PHE prescription.
2. Calculate amount of TYR supplied by Phenex (Table 1-4, p 27) required to fill protein
prescription.
3. Added together, values calculated above should fall within range of TYR intake recommended
in Table 1-1, p 12.
4. Supply remaining prescribed TYR as pure suspension. Add supplemental L-TYR only if
plasma TYR concentration is below normal.
a. For infants, mix weighed amounts of L-TYR powder with boiled, cooled water to yield
0.5 mg/mL (eg, 500 mg of L-TYR with enough water to yield 1 liter).
b. Refrigerate suspension in sterilized, closed container until used. Discard unused
suspension after 1 week, if not frozen.
c. Shake well before using. Measure L-TYR (Appendix 26, p A-28) suspension into medical
food mixture with disposable syringe.
5. For children or adults, L-TYR powder may be mixed with fruit purées such as applesauce,
soups, puréed vegetables, and mashed potatoes.

© 2001 Ross Products Division Phenylketonuria 5


6. L-TYR tablets may be used if patient can swallow them. Tablets are available at some
pharmacies.

D. Energy
1. Calculate energy provided by infant formula with iron, human milk, beikost, whole cow's milk,
or table foods (Table 1-2, p 12) and Phenex (Table 1-4, p 27) required to fill PHE and protein
prescriptions.
2. Subtract amount determined above from total energy prescription.
3. Provide remaining prescribed energy with Polycose ® Glucose Polymers powder
(23 kcal/Tbsp, 3.8 kcal/g) or liquid (2 kcal/mL) (Appendix 9, p A-9); Pro-Phree ® Protein-Free
Energy Module With Iron, Vitamins & Minerals (Appendix 11, p A-10); sugar (48 kcal/Tbsp); or
Free Foods B (Table 1-2, p 12), depending on age of patient.
a. Do not use corn syrup or table sugar for infants because of osmolarity they yield (45).
b. Do not use honey for infants because it may contain botulinum toxin (67).
E. Fluid and Mixing Instructions
1. Add sufficient boiled, cooled water to infant formula or human milk, Phenex, carbohydrate,
and L-TYR (if needed) to yield prescribed volume. Tap water may replace boiled, cooled
water when preparing Phenex for older infants, children, and adults.
2. Mix with sterilized blender at lowest speed for no longer than 3 to 4 seconds. Excess mixing
may destabilize emulsion. Medical food may also be mixed in sterilized, tightly closed
container by shaking vigorously for 10 to 12 seconds.
3. Refrigerate in sterilized, closed containers until used. Discard unused portion 24 hours after
mixing because of nutrient loss. Store unopened cans at room temperature. Cover opened
can and store in refrigerator. Use within 1 month after opening.
4. Do not use terminal sterilization or boil because of Maillard reaction (Practical Aspects of
Nutrition Support, p viii).
5. Warm or cool medical food mixture to room temperature before feeding to infants. Shake well
before feeding.
6. Do not warm medical food mixture in microwave oven. Unevenly heated formula can burn
infants and steam can make bottles explode.
7. Notify parents or caretakers when they may discontinue using aseptic technique in preparing
medical food mixture for infants.
8. For children and adults, chill Phenex medical food mixture to improve taste.
F. Diet Guide
1. Provide parents, caretakers, or patient with completed Diet Guide (Appendix 22, p A-24) with
each diet change.
2. Feed young infants 6 to 8 times daily (35, 55).
3. Feed older infants, children, and adults 4 to 6 times daily (35, 55).

IX. Evaluate Adequacy and Safety of Planned Nutrition Support


A. Nutrient Adequacy
1. Determine if diet provides nutrients in amounts prescribed in Section VII, Establish
Prescription, p 3.
a. See Table 1-4, p 27, for composition of Phenex and Table 1-2, p 12, for nutrient
composition of infant formulas, human milk, and whole cow's milk.
b. See Appendix 9, p A-9, for composition of Polycose and Appendix 11, p A-10, for
composition of Pro-Phree.
2. Check diet to determine if it supplies Recommended Dietary Intakes (RDIs) for minerals and
vitamins (Appendices 4 through 8, 13, and 14, pp A-4 through A-8, A-14, and A-15).
a. Appendix 23, p A-25, may be used to check adequacy of nutrients if computer program is
not available.
b. If Phenex mixture provides < 100% of RDIs for infants and < 75% of RDIs for children and
adults, supplement diet with needed minerals and vitamins if not provided by beikost or
table foods and laboratory tests indicate need (Appendix 11, p A-10, for composition of
supplements).
6 Phenylketonuria © 2001 Ross Products Division
B. Osmolarity
1. If concentration of prescribed medical food mixture is > 24 kcal/fl oz, determine if osmolarity
is in acceptable range.
a. Determine osmolarity by laboratory analysis or use mathematical formula given in
Appendix 18, p A-20.
b. Osmolarity per gram of Phenex is listed in Appendix 19, p A-21.
2. If osmolarity is > 450 mosm/L for neonates, > 750 mosm/L for children, > 1,000 mosm/L for
adults (62), or greater than tolerated by patient, increase water content of prescribed medical
food mixture and recalculate its osmolarity (44, 65).
C. Potential Renal Solute Load
1. Dehydration will result if renal solute load is greater than renal-concentrating ability of patient.
2. If concentration of medical food mixture prescribed is > 24 kcal/fl oz, estimate its potential
renal solute load.
a. This step is important to prevent dehydration of infants who may have renal-concentrating
capacity as low as 600 mosm/L.
b. Upper limit of renal solute load for neonates is approximately 1,100 mosm/L (61).
3. A method for estimating potential renal solute load is given in Appendix 20, p A-22.
4. If potential renal solute load is excessive, increase water content of medical food mixture and
recalculate.

X. Suggested Evaluation of Nutrition Support


A. Plasma PHE and TYR Concentrations (46, 64)
1. Initial.
a. Evaluate twice weekly by quantitative methods until plasma concentrations stabilize and
approximate dietary PHE and TYR requirements are known.
2. Ongoing.
a. Frequent evaluations help ensure adherence to nutrition support plan.
b. Evaluate plasma PHE concentration weekly by bacterial inhibition assay or fluorometric
method.
c. Evaluate plasma PHE and TYR concentrations monthly by quantitative methods.
3. Unacceptable PHE concentrations.
a. If plasma PHE concentration is not detected and patient has ingested full prescription:
1) Add 50 mg to prescribed PHE and reevaluate plasma PHE concentration in 3 days.
2) If plasma PHE concentration continues undetected, repeat above process until value
is in treatment range.
b. If plasma PHE concentration is < 120 µmol/L (2 mg/dL) and patient has ingested full
prescription:
1) Add 15 mg to prescribed PHE and reevaluate plasma PHE concentration in 3 days.
2) If plasma PHE concentration continues < 120 µmol/L (2 mg/dL), repeat above process
until value is in treatment range.
c. If plasma PHE concentration is > 300 µmol/L (5 mg/dL) and < 605 µmol/L (10 mg/dL) and
patient is not ill and has not ingested more PHE or significantly less protein and energy
than prescribed:
1) Subtract 15 mg from prescribed PHE and reevaluate plasma PHE concentration in
3 days.
2) If plasma PHE concentration continues > 300 µmol/L (5 mg/dL), repeat above process
until value is in treatment range.
d. If plasma PHE concentration is > 605 µmol/L (10 mg/dL) and patient is not ill and has not
ingested more PHE or significantly less protein and energy than prescribed:
1) Subtract 30 mg from prescribed PHE and reevaluate plasma PHE concentration in
3 days.
2) If plasma PHE concentration continues > 605 µmol/L (10 mg/dL), repeat above
process until value is in treatment range.

© 2001 Ross Products Division Phenylketonuria 7


B. Protein Status
1. Evaluate plasma transthyretin concentration every 3 months until patient is 1 year of age and
every 6 months thereafter (Appendix 17, p A-18, for standards).
a. Plasma transthyretin concentrations provide a more reliable and rapid indication of protein
status than plasma albumin concentrations.
b. Plasma albumin concentrations may be in the normal range when plasma transthyretin
concentrations show a clear deficiency (11).
2. If plasma transthyretin concentration is below standard:
a. Increase prescribed protein by 5% to 10% and reevaluate plasma transthyretin
concentration in 1 month. If plasma PHE concentration is in treatment range, use Phenex
to increase protein.
b. If plasma transthyretin concentration continues below standard, repeat above process until
value is in normal range.

C. Iron Status
1. Plasma ferritin concentration (13-15).
a. Evaluate at 6, 9, and 12 months of age and every 6 months thereafter (Appendix 17,
p A-18, for standards).
b. If plasma ferritin concentration is below standard:
1) Increase iron intake to 4 mg/kg with supplements (ferrous sulfate).
2) Evaluate plasma ferritin concentration monthly on increased iron intake.
3) Continue iron supplements until plasma ferritin concentration is in normal range.
2. Complete blood count.
a. Hemoglobin and hematocrit concentrations should be evaluated at 6, 9, and 12 months of
age and every 6 months thereafter (Appendix 17, p A-18, for standards).
D. Serum/Erythrocyte Vitamin B12 and Folate
1. Patients who routinely fail to ingest prescribed amounts of medical food are at risk of
vitamin B12 and folate deficiencies (32).
2. Serum or erythrocyte vitamin B12 and folate should be routinely analyzed if medical food
prescribed is not ingested.
3. Serum and erythrocyte concentrations should be maintained between the following values:
Tissue Vitamin B12 (74) Folate (34)
Serum > 300 pg/mL > 5 to < 10 ng/mL
Erythrocyte --- > 200 to < 300 ng/mL
4. Both vitamin B12 and folate tablets should be administered daily if the patient will not ingest
prescribed amounts of medical food.
E. Growth Status
1. Length/height and weight.
a. Measure monthly to 1 year, every 3 months to 4 years, and every 6 months thereafter.
Plot measurements on NCHS growth charts.
b. Maintain length/height and weight between 10th and 90th percentiles. Some normal
infants, children, and adults will fall above or below these percentiles.
2. If length/height or weight falls below usual growth channel:
a. Increase prescribed protein and energy by 5% to 10% and remeasure in 1 month.
b. If length/height or weight remains low, repeat above process until usual growth channel is
achieved.
3. For previously untreated adult with PKU, weigh weekly after diet is initiated until weight is
stabilized at appropriate weight for height, then weigh monthly.
a. Liberal use of very-low-protein foods, Free Foods A (p 24), and Free Foods B (p 25) will
help minimize weight loss.
F. Nutrient Intake
1. Maintain records of food intake for 3 days immediately before each blood test (Appendices 24
and 25, pp A-26 and A-27).

8 Phenylketonuria © 2001 Ross Products Division


2. For previously untreated adult with PKU who lives in an institution or group home that uses
cycle menus, actual amounts of foods eaten should be noted in medical record.
3. Previously untreated adults with PKU who live independently will require help with grocery
shopping, meal planning, cooking, and record keeping (75). They should be taught to use
pictures or models of food to help them keep food diaries if they are illiterate, or if their
guardian cannot maintain records.
4. Evaluate intakes of PHE, TYR, protein, and energy before each blood test.
5. Evaluate mineral and vitamin intakes after each diet change.
a. Appendix 23, p A-25, may be used to check adequacy of nutrients if computer program is
not available.
b. See Appendix 28, p A-29, for information about ordering software for diet evaluation.
G. Clinical Summary
1. A summary record of growth, laboratory, and nutrient intake data is useful for patient
management (Table 1-5, p 29).

XI. Sample Prescriptions


A. Example 1
Establish and fill prescription for newborn weighing 3.3 kg who has diagnostic plasma PHE
concentration of 1510 µmol/L (41 mg/dL) using Recommended Daily Nutrient Intakes from
Table 1-1, p 12, and average nutrient contents from Tables 1-2 and 1-4, pp 12 and 27.
1. Establish prescription.
PHE 45 mg/kg x 3.3 kg = 148 mg/day
TYR 350 mg/kg x 3.3 kg = 1,155 mg
Protein 3.5 g/kg x 3.3 kg = 11.5 g
Energy 127 kcal/kg x 3.3 kg = 420 kcal
Fluid 160 mL/kg x 3.3 kg = 528 mL
2. Fill prescription.
Medical Food Mixture Measure PHE TYR Protein Energy
(mg) (mg) (g) (kcal)
Phenex-1 54 g 0 810 8.1 259
Similac With Iron RTF 251 mL 148 146 3.5 171
L-Tyrosine 199 mg 0 199 0.0 0
Add water to make 530 mL (18 fl oz).
Total per day 148 1,155 11.6 430
Total per kg 45 350 3.5 130
Approximate osmolarity of medical food mixture is < 450 mosm/L. Estimated potential renal solute
load is < 160 mosm.

B. Example 2
Establish and fill prescription for 2-year-old child weighing 13 kg using Recommended Daily
Nutrient Intakes from Table 1-1, p 12, and Average nutrient contents from Tables 1-2 and 1-4,
pp 12 and 27.
1. Establish prescription.
PHE 200 mg/day
TYR 3,000 mg
Protein 30 g
Energy 1,300 kcal
Fluid 1,375 mL

© 2001 Ross Products Division Phenylketonuria 9


2. Fill prescription.
Medical Food Mixture Measure PHE TYR Protein Energy
(mg) (mg) (g) (kcal)
Phenex-1 164 g 0 2,460 24.6 787
L-Tyrosine 402 mg 0 402 0.0 0
Sugar 8 g (2 tsp) 0 0 0.0 32
Add water to make 710 mL (24 fl oz). Offer additional fluid ad libitum daily.

Food List Servings


Breads/Cereals 3 90 60 1.8 90
Fats 2 10 8 0.2 120
Fruits 2 30 20 1.0 120
Vegetables 5 75 50 2.5 50
Free Foods B 2 0 0 0.0 110
Total per day 205 3,000 30.1 1,309
Approximate osmolarity of medical food mixture is < 700 mosm/L.

C. Example 3
Establish and fill prescription for 6-year-old child using Recommended Daily Nutrient Intakes from
Table 1-1, p 12, and average nutrient contents from Tables 1-2 and 1-4, pp 12 and 27.
1. Establish prescription.
PHE 235 mg/day
TYR 3,500 mg
Protein 35.0 g
Energy 1,700 kcal
Fluid 1,700 mL
2. Fill prescription.
Medical Food Measure PHE TYR Protein Energy
Mixture (mg) (mg) (g) (kcal)
Phenex-2 97 g 0 2,910 29.1 398
L-Tyrosine 430 mg 0 430 0.0 0
Sugar 84 g (7 Tbsp) 0 0 0.0 336
Add water to make 946 mL (32 fl oz). Offer additional fluid ad libitum daily.

Food List Servings


Breads/Cereals 4 120 80 2.4 120
Fats 2 10 8 0.2 120
Fruits 3 45 30 1.5 180
Vegetables 3 45 30 1.5 30
Free Foods A 3 15 12 0.3 195
Free Foods B 6 0 0 0.0 330
Total per day 235 3,500 35.0 1,709
Approximate osmolarity of medical food mixture is < 800 mosm/L.

D. Example 4
Establish and fill prescription for 20-year-old woman using Recommended Daily Nutrient Intakes
from Table 1-1, p 12, and average nutrient contents from Tables 1-2 and 1-4, pp 12 and 27.
1. Establish prescription.
PHE 220 mg/day
TYR 5,000 mg
Protein 50 g
Energy 2,100 kcal
Fluid 2,100 mL

10 Phenylketonuria © 2001 Ross Products Division


2. Fill prescription.
Medical Food Measure PHE TYR Protein Energy
Mixture (mg) (mg) (g) (kcal)
Phenex-2 149 g 0 4,470 44.7 611
L-Tyrosine 376 mg 0 376 0.0 0
Sugar 60 g (5 Tbsp) 0 0 0.0 240
Add water to make 1183 mL (40 fl oz). Offer additional fluid ad libitum daily.

Food List Servings


Breads/Cereals 4 120 80 2.4 120
Fats 3 15 12 0.3 180
Fruits 3 45 30 1.5 180
Vegetables 2 30 20 1.0 20
Free Foods A 3 15 12 0.3 195
Free Foods B 10 0 0 0.0 550
Total per day 225 5,000 50.2 2,096
Approximate osmolarity of medical food mixture is < 800 mosm/L.

XII. Nutrition Support During Febrile Illness or Following Trauma


A. Rationale
1. In normal persons, febrile illness and trauma are accompanied by catabolism of body
protein (72).
2. Well-nourished patients with PKU respond to infection and trauma as do normal persons.
3. Extent of protein catabolism determines subsequent elevation in plasma PHE concentration.
B. Objectives of Nutrition Support
1. Maintain hydration and electrolyte balance.
a. Offer infants and toddlers Pedialyte ® Oral Electrolyte Maintenance Solution ad libitum
(Appendix 9, p A-9).
2. Depress catabolism.
a. Enhance energy intake when possible by offering fruit juices ad libitum as tolerated, liquid
Jell-O ®, Polycose powder or liquid (Appendix 9, p A-9), or Pro-Phree (Appendix 11, p A-
10) added to fruit juices or Pedialyte if tolerated and caffeine-free soft drinks (not diet
drinks).
1) 1/3 cup of Polycose powder may be added to liquid Pedialyte to yield 8 fl oz.
b. Return patient to Phenex medical food mixture and pre-illness diet as rapidly as possible.
1) Begin with 1/2 original strength of Phenex medical food mixture.
2) Increase to original strength as tolerated.
C. Parenteral Nutrition
1. If parenteral amino acid solutions are indicated, see Appendix 26, p A-28.

© 2001 Ross Products Division Phenylketonuria 11


TABLE 1-1. Recommended Daily Nutrient Intakes (Ranges) for Infants, Children, and Adults With PKU

Age Nutrient
1-3 1
PHE TYR Protein4 Energy4 Fluid5
(mg/kg) (mg/kg) (g/kg) (kcal/kg) (mL/kg)
Infants
0 to < 3 mo 25 - 70 300 - 350 3.50 - 3.00 120 (145 - 95) 160 - 135
3 to < 6 mo 20 - 45 300 - 350 3.50 - 3.00 120 (145 - 95) 160 - 130
6 to < 9 mo 15 - 35 250 - 300 3.00 - 2.50 110 (135 - 80) 145 - 125
9 to < 12 mo 10 - 35 250 - 300 3.00 - 2.50 105 (135 - 80) 135 - 120
(mg/day) (g/day) (g/day) (kcal/day) (mL/day)
Girls and Boys
1 to < 4 yr 200 - 400 1.72 - 3.00 ≥ 30 1,300 ( 900 - 1800) 900 - 1,800
4 to < 7 yr 210 - 450 2.25 - 3.50 ≥ 35 1,700 (1300 - 2300) 1,300 - 2,300
7 to < 11 yr 220 - 500 2.55 - 4.00 ≥ 40 2,400 (1650 - 3300) 1,650 - 3,300
Women
11 to < 15 yr 250 - 750 3.45 - 5.00 ≥ 50 2,200 (1500 - 3000) 1,500 - 3,000
15 to < 19 yr 230 - 700 3.45 - 5.00 ≥ 55 2,100 (1200 - 3000) 1,200 - 3,000
≥ 19 yr 220 - 700 3.75 - 5.00 ≥ 60 2,100 (1400 - 2500) 2,100 - 2,500
Men
11 to < 15 yr 225 - 900 3.38 - 5.50 ≥ 55 2,700 (2000 - 3700) 2,000 - 3,700
15 to < 19 yr 295 - 1,100 4.42 - 6.50 ≥ 65 2,800 (2100 - 3900) 2,100 - 3,900
≥ 19 yr 290 - 1,200 4.35 - 6.50 ≥ 70 2,900 (2000 - 3300) 2,000 - 3,300
1
See Section VII, Establish Prescription, p 3, for initial dietary PHE to prescribe based on diagnostic plasma PHE.
Modify prescription based on frequently obtained blood and/or plasma values and growth in infants and children and
frequently obtained plasma values and weight maintenance in adults.
2
PHE requirements of premature infants may be greater than highest value noted (59).
3
Modified from references 1, 3-5, 19, 43.
4
Modified from reference 22.
5
Modified from reference 13. Under normal circumstances, offer minimum of 1.5 mL fluid to neonates and 1.0 mL to
children and adults for each kcal ingested.

TABLE 1-2. Serving Lists for PHE-Restricted Diets: Average Nutrient Content per Serving1

Food List Nutrient


PHE TYR Protein Energy
(mg) (mg) (g) (kcal)
Breads/Cereals 30 20 0.6 30
Fats 5 4 0.1 60
Fruits 15 10 0.5 60
Vegetables 15 10 0.5 10
Free Foods A 5 4 0.1 65
Free Foods B 0 0 0.0 55
Alimentum ® Protein Hydrolysate Formula With Iron, Ready to Feed , 100 mL 86 29 1.86 68
2

Human Milk, 100 mL, 3 48 55 1.07 72


Isomil ® Soy Formula With Iron, Ready to Feed, 100 mL 2 88 60 1.66 68
2
Similac ® With Iron Infant Formula, Ready to Feed, 100 mL 59 58 1.40 68
3
Whole cow's milk, 100 mL 164 164 3.39 63
1
From reference 19.
2
See Appendices 4 through 7, pp A-4 to A-7, for complete nutrient composition of infant formulas.
3
From reference 49. See Appendix 8, p A-8, for complete nutrient composition.

12 Phenylketonuria © 2001 Ross Products Division


© 2001 Ross Products Division Phenylketonuria 13
TABLE 1-3. Serving Lists for PHE-Restricted Diets: Gerber ® Baby Food (Beikost)

Food Weight Approximate PHE TYR Protein Energy


(g) Measure (mg) (mg) (g) (kcal)
For greatest accuracy, weigh food on scale that reads in grams. All measures are level.

BREADS AND CEREALS

Baked Finger Snacks, Graduates


Animal crackers, cinnamon graham 10 1-1/2 cracker 29 10 0.6 45
Apple cinnamon cookies 10 1 cookie 31 12 0.8 43
Banana cookies 10 1-1/4 cookie 30 11 0.7 43
Strawberry fruit bars 12 1-1/3 bar 31 12 0.6 49
Veggie crackers 7 10 crackers 30 10 0.6 33

Cereals, Dry
Barley 4 1 Tbsp + 1/4 tsp 28 15 0.5 15
Mixed 6 1 Tbsp + 2 tsp 30 15 0.6 23
Oatmeal 3 3/4 Tbsp 27 14 0.4 12
Oatmeal/banana 4 1 Tbsp + 1/4 tsp 27 17 0.4 16
Oatmeal/mixed fruit 6 1 Tbsp + 2 tsp 32 17 0.6 25
Rice 6 1 Tbsp + 2 tsp 28 16 0.5 23
Rice/apples 11 3 Tbsp 30 21 0.6 43
Rice/apple bits 8 2 Tbsp + 1/2 tsp 29 15 0.6 32
Rice/bananas 9 2 Tbsp + 1-1/2 tsp 30 19 0.6 35
Rice/mixed fruit 9 2 Tbsp + 1-1/2 tsp 31 23 0.6 35

Cereals, Jarred
1st Foods ®
Oatmeal 34 2 Tbsp + 1 tsp 30 20 0.6 19
2nd Foods ®
Mixed/applesauce/bananas 57 1/4 cup 30 15 0.6 49
Oatmeal/applesauce/bananas 42 3 Tbsp 30 13 0.5 35
Rice/applesauce 57 1/4 cup 30 15 0.4 52
3rd Foods ®
Mixed/apples/bananas 54 3 Tbsp + 2 tsp 30 16 0.6 41
Oatmeal/apples/cinnamon 53 3 Tbsp + 2 tsp 30 16 0.6 36
Tender Harvest ™
Greenbeans/potatoes 26 ND 30 23 0.6 16
Spring garden vegetables 60 ND 30 18 0.9 21

Vegetables
1st Foods ®
Peas 24 1 Tbsp + 2 tsp 30 19 0.7 12
Potatoes 75 5 Tbsp + 1 tsp 30 25 0.8 35
Sweet potatoes 45 3 Tbsp 30 12 0.5 29
2nd Foods ®
Creamed corn 31 2 Tbsp 30 20 0.6 19
Creamed spinach 20 1 Tbsp + 1-1/2 tsp 30 23 0.6 9
Garden vegetables 30 2 Tbsp 30 18 0.4 11
Peas 24 1 Tbsp + 2 tsp 30 19 0.7 12
Sweet potatoes 48 3 Tbsp + 1 tsp 30 12 0.5 30
3rd Foods ®
Peas/rice 23 1 Tbsp + 2 tsp 30 15 0.2 12
Sweet potatoes 48 3 Tbsp + 1 tsp 30 15 0.5 29

FRUITS/JUICES

Mixed fruit juice 125 4 fl oz 15 6 0.3 60


Pear juice 202 6 2/5 fl oz 15 4 0.6 99
1st Foods ®
Bananas 47 3 Tbsp + 3/4 tsp 15 8 0.5 47

14 Phenylketonuria © 2001 Ross Products Division


Food Weight Approximate PHE TYR Protein Energy
(g) Measure (mg) (mg) (g) (kcal)
For greatest accuracy, weigh food on scale that reads in grams. All measures are level.
Peaches 88 6 Tbsp + 1/2 tsp 15 9 0.6 38
Pears 68 1/4 cup + 2 tsp 15 4 0.3 39
Prunes 58 1/4 cup 15 5 0.6 58
2nd and 3rd Foods ®
Applesauce/apricot 100 7 Tbsp 15 6 0.3 52
Apricots/mixed fruit 75 5 Tbsp + 1 tsp 15 7 0.4 45
Bananas 47 3 Tbsp + 3/4 tsp 15 8 0.5 42
Bananas/apples/pears 43 3 Tbsp 15 5 0.4 36
Banana/pineapple 43 3 Tbsp 15 6 0.4 32
Banana/strawberry 60 1/4 cup 15 8 0.6 54
Hawaiian delight dessert, 2nd Foods ® 24 1 Tbsp + 2 tsp 15 9 0.3 20
Hawaiian delight dessert, 3rd Foods ® 21 1 Tbsp + 1-1/2 tsp 15 8 0.3 18
Peach cobbler dessert, 2nd Foods ® 136 9 Tbsp + 1-1/2 tsp 15 7 0.7 103
Peach cobbler dessert, 3rd Foods ® 125 1/2 cup + 2 tsp 14 4 0.6 54
Peaches, 2nd Foods ® 88 6 Tbsp + 1/2 tsp 15 9 0.6 56
Peaches, 3rd Foods ® 83 5 Tbsp + 2 tsp 15 7 0.6 53
Pear/pineapple 71 1/3 cup 15 4 0.3 39
Pears 88 6 Tbsp + 1/2 tsp 15 8 0.4 65
Plums/apples, 2nd Foods ® 94 6 Tbsp + 2 tsp 15 5 0.4 66
Plums/apples, 3rd Foods ® 71 5 Tbsp 15 4 0.3 49
Prunes/apples 71 1/3 cup 15 6 0.4 55

Fruit Dices, Graduates™


Apples 136 ND 15 4 0.3 65
Mixed fruit 115 ND 15 6 0.3 56
Peaches 94 ND 15 6 0.5 46
Pears 136 ND 15 7 0.4 73

Fruit/Vegetable Juices
Apple/carrot 214 6-3/4 fl oz 15 11 0.2 89
Apple/sweet potato 125 4 fl oz 15 9 0.4 62
Tender Harvest™
Apple/sweet potato 125 ND 15 8 0.3 72
Banana/oatmeal/peach 27 ND 15 6 0.3 20
Pear/wild blueberry 100 ND 15 5 0.4 61
Pears/winter squash 25 ND 15 6 0.3 13
Tropical fruit blend 68 ND 15 7 0.4 50

VEGETABLES

1st Foods ®
Carrots 75 5 Tbsp + 1 tsp 15 10 0.7 26
Green beans 23 1 Tbsp + 2 tsp 15 9 0.4 9
Squash 50 3 Tbsp + 1-1/2 tsp 15 14 0.4 17
2nd Foods ®
Carrots 75 5 Tbsp + 1 tsp 15 10 0.6 22
Green beans 31 2 Tbsp 15 11 0.4 10
Mixed vegetables 27 1 Tbsp + 2 tsp 15 11 0.3 11
Squash 33 2 Tbsp + 1 tsp 15 7 0.2 10
3rd Foods ®
Carrots 65 4 Tbsp + 1-1/2 tsp 15 10 0.5 19
Green beans/rice 28 2 Tbsp 15 11 0.3 12
Squash 71 1/3 cup 15 11 0.6 23
Tender Harvest™
Butternut squash/corn 25 ND 15 10 0.5 12
Garden carrots/brown rice 47 ND 15 9 0.4 20

© 2001 Ross Products Division Phenylketonuria 15


Food Weight Approximate PHE TYR Protein Energy
(g) Measure (mg) (mg) (g) (kcal)
For greatest accuracy, weigh food on scale that reads in grams. All measures are level.
Vegetable Dices, Graduates
Carrots 38 ND 15 8 0.2 9
Green beans 28 ND 15 12 0.3 7

FREE FOODS A

Apple juice 218 7 fl oz 5 5 0.2 109


Apple/banana juice 93 3 fl oz 5 4 0.2 50
Apple/cherry juice 124 4 fl oz 5 3 0.3 62
Apple/cranberry juice 93 3 fl oz 5 4 0.2 46
Apple/grape juice 218 7 fl oz 5 5 0.2 112
Apple/prune juice 124 4 fl oz 5 4 0.3 69
Fruit medley tropical fruit dessert 100 7 Tbsp 5 2 0.2 64
Guava tropical fruit dessert 83 1/3 cup + 2-1/2 tsp 5 2 0.1 58
Mango/banana/passion fruit juice 57 1-3/4 fl oz 6 3 0.1 34
Mango tropical fruit dessert 50 3 Tbsp + 1-1/2 tsp 5 3 0.1 43
Mixed fruit juice 163 5 fl oz 5 2 0.5 80
Orange juice 100 3-1/5 fl oz 7 3 0.6 47
Papaya tropical fruit dessert 83 1/3 cup + 2-1/2 tsp 5 2 0.2 53
Peach/mango dessert 78 1/3 cup + 1 tsp 5 3 0.2 47
1st and 2nd Foods ®
Applesauce 86 1/4 cup + 2 Tbsp 5 3 0.2 48
Apple/blueberry 83 5 Tbsp + 2 tsp 5 3 0.2 42
3rd Foods ®
Fruit salad 50 3 Tbsp + 1-1/2 tsp 5 3 0.2 32

Beverages, Graduates ®
Berry punch 218 7 fl oz 5 5 0.2 111
Fruit punch 218 7 fl oz 5 5 0.2 113
Tender Harvest™
Apple/mango/kiwi 100 7 Tbsp 5 3 0.1 60
Apple/strawberry 100 7 Tbsp 5 3 0.1 60
1
Prepared from 1998 and 1999 data from Gerber Products Co, Fremont, MI 49413.
ND = No data.

Weights and Measures


Except for Dry Cereals and Food Dices, the following weights apply:
Level = Level
1 tsp = 1/3rd Tbsp = 4.8 g
1 Tbsp = 1/16th cup = 14.3 g
1/4 cup = 4 Tbsp = 57.2 g
1/3 cup = 5-1/3rd Tbsp = 76.2 g
1/2 cup = 8 Tbsp = 114.3 g
2/3 cup = 10 2/3rd Tbsp = 152.5 g
3/4 cup = 12 Tbsp = 171.5 g
1 cup = 16 Tbsp = 228.6 g

16 Phenylketonuria © 2001 Ross Products Division


1
TABLE 1-3. Serving Lists for PHE-Restricted Diets: Table Foods

Food Weight Approximate PHE TYR Protein Energy


(g) Measure (mg) (mg) (g) (kcal)
For greatest accuracy, weigh food on scale that reads in grams. All measures are level.

BREADS AND CEREALS

Cereals, Cooked. Measure after cooking.


Corn grits
instant
cheese flavor 36 1/4 packet 36 29 0.7 27
plain 34 1/4 packet 27 22 0.5 20
regular, quick (plain) 45 3 Tbsp 33 28 0.6 28
Cream of Rice 81 1/3 cup 30 40 0.7 42
Cream of Wheat
instant 30 2 Tbsp 30 18 0.6 19
Mix'n Eat
flavored 38 1/4 packet 33 20 0.6 33
plain 36 1/4 packet 37 22 0.7 26
quick 30 2 Tbsp 25 14 0.4 16
regular 30 2 Tbsp 30 18 0.5 19
Farina 44 3 Tbsp 34 20 0.6 22
Maltex ® 31 2 Tbsp 33 19 0.7 22
Malt-o-Meal ® 35 2 Tbsp + 1 tsp 29 16 0.5 18
Maypo ® Oat 30 2 Tbsp 34 20 0.7 21
Oats, regular, quick, and instant 20 1 Tbsp + 1 tsp 28 18 0.5 12
Pettijohns ® 30 2 Tbsp 24 14 0.5 20
Ralston ® 32 2 Tbsp 32 19 0.7 17
Roman Meal ® (plain) 22 1 Tbsp + 1-1/2 tsp 31 22 0.6 14
Wheatena ® 30 2 Tbsp 29 17 0.6 22
Whole Wheat Hot Natural 30 2 Tbsp 29 17 0.6 19

Cereals, Ready To Eat


All Bran ® 5 1 Tbsp 29 22 0.8 13
Alpha-Bits ® 7 1/4 cup 29 20 0.5 28
Apple Jacks ® 9 1/3 cup 26 18 0.5 36
100% Bran ® 6 1 Tbsp + 1-1/2 tsp 30 22 0.8 17
Bran Buds ® 5 1 Tbsp 28 21 0.7 14
Bran Chex ® 6 2 Tbsp 29 23 0.6 20
Cap'n Crunch ® 12 1/3 cup 33 25 0.6 51
Cap'n Crunch's ® Crunch Berries 12 1/3 cup 32 25 0.6 49
Cap'n Crunch's ® Peanut Butter 9 1/4 cup 33 27 0.6 38
Cheerios ® 4 3 Tbsp 35 23 0.6 17
Cinnamon Toast Crunch ® 19 1/2 cup 30 18 0.7 80
Cocoa Krispies ® 12 1/3 cup 27 34 0.6 46
Cocoa Pebbles ® 16 1/2 cup 33 42 0.8 66
Cocoa Puffs ® 19 2/3 cup 31 26 0.7 73
Cookie Crisp ® 10 1/3 cup 26 19 0.5 39
Corn Bran ® 9 1/4 cup 32 24 0.6 31
Corn Chex ® 7 1/4 cup 26 22 0.5 28
Corn Flakes ® 7 1/3 cup 31 26 0.6 29
Crispy Rice 9 1/3 cup 26 34 0.6 37
Crispy Wheat 'n Raisins ® 11 1/4 cup 35 21 0.7 37
C W Post ®
plain 6 1 Tbsp 29 21 0.5 27
w/ raisins 7 1 Tbsp 29 21 0.6 28
Fortified Oat Flakes 3 1 Tbsp 29 21 0.6 11
40% Bran Flakes (Post ®) 6 2 Tbsp 30 20 0.7 19
Froot Loops ® 9 1/3 cup 29 20 0.6 37

© 2001 Ross Products Division Phenylketonuria 17


Food Weight Approximate PHE TYR Protein Energy
(g) Measure (mg) (mg) (g) (kcal)
For greatest accuracy, weigh food on scale that reads in grams. All measures are level.
Frosted Mini-Wheats ® 8 1 biscuit 38 22 0.8 28
Frosted Rice Krinkles ® 16 1/2 cup 34 44 0.8 62
Frosted Rice Krispies ® 14 1/2 cup 28 37 0.6 54
Fruit Wheat Squares 10 2 Tbsp 32 19 0.7 35
Fruity Pebbles™ 16 1/2 cup 28 37 0.6 66
Golden Grahams ® 10 1/4 cup 28 22 0.5 38
Grape Nuts Flakes ® 6 3 Tbsp 33 20 0.7 22
Honey Nut Cheerios ® 5 2 Tbsp 27 18 0.5 18
Honey Nut Corn Flakes ® 9 1/4 cup 31 25 0.6 38
Honeycomb ® 11 1/2 cup 33 26 0.6 43
King Vitaman ® 11 1/2 cup 29 23 0.5 43
Kix ® 6 1/3 cup 29 23 0.6 24
Life ® 3 1 Tbsp 28 20 0.5 10
Lucky Charms ® 6 3 Tbsp 30 20 0.5 23
Nutri-Grain ®
barley 5 2 Tbsp 31 19 0.6 19
corn 8 3 Tbsp 32 27 0.6 30
rye 8 3 Tbsp 31 21 0.7 27
wheat 5 2 Tbsp 25 15 0.5 20
Oat Flakes 3 1 Tbsp 29 21 0.6 11
Product 19 ® 6 3 Tbsp 31 23 0.6 24
Quisp ® 11 6 Tbsp 30 23 0.6 47
Raisin Bran (Post ®) 7 2 Tbsp 26 17 0.7 22
Rice Chex ® 13 1/2 cup 29 38 0.7 50
Rice Krispies ® 9 1/3 cup 27 36 0.6 37
Rice, puffed 10 3/4 cup 28 37 0.7 42
Special K ® 4 2 Tbsp 31 34 0.7 14
Sugar Frosted Flakes ® 12 1/3 cup 30 25 0.6 44
Sugar Pops ® 11 6 Tbsp 29 24 0.6 43
Sugar Smacks ® 9 1/4 cup 34 20 0.7 35
Sugar Sparkled Flakes 13 1/2 cup 35 29 0.7 64
Super Sugar Crisp ® 8 1/4 cup 28 16 0.5 31
Team ® 11 1/4 cup 32 31 0.7 41
Toasties (Post ®) 7 1/3 cup 29 24 0.6 27
Total ® 6 3 Tbsp 30 18 0.6 22
Trix ® 9 1/3 cup 27 21 0.5 35
Wheat
puffed 4 1/3 cup 30 17 0.6 14
shredded 5 1 Tbsp + 1-1/2 tsp 28 17 0.6 19
Wheat Chex ® 6 2 Tbsp 30 17 0.6 21
Wheaties ® 7 1/4 cup 33 20 0.7 25

Grains
Corn
cob (medium ear) 21 1/3 ear 30 25 0.6 19
cooked
cream style 32 2 Tbsp 26 21 0.6 23
whole kernel 20 2 Tbsp 32 26 0.7 22
Rice, prepared
brown, 25 2 Tbsp 32 24 0.6 27
cakes 9 1 cake 34 45 0.8 35
fried 23 1 Tbsp + 2 tsp 30 23 0.7 30
pilaf 15 1 Tbsp 30 20 0.6 23
Rice-A-Roni ® 21 1 Tbsp + 1 tsp 28 20 0.7 27
Spanish 30 2 Tbsp 26 21 0.5 26

18 Phenylketonuria © 2001 Ross Products Division


Food Weight Approximate PHE TYR Protein Energy
(g) Measure (mg) (mg) (g) (kcal)
For greatest accuracy, weigh food on scale that reads in grams. All measures are level.
white
long-grain 26 2 Tbsp 36 23 0.7 33
long-grain, instant 31 3 Tbsp 34 21 0.6 30
medium- and short-grain 26 2 Tbsp 32 20 0.6 33

Pasta, cooked
Macaroni 12 1 Tbsp + 1-1/2 tsp 31 18 0.6 18
Noodles 13 1 Tbsp + 1 tsp 26 14 0.5 17
Ramen ® Noodles 10 1 Tbsp 25 15 0.6 22
Spaghetti 19 2 Tbsp 33 17 0.6 21

Tubers
Potatoes, sweet
baked, w/ skin, mashed 25 2 Tbsp 26 18 0.4 26
boiled, no skin, mashed 31 1 Tbsp + 1-1/2 tsp 30 21 0.5 32
canned, packed in syrup 49 1/4 cup 26 18 0.4 67
Potatoes, white
baked, no skin 30 1/4 cup 31 26 0.7 33
boiled
no skin 39 1/4 cup 30 25 0.7 34
w/ skin 40 1/4 cup 32 28 0.8 34
canned 45 1/4 cup 28 24 0.3 27
French fries (1/2" x 1/2" x 2") 20 4 fries 32 19 0.7 64
hash browns, frozen/cooked 20 2 Tbsp 26 15 0.6 43
microwaved, w/ skin 29 3 Tbsp 27 23 0.6 29
pan fried 29 3 Tbsp 30 18 0.7 61
Tater Tots ® 37 4 pieces 33 19 0.8 61
Yams, baked or boiled 42 1/3 cup 29 17 0.6 49

Miscellaneous
Chocolate sauce (Hershey's ®) 20 1 Tbsp 25 18 0.5 49
Chow mein noodles 7 2 Tbsp 35 21 0.8 38
Flour, cake 8 1 Tbsp + 1 tsp 31 19 0.6 30
Jell-O ®, w/ sugar 80 1/3 cup 30 3 0.6 65

Snack Foods
Barnum's Animal Crackers ® 10 4 crackers 34 21 0.7 45
Cookies
fig bar 16 1 cookie 33 21 0.6 57
Ho Ho's ® 14 1/2 Ho Ho 27 17 0.6 60
Oreo ® 11 1 cookie 24 15 0.5 53
Social Tea Biscuit ® 11 2 biscuits 28 17 0.6 48
Sugar Wafer (Nabisco ®) 17 3 wafers 30 18 0.7 80
vanilla wafer 12 3 wafers 32 19 0.6 55
Crackers
Goldfish ®, original 9 15 crackers 29 19 0.6 44
graham cracker (2" x 2") 7 1 cracker 28 17 0.6 27
Ritz ® 10 3 crackers 32 19 0.7 50
Ritz Bits ® (cheese) 6 8 crackers 28 18 0.5 28
Rye Thins ® 8 3 crackers 27 12 0.6 39
Rykrisp ® 6 1 cracker 30 21 0.6 23
saltine 6 2 crackers 27 16 0.5 26
soda 7 1 cracker 35 19 0.7 30
Waverly ® 7 1 cracker 24 15 0.5 35
Wheat Thins ® 9 5 crackers 31 19 0.7 43
Doodads ® 7 2 Tbsp 34 22 0.8 35

© 2001 Ross Products Division Phenylketonuria 19


Food Weight Approximate PHE TYR Protein Energy
(g) Measure (mg) (mg) (g) (kcal)
For greatest accuracy, weigh food on scale that reads in grams. All measures are level.
Doritos ® 9 5 chips 28 17 0.7 44
Doughnuts, Ener-G ® Banana 84 2 doughnuts 31 10 0.8 309
Fritos ® 10 5 chips 30 22 0.7 55
Ice cream cone, wafer type 4 1 (cone only) 22 13 0.4 17
Popcorn
buttered 6 2/3 cup 31 26 0.6 27
caramel 9 1/4 cup 28 23 0.5 34
plain 4 2/3 cup 26 22 0.5 15
Potato chips (2" diameter) 10 5 chips 29 24 0.6 52
Rice cakes 9 1 cake 34 45 0.8 35
Tortillas
chips 8 1 chip 36 29 0.7 27
corn (6" diameter) 8 1/4 tortilla 36 29 0.7 27
flour (6" diameter) 8 1/4 tortilla 33 19 0.7 27

FATS

Butter, stick 14 1 Tbsp 6 6 0.1 101


Gravy
mushroom, canned 10 2 tsp 6 4 0.1 5
mushroom mix, dry 1 2 tsp 4 3 0.1 3
onion mix, dry 1 2 tsp 5 3 0.1 3
Margarine
liquid 5 1 tsp 4 4 0.1 34
soft 14 1 Tbsp 5 5 0.1 102
stick or brick 14 1 Tbsp 6 6 0.1 101
Nondairy creamers, w/ sodium caseinate
liquid 10 2 tsp 6 4 0.1 14
powder 2 1 tsp 5 5 0.1 11
Rich's ® Coffee Rich 29 2 Tbsp 4 3 0.1 44
Polyrich ® 29 2 Tbsp 4 3 0.1 44
Olives, black or green 10 2 olives 4 4 0.2 15
Salad dressings, commercial
French 16 1 Tbsp 4 4 0.1 67
Italian 15 1 Tbsp 4 4 0.1 69
mayonnaise 9 2 tsp 5 4 0.1 66
Thousand Island 16 1 Tbsp 6 6 0.1 59
Toppings, commercial
Cool Whip ®
extra creamy 5 1 Tbsp 6 6 0.1 15
regular 8 2 Tbsp 6 6 0.1 22
Richwhip ®
pressurized 22 3 Tbsp 5 4 0.1 60
prewhipped 8 2 Tbsp 5 4 0.1 24
Whipped cream, pressurized 4 1 Tbsp 6 6 0.1 10

FRUITS
Fruits are raw unless otherwise noted. Weight of raw fruits is only for parts that can be eaten. Drain canned, cooked, and frozen fruits before
measuring or weighing. Do not use any fruits that contain NutraSweet®, SweetMate®, or aspartame.

Apricots
canned, heavy syrup 64 1/4 cup 14 8 0.3 54
dried, halves 11 3 16 9 0.4 25
frozen, sweetened 60 1/4 cup 16 9 0.4 60
nectar, canned 94 3 fl oz 15 9 0.3 53
whole 35 1 fruit 18 10 0.5 17
Avocados, all varieties, mashed 23 1 Tbsp + 2 tsp 17 12 0.5 38
Bananas, sliced 42 3 Tbsp 16 10 0.4 39

20 Phenylketonuria © 2001 Ross Products Division


Food Weight Approximate PHE TYR Protein Energy
(g) Measure (mg) (mg) (g) (kcal)
For greatest accuracy, weigh food on scale that reads in grams. All measures are level.
Blackberries
canned, heavy syrup 25 2 Tbsp + 1-1/2 tsp 16 19 0.6 39
frozen 50 1/2 cup 17 20 0.6 32
raw 72 1/2 cup 15 17 0.5 38
Blueberries
canned, heavy syrup 64 1/4 cup 15 5 0.4 56
frozen, sweetened 115 1/2 cup 16 6 0.5 93
raw 72 1/2 cup 17 6 0.5 41
Boysenberries, canned, heavy syrup 64 1/4 cup 18 13 0.6 56
Cherries
canned, heavy syrup
sour red 77 1/3 cup 12 5 0.6 70
sweet 86 1/3 cup 15 10 0.5 67
raw 48 1/3 cup 13 5 0.6 34
Dates 25 3 fruits 14 8 0.5 68
Figs
canned, heavy syrup 168 3/4 cup 15 32 0.7 180
dried, uncooked 19 1 fruit 14 25 0.6 48
whole, large 83 1-2/3 fruit 15 27 0.6 61
Fruit cocktail, canned, heavy syrup 128 1/2 cup 14 9 0.4 93
Fruit salad, canned, heavy syrup 128 1/2 cup 14 10 0.4 94
Gooseberries, canned, light syrup 63 1/4 cup 15 5 0.4 46
Grapefruit, all varieties
canned, light syrup 85 1/3 cup 15 8 0.5 50
juice, canned, unsweetened 124 4 fl oz 19 13 0.6 48
sections 77 1/3 cup 16 8 0.5 24
Grapes
adherent skin 120 3/4 cup 16 14 0.8 86
juice, canned 126 4 fl oz 15 4 0.7 78
slipskin 92 1 cup 12 10 0.6 58
Thompson, seedless, canned, heavy syrup 128 1/2 cup 13 10 0.6 93
Kiwi fruit 50 2/3 piece 16 13 0.5 31
Mangoes, sliced 82 1/2 cup 14 9 0.4 54
Melons, cubed
cantaloupe 53 1/3 cup 13 8 0.5 18
casaba 57 1/3 cup 15 10 0.5 15
honeydew 85 1/2 cup 11 8 0.4 30
Mixed fruit, canned, heavy syrup 127 1/2 cup 14 10 0.5 92
Nectarines, sliced 52 6 Tbsp 16 12 0.5 25
Oranges
juice
canned 249 8 fl oz 17 7 1.5 105
frozen, diluted 187 6 fl oz 15 8 1.3 84
sections 45 1/4 cup 14 7 0.4 21
Papaya, cubed 140 1 cup 13 7 0.9 54
Passion fruit
juice 124 4 fl oz 14 10 0.5 63
whole, small 18 1 fruit 12 8 0.4 73
Peaches
canned, heavy syrup 128 1/2 cup 18 16 0.6 95
dried 13 1/2 cup 15 12 0.5 31
frozen, sweetened 83 1/3 cup 17 13 0.5 78
nectar 187 6 fl oz 16 13 0.5 100
sliced 85 1/2 cup 18 16 0.6 37
spiced, canned, heavy syrup 121 1/2 cup 16 13 0.5 90
Pears
canned, heavy syrup 255 1 cup 13 5 0.5 188

© 2001 Ross Products Division Phenylketonuria 21


Food Weight Approximate PHE TYR Protein Energy
(g) Measure (mg) (mg) (g) (kcal)
For greatest accuracy, weigh food on scale that reads in grams. All measures are level.
halves, dried 35 2 17 6 0.7 92
sliced 165 1 cup 17 5 0.6 97
Persimmons, Japanese 56 1/3 fruit 15 9 0.4 39
Pineapple
canned, heavy syrup, chunks, tidbits, or crushed 191 3/4 cup 17 15 0.8 149
diced 116 3/4 cup 14 14 0.4 58
frozen, sweetened, chunks 122 1/2 cup 15 16 0.5 104
juice, canned, frozen, diluted 125 4 fl oz 15 13 0.5 65
Plantains, cooked 51 1/3 cup 14 10 0.4 60
Plums
cubed 82 1/2 cup 14 5 0.7 45
purple, canned, heavy syrup 194 3/4 cup 16 6 0.7 172
Prunes
juice 128 4 fl oz 17 6 0.8 90
whole, dried 25 3 fruits 15 6 0.7 60
Raisins, seedless 18 2 Tbsp 12 11 0.6 55
Raspberries
canned, heavy syrup 64 1/4 cup 15 18 0.5 58
raw 62 1/2 cup 16 19 0.6 30
red, frozen, sweetened 83 1/3 cup 17 20 0.6 85
Rhubarb, cooked, sweetened 120 1/2 cup 14 9 0.5 139
Strawberries, sliced
frozen, sweetened 85 1/3 cup 13 15 0.5 82
raw 74 1/2 cup 13 16 0.5 23
Tangerines
canned, light syrup 84 1/3 cup 13 7 0.4 51
juice
canned, sweetened 249 8 fl oz 15 7 1.2 125
frozen, diluted 241 8 fl oz 12 5 1.0 110
whole, medium 84 1 fruit 18 9 0.5 37
Watermelon, cubed 120 3/4 cup 18 14 0.7 38

VEGETABLES
Vegetables are raw unless otherwise noted. Weight of raw vegetables is only for parts that can be eaten. Drain canned and cooked
vegetables before measuring or weighing.

Asparagus
canned
green 30 2 Tbsp or 2 spears 15 9 0.6 6
white 38 2 spears 19 13 0.6 7
fresh or frozen, cooked 22 1-1/2 spears 16 10 0.6 6
raw 21 1-1/2 spears 16 10 0.7 7
Bamboo shoots, canned, sliced 25 3 Tbsp 15 12 0.4 5
Beans,
snap, green
canned 34 1/4 cup 14 9 0.4 7
fresh, cooked 16 2 Tbsp 14 9 0.4 7
frozen, cooked 34 1/4 cup 17 11 0.5 9
sprouts
mung (seed attached to sprout)
cooked 16 2 Tbsp 14 6 0.3 3
raw 13 2 Tbsp 15 7 0.4 4
soy
cooked 8 1 Tbsp 13 12 0.4 3
raw 6 1 Tbsp 12 11 0.4 3
yellow wax
canned 34 1/4 cup 14 9 0.4 7

22 Phenylketonuria © 2001 Ross Products Division


Food Weight Approximate PHE TYR Protein Energy
(g) Measure (mg) (mg) (g) (kcal)
For greatest accuracy, weigh food on scale that reads in grams. All measures are level.
frozen, cooked 34 1/4 cup 14 11 0.5 9
Beets
red, sliced
fresh or canned, cooked 50 1/3 cup 15 12 0.5 15
pickled 50 1/3 cup 15 12 0.5 15
greens, cooked 18 2 Tbsp 12 11 0.5 5
Broccoli, fresh or frozen
cooked 20 2 Tbsp 18 13 0.6 6
raw 16 3 Tbsp 14 7 0.3 3
Brussels sprouts, fresh or frozen, cooked 21 1 sprout 16 12 0.5 8
Cabbage, shredded
Chinese (Pak-choi)
cooked 32 3 Tbsp 15 10 0.5 4
raw 35 1/2 cup 15 10 0.5 5
red
cooked 37 1/4 cup 13 7 0.4 8
raw 35 1/2 cup 15 8 0.5 10
white
cooked 52 1/3 cup 15 8 0.5 10
raw 35 1/2 cup 14 7 0.4 8
Carrots
canned 50 1/2 cup 15 9 0.5 17
fresh or cooked 39 1/4 cup 14 8 0.4 18
sliced 55 1/2 cup 18 11 0.6 24
Cauliflower
cooked 23 3 Tbsp 16 10 0.4 6
frozen, cooked 22 2 Tbsp 13 8 0.4 4
raw 25 1/4 cup 18 11 0.5 6
Celery, diced
cooked 75 1/2 cup 11 5 0.4 11
raw 60 1/2 cup 11 5 0.4 9
Chard, cooked 14 1 Tbsp + 1 tsp 15 11 0.2 3
Chayote, fruit, cooked 40 1/4 cup 14 10 0.2 10
Collards, cooked, chopped
fresh 48 1/4 cup 18 15 0.5 6
frozen 14 1 Tbsp + 1 tsp 14 11 0.4 5
Cucumber, pared, sliced 104 1 cup 16 9 0.6 14
Eggplant, cubed
cooked 48 1/2 cup 17 11 0.4 13
raw 31 6 Tbsp 14 9 0.3 8
Endive, raw, shredded 25 1/2 cup 13 10 0.3 4
Kale, cooked
fresh 16 2 Tbsp 16 11 0.3 5
frozen 11 1 Tbsp + 1 tsp 15 11 0.3 4
Kohlrabi, sliced
cooked 41 1/4 cup 17 12 0.7 12
raw 35 1/4 cup 14 17 0.6 10
Lettuce
bibb and Boston, raw 30 4 leaves 16 10 0.4 4
iceberg, shredded 28 1/2 cup 14 8 0.3 4
Romaine and cos, raw 20 2 leaves 14 8 0.3 4
Mushrooms,
Agaricus bisporus
cooked or canned 19 1/4 cup 15 8 0.4 5
raw, sliced 18 1 mushroom 15 8 0.4 5
Shitake
cooked 18 2 Tbsp 12 8 0.3 10

© 2001 Ross Products Division Phenylketonuria 23


Food Weight Approximate PHE TYR Protein Energy
(g) Measure (mg) (mg) (g) (kcal)
For greatest accuracy, weigh food on scale that reads in grams. All measures are level.
dried 4 1 mushroom 17 12 0.3 11
Mustard greens, cooked 26 3 Tbsp 16 31 0.6 4
Okra, pods or sliced, cooked 23 2 Tbsp 16 21 0.5 8
Onions
cooked 75 1/3 cup 15 15 0.7 20
raw, chopped 50 1/3 cup 15 15 0.6 15
rings, canned 25 1/2 cup 18 12 0.4 90
Parsnips, cooked 58 6 Tbsp 15 12 0.6 48
Peas, green, canned or frozen, cooked 10 1 Tbsp 17 10 0.5 7
Peppers, green, diced
cooked 68 1/2 cup 13 9 0.4 12
raw 50 1/2 cup 13 9 0.4 13
Pickles, cucumber
dill 104 1 large 16 9 0.6 14
dill relish 83 1/3 cup 12 7 0.4 14
sweet 83 1/3 cup 12 7 0.4 114
Pumpkin, canned 46 3 Tbsp 16 21 0.5 15
Radish
red, small 67 15 radishes 15 9 0.4 10
white icicle, sliced 50 1/2 cup 18 11 0.6 7
Rutabagas
cooked, mashed 60 1/4 cup 17 13 0.7 20
raw, cubed 44 1/3 cup 14 10 0.5 16
Sauerkraut 59 1/4 cup 17 9 0.5 11
Shallots, chopped 20 2 Tbsp 16 14 0.5 14
Spinach
fresh or frozen, cooked 12 1 Tbsp 16 13 0.4 2
raw, chopped 14 1/4 cup 18 15 0.4 3
Squash, summer, all varieties
fresh or frozen, cooked 45 1/4 cup 15 11 0.4 9
sliced 33 1/4 cup 14 10 0.4 7
Squash, winter
acorn
baked, cubed 38 3 Tbsp 17 15 0.4 21
boiled, mashed 61 1/4 cup 16 14 0.4 20
butternut
baked, cubed 51 1/4 cup 18 16 0.5 20
boiled, mashed 30 2 Tbsp 15 12 0.4 12
Hubbard
baked, cubed 26 2 Tbsp 15 13 0.6 13
boiled, mashed 30 2 Tbsp 17 15 0.4 9
spaghetti, cooked 51 1/3 cup 12 10 0.3 15
Taro, cooked 66 1/2 cup 18 13 0.3 94
leaves 18 2 Tbsp 20 18 0.5 4
root, sliced
Tomato
canned or fresh, cooked 60 1/4 cup 17 12 0.7 15
catsup 31 2 Tbsp 15 8 0.6 33
fresh
juice 92 3 fl oz 15 9 0.7 16
paste 16 1 Tbsp 13 8 0.6 14
purée 47 3 Tbsp 16 10 0.8 19
sauce
canned, w/ onions, green pepper, and celery 61 1/4 cup 17 11 0.8 19
marinara 47 3 Tbsp 16 10 0.8 32
whole, small 66 1/2 tomato 14 9 0.5 12

24 Phenylketonuria © 2001 Ross Products Division


Food Weight Approximate PHE TYR Protein Energy
(g) Measure (mg) (mg) (g) (kcal)
For greatest accuracy, weigh food on scale that reads in grams. All measures are level.
Turnips
greens
canned 25 2 Tbsp 17 10 0.4 4
fresh or frozen, cooked 18 2 Tbsp 12 8 0.2 4
root, diced
cooked 78 3/4 cup 16 12 0.9 21
raw 65 3/4 cup 16 12 0.9 27
Vegetable juice cocktail 91 3 fl oz 12 7 0.6 17

Soups, Campbell's ® Condensed. Weigh or measure before diluting and dilute with water only.
Asparagus, Cream of 21 1 Tbsp + 1 tsp 16 12 0.4 15
Celery, Cream of 31 2 Tbsp 20 14 0.4 22
Chicken Gumbo 21 1 Tbsp + 1 tsp 16 12 0.4 9
Chicken Vegetable 16 1 Tbsp 17 12 0.5 9
Mushroom, Cream of 20 1 Tbsp + 1 tsp 16 12 0.4 20
Onion 20 1 Tbsp + 1 tsp 16 15 0.7 9
Potato, Cream of 24 1 Tbsp + 1-1/2 tsp 15 12 0.3 14
Tomato 32 2 Tbsp 18 11 0.5 21
Tomato Bisque 26 1 Tbsp + 2 tsp 16 12 0.5 25
Tomato Rice 32 2 Tbsp 18 11 0.5 30
Vegetable, Old Fashioned 15 1 Tbsp 13 6 0.3 9
Vegetarian, Vegetable 15 1 Tbsp 13 6 0.3 9

FREE FOODS A
Limit to prescribed number of servings. Do not use beverages or foods that contain NutraSweet ®, SweetMate ®, or aspartame.

Desserts
Butterscotch chips 5 5 pieces 5 5 0.1 15
Gelatin pop 22 1/2 pop 5 1 0.3 16
Marmalade 19 1 Tbsp 3 2 0.1 50
Marshmallow 8 1 large 4 1 0.2 26
M&M ® candy, plain 2 2 pieces 6 4 0.2 8
Mocha Mix, frozen
chocolate 8 1 Tbsp 7 5 0.2 17
vanilla 8 1 Tbsp 5 4 0.1 17
Raisins, chocolate covered 2 2 raisins 6 6 0.2 12
Sorbet
peach 30 2 Tbsp 4 4 0.1 30
pineapple 59 1/4 cup 7 7 0.2 58
strawberry 59 1/4 cup 7 8 0.2 58

Fruits/Fruit Products
Apple
butter 40 2 Tbsp 4 3 0.2 74
canned, sweetened, sliced 102 1/2 cup 5 3 0.2 68
chips (Nature's Favorite ®) 15 1/4 cup 6 4 0.2 60
dried 21 1/4 cup 6 4 0.2 52
dried, cooked 64 1/4 cup 4 3 0.1 36
juice, frozen, diluted 120 2 fl oz 4 3 0.2 56
sauce, sweetened, canned 128 1/2 cup 6 4 0.2 97
whole, small 100 1 fruit 5 4 0.2 59
Cranberry sauce, canned 69 1/4 cup 5 1 0.1 104
Fruit bars, frozen
orange 37 1/2 bar 5 2 0.1 35
pineapple 37 1/2 bar 4 4 0.1 35
strawberry 74 1 bar 6 7 0.2 60
Fruit ice 48 1/4 cup 6 3 0.2 62

© 2001 Ross Products Division Phenylketonuria 25


Food Weight Approximate PHE TYR Protein Energy
(g) Measure (mg) (mg) (g) (kcal)
For greatest accuracy, weigh food on scale that reads in grams. All measures are level.
Fruit pie filling
apple 123 1/2 cup 4 3 0.1 135
cherry 47 3 Tbsp 5 2 0.2 49
peach 50 3 Tbsp 5 4 0.2 54
strawberry 31 2 Tbsp 5 5 0.2 34
Fruit Roll-Ups ® 14 1 piece 4 3 0.2 55
Lemonade 125 4 fl oz 4 2 0.1 55
Nectar
papaya 250 8 fl oz 5 3 0.4 142
peach 62 2 fl oz 5 4 0.2 34
pear 125 4 fl oz 4 1 0.1 75

Miscellaneous
Barbecue sauce 16 1 Tbsp 6 4 0.3 12
Chocolate
drink powder 3 1 tsp 4 3 0.1 11
pudding mix 7 2 tsp 6 4 0.1 23
syrup 6 1 tsp 5 4 0.1 14
Coconut, dried, sweetened w/ sugar 3 2 tsp 5 3 0.1 15
Coffee, instant, powder 2 1 tsp 5 3 0.2 4
Horseradish 2 2 tsp 4 4 0.1 2

FREE FOODS B
These foods contain little or no PHE or TYR. They may be used as desired if patient is not overweight and they do not depress appetite for
prescribed foods. Do not use beverages or foods that contain NutraSweet ®, SweetMate ®, or aspartame.

Beverages
Apple juice, canned 124 4 fl oz 2 2 0.1 60
Beer, regular 28 1 fl oz 2 4 0.1 12
Carbonated beverages, caffeine-free 113 4 fl oz 0 0 0.0 52
Cranberry juice cocktail 126 4 fl oz 1 1 0.0 72
Exceed ® Energy Drink 124 4 fl oz 0 0 0.0 35
Gatorade ® 125 4 fl oz 0 0 0.0 25
Kool-Aid ®, sweetened w/ sugar 125 4 fl oz 0 0 0.0 48
Liquor 28 1 fl oz 0 0 0.0 70
Limeade, sweetened w/ sugar 125 4 fl oz 0 0 0.0 51
Tang ® 125 4 fl oz 0 0 0.0 59
Tea, instant, powder 1 1 Tbsp 1 1 0.1 3
Wine 28 1 fl oz 1 1 0.1 21

Desserts/Sweeteners 1
Candies
Candy corn 16 10 pieces 0 0 0.0 58
Gumdrops 4 2 pieces 0 0 0.0 14
Hard candy 10 2 pieces 0 0 0.0 39
Jelly beans 28 10 pieces 0 0 0.0 103
Lollipop 28 1 medium 0 0 0.0 108
Frosting, strawberry and vanilla 16 1 Tbsp 0 0 0.0 69
Honey 21 1 Tbsp 3 2 0.1 64
Lemon pudding, canned (Hunt's ®) 121 1 can 0 0 0.0 151
Molasses 21 1 Tbsp 0 0 0.0 48
Popsicle ®, twin 128 1 popsicle 0 0 0.0 95
Sugar
brown 14 1 Tbsp 0 0 0.0 52
powdered 8 1 Tbsp 0 0 0.0 31
table 12 1 Tbsp 0 0 0.0 48

26 Phenylketonuria © 2001 Ross Products Division


Food Weight Approximate PHE TYR Protein Energy
(g) Measure (mg) (mg) (g) (kcal)
For greatest accuracy, weigh food on scale that reads in grams. All measures are level.
Syrup
corn 20 1 Tbsp 0 0 0.0 58
maple 20 1 Tbsp 0 0 0.0 50
table 20 1 Tbsp 0 0 0.0 50

Fruits/Fruit Products
Fruit butters 7 1 tsp 1 1 < 0.1 13
Fruit ices 1/2 cup 0 0 trace 69
Fruit juice bar 52 1 bar 2 1 0.1 43
Fun Fruits ® 26 1 piece 2 1 0.1 100
Guava
raw 90 1 fruit 2 9 0.7 45
sauce 119 1/2 cup 1 5 0.4 43
Jams 7 1 tsp 1 1 < 0.1 18
Jellies 20 1 Tbsp 0 0 0.0 50

Miscellaneous
Cornstarch 8 1 Tbsp 0 0 trace 29
Lard 13 1 Tbsp 0 0 0.0 115
Oil, vegetable 14 1 Tbsp 0 0 0.0 120
Richwhip ®, liquid 14 1 Tbsp 0 0 0.0 40
Shortening 13 1 Tbsp 0 0 0.0 113
Tapioca, dry 10 1 Tbsp 1 1 0.1 36
Vinegar/oil dressing 16 1 Tbsp 0 0 0.0 70
Wheat starch 8 1 Tbsp 1 1 trace 25
For nutrient composition of very-low-protein foods, see Appendix 12, p A-11.

© 2001 Ross Products Division Phenylketonuria 27


TABLE 1-4. Nutrient Composition of PHENEX™-1 1, 3 and PHENEX-™2 2, 3
© 2001 Ross Products Division

Nutrient Phenex-1 Phenex-2, Unflavored Phenex-2, Flavored


Per 100 g pwd Per g protein equiv Per 100 g pwd Per g protein equiv Per 100 g pwd Per g protein equiv
Energy, kcal 480 32 410 13.7 410 13.7
Protein equiv, g 15.00 1.000 30 1.000 30 1.000
Nitrogen, g 2.40 0.160 4.80 0.160 4.80 0.160
Amino acids, g 15.79 1.053 31.58 1.053 31.58 1.053
Cystine, g 0.15 0.010 0.30 0.010 0.30 0.010
Histidine, g 0.42 0.028 0.84 0.028 0.84 0.028
Isoleucine, g 1.08 0.072 2.16 0.072 2.16 0.072
Leucine, g 1.68 0.112 3.36 0.112 3.36 0.112
Lysine, g 1.00 0.067 2.00 0.067 2.00 0.067
Methionine, g 0.30 0.020 0.60 0.020 0.60 0.020
Phenylalanine, g trace 0 trace 0 trace 0
Threonine, g 0.70 0.047 1.40 0.047 1.40 0.047
Tryptophan, g 0.17 0.011 0.34 0.011 0.34 0.011
Tyrosine, g 1.50 0.100 3.00 0.100 3.00 0.100
Valine, g 1.22 0.081 2.44 0.081 2.44 0.081
Other Nitrogen-Containing Compounds
Carnitine, mg 20 1.33 40 1.33 40 1.33
Taurine, mg 40 2.67 50 1.67 50 1.67
Carbohydrate, g 53.0 3.53 35 1.17 36 1.20
Fat, g 21.7 1.45 14 0.47 13.5 0.45
Linoleic acid, g 2.00 4 0.133 1.50 5 0.050 1.50 5 0.050
6
α-Linolenic acid, g 0.36 0.024 0.17 7 0.006 0.17 7 0.006
Minerals
Calcium, mg 575 38 880 29 880 29
Chloride, mg/mEq 325/9.17 21.7/0.61 940/26.51 31.33/0.88 940/26.51 31.33/0.88
Chromium, µg 11 0.73 27 0.90 27 0.90
Copper, mg 1.10 0.073 1.00 0.033 1.00 0.033
Iodine, µg 65 4.33 100 3.33 100 3.33
Iron, mg 9.0 0.60 13 0.43 13 0.43
Phenylketonuria 27

Magnesium, mg 50 3.33 225 7.50 225 7.50


Manganese, mg 0.50 0.033 0.80 0.027 0.80 0.027
28 Phenylketonuria

Nutrient Phenex-1 Phenex-2, Unflavored Phenex-2, Flavored


Per 100 g pwd Per g protein equiv Per 100 g pwd Per g protein equiv Per 100 g pwd Per g protein equiv
Molybdenum, µg 12 0.80 30 1.00 30 1.00
Phosphorus, mg 400 27 760 25 760 25
Potassium, mg/mEq 675/17.26 45./1.15 1,370/35.04 45.7/1.17 1,370/35.04 45.7/1.17
Selenium, µg 20 1.33 35 1.17 35 1.17
Sodium, mg/mEq 190/8.26 12.7/0.55 880/38.28 29.3/1.28 880/38.28 29.3/1.28
Zinc, mg 8.0 0.53 13 0.43 13 0.43
Vitamins
A, µg RE 420 28 660 22 660 22
D, µg 7.50 0.50 7.50 0.25 7.50 0.25
E, mg α-TE 10.10 0.67 12.10 0.40 12.10 0.40
K, µg 50 3.33 60 2.00 60 2.00
Ascorbic acid, mg 50 3.33 60 2.00 60 2.00
Biotin, µg 65 4.33 100 3.33 100 3.33
B6, mg 0.75 0.050 1.30 0.043 1.30 0.043
B12, µg 4.90 0.327 5.00 0.167 5.0 0.167
Choline, mg 80 5.33 100 3.33 100 3.33
Folate, µg 230 15 450 15 450 15
Inositol, mg 40 2.67 70 2.33 70 2.33
Niacin equiv, mg 12.80 0.850 21.7 0.72 21.7 0.72
Pantothenic acid, mg 6.90 0.460 8.00 0.267 8.0 0.267
Riboflavin, mg 0.90 0.060 1.80 0.060 1.80 0.060
Thiamin, mg 1.90 0.127 3.25 0.108 3.25 0.108
1 2
3
Designed for infants and toddlers. Designed for children, adolescents, and adults.
Approximate packed weights in level, dry US standard household measures:
Phenex-1 Phenex-2, unflavored Phenex-2, flavored
1 Tbsp = 7g 8g 9g
1/4 cup = 26 g 32 g 30 g
© 2001 Ross Products Division

1/3 cup = 35 g 41 g 40 g
1/2 cup = 53 g 61 g 59 g
1 cup = 105 g 117 g 116 g
4
Analytical data at manufacture = 4.32 g/100 g powder.
5
Analytical data at manufacture = 2.66 g/100 g powder in flavored.
6
Analytical data at manufacture = 0.40 g/100 g powder.
7
Analytical data at manufacture = 0.28 g/100 g powder in unflavored, 0.27 g/100 g powder in flavored.
© 2001 Ross Products Division
TABLE 1-5. PKU Clinical Summary Sheet

Name: Hospital Number:

Date of Birth: __________/__________/__________


Mo Day Year

Date Age Physical Data Laboratory Data Nutrient Intake Data


Length/ Weight Head Hgb Ferritin Transthyretin PHE1 TYR1 PHE TYR Protein Energy
Height Circum
(mo/d/yr) (yrs/mo) (cm) (kg) (cm) (g/dL) (ng/mL) (mg/dL) (mg) (mg) (g) (kcal)
Phenylketonuria 29

1
Indicate if mg/dL or µmol/L.
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19. Elsas LJ, Acosta PB: Nutrition support of inherited metabolic diseases. In Shils ME, et al (eds): Modern Nutrition in
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26. Gropper S, Acosta PB: Effect of simultaneous ingestion of L-amino acids and whole protein on plasma amino acid
and urea nitrogen concentrations in humans. JPEN 1991;15:48-53.
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29. Gropper SS, Yannicelli S: Plasma molybdenum concentrations in children with and without phenylketonuria. Biol
Trace Elem Res 1993;38:227-231.

© 2001 Ross Products Division Phenylketonuria 31


30. Guldberg P, Mikkelsen I, Henriksen KF, et al: In vivo assessment of mutations in the phenylalanine hydroxylase
gene by phenylalanine loading: Characterization of seven common mutations. Eur J Pediatr 1995;154:551-556.
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mixture on different amounts of single dose ingested. A case report. Eur J Pediatr 1994;153:501-503.
36. Hillman L, Schlotzhauer C, Lee D, et al: Decreased bone mineralization in children with phenylketonuria under
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38. Jones BJM, Lees R, Andrews J, et al: Comparison of an elemental and polymeric enteral diet in patients with
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Am J Clin Nutr 1983;37:778-785.
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32 Phenylketonuria © 2001 Ross Products Division


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© 2001 Ross Products Division Phenylketonuria 33


PROTOCOL 2 — Maternal Phenylketonuria (MPKU)

Nutrition Support of Pregnant Women With Phenylketonuria (PKU) With


PHENEX™-2 Amino Acid-Modified Medical Food
I. Introduction
Phenylketonuria (PKU) that is untreated at conception and during gestation is associated with poor
reproductive outcomes. Intrauterine growth retardation and congenital anomalies, often severe and
incompatible with life, are common. Most investigators attribute these effects to elevated maternal
plasma phenylalanine (PHE) concentrations. Lenke and Levy (25) described outcomes of
524 pregnancies in 155 women with PKU. The incidence of low birth weight, microcephaly, congenital
anomalies, and mental retardation in offspring was significantly higher than in the normal population.
The pathogenesis of fetal damage is uncertain, but is believed to be related to an elevated maternal
blood concentration of PHE (12, 20, 27) because PHE is actively transported across the placenta to
the fetus (24). Fetal blood PHE concentrations usually are significantly greater than those of maternal
blood (15) and interfere with embryonic development, although the mechanism of effect is not yet
known (12, 20, 27).
Offspring who survive fail to grow and develop normally. In fact, Kirkman (21) predicted that if these
women have normal fertility and dietary PHE intake is not controlled, the incidence of PKU-related
mental retardation could return to the prescreening level after only one generation.

II. Effects of Nutrition Support on Reproductive Outcome


A PHE-restricted diet and the gestational age at which it is initiated affect reproductive outcome. Of
576 pregnancies in the Maternal PKU Collaborative Study (MPKUCS), 414 resulted in live births
(22, 37). Only 125 women achieved and maintained blood PHE concentration < 600 µmol by
10 weeks gestation. Women who started the PHE-restricted diet before conception had a mean
plasma PHE concentration of 461 µmol/L (± SD of 233) during their 1st trimester of pregnancy. Those
who started the diet during the 1st trimester had a mean concentration of 661 µmol/L (± SD of 267).
Both mean concentrations were greater than the target range of 120 to 360 µmol/L.
Mean median head circumference percentile of offspring of the 25 women whose plasma PHE
concentration was less than 360 µmol/L by 10 weeks' gestation was significantly greater (58%) than
that of offspring of 35 women whose plasma PHE concentration was between 360 and 600 µmol/L by
10 weeks (41%). The mean General Cognitive Index (GCI) (McCarthy score) of offspring of women
who achieved control of plasma PHE concentration before 10 weeks' gestation was 94. Offspring of
women achieving control of plasma PHE concentration between 10 and 20 weeks' gestation had a
mean GCI of 87 and offspring of women not achieving control until after 20 weeks had a mean GCI of
72 (22, 23).
Rouse, et al (40) reported incidence of facial dysmorphology and major malformations in 35 infants in
the MPKUCS. Abnormally shaped ears, a wide palpebral fissure, epicanthical folds, and a long
philtrum were manifested in 50% to 70% of the offspring of mothers whose blood PHE concentration
was between 240 and 600 µmol/L. Fifteen percent of offspring of treated mothers had cardiac defects.
Intrauterine growth retardation ranged from 10% in offspring of women whose plasma PHE
concentration was between 240 and 600 µmol/L, to 100% in infants whose mother's PHE
concentration was more than 1200 µmol/L. Rouse, et al suggested that the mother's blood PHE
concentration should be lower than 360 µmol/L during pregnancy for the best outcome.
Smith et al (43) studied 94 infants of women with PKU, evaluating subjects by maternal blood PHE
concentration around the time of conception. Regression analysis of data from all 94 infants indicated
that birth weight decreased by 98 g and head circumference decreased by 0.46 cm for each
200 µmol/L increase in maternal blood PHE concentration above the normal range. Smith, et al
advised that a PHE-restricted diet should be started before conception and that blood PHE
concentration should be maintained between 60 and 180 µmol/L (43).

III. Establish Diagnosis


A. This protocol addresses nutrition support of women diagnosed with PHE hydroxylase deficiency.
See Protocol 1, p 2.

34 Maternal Phenylketonuria 2001 Ross Products Division


IV. Rationale for Nutrition Support
A. Correct Primary Imbalance in Metabolic Relationships
1. Restrict dietary PHE to amount tolerated by patient to maintain treatment plasma PHE
concentration.
B. Supply Product of Blocked Primary Pathway
1. Supplement dietary tyrosine (TYR) as necessary to maintain normal plasma TYR
concentration.

V. Establish Goals of Nutrition Support


A. Plasma PHE Concentration
1. Maintain 2- to 4-hour postprandial plasma PHE concentration between 2 and 4 mg/dL when
measured by bacterial inhibition assay and 120 and 240 µmol/L when measured by
quantitative methods) (10, 11, 29, 43, 46) or within normal range established by laboratory
used.
a. Frequent assessment of plasma PHE concentration is necessary for optimal nutrition
support and fetal outcome.
2. In practice, obtaining blood 2 to 4 hours postprandially is not always possible. Acceptable local
standards should be developed if plasma amino acids are evaluated at other times (Practical
Aspects of Nutrition Support, p viii).
3. Differences of opinion exist as to best concentrations of plasma PHE and TYR for support of
normal fetal development and growth. Concentrations of plasma PHE and TYR as close to
normal as possible without restricting fetal growth are recommended (10, 30, 40, 43).
B. Plasma TYR Concentration
1. Maintain 2- to 4-hour postprandial plasma TYR concentration between 50 and 100 µmol/L
(0.9 and 1.8 mg/dL) or within normal range established by laboratory used.
C. Weight and Nutrition Status
1. Support normal and appropriate weight gain based on height, prepregnancy weight, and
gestational age (Table 2-1, p 41).
2. Recommended weight gain depends on weight at conception (47).
a. Normal-weight women should gain:
1) 1.60 kg (3.50 lb) in 1st trimester.
2) 0.44 kg (0.97 lb) per week during remainder of pregnancy.
3) 11 to 16 kg (25 to 35 lb) by 40 weeks' gestation.
b. Underweight women should gain:
1) 2.30 kg (5 lb) in 1st trimester.
2) 0.49 kg (1.08 lb) per week during remainder of pregnancy.
3) 15 to 18 kg (34 to 40 lb) by 40 weeks' gestation.
c. Overweight women should gain:
1) 0.9 kg (2 lb) in 1st trimester.
2) 0.3 kg (0.66 lb) per week during remainder of pregnancy.
3) 7 to 11.5 kg (15 to 25 lb) by 40 weeks' gestation.
3. Maintain normal nutrition status for pregnant woman (3, 8).

VI. Establish Prescription


A. PHE
1. Prescribe PHE intake that promotes goals of nutrition support.
2. PHE requirements vary widely:
a. From patient to patient, depending on activity of PHE hydroxylase which is dependent on
genotype (9).
b. In same patient, depending on:
1) Age.
2) Weight gain (39).
3) Trimester of pregnancy (39).
4) Adequacy of energy and protein intakes.
5) State of health.
© 2001 Ross Products Division Maternal Phenylketonuria 35
3. Lowest value for PHE in Table 2-2, p 41, is suggested to begin therapy.
a. Changing requirements are established only by frequent monitoring of plasma PHE
concentration of patient.
b. See Section IX, Suggested Evaluation of Nutrition Support, p 37.
4. PHE requirements usually increase at approximately 20 weeks' gestation (39, 46).
Warning: Inadequate PHE intake may lead to low maternal weight gain and poor
reproductive outcome.
B. TYR
1. Prescribe TYR intake that maintains treatment plasma TYR concentration.
2. Lowest value for TYR listed in Table 2-2, p 41, is suggested to start therapy.
3. Changing requirements of patients are determined only by frequent monitoring of plasma TYR
concentration.
C. Protein
1. See Table 2-2, p 41, for Recommended Protein Intakes.
2. Requirements are greater than Recommended Dietary Allowances (RDAs) when L-amino
acids supply majority of protein equivalent as result of:
a. Rapid amino acid absorption (14).
b. Early and high peak of plasma amino acid concentrations after ingestion of meals where
large part of protein is supplied by L-amino acids (14).
c. Rapid catabolism of amino acids (18, 19, 42, 44).
d. Possible decreased total amino acid absorption (34)
Warning: Inadequate protein intake is correlated with low birth length and poor weight
gain of offspring (1, 2, 30, 33).
3. Total protein intake of women in the MPKUCS was negatively correlated with plasma PHE
concentration throughout pregnancy and positively correlated with offspring birth measures
(2, 33).
4. Inadequate protein intake by women in the MPKUCS was associated with very low
intakes of folate and vitamin B12 and congenital heart defects in offspring (16, 17, 31,49).
D. Fat
1. Fat should supply 35% to 40% of energy.
a. 7% to 10% of energy should be obtained from linoleic acid (C18:2,n-6) (13).
b. 0.7% to 2.5% of energy should be obtained from α-linolenic acid (C18:3,n-3) (13).
2. Fat intake of women in the MPKUCS was negatively correlated with plasma PHE
concentration during pregnancy and positively correlated with offspring birth measures (2, 33).
E. Energy
1. Prescribe amount that should support appropriate weight gain (Table 2-2, p 41). Infant birth
measures are influenced by maternal energy intake and maternal weight gain (1, 2, 30, 33).
2. Requirements vary widely and may be greater than normal when L-amino acids supply
majority of protein equivalent (38).
3. Energy intake was negatively correlated with plasma PHE concentration during the last two
trimesters of pregnancy (2, 33).
Warning: Inadequate energy intake is associated with poor maternal weight gain,
decreased birth length and birth weight of offspring (1, 2, 31, 33), and
decreased maternal PHE tolerance.
F. Fluid
1. Prescribe amount that will supply water requirements (Table 2-2, p 41). Under normal
circumstances offer minimum of 1.0 mL for each kcal ingested.
VII. Fill Prescription
A. PHE
1. Calculate amount of table foods required to fill PHE prescription (Table 2-3, p 42).
a. Patients may select any food in prescribed Servings Lists for PHE-Restricted Diets
(Protocol 1, pp 16-26) in specified amounts to fill diet prescription.

36 Maternal Phenylketonuria 2001 Ross Products Division


2. If patient's appetite is small and PHE requirement is high:
a. Use bread, cheese, eggs, or whole cow's milk to help fill PHE prescription (Tables 2-3 and
2-4, p 42). These high-PHE foods usually are not required before 3rd trimester.
b. Measure whole cow's milk with large disposable syringe or standard volumetric flask.
B. Protein
1. Calculate amount of protein provided by table foods, bread, cheese, egg, or whole cow's milk
(Table 2-3, p 42) required to fill PHE prescription.
2. Subtract amount determined above from total protein prescription.
3. Supply any remaining prescribed protein with Phenex-2 (Table 2-5, p 43).
a. Weigh Phenex-2 powder on scale that reads in grams because of variability of household
measuring equipment (Practical Aspects of Nutrition Support, p vii) and changes in
density during shipping.
b. See Table 2-5 (p 43, footnote 1) for approximate packed weight of Phenex-2 powder in
level, dry US standard household measures.
C. TYR
1. Calculate approximate amount of TYR provided by table foods, breads, whole cow's milk, or
whole egg (Table 2-3, p 42) required to fill PHE prescription.
2. Calculate amount of TYR supplied by Phenex-2 (Table 2-5, p 43) required to fill protein
prescription.
3. Subtract amounts determined above from total TYR prescription.
4. Provide any remaining prescribed TYR as L-TYR (Appendix 26, p A-28).
a. Supplement with L-TYR only if plasma TYR concentration is below 50 µmol/L
(0.9 mg/dL).
5. Make suspension of L-TYR of known TYR content per milliliter:
a. Weigh L-TYR powder and add sufficient boiled, cooled water to yield known volume.
b. Refrigerate in closed container until used. May be stored up to 1 week, if not frozen.
c. Shake well before using. Measure L-TYR into medical food mixture with disposable
syringe.
d. Solubility of L-TYR in water is low, about 50 mg/100 mL. Because of its low solubility,
some L-TYR may be mixed with fruit purées such as applesauce, sauces, soups, and
juices from Free Foods A and B in Servings Lists for PHE-Restricted Diets (Protocol 1,
pp 16-26).
6. L-TYR tablets (500 mg) are available at some pharmacies.
D. Fat
1. Use fats containing canola or soy oil as first ingredient to help supply α-linolenic acid.
E. Energy
1. Calculate energy provided by table foods, bread, cheese, egg, whole cow's milk (Table 2-3,
p 42), and Phenex-2 (Table 2-5, p 43) required to fill PHE and protein prescriptions.
2. Subtract amount of energy determined above from total energy prescription.
3. Provide any remaining prescribed energy with Free Foods B (Table 2-3, p 42), Polycose ®
Glucose Polymers Powder (23 kcal/Tbsp, 3.8 kcal/g), sugar (48 kcal/Tbsp), or other nitrogen-
free energy sources.
F. Fluid and Mixing Instructions
1. Add sufficient tap water or other fluid to ingredients to yield prescribed volume of medical food
mixture.
2. Mix with blender at lowest speed no longer than 4 seconds. Excess mixing may destabilize
emulsion. Medical food mixture may also be mixed in tightly closed container by shaking
vigorously for 10 to 12 seconds.
3. Place in container, cap, and store in refrigerator until used. Discard unused portion 24 hours
after mixing because of nutrient loss.
4. Do not heat because of Maillard reaction (Practical Aspects of Nutrition Support, p viii).
5. Chill Phenex-2 medical food mixture to improve taste.
6. Shake well before using.
© 2001 Ross Products Division Maternal Phenylketonuria 37
G. Diet Guide
1. Provide patient with completed Diet Guide (Table 2-6, p 44) with each diet change.
2. Six small meals, including late-evening snack, may be better tolerated than three meals.
3. Late-evening snack containing at least 12 g of protein equivalent and 400 kcal may be helpful
in preventing usual early morning rise in blood PHE concentration (11).

VIII. Evaluate Adequacy and Safety of Planned Nutrition Support


A. Nutrient Adequacy (29)
1. Determine if diet provides nutrients in amounts prescribed in Section VI, Establish
Prescription, p 34.
2. Check Phenex-2 medical food mixture to determine if it supplies Recommended Dietary
Intakes (RDIs) for minerals and vitamins.
a. See Table 2-7, p 45, for RDIs.
b. See Appendix 8, p A-8, for complete nutrient composition of whole cow's milk and eggs.
c. Appendix 23, p A-25, may be used to check adequacy of nutrients if computer program is
not available.
d. If medical food used contains inadequate or no selenium, selenium deficiency and
decreased active thyroid concentration may occur (6).
3. If Phenex-2 mixture provides < 80% of RDIs, supplement diet with needed minerals and
vitamins if not supplied by table foods and laboratory tests indicate need.
a. Trace- and ultra-trace mineral deficiencies may occur if Phenex-2 fails to supply adequate
amounts (3).
b. Vitamin A from diet plus supplements should not exceed 400% of RDIs.
c. Folate and vitamin B12 supplementation are necessary prior to conception and
during trimester 1 if ingested medical food fails to supply requirements (31, 41).
d. Prenatal vitamin supplements are contraindicated if adequate medical food is ingested
due to the vitamin A they supply.
B. Osmolarity
1. If concentration of Phenex-2 is > 19 g mixed with water to yield 100 mL (3.3 fl oz), determine
if osmolarity is in acceptable range.
a. Determine osmolarity by laboratory analysis or use mathematical formula given in
Appendix 18, p A-20.
b. Osmolarity per gram of Phenex-2 is listed in Appendix 19, p A-21.
2. If osmolarity is > 1,000 mosm/L, or if patient does not tolerate initial feeds, dilute subsequent
feeds by equal volume of water (45).
a. Gradually increase concentration over 3 days, as tolerated.

IX. Suggested Evaluation of Nutrition Support


A. Plasma PHE Concentration
1. Evaluate twice weekly by quantitative methods.
2. Unacceptable PHE concentrations.
a. If plasma PHE concentration is not detected and patient has ingested full prescription:
1) Increase prescribed PHE by 25% and reevaluate plasma PHE concentration in 3 days.
2) If plasma PHE concentration continues undetected, repeat above process until value
is in treatment range.
b. If plasma PHE concentration is < 120 µmol/L (2 mg/dL) and patient has ingested full
prescription:
1) Increase prescribed PHE by 5% to 10% and reevaluate plasma PHE concentration in
3 days.
2) If plasma PHE concentration continues < 120 µmol/L (2 mg/dL), repeat above process
until value is in treatment range.
c. If plasma PHE concentration is > 240 µmol/L (4 mg/dL) and patient is not ill and has not
ingested more PHE or significantly less protein and energy than prescribed:
1) Decrease prescribed PHE by 5% to 10% and reevaluate plasma PHE concentration in
3 days.

38 Maternal Phenylketonuria 2001 Ross Products Division


2) If plasma PHE concentration continues > 240 µmol/L (4 mg/dL), repeat above process
until value is in treatment range.
B. Plasma amino acid concentrations (all) should be evaluated monthly by quantitative analysis.
1. Follow appropriate steps in Section IX, Suggested Evaluation of Nutrition Support, p 37,
Plasma PHE Concentration, if plasma PHE concentration is not in appropriate range.
C. Protein Status
1. Evaluate plasma transthyretin concentration monthly (Appendix 17, p A-18, for standards).
a. Plasma transthyretin concentrations provide a more reliable and rapid indication of protein
status than plasma albumin concentrations.
b. Plasma albumin concentrations may be in the normal range when plasma transthyretin
concentrations show a clear deficiency (4).
2. If plasma transthyretin concentration is below standard:
a. Increase prescribed protein by 5% to 10% and reevaluate plasma transthyretin
concentration in 1 month. If plasma PHE concentration is in treatment range, use
Phenex-2 to increase protein.
b. Repeat above process until transthyretin concentration is in treatment range.
D. Iron Status
1. Plasma ferritin concentration.
a. Evaluate monthly (Appendix 17, p A-18, for standards).
b. If plasma ferritin concentration is below standard:
1) Add 60 mg elemental iron as ferrous sulfate daily and reevaluate in 1 month.
2) Continue iron supplements until plasma ferritin concentration is in treatment range.
2. Complete blood count
a. Hemoglobin and hematocrit should be evaluated each trimester (Appendix 17, p A-18, for
standards).
E. Erythrocyte Folate and Serum Vitamin B12 Concentrations
1. Evaluate preconception, at first visit after conception, and each trimester (8, 16, 17, 39, 49).
2. If erythrocyte folate concentration is < 200 ng/mL (17):
a. Supplement with 400 to 800 µg of folacin daily and reevaluate in 1 month.
b. If folacin concentration is not in normal range, continue supplement and reevaluate in
1 month.
3. If serum vitamin B12 is < 300 pg/mL (49):
a. Supplement with 2.2 to 4.0 µg vitamin B12 per day and reevaluate in 1 month.
b. If vitamin B12 concentration is not in normal range, continue supplement and reevaluate
again after 1 month.
F. Weight Gain
1. Evaluate weekly during 1st month of treatment and monthly thereafter.
2. If weight gain is below recommended (Section V, Establish Goals of Nutrition Support, p 34)
and all prescribed diet has been regularly ingested:
a. Increase prescribed energy by 5% to 10% and reevaluate weight gain in 1 week.
b. If weight gain is still inadequate, repeat above process until appropriate weight gain occurs.
G. Nutrient Intake
1. Maintain records of food intake for 3 days immediately before each blood test (Appendices 24
and 25, pp A-26 and A-27).
2. Evaluate intakes of PHE, TYR, protein, energy, minerals, and vitamins for 3 days immediately
before each blood test.
a. Vitamin A intakes > 4500 µg RE (15,000 IU) daily MUST be avoided (48) because
excess vitamin A is a teratogen.
3. After each diet change, evaluate mineral and vitamin intakes:
a. See Table 2-7, p 45, for normal standards for pregnant women.
b. See Appendix 28, p A-29, for information about ordering software for diet evaluation.
c. See Appendix 8, p A-8, for nutrient composition of whole cow's milk and eggs.
4. For further information on nutrition support of pregnant women, see reference 32.

© 2001 Ross Products Division Maternal Phenylketonuria 39


H. Clinical Summary
1. A summary record of weight gain, laboratory, and nutrient intake data is useful for patient
management (Table 2-8, p 46).

X. Sample Prescriptions
A. Example 1
Establish and fill prescription for pregnant 24-year-old woman who is 167.6 cm tall and weighs
56 kg (normal weight) at beginning of pregnancy and 63.3 kg at 27 weeks' gestation using
Recommended Daily Nutrient Intakes from Table 2-2, p 41, and average nutrient contents from
Tables 2-3 and 2-5, pp 42 and 43.
1. Establish prescription for 1st trimester.
PHE 200 mg/day
TYR 7,000 mg (7.0 g)
Protein 70 g
Energy 2,500 kcal
Fluid 2,500 mL
2. Fill prescription for 1st trimester.
Medical Food Mixture Measure PHE TYR Protein Energy
(mg) (mg) (g) (kcal)
Phenex-2 217 g 0 6,510 65.1 890
L-TYR 352 mg 0 352 0.0 0
Add water to make 1183 mL (40 fl oz). Additional fluid should be consumed ad libitum daily.

Food List Servings


Breads/Cereals 3 90 60 1.8 90
Fats 5 25 20 0.5 300
Fruits 3 45 30 1.5 180
Vegetables 2 30 20 1.0 30
Free Foods A 2 10 8 0.2 130
Free Foods B 16 0 0 0.0 880
Total per day 200 7,000 70.1 2,500
Approximate osmolarity of medical food mixture is < 960 mosm/L.
3. Establish prescription for 3rd trimester.
PHE 875 mg/day
TYR 7,000 mg (7.0 g)
Protein 70 g
Energy 2,500 kcal
Fluid 2,500 mL

40 Maternal Phenylketonuria 2001 Ross Products Division


4. Fill prescription for 3rd trimester.
Medical Food Mixture Measure PHE TYR Protein Energy
(mg) (mg) (g) (kcal)
Phenex-2 169 g 0 5,070 50.7 693
Whole cow's milk 195 mL 320 320 6.6 123
Sugar 2 tsp 0 0 0 32
1
L-TYR 1,234 mg 0 1,234 0 0
Add water to make 1183 mL (40 fl oz). Additional fluid should be consumed ad libitum daily.

Food List Servings


Breads/Cereals 13 390 260 7.8 390
Fats 9 45 36 0.9 540
Fruits 4 60 40 2.0 240
Vegetables 4 60 40 2.0 40
Free Foods B 8 0 0 0.0 440
Total per day 875 7,000 70.0 2,498
Approximate osmolarity of medical food mixture is < 800 mosm/L.
1
Mix with soups, purées, and juices from Free Foods B in Servings Lists for PHE-Restricted Diets
(Protocol 1, pp 13-26), or use L-TYR tablets.

XI. Management of Problems During Pregnancy (7)


A. Nausea
1. Suggest patient try one or more of following:
a. Eat small amounts of prescribed food hourly while awake.
b. Eat some prescribed low-protein crackers before rising in morning.
c. Drink fluids (except medical food mixture) between meals.
d. Avoid fried foods.
e. Eat lightly seasoned foods.
f. Eat plain fruits and vegetables.
g. Eat some prescribed food before preparing meal.
h. Avoid strong, unpleasant odors.
B. Heartburn
1. Suggest patient try one or more of following:
a. Eat slowly.
b. Chew food well.
c. Eat small, frequent meals.
d. Avoid spicy and/or fried foods.
e. Sit straight up or walk after eating.
f. Avoid bending or stooping after eating.
C. Constipation
1. Suggest patient try one or more of following:
a. Drink more water.
b. Eat some fruits with skins and raw vegetables.
c. Increase fiber by selecting cereal with fiber.
d. Drink some prune juice daily (may be mixed with soft drinks, not diet, to improve flavor).
e. Exercise daily.

© 2001 Ross Products Division Maternal Phenylketonuria 41


TABLE 2-1. Prepregnancy Weights for Heights

Height Underweight If Normal Weight Range1 Midpoint of Overweight If


Without Shoes This Weight or Normal Weight This Weight or
Less Range More
(ft/in) (cm) (lb) (kg) (lb) (kg) (lb) (kg) (lb) (kg)
4'10" 147.32 88 40.0 89 - 108 40.4 - 49.0 98.5 44.7 109 49.5
4'11" 149.86 91 41.4 92 - 112 41.8 - 50.9 102.0 46.4 113 51.4
5' 152.40 94 42.7 95 - 115 43.2 - 52.3 105.0 47.7 116 52.7
5'1" 154.94 99 45.0 100 - 121 45.5 - 55.0 110.5 50.2 122 55.5
5'2" 157.48 104 47.3 105 - 127 47.7 - 57.7 116.0 52.7 128 58.2
5'3" 160.02 108 49.0 109 - 132 49.5 - 60.0 120.5 54.8 133 60.5
5'4" 162.56 113 51.4 114 - 138 51.8 - 62.7 126.0 57.3 139 63.2
5'5" 165.10 118 53.6 119 - 144 54.1 - 64.5 131.5 59.8 145 65.9
5'6" 167.64 123 55.9 124 - 150 56.4 - 68.2 137.0 62.3 151 68.6
5'7" 170.18 127 57.7 128 - 155 58.2 - 70.5 141.5 64.3 156 70.9
5'8" 172.72 132 60.0 133 - 161 60.5 - 73.2 147.0 66.8 162 73.6
5'9" 175.26 137 62.3 138 - 167 62.7 - 75.9 152.5 69.3 168 76.4
5'10" 177.8 142 64.5 143 - 173 65.0 - 78.6 158.0 71.8 174 79.1
5'11" 180.34 146 66.4 147 - 178 66.8 - 80.9 162.5 73.0 179 81.4
6' 182.88 151 68.6 152 - 184 69.1 - 83.6 168.0 76.4 185 84.1
1
Normal weight for "thin-boned" women will be closer to lower end of range. For "big-boned" women, weight will be
closer to higher end.

TABLE 2-2. Recommended Daily Nutrient Intakes (Ranges) for Pregnant Women With PKU

Trimester and Age Nutrient


(yrs) PHE1,2 TYR 1, 2 Protein3 Energy 3, 4 Fluid5
(mg/day) (g/day) (g/day) (kcal/day) (mL/day)
1st Trimester
15 to < 19 200 - 600 5.75 - 7.50 ≥ 75 2,500 (2000 - 3500) 2,000 - 3,500
≥ 19 200 - 600 4.50 - 7.00 ≥ 70 2,500 (2000 - 3000) 2,000 - 3,000

2nd Trimester
15 to < 19 200 - 900 5.75 - 7.50 ≥ 75 2,500 (2000 - 3500) 2,000 - 3,500
≥ 19 200 - 900 4.50 - 7.00 ≥ 70 2,500 (2000 - 3000) 2,000 - 3,000

3rd Trimester
15 to < 19 300 - 1200 5.75 - 7.50 ≥ 75 2,500 (2000 - 3500) 2,000 - 3,500
≥ 19 300 - 1200 4.50 - 7.00 ≥ 70 2,500 (2000 - 3000) 2,000 - 3,000
1
Initiate prescription with lowest value for age and trimester. Actual requirement may vary considerably. Modify
prescription based on frequently obtained plasma values and maternal weight gain.
2
From references 1, 2, 26, 30, 32, 33.
3
Modified from reference 13.
4
For 15- to < 19-year-old, energy intake should never be < 45 kcal/kg of ideal pregnancy weight. For women
≥ 19 years of age, energy intake should never be < 35 kcal/kg of ideal pregnancy weight (35). Adequate energy to
support recommended weight gain (Section V, Establish Goals of Nutrition Support, p 34) should be prescribed even
if number is greater than highest number listed for trimester and age.
5
Under normal circumstances, offer minimum of 1 mL fluid for each kcal ingested (5).

42 Maternal Phenylketonuria 2001 Ross Products Division


TABLE 2-3. Serving Lists for PHE-Restricted Diets: Average Nutrient Content per Serving1

Food List Nutrient


PHE TYR Protein Energy
(mg) (mg) (g) (kcal)
Breads/Cereals 30 20 0.6 30
Fats 5 4 0.1 60
Fruits 15 10 0.5 60
Vegetables 15 10 0.5 10
Free Foods A 5 4 0.1 65
Free Foods B 0 0 0.0 55
Breads 116 67 2.2 79
Cheeses 365 337 6.8 95
Egg, whole, 1 large (~50 g), 2 332 255 6.2 74
Whole cow's milk, 100 mL 2 164 164 3.39 63
1
From reference 10.
2
From reference 36. See Appendix 8, p A-8, for complete nutrient composition.

TABLE 2-4. Serving Lists for PHE-Restricted Diets: Supplemental Foods

Food Weight Approximate PHE TYR Protein Energy


(g) Measure (mg) (mg) (g) (kcal)
For greatest accuracy, weigh food on scale that reads in grams.
BREADS
Biscuit, commercially baked 35 1 biscuit 108 67 2.2 127
Bun, hamburger and hot dog, plain 43 1 bun 179 106 3.6 123
Cracked wheat 25 1 slice 105 63 2.2 65
French, Vienna or sourdough 25 1 slice 109 62 2.2 68
Italian 20 1 slice 87 50 1.8 54
Pumpernickel 26 1 slice 110 62 2.3 65
Raisin 26 1 slice 94 53 2.0 71
Rye, American 32 1 slice 132 68 2.7 83
White 25 1 slice 101 59 2.0 67
Whole wheat 28 1 slice 130 81 2.7 69
Mean 116 67 2.2 79

CHEESE
American, processed 28 1 slice 319 344 6.3 106
Blue (3/4" x 1" x 1") 28 1 piece 308 367 6.1 100
Camembert 28 1 slice 313 325 5.6 85
Cheddar 28 1 slice 372 341 7.1 114
Colby 28 1 slice 355 325 6.7 112
Cottage, creamed 56 1/4 cup 378 374 7.0 58
Gouda 28 1 slice 406 412 7.0 101
Monterey Jack 28 1 slice 365 335 6.9 106
Mozzarella, low-moisture, part skim 28 1 slice 407 450 7.8 79
Muenster 28 1 slice 352 318 6.6 104
Parmesan, grated 16 3 Tbsp 336 348 6.2 68
Provolone 28 1 slice 365 431 7.2 100
Swiss 28 1 slice 471 480 8.1 106
Mean 365 337 6.8 95

© 2001 Ross Products Division Maternal Phenylketonuria 43


TABLE 2-5. Nutrient Composition of PHENEX™-2 1

Nutrient Phenex-2, Unflavored Phenex-2, Flavored


Per 100 g pwd Per g protein equiv Per 100 g pwd Per g protein equiv
Energy, kcal 410 13.7 410 13.7
Protein equiv, g 30.00 1.000 30.00 1.000
Nitrogen, g 4.80 0.160 4.80 0.160
Amino acids, g 31.58 1.053 31.58 1.053
Cystine, g 0.30 0.010 0.30 0.010
Histidine, g 0.84 0.028 0.84 0.028
Isoleucine, g 2.16 0.072 2.16 0.072
Leucine, g 3.36 0.112 3.36 0.112
Lysine, g 2.00 0.067 2.00 0.067
Methionine, g 0.60 0.020 0.60 0.020
Phenylalanine, g trace 0 trace 0
Threonine, g 1.40 0.047 1.40 0.047
Tryptophan, g 0.34 0.011 0.34 0.011
Tyrosine, g 3.00 0.100 3.00 0.100
Valine, g 2.44 0.081 2.44 0.081
Other Nitrogen-Containing Compounds
Carnitine, mg 40 1.33 40 1.33
Taurine, mg 50 1.67 50 1.67
Carbohydrate, g 35 1.17 36 1.20
Fat, g 14 0.47 13.5 0.45
2 2
Linoleic acid, g 1.50 0.050 1.50 0.050
α-Linolenic acid, g
3 3
0.17 0.006 0.17 0.006
Minerals
Calcium, mg 880 29 880 29
Chloride, mg/mEq 940/26.51 31.33/0.88 940/26.51 31.33/0.88
Chromium, µg 27 0.90 27 0.90
Copper, mg 1.00 0.033 1.00 0.033
Iodine, µg 100 3.33 100 3.33
Iron, mg 13 0.43 13 0.43
Magnesium, mg 225 7.50 225 7.50
Manganese, mg 0.80 0.027 0.80 0.027
Molybdenum, µg 30 1.00 30 1.00
Phosphorus, mg 760 25 760 25
Potassium, mg/mEq 1,370/35.04 45.7/1.17 1,370/35.04 45.7/1.17
Selenium, µg 35 1.17 35 1.17
Sodium, mg/mEq 880/38.28 29.3/1.28 880/38.28 29.3/1.28
Zinc, mg 13 0.43 13 0.43
Vitamins
A, µg RE 660 22 660 22
D, µg 7.50 0.25 7.50 0.25
E, mg α-TE 12.10 0.40 12.10 0.40
K, µg 60 2.00 60 2.00
Ascorbic acid, mg 60 2.00 60 2.00
Biotin, µg 100 3.33 100 3.33
B6, mg 1.30 0.043 1.30 0.043
B12, µg 5.0 0.167 5.0 0.167
Choline, mg 100 3.33 100 3.33
Folate, µg 450 15 450 15
Inositol, mg 70 2.33 70 2.33
Niacin equiv, mg 21.7 0.72 21.7 0.72
Pantothenic acid, mg 8.00 0.267 8.00 0.267
Riboflavin, mg 1.80 0.06 1.80 0.06
Thiamin, mg 3.25 0.108 3.25 0.108
1
Approximate packed weight in level, dry US standard household measures:
Phenex-2, unflavored Phenex-2, flavored
1 Tbsp = 8g 9g
1/4 cup = 32 g 30 g
1/3 cup = 41 g 40 g
1/2 cup = 61 g 59 g
1 cup = 117 g 116 g
2
Analytical data at manufacture = 2.75 g/100 g powder in unflavored and 2.66 g/100 g powder in flavored.
3
Analytical data at manufacture = 0.28 g/100 g powder in unflavored and 0.27 g/100 g powder in flavored.

44 Maternal Phenylketonuria 2001 Ross Products Division


TABLE 2-6. PHE-Restricted Diet Guide
Name: _____________________________________________________
Date: ______ _/__ _____/_ ______ Weight: ______________________(kg)
Mo Day Year

Medical Food Amount


Phenex-2, unflavored, flavored Tbsp/cup/g
Tbsp/cup/g
Tbsp/cup/g
Add water to make ____________________ mL (__________________ fl oz).

Daily Intake Servings PHE TYR Protein Energy


(mg) (mg) (g) (kcal)
BREAKFAST
Medical Food Mixture, fl oz
Breads/Cereals
Fats
Fruits
Cheese/Eggs/Regular Bread
Free Foods A
Free Foods B
MIDMORNING SNACK

LUNCH
Medical Food Mixture, fl oz
Breads/Cereals
Fats
Fruits
Vegetables
Cheese/Eggs/Regular Bread
Free Foods A
Free Foods B
MIDAFTERNOON SNACK

DINNER
Medical Food Mixture, fl oz
Breads/Cereals
Fats
Fruits
Vegetables
Cheese/Eggs/Regular Bread
Free Foods A
Free Foods B
BEDTIME SNACK

DAILY TOTAL

Comments:

_____________________________________________
Nutritionist
© 2001 Ross Products Division Maternal Phenylketonuria 45
TABLE 2-7. Recommended Dietary Intakes (RDIs) for Pregnant Women1

Nutrient Age (yr)


15 to <19 > 19
Minerals
Calcium, mg 1,300 1,000
Chloride, mEq 40 - 117 48 - 144
Copper, mg 2.5 2.5
Iodine, µg 175 175
Iron 2, mg 48 48
Magnesium, mg 450 450
Manganese, mg 3.75 3.75
Phosphorus, mg 1,250 1,250
Potassium, mEq 39 - 117 48 - 144
Selenium, µg 65 65
Sodium, mEq 39 - 117 48 - 144
Zinc, mg 20 20

Vitamins
A, µg RE 1,000 1,000
D, µg 5 5
E, mg α-TE 15 15
K, µg 65 65
Ascorbic acid, mg 80 85
Biotin, µg 30 30
B6, mg 2.6 2.6
B12, µg 4 4
Folate, µg 800 800
Niacin equiv3, mg 18 18
Pantothenic acid, mg 6.0 6.0
Riboflavin, mg 1.6 1.6
Thiamin, mg 1.5 1.5
1
Modified from references 13, 50.
2
From reference 3.
3
From reference 28.

46 Maternal Phenylketonuria 2001 Ross Products Division


46 Maternal Phenylketonuria
TABLE 2-8. MPKU Clinical Summary Sheet
Name: Hospital Number:

Date of Birth: __________/__________/__________ Age: _______(yrs) Usual Prepregnancy Weight: __________ kg Height:________ (cm)
Mo Day Year

Date of Last Menstrual Period: _________/__________/_________ Diet Started: _________/__________/_________


Mo Day Year Mo Day Year

Wks Preconception: _________________ Wks Gestation: _________________ When Diet Initiated: _________________

Date Physical Data Laboratory Data Nutrient Intake Data


Gestation Weight Weight Hgb Hct Transthyretin Ferritin Folate1 PHE2 TYR2 PHE TYR Protein Energy
Age Gain
(mo/d/yr) (wk) (kg) (kg) (g/dL) (%) (mg/dL) (µg/L) (mg) (mg) (g) (kcal)
© 2001 Ross Products Division

1
2
Indicate if RBC or serum and method.
Indicate if mg/dL or µmol/L.
REFERENCES
1. Acosta PB: Nutrition support of maternal PKU. Sem Perinat 1995;19;182-190.
2. Acosta PB, Michals-Matalon K, Austin V, et al: Nutrition findings and requirements in pregnant women with
phenylketonuria. In Platt L (ed): Effects of Genetic Disorders on Pregnancy Outcome. London: Parthenon Publ,
1997, pp 21-32.
3. Acosta PB, Stepnick-Gropper S, Clarke-Sheehan N, et al: Trace element status of PKU children ingesting an
elemental diet. JPEN 1987;11:287.
4. Arnold GL, Vladutiu CJ, Kirby RS: Protein insufficiency and impaired growth in children with PKU. J Inher Metab
Dis 2000;23 (Suppl 1):29A.
5. Behrman RE, Kliegman RM, Arvin AA (eds): Nelson Textbook of Pediatrics, ed 15. Philadelphia: WB Saunders Co,
1996.
6. Calomme MR, Vanderpas JB, Francois B, et al: Thyroid function parameters during a selenium repletion/depletion
study. Experientia 1995;51:1208-1215.
7. Castiglioni LL, Rouse BM: The Young Woman With PKU. Galveston, Texas: University of Texas, 1986.
8. Committee on Nutrition of the Mother and Preschool Child, Food and Nutrition Board, National Research Council:
Laboratory Indices of Nutritional Status in Pregnancy. Washington, DC: National Academy of Sciences, 1978.
9. Danks DM, Cotton RGH: Future developments in phenylketonuria. In Tada T, et al (eds): Recent Advances in
Inborn Errors of Metabolism. New York: S Karger, 1987.
10. Elsas LJ, Acosta PB: Nutrition support of inherited metabolic diseases. In Shils ME, et al (eds): Modern Nutrition in
Health and Disease, ed 9. Baltimore: Williams & Wilkins, 1999, pp 1003-1056.
11. Farquhar DL, Steven F, Westwood A: Preliminary report on inverse diurnal variation of phenylalanine: Implications
in maternal phenylketonuria. Hum Nutr Appl Nutr 1985;39A:224-226.
12. Fisch RO, Burke B, Bass J, et al: Maternal phenylketonuria — Chronology of the detrimental effects on
embryogenesis and fetal development: Pathological report, survey, clinical application Pediatr Pathol
1986;5:449-461.
13. Food and Nutrition Board, Committee on Dietary Allowances: Recommended Dietary Allowances, eds 9 and 10.
Washington, DC: National Academy of Sciences, 1980 and 1989.
14. Gropper S, Acosta PB: Effect of simultaneous ingestion of L-amino acids and whole protein on plasma amino acid
and urea nitrogen concentrations in humans. JPEN 1991;15:48-53.
15. Hanley WB, Clarke JTR, Schoonheyt W: Maternal phenylketonuria (MPKU): A review. Clin Biol 1986:20:149-56.
16. Hanley WB, Feigenbaum ASJ, Clarke JTR, et al: Vitamin B12 deficiency in adolescents and young adults with
phenylketonuria. Eur J Pediatr 1996;S155:S145-S147.
17. Herbert V: Folic acid. In Shils ME, et al (eds): Modern Nutrition in Health and Disease, ed 9. Baltimore: Williams &
Wilkins, 1999, pp 433-446.
18. Herrmann ME, Broesicke HG, Keller M, et al: Dependence of the utilization of a phenylalanine-free amino acid
mixture on different amounts of a single dose ingested. A case report. Eur J Pediatr 1994;153:501-503.
19. Jones BJM, Lees R, Andrews J, et al: Comparison of an elemental and polymeric enteral diet in patients with
normal gastrointestinal function. Gut 1983;24:78-84.
20. Kirby ML, Miyagawa ST: The effects of high phenylalanine concentration on chick embryonic development. J Inher
Metab Dis 1990;13:634-640.
21. Kirkman HN: Projections of a rebound in frequency of mental retardation from phenylketonuria. Appl Res Mental
Retard 1982;3:319-328.
22. Koch R, Friedman E, Azen C, et al: The international collaborative study of maternal phenylketonuria status report
1998. Mental Retard Devpt Disabilities Research Rev 1999;5:117-121.
23. Koch R, Friedman EG, Wenz E, et al: Maternal phenylketonuria. J Inher Metab Dis 1986;9 (Suppl 2):159-168.
24. Kudo Y, Boyd CAR: Transport of amino acids by the human placenta: Predicted effects thereon of maternal
hyperphenylalaninemia. J Inher Metab Dis 1990;13:617-626.
25. Lenke RR, Levy HL: Maternal phenylketonuria and hyperphenylalaninemia. An international survey of the outcome
of untreated and treated pregnancies. N Engl J Med 1980;303:1202-1208.
26. Leverton RM, Johnson N, Ellison J, et al: The quantitative amino acid requirements of young women.
IV. Phenylalanine, with and without tyrosine. J Nutr 1956;58:341-353.
27. Levy HL: Maternal phenylketonuria: Review with emphasis on pathogenesis. Enzyme 1987;38:312-320.
28. Lewis JS, Loskill S, Bunker ML, et al: N-Methylnicotinamide excretion of phenylketonuric children and a child with
Hartnup disease before and after phenylalanine and tryptophan load. Fed Proc 1974;33:666A.
29. Lynch BC, Pitt DB, Maddison TG, et al: Maternal phenylketonuria: Successful outcome in four pregnancies treated
prior to conception. Eur J Pediatr 1988;148:72-75.
30. Matalon R, Michals K, Azen C, et al: Maternal PKU collaborative study: The effect of nutrient intake on pregnancy
outcome. J Inher Metab Dis 1991;14:371-374.
31. Matalon KM, Acosta PB, Azen C, Matalon R: Congenital heart disease in maternal phenylketonuria: Effects of
blood phenylalanine and nutrient intake. Mental Retard Devpt Disabilities Research Rev 1999;5:122-124.

48 Maternal Phenylketonuria © 2001 Ross Products Division


32. Matalon K, Acosta PB, Castiglioni L, et al: Protocol for Nutrition Support of Maternal Phenylketonuria. Bethesda.
The National Institute of Child health and Human Development, 1999.
33. Michals K, Acosta PB, Austin V, et al: Nutrition and reproductive outcome in maternal phenylketonuria. Eur J
Pediatr 1996;155 (Suppl 1): S165-S168.
34. Ohkohchi N, Andoh T, Ohi R, Mori S: Defined formula diets alter characteristics of the intestinal transport of amino
acids and peptides in growing rats. J Pediatr Gastroenterol Nutr 1990;10:490-496.
35. Oldham H, Sheft BB: Effect of caloric intake on nitrogen utilization during pregnancy. J Amer Diet Assoc
1951;27:847-854.
36. Posati LP, Orr ML: Composition of Foods: Dairy and Egg Products, Agriculture Handbook No. 8-1. Washington,
DC: US Dept of Agriculture, Agricultural Research Service, 1976.
37. Platt LD, Koch R, Hanley WB, et al: The international study of pregnancy outcome in women with maternal
phenylketonuria. Report of a 12-year study. Am J Obstet Gynecol 2000;182:1-8.
38. Pratt EL, Snyderman SE, Cheung MW, et al: The threonine requirement of the normal infant. J Nutr
1955;56:231-251.
39. Rohr FJ, Doherty LB, Waisbren SE, et al: New England maternal PKU project: Prospective study of untreated and
treated pregnancies and their outcomes. J Pediatr 1987;110:391-398.
40. Rouse B, Azen C, Koch R, et al: Maternal phenylketonuria collaborative study (MPKUCS) offspring: Facial
anomalies, malformations, and early neurological sequelae. Am J Med Genet 1997;69:89-95.
41. Rouse B, Matalon R, Koch R, et al: Maternal phenylketonuria syndrome: Congenital heart defects, microcephaly,
and developmental outcomes. J Pediatr 2000;136:57-61.
42. Schoeffer A, Herrmann ME, Broesicke HG, Moench E: Effect of dosage and timing of amino acid mixtures on
nitrogen retention in patients with phenylketonuria. J Nutr Med 1994;4:415-418.
43. Smith I, Glossop J, Beasley M: Fetal damage due to maternal phenylketonuria: Effects of dietary treatment and
maternal phenylalanine concentrations around the time of conception. J Inher Metab Dis 1990;13:651-657.
44. Smith JL, Arteaga C, Heymsfield SB: Increased ureagenesis and impaired nitrogen use during infusion of a
synthetic amino acid formula - A controlled trial. N Engl J Med 1982;306:1013-1018.
45. Smith JL, Heymsfield SB: Enteral nutrition support: Formula preparation from modular ingredients. JPEN
1983;7:280-288.
46. Soeters RP, Sengers RC, van Dongen PW, et al: Maternal phenylketonuria: Comparison of two treated full-term
pregnancies. Eur J Pediatr 1986;145:221-223.
47. Subcommittee on Nutritional Status and Weight Gain During Pregnancy: Nutrition and Pregnancy. Washington,
DC: National Academy Press, 1990.
48. Rothman KJ, Moore LL, Singer MR, et al: Teratogenicity of high vitamin A intake. N Engl J Med
1995;333:1369-1373.
49. Weir D, Scott JM: Vitamin B12 "cobalamin". In Shils ME, et al (eds): Modern Nutrition in Health and Disease, ed 9.
Baltimore: Williams & Wilkins, 1999, pp 447-458.
50. Yates AA, Schlicker SA, Suitor CW: Dietary reference intakes: The new basis for recommendations for calcium
and related nutrients, B vitamins, and choline. J Amer Diet Assoc 1998;98;699-706.

© 2001 Ross Products Division Maternal Phenylketonuria 49


PROTOCOL 3 — Tyrosinemia Types Ia and Ib

Nutrition Support of Infants, Children and Adults With


TYREX ®-1 and TYREX ®-2 Amino Acid-Modified Medical Foods
I. Introduction
Five clinical forms of hereditary tyrosinemia have been reported. Type Ia is caused by a primary defect
of hepatic fumarylacetoacetate hydrolyase (FAH) (13) with production of an abnormal metabolite,
succinylacetone, which is formed from the accumulated substrate fumarylacetoacetate (Figure B). If
maleylacetoacetic acid isomerase is functional, succinylacetone is also formed from
maleylacetoacetate. Succinylacetone is extremely toxic and is associated with impaired active
transport functions and disordered hepatic enzymes, including p-hydroxyphenylpyruvic acid
dioxygenase (p-OHPPAD) and δ-aminolevulinic acid (δ-ALA) dehydratase (30). Decreased activity of
both hepatic and erythrocyte δ-ALA dehydratase has been reported in these patients and is postulated
as the mechanism by which acute porphyric-like episodes develop (30). Inhibition of p-OHPPAD using
the drug 2 (2-nitro-4-trifluoromethylbenzoyl)-1, 3-cyclo-hexanedione (NTBC) has prevented acute
porphyric episodes and decreased rates of progression of cirrhosis and Fanconi syndrome (20, 21).
Dietary protein

Tissue protein synthesis


Phenylalanine*
Tissue protein
catabolism CO2 + H2O
Melanin
Tyrosine* Epinephrine
Thyroxine

p-Hydroxyphenylpyruvic acid*

p-OH phenylpyruvic acid dioxygenase¹

Homogentisic acid
Maleylacetoacetic acid isomerase (type Ib)

Maleylacetoacetic acid*

Succinylacetoacetic
Fumarylacetoacetic acid*
acid*

Fumarylacetoacetic acid hydrolyase (type Ia)

Succinylacetone*
* Accumulates In untreated
Fumaric acid tyrosinemia type Ia
+ ¹ Inhibited by NTBC
Acetoacetic acid Enzyme malfunction

Figure B. Tyrosine metabolism in tyrosinemia types Ia and Ib


Tyrosinemia type Ia is characterized by generalized renal tubular impairment with hypophosphatemic
rickets, progressive liver failure producing cirrhosis and hepatic cancer, hypertension, episodic
behavioral and peripheral nerve deficiencies, and elevated concentrations of blood phenylalanine
(PHE) and tyrosine (TYR) with succinylacetone and δ-ALA excretion in urine (30). FAH is expressed in
amniotic and chorionic villus cells and prenatal diagnosis is available by biochemical or molecular
techniques (30). Soon after birth, infants with the acute form of tyrosinemia type Ia develop
progressive liver and kidney failure, vomiting, diarrhea, and a "cabbage-like" odor.

50 Tyrosinemia Types Ia and Ib 2001 Ross Products Division


Because some of these symptoms are similar to other inborn errors of metabolism, accurate diagnosis
is essential. Increased concentrations of PHE and TYR are found in the blood (13, 30).
The chronic form of tyrosinemia type Ia is similar to the acute form, but symptoms are usually milder
and appear later in infancy. Symptoms include rickets, liver and kidney dysfunction, high blood
pressure, and nervous system dysfunction. Liver hepatomas often develop on or before 10 years of
age, even in well-treated patients (13, 30). Incidence of tyrosinemia type Ia varies. Overall incidence
in Quebec, Canada, is 1/12,500 live births (30). Therapy with a PHE and TYR-restricted diet and
administration of NTBC to prevent succinylacetone accumulation is now the standard of care for
tyrosinemia type Ia.
Tyrosinemia type Ib, believed to be due to deficiency of maleylacetoacetate isomerase (Figure B), has
been reported in 1 infant (8, 30). Liver failure, renal tubular disease, and progressive psychomotor
retardation occurred prior to death at 1 year of age. Succinylacetone did not accumulate.

II. Outcome of Nutrition Support


Liver transplantation has significantly improved outcome in patients with tyrosinemia type Ia. Without
liver transplantation, patients develop hepatomas (12), usually within the 1st or 2nd decade of life.
NTBC has dramatically improved the course of patients with tyrosinemia type I (20, 21, 23, 26, 33).
Whether hepatomas will develop in patients treated with NTBC is unknown (23). If hepatomas do not
develop, liver transplantation may be unnecessary. Medical and nutrition support are essential to
maintain optimal health and nutrition status until a suitable liver is found. Long-term data on patients
with a liver transplant are not yet available.

III. Establish Diagnosis


A. The Defect
1. Tyrosinemia may result from defect in 1 of several enzymes.
a. Type Ia: Fumarylacetoacetate hydrolyase (17, 30).
b. Type Ib: Maleylacetoacetate isomerase (8).
c. Type II: Tyrosine aminotransferase (Protocol 4, p 63).
d. Type III: Parahydroxyphenylpyruvic acid dioxygenase (14, 30) (Protocol 4, p 63).
1) No liver enzyme activity (30).
2) Hawkinsinuria (30).
3) Transient, neonatal.
B. Clinical Screening
1. Concentration of > 4 mg TYR/dL (13) by bacterial inhibition assay of dried blood spot requires
differential diagnosis.
2. Because few states screen for tyrosinemia, infants or children with any of following clinical
findings associated with hepatosplenomegaly and nephropathy should be evaluated for
tyrosinemia types Ia and Ib (7, 12, 30):
a. Failure to thrive.
b. Vomiting and/or diarrhea.
c. Jaundice.
d. Fanconi syndrome.
e. Rickets.
f. Some patients may not develop renal tubular dysfunction or rickets (43).
C. Differential Diagnosis
1. Differential diagnosis will reveal false-positives and identify specific enzyme defect.
2. Therapy depends on enzyme defect present.
3. This protocol addresses nutrition support for patients with deficiency of FAH or
maleylacetoacetate isomerase.

IV. Rationale for Nutrition Support


A. Correct Primary Imbalance in Metabolic Relationships
1. Restrict dietary PHE and TYR to amounts tolerated by patient to maintain treatment plasma
amino acid concentrations.

© 2001 Ross Products Division Tyrosinemia Types Ia and Ib 51


B. Reduce Transcription of Gene
1. Reduce transcription of δ-ALA dehydratase gene with high-carbohydrate diet if δ-ALA is
present in urine (9).
2. The high-carbohydrate diet may be unnecessary with use of NTBC.

V. Establish Goals of Nutrition Support


A. Plasma PHE and TYR Concentrations
1. Maintain 2- to 4-hour postprandial plasma PHE and TYR concentrations in ranges noted below
when measured by quantitative methods, or within normal range for age established by
laboratory used.
Amino Acid µmol/L mg/dL
PHE 35 - 90 0.58 - 1.49
TYR 40 - 80 0.72 - 1.45
2. In practice, obtaining blood 2 to 4 hours postprandially is not always possible. Acceptable local
standards should be developed if plasma amino acids are evaluated at other times (Practical
Aspects of Nutrition Support, p viii).
3. Differences of opinion exist as to best concentrations of plasma PHE and TYR to support
normal growth and development in infants and children with tyrosinemia types Ia and 1b and
to prevent development of hepatomas.
a. In this protocol, concentrations as close to normal as possible are assumed to be best.
b. With use of NTBC, plasma TYR concentrations will be greater than without its use but
should be maintained as close to normal range as possible.
c. With plasma PHE and TYR concentrations in normal range, plasma amino acids
must be measured frequently to prevent deficiency (11).
B. Growth, Development, and Nutrition Status
1. Support normal growth rate in infants and children.
2. Support normal development.
3. Maintain normal nutrition status (10).
4. Prevent catabolism.
5. Maintain plasma bicarbonate, phosphate, and potassium in normal range for age.
6. Maintain plasma and urine free of, or containing only traces of, succinylacetone and
parahydroxyphenyl organic acids.
7. Maintain urine free of, or containing only traces of, δ-ALA.
8. Prevent rickets (19).
C. Neurologic Status
1. Prevent neurologic crises (31, 36).
D. Hepatic and Renal Status
1. Maintain normal liver and renal function (23-25, 37, 38, 43, 45).
2. Support patient nutritionally until appropriate liver can be found to transplant (37), if indicated.

VI. Establish Prescription


A. PHE Plus TYR (5)
1. Prescribe PHE plus TYR intake that promotes goals of nutrition support.
2. PHE plus TYR requirement varies widely:
a. From patient to patient, depending on activity of fumarylacetoacetate hydrolyase.
b. In same patient, depending on age, growth rate, adequacy of protein and energy intakes,
and state of health.
3. Lowest value for age for PHE plus TYR listed in Table 3-1, p 58, is suggested for initiating
therapy.
4. Changing requirements of patients are determined by frequent monitoring of:
a. Plasma PHE and TYR concentrations.
b. Plasma and urine concentrations of succinylacetone and parahydroxyphenyl organic
acids.
c. See Section IX, Suggested Evaluation of Nutrition Support, p 54.
52 Tyrosinemia Types Ia and Ib 2001 Ross Products Division
Warning: Inadequate PHE plus TYR intake results in anorexia, lethargy, hypotonia,
decreased growth rate in infants and children, decreased plasma fibrogen,
and increased plasma amino acid concentrations (except PHE and TYR) (11).
B. Protein
1. Prescribe, initially, amount greater than Recommended Dietary Allowances (RDA) (15)
(Table 3-1, p 58).
2. Requirements are greater than RDAs when L-amino acids supply majority of protein
equivalent as result of:
a. Rapid amino acid absorption (16).
b. Early and high peak of plasma amino acid concentrations after ingestion of meals where
large part of protein is supplied by L-amino acids (16).
c. Rapid catabolism of amino acids (18, 22, 39, 41).
d. Possible decreased total amino acid absorption (32).
3. If blood ammonia concentration is elevated, protein intake may need to be restricted until
ammonia level returns to normal range.
Warning: Inadequate protein intake will result in failure to thrive, weight loss, low
plasma transthyretin concentrations, osteopenia, hair loss, and decreased
PHE and TYR tolerance.
C. Energy
1. Prescribe amount that should support normal weight gain for infants and toddlers (Table 3-1,
p 58).
2. Requirements vary widely and may be greater than normal when L-amino acids supply
majority of protein equivalent (18, 35).
3. To help prevent neurologic crises if NTBC is not used, 50-65% of energy should be derived
from carbohydrate (9).
4. See Appendix 26, p A-28, for source of NTBC.
Warning: Inadequate energy intake may precipitate metabolic and neurologic crises as
result of muscle protein catabolism.
D. Fluid
1. Prescribe amount that will supply water requirements (Table 3-1, p 58). Under normal
circumstances, offer minimum of 1.5 mL fluid to neonates and 1.0 mL fluid to children and
adults for each kcal ingested.
2. Supply greater than normal amounts because of greater than normal energy intake.
E. 1,25 Dihydroxycholecalciferol (Rocaltrol ®)
1. Use in presence of elevated alkaline phosphatase and/or decreased plasma phosphate, or
radiographic evidence of rickets.
2. Prescribe 0.25-1.0 µg of Rocaltrol daily, if needed.

VII. Fill Prescription


A. PHE Plus TYR
1. Calculate amount of infant formula with iron, beikost, whole cow's milk, or table foods
(Table 3-2, p 58) required to fill PHE plus TYR prescription.
a. Low-iron infant formula, whole cow's milk, or evaporated milk should not be used as PHE
plus TYR source for infants because of low iron content.
2. Measure liquid infant formula, and whole cow's milk with disposable syringe. Weigh powdered
infant formula on scale that reads in grams.
3. Add beikost or table foods to gradually displace PHE plus TYR provided by infant formula
after infant is 3 to 4 months old or is developmentally ready.
4. Parents or patients may select any food in prescribed Servings Lists for PHE-Restricted Diets
(Protocol 1, pp 13-26) in specified amounts to fill diet prescription.
B. Protein
1. Calculate amount of infant formula with iron, beikost, whole cow's milk, or table foods
(Table 3-2, p 58) required to fill PHE plus TYR prescription.
© 2001 Ross Products Division Tyrosinemia Types Ia and Ib 53
2. Subtract amount determined above from total protein prescription.
3. Supply remaining prescribed protein with Tyrex (Table 3-3, p 59).
a. Tyrex-1 is for infants and toddlers and Tyrex-2 is for children and adults.
b. Weigh Tyrex powder on scale that reads in grams because of variability of household
measuring equipment (Practical Aspects of Nutrition Support, p vii) and changes in
density during shipping.
c. See Table 3-3 (p 59, footnote 3) for approximate packed weight of Tyrex powder in level,
dry US standard household measures.

C. Energy
1. Calculate energy provided by infant formula with iron, beikost, whole cow's milk, or table foods
(Table 3-2, p 58), and Tyrex (Table 3-3, p 59) required to fill PHE plus TYR and protein
prescriptions.
2. Subtract amount determined above from total energy prescription.
3. Provide remaining prescribed energy with Polycose ® Glucose Polymers powder
(23 kcal/Tbsp, 3.8 kcal/g) or liquid (2 kcal/mL) (Appendix 9, p A-9); Pro-Phree ® Protein-Free
Energy Module With Iron, Vitamins & Minerals (Appendix 11, p A-10); sugar (48 kcal/Tbsp); or
Free Foods B (Table 3-2, 58), depending on age of patient.
a. Do not use corn syrup or table sugar for infants because of osmolarity they yield (28).
b. Do not use honey for infants because it may contain botulinum toxin (44).
4. At least 50% of energy prescription should be derived from carbohydrate (9) if patient
tolerates osmolarity of medical food mixture.
D. Fluid and Mixing Instructions
1. Add sufficient boiled, cooled water to infant formula, Tyrex, and carbohydrate to yield
prescribed volume. Tap water may replace boiled, cooled water when preparing Tyrex for
older infants and children.
2. Mix with sterilized blender at lowest speed no longer than 3 to 4 seconds. Excess mixing
may destabilize emulsion. Medical food may also be mixed in tightly closed container by
shaking vigorously for 10 to 12 seconds.
3. Refrigerate in sterilized, closed containers until used. Discard unused portion 24 hours after
mixing because of nutrient loss.
4. Do not use terminal sterilization or boil because of Maillard reaction (Practical Aspects of
Nutrition Support, p viii).
5. Warm or cool medical food mixture to room temperature before feeding to infants. Shake
mixture well before feeding.
6. Do not warm medical food mixture for infants in microwave oven. Unevenly heated formula
can burn infants, and steam can make bottles explode.
7. Notify parents or caretakers when they may discontinue using aseptic technique in preparing
medical food mixture for infants.
8. For children and adults, chill Tyrex medical food mixture to improve taste.
E. Diet Guide
1. Provide parents or caretakers with completed Diet Guide (Appendix 22, p A-24) with each diet
change.
2. Feed infant 6 to 8 times daily (18, 39).
3. Feed children and adults 4 to 6 times daily (18, 39).

VIII. Evaluate Adequacy and Safety of Planned Nutrition Support


A. Nutrient Adequacy
1. Determine if diet provides nutrients in amounts prescribed in Section VI, Establish
Prescription, p 51.
a. See Table 3-3, p 59, for composition of Tyrex.
b. See Table 3-2, p 58, for average composition of infant formulas and whole cow's milk.
2. Check diet to determine if it supplies Recommended Dietary Intakes (RDIs) for minerals and
vitamins (Appendices 13 and 14, pp A-14 and A-15).
a. See Appendices 4 through 7, pp A-4 to A-7, for average nutrient composition of infant
formulas.

54 Tyrosinemia Types Ia and Ib 2001 Ross Products Division


b. Appendix 23, p A-25, may be used to check adequacy of nutrients if computer program is
not available.
c. If Tyrex mixture provides < 100% of RDIs for infants and < 75% for children and adults,
supplement diet with needed minerals and vitamins if not provided by beikost or table
foods and laboratory tests indicate need (Appendix 11, p A-10, for composition of
supplements).
B. Osmolarity
1. If concentration of prescribed medical food mixture is > 24 kcal/fl oz, determine if osmolarity
is in acceptable range.
a. Determine osmolarity by laboratory analysis or use mathematical formula given in
Appendix 18, p A-20.
b. Osmolarity per gram of Tyrex is listed in Appendix 19, p A-21.
2. If osmolarity is > 450 mosm/L for neonates, > 750 mosm/L for children, or is greater than that
tolerated by patient, increase water content of prescribed medical food mixture and
recalculate its osmolarity (27).
C. Potential Renal Solute Load
1. Dehydration will result if renal solute load is greater than renal-concentrating ability of patient.
2. If concentration of medical food mixture prescribed is > 24 kcal/fl oz, estimate its potential
renal solute load.
a. This step is important to prevent dehydration of infants who may have renal-concentrating
capacity as low as 600 mosm/L.
b. Upper limit of renal solute load for neonates is approximately 1,100 mosm/L (40).
3. A method for estimating potential renal solute load is given in Appendix 20, p A-22.
4. If potential renal solute load is excessive, increase water content of medical food mixture and
recalculate.

IX. Suggested Evaluation of Nutrition Support (13)


A. Plasma PHE and TYR Concentrations
1. Initial.
a. Evaluate twice weekly by quantitative methods until plasma concentrations stabilize and
approximate dietary PHE and TYR requirements are known.
2. Ongoing.
a. Frequent evaluations help ensure adherence to nutrition support plan.
b. Evaluate plasma PHE and TYR concentrations weekly until infant is 1 year old and once
or twice monthly thereafter.
3. Unacceptable plasma PHE or TYR concentrations.
a. If plasma PHE or TYR concentration is not detected and patient has ingested full
prescription:
1) Increase prescribed amount of undetected amino acid(s) by 25% and reevaluate
plasma concentrations in 3 to 4 days.
2) If plasma PHE or TYR concentration continues undetected, repeat above process
until value is in treatment range.
b. If plasma PHE concentration is < 35 µmol/L (0.58 mg/dL) or plasma TYR concentration is
< 40 µmol/L (0.72 mg/dL) and patient has ingested full prescription:
1) Increase prescribed amount of amino acid(s) that is low by 5% to 10% and reevaluate
plasma concentration in 3 to 4 days.
2) If plasma PHE or TYR concentration continues to be low, repeat above process until
value is in treatment range.
c. If plasma PHE is > 90 µmol/L (1.49 mg/dL) or plasma TYR is > 80 µmol/L (1.45 mg/dL)
and the patient is not ill and has not ingested more or less protein and energy than
prescribed:
1) Decrease prescribed amount of elevated amino acid(s) by 5% to 10% and reevaluate
plasma concentration in 3 to 4 days.
2) If plasma PHE or TYR concentration continues to be high, repeat above process until
value is in treatment range.

© 2001 Ross Products Division Tyrosinemia Types Ia and Ib 55


B. Organic Acids in Urine
1. Evaluate succinylacetone and parahydroxyphenyl organic acids monthly or if plasma TYR is
elevated.
C. Protein Status
1. Evaluate plasma transthyretin concentration every 3 months in infants and twice yearly in
children and adults (Appendix 17, p A-18, for standards).
a. Plasma transthyretin concentrations provide a more reliable and rapid indication of protein
status than plasma albumin concentrations.
b. Plasma albumin concentrations may be in the normal range when plasma transthyretin
concentrations show a clear deficiency (3).
2. If plasma transthyretin concentration is below standard:
a. Increase prescribed protein by 5% to 10% if blood ammonia is normal and reevaluate in
1 month. If plasma PHE and TYR concentrations are in treatment range, use Tyrex to
increase protein.
b. If plasma transthyretin concentration continues below standard, repeat above process until
value is in normal range.
D. Iron Status
1. Plasma ferritin concentration.
a. Evaluate at 6, 9, and 12 months of age and every 6 months thereafter (Appendix 17,
p A-18, for standards).
b. If plasma ferritin concentration is below standard:
1) Increase iron intake to 4 mg/kg body weight with supplements (ferrous sulfate).
2) Evaluate plasma ferritin concentration monthly on increased iron intake.
3) Continue iron supplements until plasma ferritin concentration is in normal range.
2. Complete blood count.
a. Hemoglobin and hematocrit concentrations should be evaluated at 6, 9, and 12 months of
age and every 6 months thereafter (Appendix 17, p A-18, for standards).
E. Plasma and Urine Biochemistries
1. Plasma and urine phosphate, potassium, and bicarbonate concentrations.
a. Evaluate monthly.
b. Maintain in normal range for age as established by laboratory used.
2. Plasma chloride, sodium, liver enzymes, and alkaline phosphatase concentrations.
a. Maintain in normal range for age and laboratory standards (29).
b. Evaluate every 3 months.
c. If alkaline phosphatase concentration is elevated, obtain radiographs of bones for
evaluation of rickets (2).
F. Growth Status
1. Length/height and weight.
a. Measure monthly to 1 year and every 6 months thereafter until adulthood. Plot
measurements on NCHS growth charts.
b. Maintain length/height and weight between 10th and 90th percentiles. Some normal
infants and children will fall above or below these percentiles.
2. If length/height or weight falls below usual growth channel:
a. Increase prescribed protein (from Tyrex) and energy by 5% to 10% and remeasure in
1 month.
b. If length/height or weight remains low, repeat above process until usual growth channel is
achieved.
G. Nutrient Intake
1. Maintain records of food intake for 3 days immediately before each blood test (Appendices 24
and 25, pp A-26 and A-27).
2. Evaluate intakes of PHE, TYR, protein, and energy before each blood test.

56 Tyrosinemia Types Ia and Ib 2001 Ross Products Division


3. Evaluate mineral and vitamin intakes after each diet change.
a. Appendix 23, p A-25, may be used to check adequacy of nutrients if computer program is
not available.
b. See Appendix 28, p A-29, for information about ordering software for diet evaluation.
I. Special Concern
1. Because of the high risk of hepatomas, periodic serum α-fetoprotein concentrations and liver
imaging studies (by computer-assisted tomography, ultrasonography, or magnetic resonance
imaging) should be obtained.
H. Clinical Summary
1. A summary record of growth, laboratory, and nutrient intake data is useful for patient
management (Table 3-4, p 60).

X. Sample Prescriptions
A. Example 1
Establish and fill prescription for newborn weighing 3.3 kg using Recommended Daily Nutrient
Intakes from Table 3-1, p 58, and nutrient contents from Tables 3-2 and 3-3, pp 58 and 59.
1. Establish prescription.
PHE and TYR 65 mg/kg x 3.3 kg = 214 mg
Protein 3.5 g/kg x 3.3 kg = 11.6 g
Energy 120 kcal/kg x 3.3 kg = 396 kcal
Fluid 148 mL/kg x 3.3 kg = 488 mL
2. Fill prescription.
Medical Food Mixture Measure PHE TYR Protein Energy
(mg) (mg) (g) (kcal)
Tyrex-1 61 g 0 0 9.2 293
Similac With Iron RTF 186 mL 110 108 2.6 126
Add water to make 488 mL (17 fl oz).
Total per day 110 108 11.8 419
Total per kg 33 33 3.6 127
Total PHE plus TYR 218
Approximate osmolarity of medical food mixture is < 450 mosm/L. Estimated potential renal solute
load is < 130 mosm.

B. Example 2
Establish and fill prescription for 3-year-old child weighing 13 kg using Recommended Daily
Nutrient Intakes from Table 3-1, p 58, and average nutrient contents from Tables 3-2 and 3-3,
pp 58 and 59.
1. Establish prescription.
PHE and TYR 380 mg
Protein 30 g
Energy 1,300 kcal
Fluid 1,365 mL

© 2001 Ross Products Division Tyrosinemia Types Ia and Ib 57


2. Fill prescription.
Medical Food Mixture Measure PHE TYR Protein Energy
(mg) (mg) (g) (kcal)
Tyrex-2 80 g 0 0 24.0 328
Sugar 102 g (8.5 Tbsp) 0 0 0.0 408
Add water to make 1000 mL (34 fl oz). Offer additional fluid ad libitum daily.

Food List Servings


Breads/Cereals 3 90 60 1.8 90
Fruits 4 60 40 2.0 240
Vegetables 4 60 40 2.0 40
Free Foods A 3 15 12 0.3 195
Total per day 225 152 30.1 1,301
Total PHE plus TYR 377
Approximate osmolarity is < 750 mosm/L.

XI. Nutrition Support During Febrile Illness or Following Trauma


A. Rationale
1. In normal persons, febrile illness and trauma are accompanied by catabolism of body
protein (46).
2. Well-nourished patients with tyrosinemia respond to infection and trauma as do normal
persons.
3. Extent of protein catabolism determines subsequent elevations in plasma PHE and TYR
concentrations.
B. Objectives of Nutrition Support
1. Maintain hydration and electrolyte balance.
a. Offer infants and toddlers Pedialyte ® Oral Electrolyte Maintenance Solution ad libitum
(Appendix 9, p A-9).
2. Depress catabolism.
a. Enhance energy intake when possible by offering fruit juices ad libitum as tolerated, liquid
Jell-O ®, Polycose powder or liquid (Appendix 9, p A-9), or Pro-Phree (Appendix 11,
p A-10) added to fruit juices or Pedialyte if tolerated and caffeine-free soft drinks (not diet
drinks).
1) 1/3 cup of Polycose powder may be added to liquid Pedialyte to yield 8 fl oz.
b. Return patient to Tyrex medical food mixture and pre-illness diet as rapidly as possible.
1) Begin with 1/2 original strength of Tyrex medical food mixture.
2) Increase to original strength as tolerated.
C. Parenteral Nutrition
1. If parenteral amino acid solutions are indicated, see Appendix 26, p A-28.

58 Tyrosinemia Types Ia and Ib 2001 Ross Products Division


TABLE 3-1. Recommended Daily Nutrient Intakes (Ranges) for Infants and Children With
Tyrosinemia Types Ia and Ib
Age Nutrient
1 2
PHE plus TYR Protein Energy2 Fluid3
(mg/kg) (g/kg) (kcal/kg) (mL/kg)
Infants
0 to < 3 mo 65 - 155 3.50 - 3.00 120 (145 - 95) 160 - 135
3 to < 6 mo 55 - 135 3.50 - 3.00 120 (145 - 95) 160 - 130
6 to < 9 mo 50 - 120 3.00 - 2.50 110 (135 - 80) 145 - 125
9 to < 12 mo 40 - 105 3.00 - 2.50 105 (135 - 80) 135 - 120

(mg/day) (g/day) (kcal/day) (mL/day)


Girls and Boys
1 to < 4 yr 380 - 800 ≥ 30 1,300 ( 900 - 1800) 900 - 1,800
4 to < 7 yr 390 - 900 ≥ 35 1,700 (1300 - 2300) 1,300 - 2,300
7 to < 11 yr 400 - 1,000 ≥ 40 2,400 (1650 - 3300) 1,650 - 3,300

Women
11 to < 15 yr 800 - 1,200 > 50 2,200 (1500 - 3000) 1,500 - 3,000
15 to < 19 yr 800 - 1,200 > 55 2,100 (1200 - 3000) 1,200 - 3,000
> 19 yr 800 - 1,000 > 60 2,100 (1400 - 2500) 1,400 - 2,500

Men
11 to < 15 yr 990 - 1,200 > 55 2,700 (2000 - 3700) 2,000 - 3,700
15 to < 19 yr 1,000 - 1,500 > 65 2,800 (2100 - 3900) 2,100 - 3,900
> 19 yr 1,000 - 1,500 > 70 2,900 (2000 - 3300) 2,000 - 3,300
1
Modified from references 1, 4, 13, 42. Initiate therapy with lowest value for age range. Modify prescription based on
frequently obtained plasma values and growth.
2
Modified from reference 15.
3
Modified from reference 6. Under normal circumstances, offer minimum of 1.5 mL fluid to neonates and 1.0 mL fluid
to children and adults for each kcal ingested.

TABLE 3-2. Serving Lists for PHE- and TYR-Restricted Diets: Average Nutrient Content per Serving1

Food List Nutrient


PHE TYR Protein Energy
(mg) (mg) (g) (kcal)
Breads/Cereals 30 20 0.6 30
Fats 5 4 0.1 60
Fruits 15 10 0.5 60
Vegetables 15 10 0.5 10
Free Foods A 5 4 0.1 65
Free Foods B 0 0 0.0 55
Alimentum ® Protein Hydrolysate Formula With Iron, Ready to Feed, 100 mL 2 86 29 1.86 68
2
Isomil ® Soy Formula With Iron, Ready to Feed, 100 mL 88 60 1.66 68
2
Similac ® With Iron Infant Formula, Ready to Feed, 100 mL 59 58 1.40 68
Whole cow's milk, 100 mL 3 164 164 3.39 63
1
From reference 13.
2
See Appendices 4 through 7, pp A-4 to A-7, for complete nutrient composition of infant formulas.
3
From reference 34. See Appendix 8, p A-8, for complete nutrient composition.

© 2001 Ross Products Division Tyrosinemia Types Ia and Ib 59


TABLE 3-3. Nutrient Composition of TYREX ®-11, 3 and TYREX ®-22, 3

Nutrient Tyrex-1 Tyrex-2


(per 100 g pwd) (per g protein equiv) (per 100 g pwd) (per g protein equiv)
Energy, kcal 480 32.0 410 13.7
Protein equiv, g 15.00 1.000 30.00 1.000
Nitrogen, g 2.40 0.160 4.80 0.160
Amino acids, g 14.73 0.982 29.46 0.982
Cystine, g 0.15 0.010 0.30 0.010
Histidine, g 0.42 0.028 0.84 0.028
Isoleucine, g 1.08 0.072 2.16 0.072
Leucine, g 1.68 0.112 3.36 0.112
Lysine, g 1.00 0.067 2.00 0.067
Methionine, g 0.30 0.020 0.60 0.020
Phenylalanine, g trace 0 trace 0
Threonine, g 0.70 0.047 1.40 0.047
Tryptophan, g 0.17 0.011 0.34 0.011
Tyrosine, g trace 0 trace 0
Valine, g 1.22 0.081 2.44 0.081
Other Nitrogen-Containing Compounds
Carnitine, mg 20 1.33 40 1.33
Taurine, mg 40 2.67 50 1.67
Carbohydrate, g 53.0 3.53 35 1.17
Fat, g 21.7 1.45 14.0 0.47
4 5
Linoleic acid, g 2.00 0.133 1.50 0.050
α-Linolenic acid, g
6 7
0.36 0.024 0.17 0.006
Minerals
Calcium, mg 575 38 880 29
Chloride, mg/mEq 325/9.17 21.7/0.61 940/26.51 31.33/0.88
Chromium, µg 11 0.73 27 0.90
Copper, mg 1.10 0.073 1.00 0.033
Iodine, µg 65 4.33 100 3.33
Iron, mg 9.0 0.60 13 0.43
Magnesium, mg 50 3.33 225 7.50
Manganese, mg 0.50 0.033 0.80 0.027
Molybdenum, µg 12 0.80 30 1.00
Phosphorus, mg 400 27 760 25
Potassium, mg/mEq 675/17.26 45/1.15 1,370/35.04 45.7/1.17
Selenium, µg 20 1.33 35 1.17
Sodium, mg/mEq 190/8.26 12.7/0.55 880/38.28 29.3/1.28
Zinc, mg 8.0 0.53 13 0.43
Vitamins
A, µg RE 420 28 660 22
D, µg 7.50 0.50 7.50 0.25
E, mg α-TE 10.10 0.67 12.10 0.40
K, µg 50 3.33 60 2.00
Ascorbic acid, mg 50 3.33 60 2.00
Biotin, µg 65 4.33 100 3.33
B6, mg 0.75 0.050 1.30 0.043
B12, µg 4.90 0.327 5.00 0.167
Choline, mg 80 5.33 100 3.33
Folate, µg 230 15 450 15
Inositol, mg 40 2.67 70 2.33
Niacin equiv, mg 12.80 0.850 21.7 0.72
Pantothenic acid, mg 6.90 0.460 8.00 0.267
Riboflavin, mg 0.90 0.060 1.80 0.060
Thiamin, mg 1.90 0.127 3.25 0.108
1 2
Designed for infants and toddlers. Designed for children and adults.
3
Approximate packed weights of Tyrex-1 and Tyrex-2 in level, dry US standard household measures:
Tyrex-1 Tyrex-2
1 Tbsp = 7g 8g
1/4 cup = 26 g 32 g
1/3 cup = 35 g 41 g
1/2 cup = 53 g 61 g
1 cup = 105 g 117 g
4 5
Analytical data at manufacture = 4.32 g/100 g powder. Analytical data at manufacture = 2.66 g/100 g powder.
6 7
Analytical data at manufacture = 0.40 g/100 g powder. Analytical data at manufacture = 0.28 g/100 g powder.

60 Tyrosinemia Types Ia and Ib 2001 Ross Products Division


60 Tyrosinemia Types Ia and Ib
TABLE 3-4. Tyrosinemia Type I Clinical Summary Sheet

Name: Hospital Number:

Date of Birth: __________/__________/__________ Age Diagnosed: __________/__________/__________


Mo Day Year Mo Day Year

Date Physical Data Laboratory Data Nutrient Intake Data


+ + -
Length/ Weight Head Na K Cl HCO3 P Alkaline SGOT SGPT Succinyl Transthyretin PHE TYR PHE TYR Protein Energy
Height Circum Phos acetone
(mo/d/yr) (cm) (kg) (cm) (mEq/L) (mEq/L) (mEq/L) (mEq/L (mg/dL) (U/L) (U/L) (U/L) (µmol/L) (mg/dL) (µmol/L) (µmol/L) (mg) (mg) (g) (kcal)
)
© 2001 Ross Products Division
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In Wapnir RA (ed): Congenital Metabolic Diseases: Diagnosis and Treatment. New York: Marcel Dekker Inc,
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2. Ameen VZ, Powell GK, Rassin DK: Cholestasis and hypermethioninemia during dietary management of hereditary
tyrosinemia type 1. J Pediatr 1986;108:949-952.
3. Arnold GL, Vladutiu CJ, Kirby RS: Protein insufficiency and impaired growth in children with PKU. J Inher Metab
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type I without liver transplantation. J Pediatr Gastroenterol Nutr 1994;19:345A.
6. Behrman RE, Kliegman RM, Arvin AA (eds): Nelson Textbook of Pediatrics, ed 15. Philadelphia: WB Saunders Co,
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7. Berger R: Biochemical aspects of type I hereditary tyrosinemia. In Bickel H, et al (eds): Inherited Diseases of
Amino Acid Metabolism. New York: Thieme Inc, 1985, pp 192-202.
8. Berger R, Michals K, Galbraeth J, Matalon R: Tyrosinemia type Ib caused by maleylacetoacetate isomerase
deficiency: A new enzyme deficiency. Pediatr Res 1988;23:328A.
9. Bonkowsky HL, Magnussen CR, Collins AR, et al: Comparative effects of glycerol and dextrose on porphyrin
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10. Calomme MR, Vanderpas JB, Francois B, et al: Thyroid function parameters during a selenium repletion/depletion
study in phenylketonuric subjects. Experientia 1995;51:1208-1215.
11. Cohn RM, Yudkoff M, Yost B, et al: Phenylalanine-tyrosine deficiency syndrome as a complication of the
management of hereditary tyrosinemia. Am J Clin Nutr 1977;30:209-214.
12. Dubois J, Garel L, Patriquin H,et al: Imaging features of type I hereditary tyrosinemia: A review of 30 patients.
Pediatr Radiol 1996;26:845-851.
13. Elsas LJ, Acosta PB: Nutrition support of inherited metabolic diseases. In Shils ME, et al (eds): Modern Nutrition in
Health and Disease, ed 9. Baltimore: Williams & Wilkins, 1999, pp 1003-1056.
14. Endo F, Kitano K, Uehara I, et al: Four-hydroxyphenylpyruvic acid oxidase deficiency with normal
fumarylacetoacetase: A new variant form of hereditary tyrosinemia. Pediatr Res 1983;17:92-96.
15. Food and Nutrition Board, Committee on Dietary Allowances: Recommended Dietary Allowances, eds 9 and 10.
Washington, DC: National Academy of Sciences, 1980 and 1989.
16. Gropper S, Acosta PB: Effect of simultaneous ingestion of L-amino acids and whole protein on plasma amino acid
and urea nitrogen concentrations in humans. JPEN 1991;15:48-53.
17. Haber BA, Chuang E, Lee W, Taub R: Variable gene expression within human tyrosinemia type I liver may reflect
region-specific dysplasia. Hepatology 1996;24:65-71.
18. Herrmann ME, Broesicke HG, Keller M, et al: Dependence of the utilization of a phenylalanine-free amino acid
mixture on different amounts of single dose ingested. A case report. Eur J Pediatr 1994;153:501-503.
19. Hillman L, Schlotzhauer C, Lee D, et al: Decreased bone mineralization in children with phenylketonuria under
treatment. Eur J Pediatr 1996;155 (Suppl 1):S148-S152.
20. Holme E, Lindstedt S: Tyrosinaemia type I and NTBC (2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione).
J Inher Metab Dis 1998;21:507-517.
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1995;10:41-43.
22. Jones BJM, Lees R, Andrews J, et al: Comparison of an elemental and polymeric enteral diet in patients with
normal gastrointestinal function. Gut 1983;24:78-84.
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28. Martin SB, Acosta PB: Osmotic behaviors of components of chemically-defined formulas. J Pediatr Perinat Nutr
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31. Mitchell G, LaRochelle J, Lambert M, et al: Neurologic crises in hereditary tyrosinemia. N Engl J Med
1990;322:432-437.
32. Ohkohchi N, Andoh T, Ohi R, Mori S: Defined formula diets alter characteristics of the intestinal transport of amino
acids and peptides in growing rats. J Pediatr Gastroenterol Nutr 1990;10:490-496.
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34. Posati LP, Orr ML: Composition of Foods: Dairy and Egg Products, Agriculture Handbook No. 8-1. Washington,
DC: US Dept of Agriculture, Agricultural Research Service, 1976.
35. Pratt EL, Snyderman SE, Cheung MW, et al: The threonine requirement of the normal infant. J Nutr
1955;56:231-251.
36. Rank JM, Pascual-Leone A, Payne W, et al: Hematin therapy for the neurologic crisis of tyrosinemia. J Pediatr
1991;118:136-139.
37. Riudor E, Ribes A, Lloret J, et al: Liver transplantation in two children with tyrosinemia type I: Biochemical
aspects. J Inher Metab Dis 1991;14:281-284.
38. Roth KS, Carter BE, Higgins ES: Succinylacetone effects on renal tubular phosphate metabolism: A model for
experimental renal Fanconi syndrome. Proc Soc Exp Biol Med 1991;196:428-431.
39. Schoeffer A, Herrmann ME, Broesicke HG, Moench E: Effect of dosage and timing of amino acid mixtures on
nitrogen retention in patients with phenylketonuria. J Nutr Med 1994;4:415-418.
40. Smith CA, Nelson NM (eds): The Physiology of the Newborn Infant, ed 4. Springfield, IL: Charles C Thomas
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41. Smith JL, Arteaga C, Heymsfield SB: Increased ureagenesis and impaired nitrogen use during infusion of a
synthetic amino acid formula - A controlled trial. N Engl J Med 1982;306:1013-1018.
42. Snyderman SE, Boyer A, Norton PM, et al: The essential amino acid requirements of infants. X. Methionine. Am J
Clin Nutr 1964;15:322-330.
43. Sovik O, Kvittingen EA, Steen-Johnsen J, Halvorsen S: Hereditary tyrosinemia of chronic course without rickets
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44. Spika JS, Shaffer N, Hargrett-Bean N, et al: Risk factors for infant botulism in the United States. Am J Dis Child
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45. Suzuki Y, Konda M, Imai I, et al: Effect of dietary treatment on the renal tubular function in a patient with
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1977;30:1269-1280.

© 2001 Ross Products Division Tyrosinemia Types Ia and Ib 63


PROTOCOL 4 — Tyrosinemia Types II and III

Nutrition Support of Infants, Children, and Adults With


TYREX ®-1 and TYREX ®-2 Amino Acid-Modified Medical Foods
I. Introduction
Tyrosinemia type II is characterized by greatly elevated concentrations of blood and urine tyrosine
(TYR) and by increases in urinary phenolic acids, N-acetyltyrosine, and tyramine. Deficiency of
hepatic cytosolic tyrosine aminotransferase (TAT) has been demonstrated (Figure C). Characteristic
physical findings include stellate corneal erosions and plaques and bullous lesions of the soles and
palms. Persistent keratitis and hyperkeratosis occur on the fingers and palms of the hands and on the
soles of the feet. These skin abnormalities respond to restriction of dietary phenylalanine (PHE) and
TYR (33, 39, 43). Intracellular crystallization of TYR is thought to cause these inflammatory
responses. Mental retardation may occur (42).
Two clinical subsets of hereditary tyrosinemia type III result from dysfunction of
p-hydroxyphenylpyruvic acid dioxygenase (p-OHPPAD) (Figure C). The most severe is type IIIa with
no hepatic p-OHPPAD activity. Neurologic abnormalities, including seizures, ataxia, and mental
retardation, have been reported in untreated patients with type IIIa. Hawkinsinuria (Type IIIb) is named
for the 2-L-cysteinyl 5-1,4-dihydroxycyclohexenyl-5, 1-acetic acid which presumably is formed from an
intermediate resulting from the impaired p-OHPPAD reaction. Metabolic acidosis and failure to thrive
with a "swimming pool"-like odor are described (42). Restriction of TYR and PHE improves the critical
condition (47).

Dietary protein

Tissue protein
Phenylalanine
Tissue protein synthesis
catabolism CO2 + H2O
Melanin
Tyrosine*
Epinephrine
Thyroxine
Tyrosine aminotransferase (tyrosinemia type II)

p-Hydroxyphenylpyruvic acid*

p-OH phenylpyruvic (Tyrosinemia type III)


acid dioxygenase¹

Homogentisic acid * Accumulates in untreated


tyrosinemia types II and III
¹ Inhibited by NTBC
Maleylacetoacetic acid Enzyme malfunction

Fumarylacetoacetic acid

Fumaric acid
+
Acetoacetic acid

Figure C. Tyrosine metabolism in tyrosinemia types II and III

II. Outcome of Nutrition Support


The PHE- and TYR-restricted diet has been successfully used in several patients, including a pregnant
woman (24), with tyrosinemia types II and III, with rapid resolution of clinical symptoms (33, 39, 43,
47).

64 Tyrosinemia Types II and III © 2001 Ross Products Division


III. Establish Diagnosis
A. The Defect
1. Tyrosinemia may result from defect in 1 of several enzymes:
a. Type Ia: Fumarylacetoacetate hydrolyase (Protocol 3, p 49).
b. Type Ib: Maleylacetoacetate isomerase (Protocol 3, p 49).
c. Type II: TAT (16, 27, 29, 33, 42).
d. Type III: p-OHPPAD (16-18, 26,42, 47).
e. Transient: p-OHPPAD immaturity (16).
B. Clinical Screening
1. Concentration > 4 mg/dL of TYR by bacterial inhibition assay of dried blood spot requires
differential diagnosis (16)
2. Because few states screen for tyrosinemia, infants, children, or adults with any of following
clinical findings should be evaluated for tyrosinemia type II (3, 5-7, 9, 10, 13, 15, 25, 27-29,
36, 48, 50):
a. Eye lesions.
1) Photophobia, redness, and/or lacrimation.
2) Persistent herpetiform dendritic ulcers.
3) Ulcerations and thick corneal or conjunctival plaques with neovascularization.
b. Skin lesions.
1) Hyperkeratosis of fingers, palms, toes, and/or soles of feet.
2) Blisters.
3) Erosions.
c. Seizures.
d. Mental retardation.
3. Patients with tyrosinemia type III have been reported with immunologic abnormalities (19, 20),
intermittent ataxia (26), neurologic abnormalities (42), and no symptoms (53).
C. Differential Diagnosis (42)
1. Differential diagnosis will reveal false-positives and identify specific enzyme defect.
2. Therapy depends on enzyme defect present.
3. This protocol addresses nutrition support for patients with TAT or p-OHPPAD deficiency.

IV. Rationale for Nutrition Support


A. Correct Primary Imbalance in Metabolic Relationships
1. Restrict dietary PHE and TYR to amounts tolerated by patient to maintain treatment plasma
amino acid concentrations.

V. Establish Goals of Nutrition Support (3, 5-7, 9, 10, 12, 13, 15, 17-20, 22, 25-29, 33, 36, 39, 47,
48)
A. Plasma PHE and TYR Concentrations
1. Maintain 2- to 4-hour postprandial plasma PHE and TYR concentrations in ranges noted
below, when measured by quantitative methods, or within normal range for age established by
laboratory used.
Amino Acid µmol/L mg/dL
PHE 35 - 90 0.58 - 1.49
TYR 40 - 80 0.72 - 1.45
2. In practice, obtaining blood 2 to 4 hours postprandially is not always possible. Acceptable local
standards should be developed if plasma amino acids are evaluated at other times (Practical
Aspects of Nutrition Support, p viii).
3. With plasma PHE and TYR concentrations in normal range, plasma amino acids must
be measured frequently to prevent deficiency (10).
B. Growth, Development, and Nutrition Status (11, 30, 35)
1. Support normal growth rate in infants and children and maintain appropriate weight for height
in adults.
2. Support normal development.

© 2001 Ross Products Division Tyrosinemia Types II and III 65


3. Maintain normal nutrition status.
4. Prevent catabolism.
5. Maintain plasma and urine free of, or containing only traces, of N-acetyltyrosine, p-tyramine,
and parahydroxyphenyl organic acids.
C. Physical Manifestations
1. Prevent oculocutaneous and/or palmo-plantar lesions.

VI. Establish Prescription


A. PHE Plus TYR
1. Prescribe PHE plus TYR intake that promotes goals of nutrition support.
2. PHE plus TYR requirement varies widely:
a. From patient to patient, depending on activity of TAT or p-OHPPAD.
b. In same patient, depending on:
1) Age
2) Growth rate
3) Adequacy of protein and energy intakes
4) State of health.
3. Lowest value for age for PHE plus TYR listed in Table 4-1, p 70, is suggested for initiating
therapy.
4. Changing requirements of patients are determined by frequent monitoring of :
a. Plasma PHE and TYR concentrations.
b. Plasma and urine concentrations of N-acetyltyrosine, p-tyramine, and parahydroxyphenyl
organic acids.
c. See Section IX, Suggested Evaluation of Nutrition Support, p 67.
Warning: Inadequate PHE plus TYR intake results in anorexia, lethargy, and hypotonia;
decreased growth rate in children; weight loss in adults; decreased plasma
fibrogen concentration; and increased plasma amino acid concentrations
(except PHE and TYR) (14).
B. Protein
1. Prescribe, initially, amount greater than Recommended Dietary Allowances (RDAs) (23)
(Table 4-1, p 70).
2. Requirements are greater than RDAs when L-amino acids supply majority of protein
equivalent as a result of:
a. Rapid amino acid absorption (31, 32).
b. Early and high peak of plasma amino acid concentrations after ingestion of meals where
large part of protein is supplied by L-amino acids (31, 32).
c. Rapid catabolism of amino acids (31, 32, 34, 37, 52).
d. Possible decreased total amino acid absorption (44).
Warning: Inadequate protein intake will result in failure to thrive in infant, weight loss
in children and adults, low plasma transthyretin, osteopenia, hair loss, and
decreased PHE and TYR tolerance.
C. Energy
1. Prescribe amount that should support normal weight gain for infants and children and maintain
weight for height in adults (Table 4-1, p 70).
2. Requirements vary and may be greater than normal when L-amino acids supply majority of
protein equivalent (46, 49).
Warning: Inadequate energy intake results in failure to thrive in infants and weight loss
in children and adults with elevated plasma PHE and TYR concentrations
resulting from muscle protein catabolism.
D. Fluid
1. Prescribe amount that will supply water requirements (Table 4-1, p 70). Under normal
circumstances, offer minimum of 1.5 mL fluid to neonates and 1.0 mL to children and adults
for each kcal ingested.

66 Tyrosinemia Types II and III © 2001 Ross Products Division


VII. Fill Prescription
A. PHE Plus TYR
1. Calculate amount of infant formula with iron, beikost, whole cow's milk, or table foods
(Table 4-2, p 70) required to fill PHE plus TYR prescription.
a. Low-iron infant formula, whole cow's milk, and evaporated milk should not be used as
PHE and TYR source for infants because of low iron content.
2. Parents or patients may select any food in prescribed Servings Lists for PHE-Restricted Diets
(Protocol 1, pp 13-26) in specified amounts to fill diet prescription.
B. Protein
1. Calculate amount of protein provided by infant formula with iron, beikost, whole cow's milk, or
table foods (Table 4-2, p 70) required to fill PHE plus TYR prescription.
2. Subtract amount determined above from total protein prescription.
3. Supply remaining prescribed protein with Tyrex (Table 4-2, p 70).
a. Weigh Tyrex powder on scale that reads in grams because of variability of household
measuring equipment (Practical Aspects of Nutrition Support, p vii) and changes in
density during shipping.
b. See Table 3-3 (p 59, footnote 3) for approximate packed weight of Tyrex powder in level,
dry US standard household measures.
C. Energy
1. Calculate energy provided by infant formula with iron, beikost, whole cow's milk, or table foods
and Tyrex (Table 4-2, p 70) required to fill PHE plus TYR and protein prescriptions.
2. Subtract amount determined above from total energy prescription.
3. Provide remaining prescribed energy with Polycose ® Glucose Polymers powder
(23 kcal/Tbsp, 3.8 kcal/g) or liquid (2 kcal/mL) (Appendix 9, p A-9); Pro-Phree ® Protein-Free
Energy Module with Iron, Vitamins & Minerals (Appendix 11, p A-10); sugar (48 kcal/Tbsp); or
Free Foods B (Table 4-2, p 70).
D. Fluid and Mixing Instructions
1. Add sufficient boiled, cooled water to infant formula, Tyrex, and carbohydrate to yield
prescribed volume. Tap water may replace boiled, cooled water when preparing Tyrex for
older infants, children, and adults.
2. Mix with sterilized blender at lowest speed for 3 to 4 seconds. Excess mixing may
destabilize emulsion. Medical foods may also be mixed in sterilized, tightly closed container
by shaking vigorously for 10 to 12 seconds.
3. Place in sterilized formula bottles. Cap and store in refrigerator until used. Discard unused
portion 24 hours after mixing because of nutrient loss.
4. Do not use terminal sterilization or boil because of Maillard reaction (Practical Aspects of
Nutrition Support, p viii).
5. Warm or cool medical food mixture to room temperature before feeding to infants. Shake well
before feeding.
6. Do not warm medical food mixture for infants in microwave oven. Unevenly heated formula
can burn infant and steam can make bottles explode.
7. Notify parents or caretakers when they may discontinue using aseptic technique in preparing
medical food mixture for infants.
8. For children and adults, chill Tyrex medical food mixture to improve taste.
E. Diet Guide
1. Provide parents, caretakers, or patient with completed Diet Guide (Appendix 22, p A-24) with
each diet change.
2. Feed young infants 6 to 8 times daily (34, 37, 51).
3. Feed older infants, children, and adults 4 to 6 times daily (34, 37, 51).

© 2001 Ross Products Division Tyrosinemia Types II and III 67


VIII. Evaluate Adequacy and Safety of Planned Nutrition Support
A. Nutrient Adequacy
1. Determine if diet provides nutrients in amounts prescribed in Section VI, Establish
Prescription, p 65.
a. See Table 4-2, p 70, for composition of Tyrex and average nutrient content of beikost or
table foods.
b. See Appendix 9, p A-9, for composition of Polycose and Appendix 11, p A-10, for
composition of Pro-Phree.
2. Check diet to determine if it supplies Recommended Dietary Intakes (RDIs) for minerals and
vitamins (Table 3-3, p 59, and Appendices 13 and 14, pp A-14 and A-15).
a. See Appendices 4 through 7, pp A-4 to A-7, for complete nutrient composition of infant
formulas and Appendix 8, p A-8, for composition of whole cow's milk.
b. Appendix 23, p A-25, may be used to check adequacy of nutrients if computer program is
not available.
c. If Tyrex mixture provides < 100% of RDIs for infants and < 75% for children and adults,
supplement diet with needed minerals and vitamins if not provided by beikost or table
foods and laboratory tests indicate need (Appendix 11, p A-10, for composition of
supplements) (11, 30, 35).
B. Osmolarity
1. If concentration of prescribed medical food mixture is > 24 kcal/oz, determine if osmolarity is
in acceptable range.
a. Determine osmolarity by laboratory analysis or use mathematical formula given in
Appendix 18, p A-20.
b. Osmolarity per gram of Tyrex is listed in Appendix 19, p A-21.
2. If osmolarity is > 450 mosm/L for neonates, > 750 mosm/L for children, > 1,000 mosm/L for
adults, or greater than tolerated by patient, increase water content of prescribed medical food
mixture and recalculate its osmolarity (40, 41).
C. Potential Renal Solute Load
1. Dehydration will result if renal solute load is greater than renal-concentrating ability of patient.
2. If concentration of medical food mixture prescribed is > 24 kcal/fl oz, estimate its potential
renal solute load.
a. This step is important to prevent dehydration of infants who may have renal-concentrating
capacity as low as 600 mosm/L.
b. Upper limit of renal solute load for neonates is approximately 1,100 mosm/L.
3. A method for estimating potential renal solute load is given in Appendix 20, p A-22.
4. If potential renal solute load is excessive, increase water content of medical food mixture and
recalculate.

IX. Suggested Evaluation of Nutrition Support (16)


A. Plasma PHE and TYR Concentrations
1. Initial.
a. Evaluate weekly by quantitative methods until 6 months of age.
2. Ongoing.
a. Evaluate monthly.
b. Frequent evaluations help ensure adherence to nutrition support plan.
3. Unacceptable PHE and TYR concentrations.
a. If plasma PHE or TYR concentration is not detected and patient has ingested full
prescription:
1) Increase prescribed amount of PHE plus TYR by 25% and reevaluate plasma
concentration in 3 to 4 days.
2) If plasma PHE or TYR concentration continues undetected, repeat above process
until value is in treatment range.
b. If plasma PHE concentration is < 35 µmol/L (0.58 mg/dL) or plasma TYR concentration is
< 40 µmol/L (0.72 mg/dL) and patient has ingested full prescription:
1) Increase prescribed amount of PHE plus TYR by 5% to 10% and reevaluate plasma
concentration in 7 days.

68 Tyrosinemia Types II and III © 2001 Ross Products Division


2) If plasma PHE or TYR concentration continues to be low, repeat above process until
value is in treatment range.
c. If plasma PHE concentration is > 90 µmol/L (1.49 mg/dL) or plasma TYR concentration is
> 80 µmol/L (1.45 mg/dL) and patient is not ill and has not ingested more or less protein
and energy than prescribed:
1) Decrease prescribed amount of PHE plus TYR by 5% to 10% and reevaluate plasma
concentrations in 7 days.
2) If plasma PHE or TYR concentration continues to be high, repeat above process until
value is in treatment range.
B. Organic Acids in Urine
1. Evaluate N-acetyltyrosine, p-tyramine, and p-hydroxyphenyl organic acids monthly or if
plasma TYR concentration is elevated.
C. Protein Status
1. Evaluate plasma transthyretin concentration at 3, 6, 9, and 12 months in infants and twice
yearly in children and adults (Appendix 17, p A-18, for standards).
a. Plasma transthyretin concentrations provide a more reliable and rapid indication of protein
status than plasma albumin concentrations.
b. Plasma albumin concentrations may be in the normal range when plasma transthyretin
concentrations show a clear deficiency (4).
2. If plasma transthyretin concentration is below standard:
a. Increase prescribed protein by 5% to 10% and reevaluate plasma transthyretin
concentration in 1 month. If plasma PHE and TYR concentrations are in treatment range,
use Tyrex to increase protein.
b. If plasma transthyretin concentration remains low, repeat above process until value is in
normal range.
D. Iron Status
1. Plasma ferritin concentration.
a. Evaluate at 6, 9, and 12 months in infants and twice yearly in children and adults
(Appendix 17, p A-18, for standards).
b. If plasma ferritin concentration is below standard:
1) Increase iron intake to 4 mg/kg body weight with supplements (ferrous sulfate).
2) Evaluate plasma ferritin concentration monthly on increased iron intake.
3) Continue iron supplements until plasma ferritin concentration is in normal range.
2. Complete blood count
a. Hemoglobin and hematocrit concentrations should be evaluated at 6, 9, and 12 months of
age and every 6 months thereafter (Appendix 17, p A-18, for standards).
E. Growth Status
1. Height and weight.
a. Measure infants every 3 months and children and adults every 6 months. Plot
measurements on NCHS growth charts.
b. Maintain height and weight between 10th and 90th percentiles. Some normal children and
adults will fall above or below these percentiles.
2. If height or weight falls below usual growth channel:
a. Increase prescribed protein and energy by 5% to 10% and remeasure in 1 month.
b. If height or weight remains low, repeat above process until usual growth channel is
achieved.
F. Nutrient Intake
1. Maintain records of food intake for 3 days immediately before each blood test (Appendices 24
and 25, pp A-26 and A-27).
2. Evaluate intakes of PHE, TYR, protein, and energy before each blood test.
3. Evaluate mineral and vitamin intakes after each diet change.
a. Appendix 23, p A-25, may be used to check adequacy of nutrients if computer program is
not available.
b. See Appendix 28, p A-29, for information about ordering software for diet evaluation.

© 2001 Ross Products Division Tyrosinemia Types II and III 69


G. Clinical Summary
1. A summary record of growth, laboratory, and nutrient intake data is useful for patient
management (Table 4-3, p 71).

X. Sample Prescription
A. Example
Establish and fill prescription for 5-year-old weighing 20 kg who has tyrosinemia type II using
Recommended Daily Nutrient Intakes in Table 4-1, p 70, and average nutrient contents from
Table 4-2, p 70. Plasma PHE concentration is 100 µmol/L and plasma TYR is 500 µmol/L.
1. Establish prescription.
PHE and TYR 510 mg
Protein 35 g
Energy 1,300 kcal
Fluid 1,300 mL
2. Fill prescription.
Medical Food Mixture Measure PHE TYR Protein Energy
(mg) (mg) (g) (kcal)
Tyrex-2 93 g 0 0 27.9 381
Add water to make 946 mL (32 fl oz). Offer additional fluid ad libitum daily.

Food List Servings


Breads/Cereals 6 180 120 3.6 180
Fats 6 30 24 0.6 360
Fruits 4 60 40 2.0 240
Vegetables 2 30 20 1.0 20
Free Foods A 1 5 4 0.1 65
Free Foods B 1 0 0 0.0 55
Total per day 305 208 35.2 1,301
Total PHE plus TYR 513
Approximate osmolarity of medical food mixture is < 600 mosm/L.

XI. Nutrition Support During Febrile Illness or Following Trauma


A. Rationale
1. In normal person, febrile illness and trauma are accompanied by catabolism of body
protein (54).
2. Well-nourished patients with tyrosinemia type II or III respond to infection and trauma as do
normal persons.
3. Extent of protein catabolism determines subsequent elevation in blood PHE and TYR
concentrations.

B. Objectives of Nutrition Support


1. Maintain hydration and electrolyte balance.
2. Depress catabolism.
a. Enhance energy intake when possible by offering fruit juices ad libitum as tolerated; liquid
Jell-O ®; Polycose liquid or powder (Appendix 9, p A-9) added to fruit juices if tolerated;
and caffeine-free soft drinks (not diet).
b. 1/3 cup Polycose powder may be added to liquid Pedialyte to yield 8 fl oz.
c. Return patient to Tyrex medical food mixture and pre-illness diet as rapidly as possible.
1) Begin with 1/2 original strength of Tyrex medical food mixture.
2) Increase to original strength, as tolerated.

C. Parenteral Nutrition
1. If parenteral amino acid solutions are indicated, see Appendix 26, p A-28.

70 Tyrosinemia Types II and III © 2001 Ross Products Division


TABLE 4-1. Recommended Daily Nutrient Intakes (Ranges) for Infants, Children, and Adults With
Tyrosinemia Types II or III

Age Nutrient
PHE 1, 2 TYR 1,2 Protein 3 Energy 3 Fluid 4
(mg/kg) (mg/kg) (g/kg) (kcal/kg) (mL/kg)
Infants
0 to < 3 mo 30 - 90 35 - 90 3.50 - 3.00 120 (145 - 95) 150-125
3 to < 6 mo 30 - 70 30 - 70 3.50 - 3.00 115 (145 - 95) 160-130
6 to < 9 mo 25 - 50 25 - 50 3.00 - 2.50 110 (135 - 80) 145-125
9 to < 12 mo 20 - 40 20 - 40 3.00 - 2.50 105 (135 - 80) 135-120

(mg/day) (mg/day) (g/day) (kcal/day) (mL/day)


Girls and Boys
1 to < 4 yr 250 - 500 200 - 450 > 30.0 1,300 ( 900 - 1800) 900 - 1,800
4 to < 7 yr 260 - 550 250 - 500 > 35.0 1,700 (1300 - 2300) 1,300 - 2,300
7 to < 11 yr 270 - 600 260 - 550 > 40.0 2,400 (1650 - 3300) 1,730 - 3,300

Women
11 to < 15 yr 300 - 650 290 - 500 > 50.0 2,200 (1500 - 3000) 1,500 - 3,000
15 to < 19 yr 280 - 700 270 - 450 > 55.0 2,100 (1200 - 3000) 1,200 - 3,000
> 19 yr 270 - 700 260 - 450 > 60.0 2,100 (1400 - 2500) 1,400 - 2,500

Men
11 to < 15 yr 275 - 700 260 - 550 > 55.0 2,700 (2000 - 3700) 2,000 - 3,700
15 to < 19 yr 350 - 750 340 - 550 > 65.0 2,800 (2100 - 3900) 2,100 - 3,900
> 19 yr 340 - 750 330 - 550 > 70.0 2,900 (2000 - 3300) 2,000 - 3,300
1
Initiate therapy with lowest value for age range. Modify prescription based on frequently obtained plasma values and
growth in infants and children and frequently obtained plasma values and weight maintenance in adults.
2
From references 1, 2, 16, 38, 49.
3
From references 21, 23.
4
From reference 8. Under normal circumstances, offer minimum of 1.5 mL fluid to neonates and 1.0 mL fluid to
children and adults for each kcal ingested.
1
TABLE 4-2. Serving Lists for PHE- and TYR-Restricted Diets: Average Nutrient Content per Serving

Food List Nutrient


PHE TYR Protein Energy
(mg) (mg) (g) (kcal)
Breads/Cereals 30 20 0.6 30
Fats 5 4 0.1 60
Fruits 15 10 0.5 60
Vegetables 15 10 0.5 10
Free Foods A 5 4 0.1 65
Free Foods B 0 0 0.0 55
Alimentum ® Protein Hydrolysate Formula With Iron, Ready to Feed, 100 mL 86 29 1.86 68
2

2
Isomil ® Soy Formula With Iron, Ready to Feed, 100 mL 88 60 1.66 68
2
Similac ® With Iron Infant Formula, Ready to Feed, 100 mL 59 58 1.40 68
Tyrex®-1 0 0 15.00 480
Tyrex®-2 0 0 30.00 410
3
Whole cow's milk, 100 mL 164 164 3.39 63
1
From reference 16.
2
See Appendices 4 through 7, pp A-4 to A-7, for complete nutrient composition of infant formulas.
3
From reference 45. See Appendix 8, p A-8, for complete nutrient composition.

© 2001 Ross Products Division Tyrosinemia Types II and III 71


© 2001 Ross Products Division

TABLE 4-3. Tyrosinemia Types II and III Clinical Summary Sheet


Name: Hospital Number:

Date of Birth: __________/__________/__________


Mo Day Year

Date Age Physical Data Laboratory Data Nutrient Intake Data


2 3
Length/ Weight Head Hgb Ferritin Transthyretin Urine PHE TYR PHE TYR Protein Energy
1
Height Circum p-OHPOA
(mo/d/yr) (yrs/mos) (cm) (kg) (cm) (g/dL) (ng/mL) (mg/dL) (mg) (mg) (g) (kcal)
Tyrosinemia Types II and III 71

1
Urine p-hydroxyphenyl organic acids.
2
Indicate if mg/dL or µmol/L.
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31. Gropper S, Acosta PB: Effect of simultaneous ingestion of L-amino acids and whole protein on plasma amino acid
and urea nitrogen concentrations in humans. JPEN 1991;15:48-53.
32. Gropper SS, Gropper DM, Acosta PB: Plasma amino acid response to ingestion of L-amino acids and whole
protein. J Pediatr Gastroenterol Nutr 1993;16:143-150.

© 2001 Ross Products Division Tyrosinemia Types II and III 73


33. Halvorsen S, Skjelkvale L: Tyrosine aminotransferase deficiency (TATD): First case diagnosed on newborn
screening and successfully treated with PHE-TYR restricted diet from early age. Pediatr Res 1977;11:1017A.
34. Herrmann ME, Broesicke HG, Keller M, et al: Dependence of the utilization of a phenylalanine-free amino acid
mixture on different amounts of single dose ingested. A case report. Eur J Pediatr 1994;153:501-503.
35. Hillman L, Schlotzhauer C, Lee D, et al: Decreased bone mineralization in children with phenylketonuria under
treatment. Eur J Pediatr 1996;155 (Suppl 1):S148-S152.
36. Hunziker N: Richner-Hanhart syndrome and tyrosinemia type II. Dermatologica 1980;160:180-189.
37. Jones BJM, Lees R, Andrews J, et al: Comparison of an elemental and polymeric enteral diet in patients with
normal gastrointestinal function. Gut 1983;24:78-84.
38. Leverton RM, Johnson N, Dazur J, Ellison J: Amino acid requirements of young adults. In Albanese AA (ed):
Protein and Amino Acid Nutrition. New York: Academic Press, 1959.
39. Machino H, Miki Y, Kawatsu T, et al: Successful dietary control of tyrosinemia II. Am Acad Dermatol
1983;9:533-539.
40. MacLean W, Graham G: Pediatric Nutrition in Clinical Practice. Menlo Park, Calif: Addison-Wesley Publishing Co,
1982.
41. Martin SB, Acosta PB: Osmotic behaviors of components of chemically-defined formulas. J Pediatr Perinat Nutr
1987;1:1-17.
42. Mitchell GA, Grompe M, Lambert M, Tanguay RM: Hypertyrosinemia. In Scriver CR, et al (eds): The Metabolic and
Molecular Bases of Inherited Disease, ed 8. New York, McGraw-Hill Medical Publishing Division, 2001,
pp 1777-1806.
43. Ney D, Bay C, Schneider JA, et al: Dietary management of oculocutaneous tyrosinemia in an 11-year-old child.
Am J Dis Child 1983;137:995-1000.
44. Ohkohchi N, Andoh T, Ohi R, Mori S: Defined formula diets alter characteristics of the intestinal transport of amino
acids and peptides in growing rats. J Pediatr Gastroenterol Nutr 1990;10:490-496.
45. Posati LP, Orr ML: Composition of Foods: Dairy and Egg Products, Agriculture Handbook No. 8-1. Washington,
DC: US Dept of Agriculture, Agricultural Research Service, 1976.
46. Pratt EL, Snyderman SE, Cheung MW, et al: The threonine requirement of the normal infant. J Nutr
1955;56:231-251.
47. Preece MA, Rylance GW, MacDonald A, et al: A new case of tyrosinaemia type III detected by neonatal screening.
J Inher Metab Dis 1996;19 (Suppl 1):32.
48. Rabinowitz LG, Williams LR, Anderson CE, et al: Painful keratoderma and photophobia: Hallmarks of tyrosinemia
type II. J Pediatr 1995;126;266-269.
49. Rose WC, Wixom RL: The amino acid requirements of man. XIV. The sparing effect of tyrosine on the
phenylalanine requirement. J Biol Chem 1955;217:95-101.
50. Sandberg HO: Bilateral keratopathy and tyrosinosis. Acta Ophthalmol 1975;53:760-764.
51. Schoeffer A, Herrmann ME, Broesicke HG, Moench E: Effect of dosage and timing of amino acid mixtures on
nitrogen retention in patients with phenylketonuria. J Nutr Med 1994;4:415-418.
52. Smith JL, Arteaga C, Heymsfield SB: Increased ureagenesis and impaired nitrogen use during infusion of a
synthetic amino acid formula - A controlled trial. N Engl J Med 1982;306:1013-1018.
53. Stoppoloni, G, Santinelli R, Priscof, et al: Benign tyrosinemia: An 18-year follow-up. J Inher Metab Dis
1995;18:641-642.
54. Wannemacher RW: Key role of various individual amino acids in host response to infection. Am J Clin Nutr
1977;30:1269-1280.

74 Tyrosinemia Types II and III © 2001 Ross Products Division


PROTOCOL 5 — Maple Syrup Urine Disease (MSUD)

Nutrition Support of Infants, Children, and Adults With


KETONEX ®-1 and KETONEX ®-2 Amino Acid-Modified Medical Foods
I. Introduction
The branched-chain amino acids (BCAAs) isoleucine (ILE), leucine (LEU), and valine (VAL) are
essential nutrients. In newborns, 75% of BCAAs ingested are used for protein synthesis. Those
present in excess of need for synthetic purposes are degraded through many steps to provide energy
(Figure D). The initial step in catabolism is reversible transamination, requiring a specific
transaminase and the coenzyme pyridoxal phosphate. The second step is irreversible oxidative
decarboxylation which uses the branched-chain-α-ketoacid dehydrogenase (BCKAD) complex. This
complex is located in the inner mitochondrial membrane and requires the coenzymes thiamin
pyrophosphate, lipoic acid, CoA, and NAD+ (36). The Figure below schematizes this overall reaction,
which is impaired in maple syrup urine disease (MSUD) (8).

Dietary protein Dietary protein Dietary protein


Tissue protein catabolism Tissue protein catabolism Tissue protein catabolism

Branched-chain amino acids


Leucine * Isoleucine * Valine *
Tissue Tissue
protein protein
synthesis synthesis

α-Ketoacids α-Ketoisocaproic acid * α-Keto-3-methylvaleric acid * α-Ketoisovaleric acid *

Thiamin Thiamin Thiamin


Branched-chain α-ketoacid
(4n) (4n) (4n)
dehydrogenase complex

Acetyl-CoA Acetyl-coA Propionyl-CoA


+ + (n)
Acetoacetate Propionyl-CoA
Enzyme defect (n) Succinyl-CoA
(n) = several steps
* Accumulates in the body in Succinyl-CoA
untreated MSUD.

Figure D. Branched-chain amino acid metabolism in maple syrup urine disease


When thiamin pyrophosphate saturates its site on BCKAD, biologic turnover of BCKAD is decreased
because the multienzyme complex undergoes a conformational change, making it more resistant to
chymotrypsin and heat degradation. The biologic half-life of the enzyme and overall activity are
increased when a new equilibrium of enzyme synthesis and degradation is reached (11, 12).
MSUD is a group of inherited disorders of ILE, LEU, and VAL metabolism (8, 11) resulting from
several mutations that impair various components of the multienzyme BCKAD (Figure D). An
autosomal recessive mode of inheritance is defined for all reported cases. The incidence of MSUD is
approximately 1/100,000 to 1/300,000 live births in the general population, and 1/760 live births in the
Mennonite population (8, 11).
Infants with MSUD appear normal at birth and are clinically well until after eating a protein-containing
feed. The most severely impaired enzymes may produce seizures, apnea, and death within 10 days of
birth. The disorder is characterized by elevated blood, urine, and cerebrospinal fluid concentrations of
the branched-chain-ketoacids (BCKAs), their amino acid precursors, and alloisoleucine (ALLO).
Progressive neurologic dysfunction and production of urine with the odor of maple syrup follow. The
sweet smell may only be evident in earwax, sensed after otoscopic

© 2001 Ross Products Division Maple Syrup Urine Disease 75


examination. Neurologic impairment in the newborn is manifested by poor sucking, irregular respiration,
rigidity alternating with flaccidity, opisthotonos, progressive loss of Moro reflex, and seizures (8, 11).
Immune suppression may occur as a result of elevated plasma organic acid concentrations (53).
Several variants with a spectrum of impaired mitochondrial BCKAD complex have been reported.
Clinical manifestations are expressed intermittently upon protein loading or with febrile illness in
patients with partial enzyme activity between 5% and 30% of normal. A thiamin-responsive form with
expression similar to the intermediate form has been described (8, 11).
Untreated patients with classic MSUD (0-2% BCKAD activity) who survive beyond early infancy
have retarded physical and mental development (8, 11). If death occurs within the 1st few days of life,
few unique abnormalities are seen in the brain. With prolonged survival, deficient myelination is
thought to be due to inhibition of enzymes involved in myelin formation, inhibition of amino acid
transport, and inhibition by BCKAs of oxidative phosphorylation (8, 11). Early diagnosis and adequate
nutrition support lead to normal growth and development.

II. Outcome of Nutrition Support


Patients diagnosed ≤ 5 days of age had an IQ (97 ± 13 SD) greater than that of normal siblings or
parents (24). Factors influencing IQ were age at diagnosis, neonatal condition, and long-term
metabolic control (32). Reproductive outcome of a woman with classic MSUD whose blood BCAAs
were controlled by diet was excellent (52).
The first attempt to manage an 8-month old infant with MSUD used pure amino acids totaling
approximately 50 g daily and 1,500 kcal/day. Mineral and vitamin mixtures were also provided.
Plasma concentrations of BCAAs decreased significantly. During the course of the diet trial, length
and weight increased from the 3rd percentile to the 50th percentile (2).
Nutrition support of a neonate with MSUD was subsequently described (2). Protein intake ranged
from 3.5-3.0 g/kg/day between 3 and 8 months of age. Energy intake was about 125 kcal/kg/day. At
birth, the infant was at the 10th percentile for length and weight; during the 1st year of life, length
increased toward the 50th percentile but weight remained at about the 10th percentile. At 55 weeks of
age, the patient had a developmental quotient of 97, which is in the normal range (2).
A number of investigators have reported poor growth in treated children with MSUD (2). Intakes of
both protein and energy by children with MSUD have been reported to be below that of comparable
aged normal children (19) and below RDA (15). Whether failure to thrive is due to the underlying
disease or to dietary deficiency is unclear. However, some investigators reported normal growth in
patients fed adequate protein and energy (2).
Selenium deficiency has been found in treated patients with MSUD who received selenium-free
medical foods (21, 28). B-vitamin deficiencies resulting in anemia, angular stomatitis, and lesions of
the skin occurred in one baby when the B-vitamin mixture was not added to the diet for 6 weeks (2).
Folic acid deficiency was reported in an infant after about 4 months on a synthetic diet (2). Metabolic
acidosis occurred in an infant treated with an amino acid mix in which several amino acids were
provided as the HCl salt (2).

III. Establish Diagnosis


A. The Defect
1. MSUD may result from 1 of several defects in the BCKAD complex.

B. Clinical Screening
1. Concentration ≥ 4 mg LEU/dL by bacterial inhibition assay requires differential diagnosis (11).
2. Infants who develop poor suck, shrill cry, lethargy, and vomiting; followed by loss of normal
tendon reflexes, alternating periods of hypertonia and hypotonia, seizures, loss of
consciousness, irregular respiration, apnea, metabolic acidosis, or maple syrup odor in warm
urine or ear wax should be evaluated (44).

C. Vitamin Responsive
1. Evaluate thiamin responsiveness in patients with any BCKAD complex activity.
2. Prescribe 100-500 mg oral thiamin per day for up to 3 months (8, 14).

76 Maple Syrup Urine Disease © 2001 Ross Products Division


IV. Rationale for Nutrition Support
A. Correct Primary Imbalance in Metabolic Relationships
1. Restrict dietary BCAAs (ILE, LEU, and VAL) to amounts tolerated by patient to maintain
treatment plasma amino acid concentrations.
B. Stabilize Altered Enzyme Protein
1. Supplement with oral thiamin if patient has any BCKAD activity (12, 14).

V. Nutrition Support During Acute Illness or at Diagnosis (20, 53-55)


A. Initiation of Nutrition Support
1. Initiate nutrition support immediately. Do not wait for confirmation of diagnosis.
2. Evaluate plasma concentrations of ILE, LEU, and VAL daily.
B. Patients Without Severe Neurologic Involvement
1. Begin high-energy feeds (120-150 kcal/kg for infants, 80-100 kcal/kg for children, and
40-50 kcal/kg for adults) that supply adequate water (Table 5-1, p 85) (11, 50).
a. Depending on clinical status, feed patient by nipple, nasogastric tube, intravenous
infusion, or combine these methods (44, 45).
1) For nipple or nasogastric feeds, use Ketonex (Table 5-2, p 86).
2) For intravenous feeds via central line, use hypertonic D-glucose and Liposyn ® II
(Appendix 26, p A-28).
3) For intravenous feeds via peripheral line, use isotonic glucose and Liposyn II
(Appendix 26, p A-28).
2. Introduce nutrition support with Ketonex as rapidly as possible.
a. See Table 5-1, p 85, for Recommended Protein, Energy, and Fluid Intakes.
b. See Table 5-2, p 86, for composition of Ketonex.
Warning: Add L-ILE to Ketonex feeds when plasma ILE concentration reaches upper
limit of treatment range (105 µmol/L), usually within 1-3 days of starting
nutrition support (45). Plasma LEU concentrations will NOT decrease to
normal range if intake of either ILE or VAL is deficient.
c. Order L-ILE and L-VAL immediately when nutrition support is initiated.
d. See Table 5-1, p 85, for Recommended ILE Intakes and Appendix 26, p A-28, for source
of L-ILE.
e. Mix weighed amount of L-ILE powder with boiled, cooled water to make known volume
that supplies 10 mg/mL (eg, 1 g L-ILE with enough water to yield 100 mL).
f. Refrigerate in closed container until used. Discard unused mixture after 1 week, if not
frozen.
g. Measure into Ketonex medical food mixture with disposable syringe.
Warning: Patient will develop severe skin and eye lesions if ILE deficiency occurs (16,
26, 33, 51).
3. Add L-VAL (Table 5-1, p 85) to Ketonex feeds when plasma VAL concentration reaches upper
limit of treatment range (318 µmol/L), usually within 2 to 4 days of starting nutrition
support (45).
a. Mix weighed amount of L-VAL powder (Appendix 26, p A-28) with boiled, cooled water to
make known volume that supplies 10 mg/mL (1 g L-VAL powder with enough water to
yield 100 mL).
b. Refrigerate in closed container until used. Discard unused mixture after 1 week, if not
frozen.
c. Measure into Ketonex medical food mixture with disposable syringe.
4. Add LEU (Table 5-1, p 85) to Ketonex feeds when plasma LEU concentration reaches upper
limit of treatment range (185 µmol/L). May require 7-10 days if L-ILE and L-VAL are
supplemented as noted in steps 3 and 4 above (44, 45).
Warning: LEU, the last amino acid to become normal in plasma, remains elevated for
prolonged period if ILE and/or VAL are deficient (10).
a. Use infant formula with iron or whole cow's milk (Table 5-3, p 87), depending on age, to fill
LEU prescription.
1) Determine amounts of ILE and VAL in infant formula or whole cow's milk required to
supply LEU.
© 2001 Ross Products Division Maple Syrup Urine Disease 77
2) Decrease volumes of L-ILE and L-VAL solutions added to medical food mixture by
amount of ILE and VAL in infant formula or whole cow's milk.
3) Use disposable syringe to measure liquid infant formula or whole cow's milk. Weigh
powdered infant formula on scale that reads in grams.
C. Comatose Patients (10, 11)
1. See References 54 and 55 for medical management.
2. Begin BCAA-free parenteral (6) or nasogastric feeding of amino acids and energy within 36 to
48 hours of initiation of dialysis using nitrogen-free (amino acid-free) dialysate.
a. See Table 5-1, p 85, for Recommended Protein and Energy Intakes
b. See Table 5-2, p 86, for Ketonex composition.
3. Begin intravenous infusion of Liposyn II (Appendix 26, p A-28) and 10% D-glucose during
nasogastric feeding, continuing until major neurologic signs subside.
4. When plasma ILE concentration reaches upper limit of treatment range (105 µmol/L), usually
within 1 to 3 days of starting nutrition support, add L-ILE (Table 5-1, p 85) to Ketonex feeds.
a. See Section VB2, p 76.
5. When plasma VAL concentration reaches upper limit of treatment range (318 µmol/L), usually
within 2 to 4 days of starting nutrition support, add L-VAL (Table 5-1, p 85) to Ketonex feeds.
a. See Section VB3, p 76.
6. When plasma LEU concentration reaches upper limit of treatment range (185 µmol/L), add
LEU (Table 5-1, p 85) to Ketonex feeds.
a. See Section VB4, p 76.
7. If parenteral amino acid solutions are indicated, see Appendix 26, p A-28.

VI. Establish Goals of Long-Term Nutrition Support


A. Plasma Amino Acid Concentrations
1. Maintain 2- to 4-hour postprandial (40) plasma concentrations of alanine (ALA), ALLO, and
BCAAs in ranges noted below when measured by quantitative methods (modified from
reference 11), or within normal range for age established by laboratory used.
Amino Acid µmol/L mg/dL
ALA 275 - 450 2.4 - 4.0
ALLO 0-0 0.0 - 0.0
ILE 50 - 105 0.6 - 1.4
LEU 50 - 185 0.6 - 2.4
VAL 130 - 318 1.5 - 3.7
2. In practice, obtaining blood 2 to 4 hours postprandially is not always possible. Acceptable local
standards should be developed if plasma amino acids are evaluated at other times (Practical
Aspects of Nutrition Support, p viii).
B. Growth, Development, and Nutrition Status
1. Support normal growth rates in infants and children and maintain appropriate weight for height
in adults.
2. Support normal development.
3. Maintain normal nutrition status (7, 21, 28).
4. Prevent catabolism.
5. Maintain urine free of branched-chain-ketoacids.

VII. Establish Prescription for Long-Term Nutrition Support


A. ILE, LEU, and VAL (1, 9, 13, 25, 27, 46-48)
1. Prescribe intakes that promote goals of nutrition support.
2. ILE, LEU, and VAL requirements vary widely:
a. From patient to patient, depending on activity of BCKAD complex.
b. In same patient, depending on:
1) Age.
2) Growth rate.
3) Adequacy of energy and protein intakes.
4) State of health.

78 Maple Syrup Urine Disease © 2001 Ross Products Division


3. Lowest values for ILE, LEU, and VAL for each age group listed in Table 5-1, p 85, are
suggested for initiating therapy.
4. Changing requirements of patient are determined by frequent monitoring of:
a. Plasma ILE, LEU, and VAL concentrations.
b. Urine concentrations of branched-chain α-ketoacids.
c. See Section X, Suggested Evaluation of Nutrition Support, p 80.
d. With ILE, LEU, and VAL concentrations in normal range, plasma amino acids must be
measured frequently to prevent deficiency.
Warning: ILE, LEU, and VAL deficiencies result in the following adverse effects:
ILE deficiency (16, 26, 46, 51): Weight loss or no weight gain; redness of
buccal mucosa; fissures at corners of mouth; tremors of extremities;
decreased plasma cholesterol and ILE concentrations; increased plasma
lysine, phenylalanine, serine, tyrosine, and VAL concentrations; and skin
desquamation.
LEU deficiency (48): Loss of appetite, apathy, irritability; weight loss or poor
weight gain; decreased plasma LEU concentration; and increased plasma
ILE, methionine, serine, threonine, and VAL concentrations.
VAL deficiency (47): Poor appetite, drowsiness; excess irritability and crying
in infants; weight loss or decrease in weight gain; and decreased plasma
albumin concentration.
Prolonged exclusion, over-restriction, or imbalance of BCAAs result in
adverse effects (31): Anemia, desquamation of skin, diarrhea, and failure
to thrive in infants.
B. Protein
1. Prescribe, initially, amount greater than Recommended Dietary Allowances (RDAs) (15)
(Table 5-1, p 85).
2. Requirements are greater than RDAs when L-amino acids supply majority of protein
equivalent as a result of:
a. Rapid amino acid absorption (17, 18).
b. Early and high peak of plasma amino acid concentrations after ingestion of meals where
large part of protein is supplied by L-amino acids (17).
c. Rapid catabolism of amino acids (17, 22, 23, 39, 42).
d. Possible decreased total amino acid absorption (34).
Warning: Long-term inadequate protein intake will result in failure to thrive in infants,
poor growth in children, weight loss in adults, low plasma albumin and
transthyretin concentrations, osteopenia, and hair loss.
3. Adequate protein intake that supports normal growth results in greater tolerance to restricted
BCAAs (3).
C. Energy
1. Prescribe amount that should support normal weight gain in infants and children and maintain
appropriate weight for height in adults (Table 5-1, p 85).
2. Requirements vary widely and may be greater than normal when L-amino acids supply
majority of protein equivalent (38).
3. At diagnosis and during metabolic acidosis resulting from infection, energy needs may be 25%
to 40% higher than values listed in Table 5-1, p 85.
Warning: Inadequate energy intake may result in failure to thrive in infants, poor growth
in children, weight loss in adults, depressed tolerance of BCAAs, and
increased concentrations of plasma BCAAs.
D. Fluid
1. Prescribe amount that will supply water requirements (Table 5-1, p 85). Under normal
circumstances, offer minimum of 1.5 mL fluid to neonates and 1.0 mL to children and adults
for each kcal ingested.

© 2001 Ross Products Division Maple Syrup Urine Disease 79


VIII. Fill Prescription
A. LEU
1. Calculate amount of infant formula with iron, beikost, whole cow's milk, or table foods
(Table 5-3, p 87) required to fill LEU prescription.
a. Low-iron infant formula, whole cow's milk, and evaporated milk should not be used as
BCAA source for infants because of low iron content.
2. Measure liquid infant formula and whole cow's milk with disposable syringe. Weigh powdered
infant formula on scale that reads in grams.
3. Add beikost or table foods to gradually displace LEU provided by infant formula after infant is
3 to 4 months old or is developmentally ready.
4. Parents or patients may select any food in prescribed food lists (Table 5-4, p 88) in specified
amounts to fill LEU prescription.
B. ILE and VAL
1. Calculate approximate amounts of ILE and VAL provided by infant formula with iron, beikost,
whole cow's milk, or table foods (Table 5-3, p 87).
2. Subtract amount determined in step B1 from total ILE and VAL prescriptions.
3. Supply any remaining prescribed ILE and VAL as individual pure solutions. If plasma
concentrations of ILE and VAL are in normal range, supplements are not required
(Appendix 26, p A-28).
a. Mix weighed amounts of L-ILE and L-VAL powders with boiled, cooled water to make
known volume of each that supplies 10 mg/mL (eg, 1 g with enough water to yield 100 mL).
b. Refrigerate solutions in separate, closed containers until used. Discard unused
suspensions after 1 week, if not frozen.
c. Measure solutions into medical food mixture with disposable syringe.
C. Protein
1. Calculate amount provided by infant formula with iron, beikost, whole cow's milk, or table
foods (Table 5-3, p 87) required to fill LEU prescription.
2. Subtract amount determined in step C1 from total protein prescription.
3. Supply any remaining prescribed protein with Ketonex (Table 5-2, p 87).
a. Ketonex-1 is for infants and toddlers and Ketonex-2 is for children, adolescents, and adults.
b. Weigh Ketonex powder on scale that reads in grams because of variability of household
measuring equipment (Practical Aspects of Nutrition Support, p vii) and changes in
density during shipping.
c. See Table 5-2 (p 86, footnote 3) for approximate packed weight of Ketonex powder in
level, dry US standard household measures.
D. Energy
1. Calculate energy provided by Ketonex (Table 5-2, p 86) and infant formula with iron, beikost,
whole cow's milk, or table foods (Table 5-3, p 87) required to fill LEU and protein prescriptions.
2. Subtract amount determined in step D1 from total energy prescription.
3. Provide any remaining prescribed energy with Polycose ® Glucose Polymers powder
(23 kcal/Tbsp, 3.8 kcal/g) or liquid (2 kcal/mL) (Appendix 9, p A-9); Pro-Phree ® Protein-Free
Energy Module With Iron, Vitamins & Minerals (Appendix 11, p A-10); sugar (48 kcal/Tbsp); or
Free Foods B (Table 5-2, p 86).
a. Do not use corn syrup or table sugar for infants because of osmolarity they yield (30).
b. Do not use honey for infants because it may contain botulinum toxin (49).
E. Fluid and Mixing Instructions
1. Add sufficient boiled, cooled water to infant formula, Ketonex, and carbohydrate (if needed) to
yield prescribed volume. Tap water may replace boiled, cooled water when preparing Ketonex
for older infants, children, and adults.
2. Mix with sterilized blender at lowest speed for no longer than 3 to 4 seconds. Excess mixing
may destabilize emulsion. Medical food may also be mixed in sterilized, tightly closed
container by shaking vigorously for 10 to 12 seconds.
3. Refrigerate in sterilized, closed containers until used. Discard unused portion 24 hours after
mixing because of nutrient loss.
80 Maple Syrup Urine Disease © 2001 Ross Products Division
4. Do not use terminal sterilization or boil because of Maillard reaction (Practical Aspects of
Nutrition Support, p viii).
5. Warm or cool medical food mixture to room temperature before feeding to infants. Shake well
before feeding.
6. Do not warm medical food mixture for infants in microwave oven. Unevenly heated formula
can burn infants, and steam can make bottles explode.
7. Notify parents or caretakers when they may discontinue using aseptic technique in preparing
medical food mixture for infants.
8. For children and adults, chill Ketonex medical food mixture to improve taste.
F. Diet Guide
1. Provide parents, caretakers, or patient with completed Diet Guide (Appendix 22, p A-24) with
each diet change.
2. Feed young infants 6 to 8 times daily (22, 39).
3. Feed older infants, children, and adults 4 to 6 times daily (22, 39).

IX. Evaluate Adequacy and Safety of Planned Nutrition Support


A. Nutrient Adequacy
1. Determine if diet provides nutrients in amounts prescribed in Section VII, Establish
Prescription for Long-Term Nutrition Support, p 77.
2. Check diet to determine if it supplies Recommended Dietary Intakes (RDIs) of minerals and
vitamins (Appendices 13 and 14, pp A-14 and A-15).
a. See Table 5-2, p 86, for composition of Ketonex and Appendices 4 through 7, pp A-4 to
A-7, for complete nutrient composition of infant formulas.
b. Appendix 23, p A-25, may be used to check adequacy of nutrients if computer program is
not available.
c. If Ketonex mixture provides < 100% of RDIs for infants and < 75% for children and adults,
supplement diet with needed minerals and vitamins if not provided by beikost or table
foods and laboratory test results indicate need. See Appendix 11, p A-10, for composition
of supplements.
B. Osmolarity
1. If concentration of prescribed medical food mixture is > 24 kcal/fl oz, determine if osmolarity
is in acceptable range.
a. Determine osmolarity by laboratory analysis or use mathematical formula given in
Appendix 18, p A-20.
b. Osmolarity per gram of Ketonex is listed in Appendix 19, p A-21.
2. If osmolarity is > 450 mosm/L for neonates, > 750 mosm/L for children, > 1,000 mosm/L for
adults, or greater than tolerated by patient, increase water content of prescribed medical food
mixture and recalculate its osmolarity (29, 43).
C. Potential Renal Solute Load
1. Dehydration will result if renal solute load is greater than renal-concentrating ability of patient.
2. If concentration of medical food mixture prescribed is > 24 kcal/fl oz, estimate its potential
renal solute load.
a. This step is important to prevent dehydration of infants who may have renal-concentrating
capacity as low as 600 mosm/L.
b. Upper limit of renal solute load for neonates is approximately 1,100 mosm/L (41).
3. A method for estimating potential renal solute load is given in Appendix 20, p A-22.
4. If potential renal solute load is excessive, increase water content of medical food mixture and
recalculate.

X. Suggested Evaluation of Nutrition Support


A. Plasma ALA, ALLO, and BCAAs (40)
1. Initial.
a. Evaluate daily by quantitative methods until plasma concentrations stabilize and
approximate BCAA requirements are known.

© 2001 Ross Products Division Maple Syrup Urine Disease 81


2. Ongoing.
a. Use bacterial inhibition assay for blood LEU evaluation - from state laboratory if available.
b. Evaluate blood LEU concentration twice weekly by bacterial inhibition assay and twice
monthly by quantitative methods until patient is 6 months old.
c. From 6 months onward, evaluate blood LEU concentration weekly by bacterial inhibition
assay and monthly by quantitative method.
3. Unacceptable amino acid concentrations.
a. If plasma ILE, LEU, or VAL concentration is not detected and patient has ingested full
prescription:
1) Increase prescribed amount of undetected amino acid(s) by 25% and reevaluate
plasma concentrations in 3 days.
2) If plasma ILE, LEU, or VAL concentration continues undetected, repeat above process
until value is in treatment range.
b. If plasma ILE concentration is < 50 µmol/L, plasma LEU concentration is < 50 µmol/L, or
plasma VAL concentration is < 95 µmol/L, and patient has ingested full prescription:
1) Increase prescribed amount for amino acid(s) that is low by 5% to 10% and
reevaluate plasma concentration in 1 week.
2) If plasma ILE, LEU, or VAL concentration continues low, repeat above process until
amino acid(s) concentration is in treatment range.
c. If plasma ILE concentration is > 105 µmol/L, plasma LEU concentration is > 185 µmol/L,
or plasma VAL concentration is > 318 µmol/L, and patient is not ill and has not ingested
more or less protein and energy than prescribed:
1) Decrease prescribed amount of elevated amino acid(s) by 5% to 10% and reevaluate
plasma BCAA concentrations in 1 week.
2) If plasma ILE, LEU, or VAL concentration continues high, repeat above process until
amino acid(s) concentration is in treatment range.
B. Urine Ketoacids by Ketostix ® or Dinitrophenylhydrazine (DNPH)
1. Evaluate once daily to 6 months of age and twice weekly thereafter.
2. If patient is ill, evaluate daily.
3. Urine should be free of ketoacids at all times (negative Ketostix or DNPH result).
4. If urine contains ketoacids (positive Ketostix or DNPH result):
a. Immediately obtain blood sample for evaluation of LEU by bacterial inhibition assay or
evaluation of BCAAs by quantitative methods.
b. Brief metabolic physician immediately on patient's illness.
C. Protein Status
1. Evaluate plasma transthyretin concentration every 3 months until 1 year of age and twice
yearly thereafter (Appendix 17, p A-18, for standards).
a. Plasma transthyretin concentrations provide a more reliable and rapid indication of protein
status than plasma albumin concentrations.
b. Plasma albumin concentrations may be in the normal range when plasma transthyretin
concentrations show a clear deficiency (4).
2. If plasma transthyretin concentration is below standard:
a. Increase prescribed protein by 5% to 10% and reevaluate plasma transthyretin
concentration in 1 month. If ILE, LEU and VAL concentrations are in treatment range, use
Ketonex to increase protein.
b. If plasma transthyretin concentration continues below standard, repeat above process until
value is in normal range.
D. Iron Status
1. Plasma ferritin concentration.
a. Evaluate at 6, 9, and 12 months of age and every 6 months thereafter (Appendix 17,
p A-18, for standards).
b. If plasma ferritin concentration is below standard:
1) Increase iron intake to 4 mg/kg of body weight with supplements (ferrous sulfate).
2) Evaluate plasma ferritin concentration monthly on increased iron intake.
3) Continue iron supplements until plasma ferritin concentration is in normal range.

82 Maple Syrup Urine Disease © 2001 Ross Products Division


2. Complete blood count and differential.
a. Hemoglobin and hematocrit concentrations and differential should be evaluated at 6, 9,
and 12 months of age and every 6 months thereafter (Appendix 17, p A-18, for
standards).
E. Growth Status
1. Length/height and weight.
a. Measure monthly to 1 year and every 3 months thereafter until final growth is achieved.
Plot measurements on NCHS growth charts.
b. Maintain length/height and weight between 10th and 90th percentiles. Some normal
infants, children, and adults will fall above or below these percentiles.
2. If length/height or weight falls below usual growth channel:
a. Increase protein and energy prescriptions by 5% to 10% and remeasure after 1 month.
b. If length/height or weight remains low, repeat above process until usual growth channel is
achieved.
F. Nutrient Intake
1. Maintain records of food intake for 3 days immediately before each blood test (Appendices 24
and 25, pp A-26 and A-27).
2. Evaluate intakes of BCAAs, protein, and energy before each blood test.
3. Evaluate mineral and vitamin intakes after each diet change.
a. See Table 5-2, p 86, for composition of Ketonex and Appendices 4 through 7, pp A-4 to
A-7, for complete nutrient composition of infant formulas.
b. Appendix 23, p A-25, may be used to check adequacy of nutrients if computer program is
not available.
c. See Appendix 28, p A-29, for information about ordering software for diet evaluation.
G. Clinical Summary
1. A summary record of growth, laboratory, and nutrient intake data is useful for patient
management (Table 5-5, p 100).

XI. Sample Prescriptions


A. Example 1
Establish and fill prescription for newborn weighing 3.3 kg using Recommended Daily Nutrient
Intakes from Table 5-1, p 85, and nutrient contents from Tables 5-2 and 5-3, pp 86 and 87.
1. Establish prescription.
ILE 60 mg/kg x 3.3 kg = 198 mg
LEU 80 mg/kg x 3.3 kg = 264 mg
VAL 70 mg/kg x 3.3 kg = 231 mg
Protein 3.5 g/kg x 3.3 kg = 11.6 g
Energy 140 kcal/kg x 3.3 kg = 462 kcal
Fluid 150 mL/kg x 3.3 kg = 495 mL
2. Fill prescription.
Medical Food Mixture Measure ILE LEU VAL Protein Energy
(mg) (mg) (mg) (g) (kcal)
Ketonex-1 60.0 g 0 0 0 9.0 288
Similac With Iron RTF 183.0 mL 137 264 152 2.6 124
ILE solution1 6.1 mL 61 0 0 0.0 0
VAL solution1 7.9 mL 0 0 79 0.0 0
Polycose Liquid 25.0 mL 0 0 0 0.0 50
Add water to make 569 mL (19 fl oz).

Total per day 198 264 231 11.6 462


Total per kg 60 80 70 3.5 140
Approximate osmolarity of medical food mixture is < 400 mosm/L. Estimated potential renal solute load
is < 100 mosm.
1
Solution is 10 mg/mL.

© 2001 Ross Products Division Maple Syrup Urine Disease 83


B. Example 2
Establish and fill prescription for 2-year-old child weighing 13 kg using Recommended Daily
Nutrient Intakes from Table 5-1, p 85, and nutrient contents from Tables 5-2 and 5-3, pp 86 and 87.
1. Establish prescription.
ILE 325 mg/day
LEU 535 mg
VAL 400 mg
Protein 30 g
Energy 1,300 kcal
Fluid 1,300 mL
2. Fill prescription.
Medical Food Mixture Measure ILE LEU VAL Protein Energy
(mg) (mg) (mg) (g) (kcal)
Ketonex-2 71 g 0 0 0 21.3 291
1
ILE solution 1 mL 10 0 0 0.0 0
Add water to make 710 mL (24 fl oz). Offer additional fluid ad libitum daily.

Food List Servings


Breads/Cereals 9 162 315 225 4.5 270
Fats 6 42 60 42 0.6 420
Fruits 4 68 100 88 2.4 300
Vegetables 2 44 60 48 1.2 30
Total per day 326 535 403 30.0 1,311
Approximate osmolarity of medical food mixture is < 550 mosm/L.
1
Solution is 10 mg/mL.

C. Example 3
Establish and fill prescription for 15-year-old boy weighing 60 kg using Recommended Daily
Nutrient Intakes from Table 5-1, p 85 , and nutrient contents from Tables 5-2 and 5-3, pp 86 and
87.
1. Establish prescription.
ILE 330 mg/day
LEU 550 mg
VAL 410 mg
Protein 55 g
Energy 2,800 kcal
Fluid 2,800 mL

84 Maple Syrup Urine Disease © 2001 Ross Products Division


2. Fill prescription.
Medical Food Mixture Measure ILE LEU VAL Protein Energy
(mg) (mg) (mg) (g) (kcal)
Ketonex-2 155 g 0 0 0 46.5 708
Sugar 96 g (1/2 cup) 0 0 0 0.0 384
ILE solution 1 1.5 mL 15 0 0 0.0 0
VAL solution 1 1.4 mL 0 0 14 0.0 0
Add water to make 1100 mL (36 fl oz). Offer additional fluid ad libitum daily.

Food List Servings


Breads/Cereals 9 162 315 225 4.5 270
Fats 9 63 90 63 0.9 630
Fruits 2 34 50 44 1.2 150
Vegetables 2 44 60 48 1.2 30
Free Foods A 4 12 20 16 0.4 200
Free Foods B 8 0 0 0 0.0 440
Total per day 326 550 410 54.7 2,812
Approximate osmolarity of medical food mixture is < 1,000 mosm/L.

XII. Nutrition Support During Febrile Illness or Following Trauma


A. Rationale
1. In normal persons, febrile illness and trauma are accompanied by catabolism of body protein.
2. Well-nourished patients with MSUD respond to infection and trauma as do normal persons.
3. Febrile illnesses and trauma are life-threatening if not diagnosed and treated promptly.
B. Management of Nutrition Support
1. See Section V, Nutrition Support During Acute Illness or at Diagnosis, p 76.

© 2001 Ross Products Division Maple Syrup Urine Disease 85


TABLE 5-1. Recommended Daily Nutrient Intakes (Ranges) for Infants, Children, and Adults With MSUD

Age Nutrient
1,2 1 1,3
ILE LEU VAL Protein 4 Energy 4 Fluid 5
(mg/kg) (mg/kg) (mg/kg) (g/kg) (kcal/kg) (mL/kg)
Infants
0 to < 3 mo 36 - 60 60 - 100 42 - 70 3.50 - 3.00 120 (145 - 95) 150 - 125
3 to < 6 mo 30 - 50 50 - 85 35 - 60 3.50 - 3.00 115 (145 - 95) 160 - 130
6 to < 9 mo 25 - 40 40 - 70 28 - 50 3.00 - 2.50 110 (135 - 80) 145 - 125
9 to < 12 mo 18 - 33 30 - 55 21 - 38 3.00 - 2.50 105 (135 - 80) 135 - 120

(mg/day) (mg/day) (mg/day) (g/day) (kcal/day) (mL/day)


Girls and Boys
1 to < 4 yr 165 - 325 275 - 535 190 - 400 ≥ 30.0 1,300 ( 900 - 1800) 900 - 1,800
4 to < 7 yr 215 - 420 360 - 695 250 - 490 ≥ 35.0 1,700 (1300 - 2300) 1,300 - 2,300
7 to < 11 yr 245 - 470 410 - 785 285 - 550 ≥ 40.0 2,400 (1650 - 3300) 1,650 - 3,300

Women
11 to < 15 yr 330 - 445 550 - 740 385 - 520 ≥ 50.0 2,200 (1500 - 3000) 1,500 - 3,000
15 to < 19 yr 330 - 445 550 - 740 385 - 520 ≥ 55.0 2,100 (1200 - 3000) 1,200 - 3,000
≥ 19 yr 300 - 450 400 - 620 420 - 650 ≥ 60.0 2,100 (1400 - 2500) 1,400 - 2,500

Men
11 to < 15 yr 325 - 435 540 - 720 375 - 505 ≥ 55.0 2,700 (2000 - 3700) 2,000 - 3,700
15 to < 19 yr 425 - 570 705 - 945 495 - 665 ≥ 65.0 2,800 (2100 - 3900) 2,100 - 3,900
≥ 19 yr 575 - 700 800 - 1100 560 - 800 ≥ 70.0 2,900 (2000 - 3300) 2,000 - 3,300
1
From references 1, 2, 9, 11, 25, 27, 35. Initiate prescription as noted in Section V, p 76. After 2 to 3 days of BCAA-
free feeds, begin diet with lowest recommended intake for age. Modify prescription based on frequently obtained
plasma values and growth in infants and children and frequently obtained plasma values and weight maintenance in
adults.
2
In general, ILE should be approximately 60% of LEU prescription.
3
In general, VAL should be approximately 70% of LEU prescription.
4
From reference 15.
5
From reference 5. Under normal circumstances, offer minimum of 1.5 mL fluid to neonates and 1.0 mL fluid to
children and adults for each kcal ingested. Fluid intake should be higher during illness to enhance urinary ketoacid
excretion.

86 Maple Syrup Urine Disease © 2001 Ross Products Division


TABLE 5-2. Nutrient Composition of KETONEX ®-1 1, 3 and KETONEX ®-2 2, 3,
Nutrient Ketonex-1 Ketonex-2
(per 100 g pwd) (per g protein equiv) (per 100 g pwd) (per g protein equiv)
Energy, kcal 480 32 410 13.7
Protein equiv, g 15.00 1.000 30.00 1.000
Nitrogen, g 2.40 0.160 4.80 0.160
Amino acids, g 14.45 0.963 28.90 0.963
Cystine, g 0.15 0.010 0.30 0.010
Histidine, g 0.42 0.028 0.84 0.028
Isoleucine, g trace 0.000 trace 0.000
Leucine, g trace 0.000 trace 0.000
Lysine, g 1.00 0.067 2.00 0.067
Methionine, g 0.30 0.020 0.60 0.020
Phenylalanine, g 0.88 0.059 1.76 0.059
Threonine, g 0.70 0.047 1.40 0.047
Tryptophan, g 0.17 0.011 0.34 0.011
Tyrosine, g 0.89 0.059 1.78 0.059
Valine, g trace 0.000 trace 0.000
Other Nitrogen-Containing Compounds
Carnitine, mg 100 6.67 200 6.67
Taurine, mg 40 2.67 50 1.67
Carbohydrate, g 53.0 3.53 35 1.17
Fat, g 21.7 1.45 14 0.47
4 5
Linoleic acid, g 2.00 0.133 1.50 0.050
α-Linolenic acid, g
6 7
0.36 0.024 0.17 0.006
Minerals
Calcium, mg 575 38 880 29
Chloride, mg/mEq 325/9.17 21.7/0.61 940/26.51 31.33/0.88
Chromium, µg 11 0.73 27 0.90
Copper, mg 1.10 0.073 1.00 0.033
Iodine, µg 65 4.33 100 3.33
Iron, mg 9.0 0.60 13 0.43
Magnesium, mg 50 3.33 225 7.50
Manganese, mg 0.50 0.033 0.80 0.027
Molybdenum, µg 12 0.80 30 1.00
Phosphorus, mg 400 27 760 25
Potassium, mg/mEq 675/17.26 45/1.15 1,370/35.04 45.7/1.17
Selenium, µg 20 1.33 35 1.17
Sodium, mg/mEq 190/8.26 12.7/0.55 880/38.28 29.3/1.28
Zinc, mg 8.0 0.53 13 0.43
Vitamins
A, µg RE 420 28 660 22
D, µg 7.50 0.50 7.50 0.25
E, mg α-TE 10.10 0.67 12.10 0.40
K, µg 50 3.33 60 2.00
Ascorbic acid, mg 50 3.33 60 2.00
Biotin, µg 65 4.33 100 3.33
B6, mg 0.75 0.050 1.30 0.043
B12, µg 4.90 0.327 5.00 0.167
Choline, mg 80 5.33 100 3.33
Folate, µg 230 15 450 15
Inositol, mg 40 2.67 70 2.33
Niacin equiv, mg 12.80 0.850 21.7 0.72
Pantothenic acid, mg 6.90 0.460 8.00 0.267
Riboflavin, mg 0.90 0.060 1.80 0.060
Thiamin, mg 1.90 0.127 3.25 0.108
1 2
Designed for infants and toddlers. Designed for children, adolescents, and adults.
3
Approximate packed weight of Ketonex in level, dry US standard household measures:
Ketonex-1 Ketonex-2
1 Tbsp = 7g 8g
1/4 cup = 26 g 32 g
1/3 cup = 35 g 41 g
1/2 cup = 53 g 61 g
1 cup = 105 g 117 g
4 5
Analytical data at manufacture = 4.32 g/100 g powder. Analytical data at manufacture = 2.66 g/100 g powder.
6 7
Analytical data at manufacture = 0.40 g/100 g powder. Analytical data at manufacture = 0.28 g/100 g powder.

© 2001 Ross Products Division Maple Syrup Urine Disease 87


TABLE 5-3. Serving Lists for BCAA-Restricted Diets: Average Nutrient Content per Serving1

Food List Nutrient


ILE LEU VAL Protein Energy
(mg) (mg) (mg) (g) (kcal)
Breads/Cereals 18 35 25 0.5 30
Fats 7 10 7 0.1 70
Fruits 17 25 22 0.6 75
Vegetables 22 30 24 0.6 15
Free Foods A 3 5 4 0.1 50
Free Foods B 0 0 0 0.0 55
Alimentum ® Protein-Hydrolysate Formula With Iron, Ready to Feed, 100 mL 108 173 140 1.86 68
2

Isomil Soy Formula With Iron, Ready to Feed, 100 mL 2 74 135 76 1.66 68
Similac With Iron Infant Formula, Ready to Feed, 100 mL 2 75 144 83 1.40 68
Whole cow's milk, 100 mL 3 205 332 227 3.39 63
1
Reference 11.
2
See Appendices 4 through 7, pp A-4 to A-7, for complete nutrient composition of infant formulas.
3
From reference 37. See Appendix 8, p A-8, for complete nutrient composition.

88 Maple Syrup Urine Disease © 2001 Ross Products Division


TABLE 5.4. Equivalency Lists for BCAA-Restricted Diets: Gerber ® Baby Foods (Beikost) 1

Food Weight Approximate ILE LEU VAL Protein Energy


(g) Measure (mg) (mg) (mg) (g) (kcal)
For greatest accuracy, weigh food on scale that reads in grams. All measures are level.

BREADS AND CEREALS

Baked Finger Snacks


Animal crackers, cinnamon graham 8 1 cracker 17 34 20 0.5 35
Banana cookies 8 1 cookie 19 38 23 0.5 35
Strawberry fruit bars 9 1 bar 20 37 23 0.5 35
Veggie crackers 8 11 crackers 20 37 23 0.5 35

Cereals, Dry
Barley 4 1 Tbsp 18 35 24 0.5 15
Mixed 5 1 Tbsp + 1 tsp 16 38 21 0.5 19
Oatmeal 3 1 Tbsp 17 33 23 0.5 12
Oatmeal/banana 4 1 Tbsp 18 34 23 0.5 15
Oatmeal/mixed fruit 4 1 Tbsp 16 35 22 0.4 17
Rice 5 1 Tbsp + 1 tsp 18 34 24 0.4 19
Rice/apple bits 6 1 Tbsp + 2 tsp 16 33 21 0.4 25
Rice/apples 8 1 Tbsp + 2 tsp 16 35 23 0.5 31
Rice/banana 6 1 Tbsp + 2 tsp 15 33 21 0.4 23
Rice/mixed fruit 6 1 Tbsp + 2 tsp 16 35 23 0.4 24

Cereals, Jarred
1st Foods ®
Oatmeal 27 2 Tbsp 18 35 26 0.5 15
2nd Foods ®
Mixed/applesauce/bananas 55 3 Tbsp + 2-1/2 tsp 19 35 26 0.6 47
Oatmeal/applesauce/bananas 38 2 Tbsp + 2 tsp 18 35 24 0.5 32
Rice/applesauce 52 3 Tbsp + 2 tsp 17 35 23 0.4 47
3rd Foods ®
Mixed/apples/bananas 44 3 Tbsp 16 35 21 0.5 33
Oatmeal/apples/cinnamon 41 2 Tbsp + 2-1/3 tsp 16 35 22 0.5 27

Vegetables
1st Foods ®
Peas 16 1 Tbsp 21 36 26 0.5 8
Potatoes 67 1/4 cup + 2 tsp 21 35 34 0.7 31
Sweet potatoes 69 1/4 cup + 2-1/2 tsp 21 35 33 0.8 45
2nd Foods ®
Creamed corn 20 1 Tbsp + 1 tsp 14 35 18 0.4 13
Garden vegetables 24 1 Tbsp + 2 tsp 19 36 24 0.6 9
Mixed vegetables 41 2 Tbsp + 2-1/2 tsp 19 35 27 0.6 19
Peas 17 1 Tbsp + 1/2 tsp 21 36 26 0.5 8
Sweet potatoes 61 1/4 cup + 1 tsp 21 35 30 0.6 38
3rd Foods ®
Green beans/rice 42 3 Tbsp 18 35 23 0.5 18
Peas/rice 20 1 Tbsp + 1 tsp 20 35 24 0.4 10
Sweet potatoes 49 3 Tbsp + 1-1/4 tsp 23 35 32 0.7 39

FRUITS/JUICES

Mixed fruit juice 125 4 fl oz 13 24 18 0.3 70


Orange juice 188 6 fl oz 14 25 22 1.4 92
Pear juice 156 5 fl oz 13 24 16 0.5 76
1st Foods ®
Bananas 27 2 Tbsp 7 25 16 0.3 27
Peaches 100 7 Tbsp 14 25 19 0.7 43
Pears 132 1/2 cup + 1 Tbsp 13 25 17 0.5 75

© 2001 Ross Products Division Maple Syrup Urine Disease 89


Food Weight Approximate ILE LEU VAL Protein Energy
(g) Measure (mg) (mg) (mg) (g) (kcal)
For greatest accuracy, weigh food on scale that reads in grams. All measures are level.
Prunes 119 1/2 cup + 1 tsp 14 25 20 1.2 120
2nd Foods ®
Apricot/mixed fruit 100 7 Tbsp 13 26 19 0.6 60
Bananas 27 2 Tbsp 7 25 16 0.3 24
Bananas/apples/pears 36 2 Tbsp + 1-1/2 tsp 9 25 15 0.3 30
Hawaiian delight 25 1 Tbsp + 2-1/4 tsp 13 25 16 0.3 21
Peaches 100 7 Tbsp 14 25 19 0.7 64
Pears 125 1/2 cup + 2 tsp 15 25 20 0.6 92
Pear/pineapple 139 1/2 cup + 1-1/2 Tbsp 14 25 18 0.6 76
Plums/apple 156 1/2 cup + 3 Tbsp 14 25 19 0.6 109
Prunes/apple 119 1/2 cup + 1 tsp 13 25 15 0.7 92
3rd Foods ®
Apricots/mixed fruit 100 7 Tbsp 13 26 19 0.6 60
Bananas 27 2 Tbsp 7 25 16 0.3 24
Banana/pineapple 34 2 Tbsp + 1 tsp 8 25 15 0.3 26
Banana/strawberry 34 2 Tbsp + 1 tsp 8 25 16 0.3 32
Hawaiian delight dessert 25 1 Tbsp + 2-1/4 tsp 13 25 16 0.3 21
Peaches 125 1/2 cup + 2 tsp 15 25 20 0.9 80
Pears 125 1/2 cup + 2 tsp 15 25 20 0.6 92

Fruit/Vegetable Juices
Apple/sweet potato 179 5-3/4 fl oz 16 25 23 0.5 93
Graduates™, Fruit Dices
Peaches 192 ND 13 25 19 1.0 94
Pears 208 ND 12 25 19 0.6 112
Tender Harvest™
Apple/sweet potato 156 1/2 cup + 3 Tbsp 14 25 19 0.5 98
Banana/oatmeal/peach 28 2 Tbsp 10 25 16 0.3 21
Pears/winter squash 58 1/4 cup 15 25 19 0.6 30
Tropical fruit blend 58 1/4 cup 9 25 17 0.3 43

VEGETABLES

1st Foods ®
Carrots 91 6 Tbsp + 1 tsp 20 30 27 0.8 32
Green beans 30 2 Tbsp 15 30 20 0.4 9
Squash 55 4 Tbsp 23 30 21 0.4 19
2nd Foods ®
Carrots 91 6 Tbsp + 1 tsp 20 30 27 0.7 27
Green beans 37 2 Tbsp + 1-1/2 tsp 16 30 21 0.5 6
Squash 62 1/4 cup + 1 tsp 19 30 21 0.5 38
3rd Foods ®
Carrots 77 1/3 cup + 1 tsp 20 30 27 0.6 22
Squash 81 1/3 cup + 2 tsp 18 30 21 0.6 27
Graduates™, Vegetable Dices
Carrots 60 ND 17 30 23 0.4 14
Green beans 29 ND 17 30 21 0.3 7
Mixed vegetables 19 ND 13 30 16 0.4 9
Tender Harvest™
Butternut squash/corn 29 2 Tbsp 13 30 16 0.6 14
Garden carrots/brown rice 73 1/3 cup 17 30 24 0.7 34
Green beans/potatoes 16 1 Tbsp 16 30 20 0.4 10
Spring garden vegetables 41 2 Tbsp + 2-1/3 tsp 18 30 23 0.6 14

FREE FOODS A

Apple juice 94 3 fl oz 3 5 3 0.1 47

90 Maple Syrup Urine Disease © 2001 Ross Products Division


Food Weight Approximate ILE LEU VAL Protein Energy
(g) Measure (mg) (mg) (mg) (g) (kcal)
For greatest accuracy, weigh food on scale that reads in grams. All measures are level.
Apple/banana juice 39 1-1/4 fl oz 3 5 3 0.1 21
Apple/carrot juice 71 2-1/3 fl oz 4 5 6 0.1 30
Apple/cherry juice 62 2 fl oz 3 5 4 0.1 31
Apple/cranberry juice 62 2 fl oz 3 5 4 0.1 27
Apple/grape juice 125 4 fl oz 3 5 7 0.1 64
Apple/prune juice 62 2 fl oz 3 5 4 0.1 34
Fruit medley tropical dessert 55 3 Tbsp + 2-1/2 tsp 3 5 4 0.1 35
Guava tropical dessert 50 3 tbsp + 1-1/2 tsp 3 5 4 0.1 35
Mango tropical dessert 31 2 Tbsp + 1/2 tsp 3 5 4 0.1 23
Papaya tropical dessert 64 1/4 cup + 1-1/2 tsp 3 5 4 0.1 40
White grape juice 78 2-1/2 fl oz 3 5 4 0.2 54
1st Foods ®
Applesauce 43 3 Tbsp 3 5 4 0.1 23
2nd Foods ®
Apple/blueberry 45 3 Tbsp 3 5 4 0.1 22
Applesauce 29 2 Tbsp 3 5 3 0.1 14
Fruit medley dessert 43 3 Tbsp 3 5 4 0.2 35
Peach cobbler 31 2 Tbsp + 1/3 tsp 2 5 3 0.2 24
3rd Foods ®
Fruit salad 28 2 Tbsp 3 5 4 0.1 19
Peach cobbler 26 1 Tbsp + 2-1/2 tsp 2 5 3 0.2 23
Plums/apples 29 2 Tbsp 3 5 3 0.1 21
Graduates ® Beverages
Apple 93 3 fl oz 3 5 3 0.1 42
Apple banana 39 1-1/4 fl oz 3 5 3 0.1 20
Apple grape 124 4 fl oz 3 5 7 0.1 58
Berry punch 124 4 fl oz 3 5 7 0.1 63
Fruit punch 124 4 fl oz 3 5 7 0.1 60

Fruit Dices
Graduates™
Apples 71 ND 2 5 4 0.1 34
Mixed fruit 50 ND 3 5 4 0.1 25
Tender Harvest ®
Pear/wild blueberry 31 2 Tbsp + 1/2 tsp 2 5 3 0.1 9
1
Prepared from 1998 and 1999 data from Gerber Products Co, Fremont, MI 49413.
ND = no data.

Weights and Measures: Except for Dry Cereals and Food Dices, the following weights apply:
Level Level
1 tsp = 1/3rd Tbsp = 4.8 g
1 Tbsp = 1/16th cup = 14.3 g
1/4 cup = 4 Tbsp = 57.2 g
1/3 cup = 5-1/3rd Tbsp = 76.2 g
1/2 cup = 8 Tbsp = 114.3 g
2/3 cup = 10 2/3rd Tbsp = 152.5 g
3/4 cup = 12 Tbsp = 171.5 g
1 cup = 16 Tbsp = 228.6 g

© 2001 Ross Products Division Maple Syrup Urine Disease 91


1
TABLE 5-4. Equivalency Lists for BCAA-Restricted Diets: Table Foods

Food Weight Approximate ILE LEU VAL Protein Energy


(g) Measure (mg) (mg) (mg) (g) (kcal)
For greatest accuracy, weigh food on scale that reads in grams. All measures are level.

BREADS AND CEREALS

Cereals, Cooked. Measure after cooking


Corn Grits, regular and quick 15 1 Tbsp 8 32 11 0.2 9
Cream of Rice ® 46 3 Tbsp 7 33 26 0.4 24
Cream of Wheat ®
instant 25 1 Tbsp + 2 tsp 20 35 22 0.4 16
quick 30 2 Tbsp 20 34 22 0.4 16
regular 31 2 Tbsp 21 36 23 0.5 17
Farina ® 29 2 Tbsp 18 32 20 0.4 14
Malt-o-Meal ® 15 1 Tbsp 17 29 22 0.4 9
Oats, regular, quick, and instant 15 1 Tbsp 17 29 22 0.4 9
Ralston ® 20 1 Tbsp + 1 tsp 20 34 22 0.4 11
Wheatena ® 23 1 Tbsp + 1-1/2 tsp 21 36 23 0.5 13
Whole Wheat Hot Natural 20 1 Tbsp 18 31 20 0.4 12

Cereals, Ready To Eat


Alpha-Bits ® 5 3 Tbsp 18 35 23 0.4 21
Apple Jacks ® 5 1/4 cup 17 35 22 0.4 16
100% Bran ® 5 1 Tbsp + 1/2 tsp 19 37 28 0.6 13
Bran Chex ® 3 1 Tbsp 12 34 16 0.3 10
40% Bran Flakes (Post ®) 5 1 Tbsp + 1-1/2 tsp 21 35 28 0.6 16
Cap'n Crunch ® 5 2 Tbsp 10 30 13 0.2 20
Cap'n Crunch's ® Crunch Berries 5 2 Tbsp 10 29 12 0.2 18
Cap'n Crunch's ® Peanut Butter 5 2 Tbsp 13 32 16 0.3 19
Cheerios ® 3 2 Tbsp 20 33 25 0.4 11
Cinnamon Toast Crunch ® 17 1/4 cup + 3 Tbsp 18 36 21 0.6 70
Cocoa Krispies ® 8 1/4 cup 22 35 27 0.4 31
Cocoa Pebbles ® 9 1/4 cup 22 35 27 0.4 37
Cocoa Puffs ® 8 1/4 cup 10 35 14 0.3 31
Cookie Crisp ® 7 1/4 cup 14 35 18 0.4 28
Corn Bran ® 4 1 Tbsp + 1-1/2 tsp 13 38 16 0.3 16
Corn Chex ® 3 2 Tbsp 8 35 11 0.2 12
Corn Flakes ® 3 2 Tbsp 9 35 11 0.2 11
Crispy Rice ® 7 1/4 cup 8 36 28 0.4 28
Crispy Wheat'n Raisins ® 8 3 Tbsp 21 37 26 0.5 28
Froot Loops ® 6 3 Tbsp 14 35 17 0.3 21
Frosted Rice Krinkles 9 1/4 cup 22 35 28 0.4 35
Frosted Rice Krispies ® 9 1/4 cup 22 35 26 0.4 34
Fruity Pebbles™ 11 1/3 cup 23 35 28 0.4 43
Golden Grahams ® 5 2 Tbsp + 3/4 tsp 12 35 15 0.3 19
Grape Nuts Flakes ® 5 2 Tbsp + 1 tsp 21 36 26 0.5 18
Honeycomb ® 5 3 Tbsp + 1-1/4 tsp 11 35 14 0.3 18
Honey Nut Cheerios ® 3 1 Tbsp + 2/3 tsp 14 39 19 0.3 11
Honey Nut Corn Flakes ® 5 2 Tbsp 11 32 14 0.3 19
King Vitaman ® 5 1/4 cup 12 35 15 0.3 21
Kix ® 3 2 Tbsp + 1-1/2 tsp 11 34 14 0.3 12
Lucky Charms ® 5 3 Tbsp 21 35 27 0.5 19
Nutri-Grain ®
corn 3 1 Tbsp 8 36 11 0.2 10
rye 6 2 Tbsp + 1 tsp 22 34 27 0.5 21
wheat 5 2 Tbsp 20 35 23 0.5 20
Product 19 ® 3 1 Tbsp + 1-1/4 tsp 11 34 14 0.3 11
Quisp ® 6 3 Tbsp + 1-1/2 tsp 12 36 15 0.3 23
Raisin Bran (Post ®) 7 2 Tbsp 22 38 28 0.6 22
Rice Chex ® 8 1/3 cup 7 34 26 0.4 31

92 Maple Syrup Urine Disease © 2001 Ross Products Division


Food Weight Approximate ILE LEU VAL Protein Energy
(g) Measure (mg) (mg) (mg) (g) (kcal)
For greatest accuracy, weigh food on scale that reads in grams. All measures are level.
Rice Krispies ® 6 1/4 cup 22 35 30 0.5 24
Rice, puffed 7 1/2 cup 23 37 29 0.5 28
Special K ® 2 1 Tbsp + 1/2 tsp 20 32 23 0.4 8
Sugar Frosted Flakes ® 5 1 Tbsp + 3/4 tsp 9 35 11 0.2 17
Sugar Pops ® 5 2 Tbsp + 2 tsp 9 36 12 0.2 18
Sugar Smacks ® 7 3 Tbsp 21 36 24 0.5 26
Super Sugar Crisp ® 8 1/4 cup 23 38 26 0.5 31
Team ® 7 1/4 cup 20 36 25 0.4 26
Toasties ® 3 2 Tbsp 9 34 12 0.2 11
Total ® 4 2 Tbsp + 1/2 tsp 18 31 22 0.4 16
Trix ® 4 2 Tbsp + 1-1/2 tsp 10 33 13 0.2 17
Wheat Chex ® 5 1 Tbsp + 2 tsp 20 34 23 0.5 18
Wheat
puffed 3 1/4 cup 19 32 21 0.5 11
shredded 5 1/5 large biscuit 20 36 25 0.5 17
Wheaties ® 5 3 Tbsp 20 36 26 0.5 19

Grains
Corn, cooked
cream style 16 1 Tbsp 11 30 16 0.3 11
whole kernel 10 1 Tbsp 14 37 20 0.3 11
Rice, prepared
brown 18 1 Tbsp + 2 tsp 18 35 26 0.5 22
fried 14 1 Tbsp 17 29 22 0.4 18
Rice-A-Roni ® 16 1 Tbsp 17 32 21 0.5 20
white
long grain 16 1 Tbsp + 2 tsp 18 36 26 0.4 21
glutinous 21 1-1/2 Tbsp 18 35 25 0.4 20
medium grain 18 1-1/2 Tbsp 19 35 26 0.4 23

Pasta, cooked
Macaroni 10 1 Tbsp + 3/4 tsp 18 35 20 0.5 15
Noodles 13 1 Tbsp + 1/2 tsp 27 36 32 0.5 17
Ramen ® noodles 10 1 Tbsp 18 35 20 0.6 22
Spaghetti 9 1 Tbsp 16 31 18 0.5 14

Tubers
Potatoes, sweet
baked, in skin, mashed 25 1/4 small 25 37 33 0.5 30
candied or canned in syrup 49 1/4 cup 22 32 28 0.4 67
Potatoes, white
baked or boiled in skin 29 3 Tbsp 22 33 31 0.5 25
French fries (1/2" x 1/2" x 2") 15 3 fries 26 37 31 0.6 47
hash browns, frozen, cooked 20 2 Tbsp 27 37 31 0.6 43
Tater Tots ® 28 3 pieces 25 34 29 0.6 46
Yams, baked or boiled. mashed 34 1/4 cup 17 32 20 0.5 39

Miscellaneous
Chow mein noodles 5 1 Tbsp + 1-1/2 tsp 18 36 21 0.6 28
Jell-O ®, prepared w/ sugar 73 1/4 cup 16 35 29 1.1 43

Snack Foods
Arrowroot ® 5 1 biscuit 16 35 224 0.4 21
Barnum's Animal Crackers ® 8 3 crackers 18 35 21 0.5 33
Cookies
Oreo ® 11 1 cookie 17 32 21 0.5 53
Social Tea Biscuits ® 11 2 biscuits 21 39 24 0.6 48

© 2001 Ross Products Division Maple Syrup Urine Disease 93


Food Weight Approximate ILE LEU VAL Protein Energy
(g) Measure (mg) (mg) (mg) (g) (kcal)
For greatest accuracy, weigh food on scale that reads in grams. All measures are level.
Sugar Wafers (Nabisco ®) 14 2-1/2 wafers 18 34 20 0.6 67
vanilla wafer 8 2 wafers 15 30 17 0.4 37
Crackers
Goldfish ®, original 7 12 crackers 18 34 20 0.5 35
graham crackers (2" x 2") 7 1 cracker 20 38 23 0.6 27
Ritz ® 7 2 crackers 15 29 17 0.5 33
saltine 6 2 crackers 19 37 22 0.6 26
Triangle Thins ® 4 2 crackers 20 34 22 0.4 20
Waverly ® 7 1 cracker 17 33 20 0.5 35
Wheat Thins ® 7 4 crackers 17 34 20 0.5 34
Doritos ® 4 2 chips 8 31 12 0.3 18
Fritos ® 4 2 chips 10 34 13 0.3 22
Ice cream cone (wafer type) 4 1 (cone only) 15 30 18 0.4 17
Popcorn
buttered 2 1/4 cup 9 34 13 0.3 10
caramel 4 1 Tbsp + 2 tsp 9 34 12 0.2 14
plain 2 1/3 cup 9 36 12 0.2 7
Potato chips (2" diameter) 8 4 chips 21 31 29 0.5 42
Rice cakes 5 1/2 cake 21 33 26 0.4 17

FATS

Butter
stick 15 1 Tbsp 9 12 9 0.1 108
whipped 11 1 Tbsp + 1-1/2 tsp 6 9 6 0.1 79
Gravy
mushroom, canned 11 2-1/4 tsp 5 10 6 0.1 6
mushroom mix, dry 1 1 Tbsp 5 9 6 0.1 4
onion mix, dry 1 1 Tbsp 5 9 5 0.1 5
Margarine
soft in tub 14 1 Tbsp 6 9 6 0.1 101
stick or brick 14 1 Tbsp 6 12 9 0.1 101
Nondairy creamers w/ sodium caseinate
liquid 11 2-1/4 tsp 6 10 6 0.1 15
powder 2 1 tsp 6 9 7 0.1 11
Rich's ® Coffee Rich 43 3 Tbsp 6 10 6 0.1 66
Polyrich ® 43 3 Tbsp 6 10 6 0.1 66
Olives
black 15 3 olives 6 10 7 0.2 28
green 10 2 olives 4 8 6 0.2 12
Salad dressings, commercial
French 18 1 Tbsp + 1 tsp 6 9 7 0.1 78
Italian 15 1 Tbsp 6 9 6 0.1 69
mayonnaise 9 2 tsp 6 9 7 0.1 66
Miracle Whip ® 28 2 Tbsp 7 10 7 0.1 140
ranch 5 1 tsp 6 9 7 0.1 26
Russian 8 1-1/2 tsp 7 10 8 0.1 38
Thousand Island 13 2-1/2 tsp 7 10 7 0.1 49
Toppings, commercial
Cool Whip ®
extra creamy 4 2-1/2 tsp 6 10 7 0.1 13
regular 7 1 Tbsp + 2-1/4 tsp 6 10 7 0.1 19
Richwhip ®
pressurized 25 3 Tbsp + 1-1/4 tsp 6 10 6 0.1 69
prewhipped 10 2 Tbsp + 1-1/2 tsp 6 10 6 0.1 30

94 Maple Syrup Urine Disease © 2001 Ross Products Division


Food Weight Approximate ILE LEU VAL Protein Energy
(g) Measure (mg) (mg) (mg) (g) (kcal)
For greatest accuracy, weigh food on scale that reads in grams. All measures are level.

FRUITS
Fruits are raw unless otherwise noted. Weight of raw fruits is only for parts that can be eaten. Drain canned, cooked, and frozen fruits before
measuring or weighing.

Apple
canned, sweetened, sliced 204 1 cup 14 22 16 0.4 136
dried
cooked, sweetened 210 3/4 cup 16 26 19 0.4 174
uncooked 43 1/2 cup 16 25 19 0.4 104
sauce, canned, sweetened 255 1 cup 18 28 20 0.5 194
whole, large 230 1 fruit 18 28 21 0.4 136
Apricots
canned, heavy syrup 86 1/3 cup 14 27 16 0.5 71
dried
cooked, sweetened 31 2 Tbsp 12 23 14 0.4 38
uncooked 10 3 halves 12 22 14 0.4 25
frozen, sweetened 60 1/4 cup 12 24 15 0.4 60
nectar, canned 126 4 fl oz 14 26 16 0.5 72
whole 35 1 fruit 14 27 17 0.5 17
Avocados, all varieties, mashed 19 1 Tbsp + 1 tsp 13 23 18 0.4 31
Bananas 38 1/3 small 13 27 18 0.4 35
Blackberries
canned, heavy syrup 32 2 Tbsp 10 21 12 0.4 30
raw 72 1/2 cup 12 26 15 0.5 37
Blueberries
canned, heavy syrup 64 1/4 cup 13 25 17 0.4 66
frozen, sweetened 115 1/2 cup 14 26 20 0.4 94
raw 72 1/2 cup 15 29 20 0.5 41
Boysenberries, canned, heavy syrup 48 3 Tbsp 14 21 18 0.5 42
Cherries
sour red, canned, heavy syrup 117 1/2 cup 16 23 21 0.9 106
sweet
canned, heavy syrup 97 6 Tbsp 17 26 22 0.6 80
raw 72 1/2 cup 17 24 22 0.9 52
Dates, dried 25 3 dates 12 22 16 0.5 68
Figs
canned, heavy syrup 130 1/2 cup 16 22 18 0.5 114
dried
cooked 49 3 Tbsp 19 27 24 0.6 52
uncooked 19 1 fig 17 25 22 0.6 48
whole 75 1-1/2 medium 18 26 21 0.6 56
Fruit cocktail, canned, heavy syrup 130 1/2 cup 12 22 20 0.5 93
Fruit salad, canned, heavy syrup 128 1/2 cup 13 23 18 0.4 94
Gooseberries, canned, light syrup 63 1/4 cup 13 25 17 0.4 46
Grapefruit, all varieties
canned, light syrup 125 1/2 cup 23 21 37 0.9 46
juice, canned, unsweetened 185 6 fl oz 26 23 41 1.0 46
sections 115 1/2 cup 19 26 31 0.7 37
Grapes
adherent skin 160 1 cup 8 22 29 1.1 114
juice, canned or bottled 210 6 2/3 fl oz 15 25 21 1.2 129
slipskin 184 2 cups 10 24 32 1.2 484

© 2001 Ross Products Division Maple Syrup Urine Disease 95


Food Weight Approximate ILE LEU VAL Protein Energy
(g) Measure (mg) (mg) (mg) (g) (kcal)
For greatest accuracy, weigh food on scale that reads in grams. All measures are level.
Thompson, seedless, canned, heavy syrup 256 1 cup 10 26 33 1.2 186
Guava, common and strawberry
diced 41 1/4 cup 12 23 12 0.3 21
sauce 119 1/2 cup 15 25 13 0.4 44
Kiwi fruit 38 1/2 fruit 11 22 21 0.4 23
Loquats 100 10 fruits 15 26 21 0.4 47
Mangoes, diced 82 1/2 cup 15 26 22 0.4 54
Melon, cubed
cantaloupe 53 1/3 cup 14 21 18 0.5 19
casaba 57 1/3 cup 15 23 19 0.5 15
honeydew 113 2/3 cup 14 23 18 0.5 38
Mixed fruit, canned, heavy syrup 128 1/2 cup 14 24 21 0.5 92
Nectarines, sliced 69 1/2 cup 19 29 25 0.6 34
Oranges, all varieties
juice
canned 249 8 fl oz 15 27 22 1.5 104
frozen, diluted 187 3/4 cup 13 24 20 1.3 84
sections 90 1/2 cup 23 22 36 0.9 42
Orange-grapefruit juice, canned 187 6 fl oz 30 28 49 1.1 96
Papaya, diced 140 1 cup 14 22 11 0.9 54
Peaches
canned, heavy syrup, sliced 85 1/3 cup 11 22 21 0.4 63
dried, uncooked 13 1/2 fruit 14 26 26 0.5 31
frozen, sweetened 62 1/4 cup 11 22 21 0.4 59
nectar, canned 187 6 fl oz 15 29 27 0.5 100
sliced 57 1/3 cup 11 23 22 0.4 24
spiced, canned, heavy syrup 121 1/2 cup 15 28 28 0.5 90
Pears
canned, heavy syrup 255 1 cup 15 26 18 0.5 188
sliced 165 1 cup 33 23 23 0.6 97
Persimmons
Japanese 56 1/3 fruit 14 24 17 0.3 39
native 42 1-2/3 fruit 15 25 18 0.3 43
Pineapple
chunks
canned, heavy syrup 196 3/4 cup 17 26 22 0.7 98
frozen, sweetened 122 1/2 cup 16 25 20 0.5 104
diced 155 1 cup 20 29 25 0.6 77
juice
canned 188 6 fl oz 20 26 25 0.6 104
frozen, diluted 156 5 fl oz 20 29 25 0.6 80
Plantains, cooked, sliced 77 1/2 cup 17 27 22 0.6 90
Plums
purple, canned, heavy syrup 258 1 cup 18 26 23 0.9 230
sliced 124 3/4 cup 20 25 23 1.0 68
Prunes
dried
cooked, unsweetened 71 1/3 cup 16 23 20 0.8 76
uncooked 34 4 fruits 17 24 22 0.9 80
juice, canned or bottled 160 5 fl oz 18 26 23 0.9 115
Raisins, seedless 41 1/4 cup 10 30 38 1.4 124
Raspberries
canned, heavy syrup 64 1/4 cup 15 24 20 0.5 58
red, frozen, sweetened 83 1/3 cup 17 26 22 0.6 85
raw 62 1/2 cup 16 25 21 0.6 30
Rhubarb, frozen, cooked, sweetened 120 1/2 cup 14 21 18 0.5 139

96 Maple Syrup Urine Disease © 2001 Ross Products Division


Food Weight Approximate ILE LEU VAL Protein Energy
(g) Measure (mg) (mg) (mg) (g) (kcal)
For greatest accuracy, weigh food on scale that reads in grams. All measures are level.
Sapodilla, pulped 100 7 Tbsp 15 24 16 0.4 83
Strawberries, sliced
frozen, sweetened 85 1/3 cup 10 23 13 0.4 82
raw 75 1/2 cup 11 23 13 0.5 22
Tangerines
canned, light syrup 252 1 cup 30 28 48 1.1 153
juice
canned, sweetened 249 8 fl oz 121 25 20 1.2 125
fresh 247 8 fl oz 12 25 20 1.2 106
whole 168 2 medium 28 26 46 1.1 74
Watermelon, diced 160 1 cup 30 29 26 1.0 50

VEGETABLES
Vegetables are raw unless otherwise noted. Weight of raw vegetables is only for parts that can be eaten. Drain canned and cooked
vegetables before measuring or weighing.

Asparagus green, raw, canned, cooked 33 2 Tbsp or 2 spears 18 32 26 0.7 9


Bamboo shoots, canned 37 1/3 cup 19 31 23 0.6 4
Beans, green, snap, or yellow wax
canned, cooked 26 3 Tbsp + 1 tsp 18 30 24 0.5 5
frozen, cooked 34 1/4 cup 17 28 23 0.5 9
Bean sprouts
mung
cooked 23 3 Tbsp 23 30 22 0.5 5
raw 17 2 Tbsp + 2 tsp 23 31 23 0.5 4
soya
cooked 14 1 Tbsp + 2 tsp 27 32 27 0.7 5
raw 12 2 Tbsp 27 32 27 0.7 6
Beets, canned, cooked
greens 27 3 Tbsp 14 31 21 0.7 8
roots, pickled, diced 74 7 Tbsp 24 33 27 0.8 23
Broccoli
fresh or frozen, cooked 20 2 Tbsp 22 27 27 0.6 6
raw, diced 22 4 Tbsp 24 29 28 0.6 6
Brussels sprouts
fresh, cooked 21 1 sprout 21 24 25 0.5 8
frozen, cooked 22 1 sprout 30 31 31 0.6 8
whole 19 1 sprout 25 29 29 0.6 8
Cabbage
Chinese
cooked 32 3 Tbsp 28 29 22 0.5 4
raw, shredded 35 1/2 cup 30 31 23 0.5 5
red, raw, shredded 39 1/3 cup 28 28 23 0.5 11
white, shredded
cooked 61 6 Tbsp 29 30 25 0.6 13
raw 52 2/3 cup 31 33 27 0.8 12
Carrots
fresh or frozen, cooked, 68 7 Tbsp 29 31 31 0.7 31
shredded 73 2/3 cup 30 31 32 0.7 31
Cauliflower
fresh or frozen, cooked 26 3 Tbsp + 1-1/4 tsp 19 30 25 0.5 6
diced 25 1/4 cup 19 29 25 0.5 6
Celery, diced
cooked 112 3/4 cup 18 27 23 0.6 17
raw 90 3/4 cup 18 28 23 0.6 14
Chard, Swiss, chopped
cooked 22 2 Tbsp 34 30 25 0.4 4

© 2001 Ross Products Division Maple Syrup Urine Disease 97


Food Weight Approximate ILE LEU VAL Protein Energy
(g) Measure (mg) (mg) (mg) (g) (kcal)
For greatest accuracy, weigh food on scale that reads in grams. All measures are level.
raw 25 3 Tbsp 26 32 23 0.6 6
Chayote fruit, cubed
cooked 53 1/3 cup 18 31 25 0.3 13
raw 33 1/4 cup 16 28 23 0.3 8
Collards, cooked, diced 47 1/4 cup 21 32 26 0.5 7
Cucumber, sliced 130 1-1/4 cup 22 30 22 0.7 17
Eggplant, cooked, diced 54 1/2 cup + 1 Tbsp 19 28 23 0.4 15
Endive, shredded 28 1/2 cup + 1 Tbsp 20 28 18 0.4 5
Kale, cooked, chopped 24 3 Tbsp 28 32 25 0.5 8
Kohlrabi, cooked 41 1/4 cup 34 29 22 0.7 12
Lettuce, shredded
bibb, Boston, or iceberg 42 3/4 cup 33 31 28 0.5 5
leaf 37 2/3 cup 31 29 26 0.5 7
Romaine or cos 28 1/2 cup 29 28 24 0.5 4
Mushrooms, Agaricus bisporus
cooked 20 2 Tbsp 17 27 20 0.4 5
raw, sliced 23 1/3 cup 19 30 23 0.5 6
Mustard greens, cooked, chopped 44 1/3 cup 36 30 39 1.0 7
Okra, cooked, sliced 30 3 Tbsp 21 29 26 0.6 10
Onions, mature
cooked, diced 105 1/2 cup 34 34 22 0.9 29
rings 10 1 ring 21 35 22 0.5 41
Parsnips, cooked, chopped 59 3/4 cup 32 28 25 0.8 47
Peas, green, fresh, or frozen, canned, cooked 10 1 Tbsp 19 32 23 0.5 8
Pepper, green, diced
cooked 85 3/4 cup 17 28 22 0.5 15
raw 66 2/3 cup 18 29 24 0.6 17
Pickle, cucumber
dill 100 1 large 22 30 24 0.7 11
sweet 100 1 large 22 30 22 0.7 146
Pumpkin, cooked 61 1/4 cup 21 31 23 0.7 21
Radishes, Oriental, cooked, sliced 74 1/2 cup 21 26 23 0.5 13
Rutabagas, cubed
cooked 85 1/2 cup 39 30 37 0.9 29
raw 70 1/2 cup 35 27 34 0.8 25
Sauerkraut, canned 58 1/4 cup 27 27 23 0.5 11
Shallots, chopped 20 2 Tbsp 21 30 22 0.5 14
Spinach, chopped
canned 13 1 Tbsp 19 29 21 0.4 3
fresh, cooked 11 1 Tbsp 17 26 19 0.3 3
frozen, cooked 12 1 Tbsp 18 29 21 0.4 8
raw 14 1/4 cup 20 31 22 0.4 3
Squash,
summer, all varieties, sliced
fresh, cooked 56 1/3 cup 19 30 23 0.5 11
frozen, cooked 50 1/4 cup 22 32 26 0.7 10
raw 43 1/3 cup 18 30 23 0.5 9
winter, all varieties
baked, boiled, or mashed 54 1/4 cup 19 27 21 0.5 21
Tomatoes
canned 84 1/3 cup 19 29 20 0.8 22
catsup 39 2 Tbsp + 1-1/2 tsp 23 31 23 0.8 41
cooked 75 1/3 cup 20 31 22 0.8 19
juice 137 41/2 fl oz 21 29 21 1.0 23
paste 29 1 Tbsp + 2-1/4 tsp 21 30 22 1.1 24
purée 62 1/4 cup 20 29 21 1.0 26

98 Maple Syrup Urine Disease © 2001 Ross Products Division


Food Weight Approximate ILE LEU VAL Protein Energy
(g) Measure (mg) (mg) (mg) (g) (kcal)
For greatest accuracy, weigh food on scale that reads in grams. All measures are level.
raw, diced 90 1/2 cup 19 30 21 0.8 17
sauce, no meat 81 1/3 cup 21 30 22 1.1 24
Turnips
greens, canned, chopped 27 3 Tbsp 16 28 21 0.3 5
root, diced
cooked 117 3/4 cup 34 30 27 0.8 21
raw 98 3/4 cup 35 32 29 0.9 26
Vegetable juice cocktail 182 6 fl oz 22 31 22 1.1 35

Soups, Campbell's ®, Condensed. Measure before diluting and dilute with water only.
Asparagus, Cream of 26 1 Tbsp + 2 tsp 20 34 24 0.5 18
Celery, Cream of 31 2 Tbsp 19 31 22 0.5 22
Chicken Gumbo 21 1 Tbsp + 1 tsp 17 28 20 0.4 9
Chicken Vegetable 15 1 Tbsp 17 29 20 0.4 9
Minestrone 15 1 Tbsp 16 30 22 0.5 10
Mushroom, Cream of 26 1 Tbsp + 2 tsp 20 33 22 0.4 27
Onion 31 2 Tbsp 33 33 22 0.9 14
Potato, Cream of 31 2 Tbsp 19 29 23 0.4 18
Tomato 42 2 Tbsp + 2 tsp 20 33 22 0.7 29
Tomato Bisque 31 2 Tbsp 19 32 21 0.5 30
Vegetarian Old-Fashioned 26 1 Tbsp + 2 tsp 21 31 21 0.5 14
Vegetarian Vegetable 25 1 Tbsp + 2 tsp 20 30 20 0.4 15
FREE FOODS A
Limit to prescribed number of servings.

Desserts
Apple butter 20 1 Tbsp 3 5 4 0.1 37
Fruit Ice 61 1/3 cup 6 6 10 0.2 78
Fruit bars, frozen
orange 56 3/4 bar 6 5 9 0.2 53
pineapple 24 1/3 bar 3 5 4 0.1 23
Gelatin Pop 15 1/3 pop 2 5 4 0.2 10
Marmalade 39 2 Tbsp 5 5 8 0.2 100
Marshmallow 8 1 large 2 5 4 0.2 26
M&M ® candy, plain 1 1 piece 3 5 3 0.1 4
Raisins, chocolate covered 1 1 raisin 3 6 4 0.1 6
Sorbet
peach 17 1 Tbsp + 1/2 tsp 2 5 5 0.1 17
pineapple 26 1 Tbsp + 2-1/4 tsp 3 5 4 0.1 25
strawberry 25 1 Tbsp + 2 tsp 2 5 3 0.1 24

Fruits/Juices
Apple juice, frozen, diluted 171 5-1/2 fl oz 3 5 3 0.1 80
Cranberry juice cocktail 253 8 fl oz 3 5 3 0.1 144
Fruit juice bar 104 2 bars 2 4 3 0.2 86
Fruit pie filling
apple 81 1/3 cup 3 5 4 0.1 89
cherry 81 2 Tbsp 3 4 4 0.2 33
peach 29 1 Tbsp + 2-1/4 tsp 29 3 5 0.1 31
strawberry 18 1 Tbsp + 1/2 tsp 2 5 3 0.1 20
Jams 20 1 Tbsp 3 6 3 0.1 54
Nectar
papaya 126 4 fl oz 3 5 4 0.2 71
pear 78 2-1/2 fl oz 2 5 3 0.1 47

© 2001 Ross Products Division Maple Syrup Urine Disease 99


Food Weight Approximate ILE LEU VAL Protein Energy
(g) Measure (mg) (mg) (mg) (g) (kcal)
For greatest accuracy, weigh food on scale that reads in grams. All measures are level.

Miscellaneous
Chocolate drink powder 3 1 tsp 3 5 3 0.1 11
Chocolate syrup 6 1 tsp 4 6 6 0.1 14
Honey 42 2 Tbsp 4 5 4 0.1 128
Vegetables
Chives, chopped 3 1 Tbsp 4 5 4 0.1 1
Cucumbers, sliced 26 1/4 cup 5 6 5 0.1 4
Horseradish 1 1-1/4 tsp 3 5 4 0.1 1
Leeks, chopped 6 1 Tbsp 4 6 4 0.1 4
Onions, spring, chopped 6 1 Tbsp 4 6 5 0.1 2
Peppers, jalapeño, canned, chopped 8 1 Tbsp 2 4 3 0.1 2
Radishes, sliced 14 2 Tbsp 4 5 5 0.1 3

FREE FOODS B
These foods contain little or no branched-chain amino acids. They may be used as desired if patient is not overweight and if they do not
depress appetite for prescribed foods.

Beverages
Carbonated beverages, caffeine-free 113 4 fl oz 0 0 0 0.0 52
Exceed ® Energy Drink 124 4 fl oz 0 0 0 0.0 35
Gatorade ® 125 4 fl oz 0 0 0 0.0 25
Kool-Aid ®, sweetened w/ sugar 125 4 fl oz 0 0 0 0.0 70
Lemonade 125 4 fl oz 1 1 1 0.0 49
Limeade, sweetened w/ sugar 125 4 fl oz 1 1 1 0.0 59
Strawberry drink powder 8 1 Tbsp 0 0 0 0.0 33
Tang ® 125 4 fl oz 0 0 0 0.0 59
Tea, instant, powder 1 1 Tbsp 0 0 0 0.0 3

Desserts/Sweeteners
Candies
candy corn 16 10 pieces 0 1 0 0.0 58
gum drops 16 8 pieces 0 1 0 0.0 56
hard candy 15 3 pieces 0 0 0 0.0 58
jelly beans 14 5 pieces 0 0 0 0.0 51
lollipop 28 1 medium 0 0 0 0.0 108
Frosting, strawberry or vanilla 16 1 Tbsp 0 0 0 0.0 69
Jellies 20 1 Tbsp 0 0 0 0.0 54
Lemon pudding, canned (Hunt's ®) 121 1 can 0 0 0 0.0 151
Molasses 21 1 Tbsp 0 0 0 0.0 48
Popsicle ®, twin 128 1 popsicle 0 0 0 0.0 95
Sugar
brown 14 1 Tbsp 0 0 0 0.0 52
powdered 8 1 Tbsp 0 0 0 0.0 31
table 12 1 Tbsp 0 0 0 0.0 48
Syrup
corn 20 1 Tbsp 0 0 0 0.0 58
maple 20 1 Tbsp 0 0 0 0.0 50
table 20 1 Tbsp 0 0 0 0.0 50

Miscellaneous
Salad dressing, oil/vinegar 16 1 Tbsp 0 0 0 0.0 70
1
See Appendix 12, p A-11, for composition of very-low-protein foods.

100 Maple Syrup Urine Disease © 2001 Ross Products Division


100 Maple Syrup Urine Disease
TABLE 5-5. MSUD Clinical Summary Sheet

Name: Hospital Number:

Date of Birth: __________/__________/__________


Mo Day Year

Date Age Physical Data Laboratory Data Nutrient Intake Data


1 1 1
Length/ Weight Head Allo- ILE LEU VAL Hgb Hct FerritinTransthyretin Ketostix ® ILE LEU VAL Protein Energy
1
Height Circum isoleucine or DNPH
(mo/d/yr) (yrs/mos) (cm) (kg) (cm) (g/dL) (%) (ng/mL) (mg/dL) (mg) (mg) (mg) (g) (kcal)
© 2001 Ross Products Division

1
Indicate if µmol/L or mg/dL.
REFERENCES

1. Acosta PB: The contribution of therapy of inherited amino acid disorders to knowledge of amino acid requirements.
In Wapnir RA (ed): Congenital Metabolic Diseases: Diagnosis and Treatment. New York: Marcel Dekker Inc,
1985, 115-135.
2. Acosta PB, Yannicelli S: Nutrition support of inherited disorders of amino acids metabolism: Part 2. Top Clin Nutr
1995;10:48-72 (review).
3. Acosta PB, Yannicelli S: Protein intake affects phenylalanine requirements and growth of infants with
phenylketonuria. Acta Paediatr 1994;407 (Suppl):66-67.
4. Arnold GL, Vladutiu CJ, Kirby RS: Protein insufficiency and impaired growth in children with PKU. J Inher Metab
Dis 2000;23 (Suppl) 1:29A.
5. Behrman RE, Kliegman RM, Arvin AA (eds): Nelson Textbook of Pediatrics, ed 15. Philadelphia: WB Saunders Co,
1996.
6. Berry GT, Heidenreich R, Kaplan P, et al: Branched-chain amino acid free parenteral nutrition in the treatment of
acute metabolic decompensation in patients with maple syrup urine disease. N Engl J Med 1991;324:175-179.
7. Calomme MR, Vanderpas JB, Francois B, et al: Thyroid function parameters during a selenium repletion/depletion
study in phenylketonuric subjects. Experientia 1995;51:1208-1215.
8. Chuang DT, Shih VE: Maple syrup urine disease (Branched-chainketoaciduria). In Scriver CR, et al (eds): The
Metabolic and Molecular Bases of Inherited Disease, ed 8. New York: McGraw-Hill Medical Publishing Division,
2001, pp 1971-2005.
9. Clow CL, Reade TM, Scriver CR: Outcome of early and long-term management of classical maple syrup urine
disease. Pediatrics 1981;68:856-862.
10. DiGeorge AM, Rezvani I, Garibaldi LR, et al: Prospective study of maple syrup urine disease for the first four days
of life. N Engl J Med 1982;307:1492-1495.
11. Elsas LJ, Acosta PB: Nutrition support of inherited metabolic diseases. In Shils ME, et al (eds): Modern Nutrition in
Health and Disease, ed 9. Baltimore: Williams & Wilkins, 1999, pp 1003-1056.
12. Elsas LJ, Danner DJ: The role of thiamine in maple syrup urine disease. Ann NY Acad Sci 1982;378:404-421.
13. Elsas LJ, Ellerine NP, Klin PD: Practical methods to estimate whole body leucine oxidation in maple syrup urine
disease. Pediatr Res 1993;33:445-451.
14. Fernhoff PM, Lubitz D, Danner DJ, et al: Thiamine response in maple syrup urine disease. Pediatr Res
1985;19:1011-1016.
15. Food and Nutrition Board, Committee on Dietary Allowances: Recommended Dietary Allowances, eds 9 and 10.
Washington, DC: National Academy of Sciences, 1980 and 1989.
16. Giacoia GP, Berry GT: Acrodermatitis enteropathica-like syndrome secondary to isoleucine deficiency during
treatment of maple syrup urine disease. Am J Dis Child 1993;147;954-956.
17. Gropper S, Acosta PB: Effect of simultaneous ingestion of L-amino acids and whole protein on plasma amino acid
concentrations and urea nitrogen in humans. JPEN 1991;15:48-53.
18. Gropper SS, Gropper DM, Acosta PB: Plasma amino acid response to ingestion of L-amino acids and whole
protein. J Pediatr Gastroenterol Nutr 1993;16:143-150.
19. Gropper SS, Naglak MC, Nardella M, et al: Nutrient intakes of adolescents with PKU and infants and children with
MSUD on semisynthetic diets. J Am Col Nutr 1993;12:108-114.
20. Hammerson G, Wille L, Schmidt H, et al: Maple syrup urine disease: Treatment of the acutely ill newborn. Eur J
Pediatr 1978;129:157-165.
21. Henstenburg JD, Mazur AT, Kaplan PB, et al: Nutritional assessment and body composition in children with maple
syrup urine disease (MSUD). J Amer Diet Assoc 1990;90:A-32.
22. Herrmann ME, Broesicke HG, Keller M, et al: Dependence of the utilization of a phenylalanine-free amino acid
mixture on different amounts of single dose ingested. A case report. Eur J Pediatr 1994;153:501-503.
23. Jones BJM, Lees R, Andrews J, et al: Comparison of an elemental and polymeric enteral diet in patients with
normal gastrointestinal function. Gut 1983;24:78-84.
24. Kaplan P, Mazur A, Field M, et al: Intellectual outcome in children with maple syrup urine disease. J Pediatr
1991;119:46-50.
25. Kindt E, Halvorsen S: The need of essential amino acids in children: An evaluation based on the intake of
phenylalanine, tyrosine, leucine, isoleucine, and valine in children with phenylketonuria, tyrosine amino
transferase defect, and maple syrup urine disease. Am J Clin Nutr 1980;33:279-286.
26. Koch SE, Packman S, Koch TK, Williams ML: Dermatitis in treated maple syrup urine disease. J Am Acad
Dermatol 1993;28:289-292.
27. Leverton RM, Johnson N, Dazur J, Ellison J: Amino acid requirements of young adults. In Albanese AA (ed):
Protein and Amino Acid Nutrition. New York: Academic Press, 1959.
28. Lombeck I, Kasperek K, Harbisch HD, et al: The selenium state of children. II. Selenium content of serum, whole
blood, hair and the activity of erythrocyte glutathione peroxidase in dietetically treated patients with PKU and
MSUD. Eur J Pediatr 1978;128:213-223.

102 Maple Syrup Urine Disease © 2001 Ross Products Division


29. MacLean W, Graham G: Pediatric Nutrition in Clinical Practice. Menlo Park, Calif: Addison-Wesley Publishing Co,
1982.
30. Martin SB, Acosta PB: Osmotic behaviors of components of chemically-defined formulas. J Pediatr Perinat Nutr
1987;1:1-17.
31. Naglak ME, Elsas LJ: Nutrition support of maple syrup urine disease. Metabolic Currents 1988;1:15-18.
32. Nord A, van Doorninck WJ, Greene C: Developmental profile of patients with maple syrup urine disease. J Inher
Metab Dis 1991;14:881-889.
33. Northrup H, Sigman ES, Herbert AA: Exfoliative erythroderma resulting from inadequate intake of branched-chain
amino acids in infants with MSUD. Arch Dermatol 1993;129:384-385.
34. Ohkohchi N, Andoh T, Ohi R, Mori S: Defined formula diets alter characteristics of the intestinal transport of amino
acids and peptides in growing rats. J Pediatr Gastroenterol Nutr 1990;10:490-496.
35. Parsons HG, Carter RJ, Unrath M, Snyder FF: Evaluation of branched chain amino acid intake in children with
maple syrup urine disease and methylmalonic aciduria. J Inher Metab Dis 1990;13:125-136.
36. Peinemann F, Danner DJ: Maple syrup urine disease 1954 to 1993. J Inher Metab Dis 1994;17:3-15.
37. Posati LP, Orr ML: Composition of Foods: Dairy and Egg Products, Agriculture Handbook No. 8-1. Washington,
DC: US Dept of Agriculture, Agricultural Research Service, 1976.
38. Pratt EL, Snyderman SE, Cheung MW, et al: The threonine requirement of the normal infant. J Nutr
1955;56:231-251.
39. Schoeffer A, Herrmann ME, Broesicke HG, Moench E: Effect of dosage and timing of amino acid mixtures on
nitrogen retention in patients with phenylketonuria. J Nutr Med 1994;4:415-418.
40. Schwahn B, Wendel U, Schadewaldt P, et al: Diurnal changes in plasma amino acids in maple syrup urine
disease. Acta Paediatr 1998;87:1245-1246.
41. Smith CA, Nelson NM (eds): The Physiology of the Newborn Infant, ed 4. Springfield, IL: Charles C Thomas
Publisher, 1976.
42. Smith JL, Arteaga C, Heymsfield SB: Increased ureagenesis and impaired nitrogen use during infusion of a
synthetic amino acid formula - A controlled trial. N Engl J Med 1982;306:1013-1018.
43. Smith JL, Heymsfield SB: Enteral nutrition support: Formula preparation from modular ingredients. JPEN
1983;7:280-288.
44. Snyderman SE: Maple syrup urine disease. In Wapnir RA (ed): Congenital Metabolic Diseases: Diagnosis and
Treatment. New York: Marcel Dekker Inc, 1985.
45. Snyderman SE: The treatment of branched chain ketoacidemia. In Nutrition Committee: Diet Therapy for MSUD
and Organic Acidurias. Elk Grove Village, Ill: American Academy of Pediatrics, 1978.
46. Snyderman SE, Boyer A, Norton PM, et al: The essential amino acid requirements of infants: IX. Isoleucine. Am J
Clin Nutr 1964;15:313-321.
47. Snyderman SE, Holt LE, Smellie F, et al: The essential amino acid requirements of infants: Valine. Am J Dis Child
1959;97:186-191.
48. Snyderman SE, Roitman EL, Boyer A, et al: The essential amino acid requirements of infants: Leucine. Am J Dis
Child 1961;102:157-162.
49. Spika JS, Shaffer N, Hargrett-Bean N, et al: Risk factors for infant botulism in the United States. Am J Dis Child
1989;143:828-832.
50. Thompson GN, Francis DEM, Halliday D: Acute illness in maple syrup urine disease: Dynamics of protein
metabolism and implications for management. J Pediatr 1991;119:33-41.
51. Tornqvist K, Tornqvist H: Corneal deepithelialization caused by acute deficiency of isoleucine during treatment of a
patient with maple syrup urine disease. Acta Ophthalmol Scand 1996;74 (Suppl 219):48-49.
52. van Calcar S, Harding CO, Davidson SR, et al: Case reports of successful pregnancy in women with maple syrup
urine disease and propionic acidemia. Am J Med Genet 1992;44:641-646.
53. Wajner M, Schlottfeldt JL, Kless C, Wannmacher CMD: Immunosuppresive effects of organic acids accumulating
in patients with maple syrup urine disease. J Inher Metab Dis 1995;18:165-168.
54. Wendel U, Becker K, Przyrembel H, et al: Peritoneal dialysis in maple syrup urine disease: Studies on branched-
chain amino and ketoacids. Eur J Pediatr 1980;134:57-63.
55. Wendel U, Langenbeck U, Lombeck I, et al: Exchange transfusion in acute episodes of maple syrup urine disease.
Eur J Pediatr 1982;138:293.

© 2001 Ross Products Division Maple Syrup Urine Disease 103


PROTOCOL 6 — Disorders of Leucine Catabolism

Nutrition Support of Infants, Children, and Adults With


I-VALEX ®-1 and I-VALEX ®-2 Amino Acid-Modified Medical Foods
I. Introduction
Five mitochondrial enzyme defects have been identified in the catabolic pathway for essential leucine
(LEU) which normally produces acetoacetic acid and acetyl-CoA: branched-chain-α-ketoacid
dehydrogenase complex deficiency (Protocol 5); isovaleryl-CoA dehydrogenase deficiency;
3-methylcrotonyl-CoA carboxylase deficiency; 3-methylglutaconyl-CoA hydratase deficiency; and
3-hydroxy-3-methylglutaryl-CoA lyase deficiency (HMG-CoA lyase deficiency) (20, 68).
Isovaleric acidemia was first described in 1967 and was identified by urinary excretion of
isovaleric acid (IVA). Subsequently, a deficiency of isovaleryl-CoA dehydrogenase (IVD) was defined
in cultured skin fibroblasts. This enzyme is a mitochondrial flavoprotein and uses electron transfer
factor. Deficiency of IVD results in a block in catabolism of LEU at the step after branched-chain-α-
ketoacid dehydrogenase complex (Figure E) (20, 68).
IVA, 3-hydroxyisovaleric acid (3-OHIVA), and isovalerylglycine (IVG) accumulate in body fluids.
The phenotypic abnormalities result from toxic accumulation of free IVA. An alternate pathway
producing IVG reduces accumulation of toxic precursors. Carnityl adducts offer an additional alternate
pathway to detoxify free IVA (20, 23, 68).

Dietary protein Tissue protein

Isovaleric acid
L-Leucine Isovalerylglycine
Transaminase 3-Hydroxyisovaleric acid
4-Hydroxyisovaleric acid
Mesaconic acid
2-Keto-isocaproic acid Methylsuccinic acid
Branched-chain α-ketoacid Isovalerylglucuronide
dehydrogenase Isovalerylglutamic acid
Isovaleryl-CoA Isovalerylalanine
Isovalerylsarcosine
3-Hydroxyisoheptanoic acid
Isovalerylcarnitine
Isovaleryl-CoA dehydrogenase
3-Methylcrotonic acid
3-Methylcrotonyl-CoA 3-Methylcrotonylglycine
3-Hydroxyisovaleric acid
3-Methylcrotonyl-CoA carboxylase
3-Methylglutaconic acid
3-Methylglutaconyl-CoA 3-Methylglutaric acid
3-Methylglutarylcarnitine
3-Methylglutaconyl-CoA hydratase

3-Hydroxy-3-Methylglutaric acid
3-Hydroxy-3-methylglutaryl-CoA

3-Hydroxy-3-methylglutaryl-CoA
lyase 3-Hydroxy-3-methylglutaryl-CoA
reductase

Acetoacetic acid Acetyl-CoA Mevalonic acid Mevalonic acid


(Mevalonolactone)
Site of enzyme defect Cholesterol
¹ Modified from reference 68.

Figure E. Metabolism of leucine in disorders of leucine catabolism (excluding MSUD)


Two forms of isovaleric acidemia are reported: acute and chronic intermittent. Those patients with
acute isovaleric acidemia appear to be normal full-term infants. Within the 1st days of life, poor
feeding, tachypnea, vomiting, and a characteristic “sweaty-feet” odor of the blood and urine are
frequently noted. Diarrhea, lethargy, hypotonia, and tremors may also be found. Some patients fail to
respond to treatment and expire. The exact cause of death is frequently unknown. Severe metabolic
acidosis, hyperammonemia, central nervous system (CNS) hemorrhage, cardiac arrest, and sepsis

104 Disorders of Leucine Catabolism © 2001 Ross Products Division


are some probable causes. Infants who are detected early and respond to treatment survive the
neonatal period and develop appropriately. If acute neonatal disease is prevented, they progress into
chronic intermittent isovaleric acidemia (20, 68).
In the chronic intermittent form, babies are normal at birth. During late infancy, they may develop
episodes of vomiting, metabolic acidosis, stupor, and coma. “Sweaty-feet” odor is usually present, and
transient alopecia is occasionally seen. Episodes may begin as early as 2 weeks of age and the
frequency of attacks seems to decrease with age. Urinary tract and upper respiratory infections
frequently trigger episodes, as do excessive intake of protein and aspirin. Many children affected by
the intermittent form have a stronger preference for fruits and vegetables over meat and milk (20, 68).
Several patients with either acute or chronic isovaleric acidemia have had moderate to severe
hematologic abnormalities, including leukopenia and thrombocytopenia, with pancytopenia most
common. IVA is an inhibitor of granulopoietic progenitor cell proliferation in bone marrow cell cultures
and may account for the neutropenia often seen in isovaleric acidemia (39). Depressed hemoglobin
concentrations were also seen in several patients. Transient alopecia seems to be more common with
the chronic intermittent form than with the acute form of the disease and may be nutritionally related.
Hyperammonemia (up to 1200 µmol) has also been reported during neonatal crisis (72).

II. Outcome of Nutrition Support


A male infant with isovaleric acidemia, treated from the neonatal period with medical food designed for
MSUD with added L-isoleucine and L-valine and whole protein to supply essential restricted LEU, had
normal growth and development. Height and weight were between the 25th and 50th percentiles. Head
circumference was at 50th percentile. On average, diet supplied 2.5-3.0 g protein/kg/day and 100 mg
LEU/kg/day (44). L-carnitine and glycine (GLY) were not a part of the diet regimen.
Growth of a male infant with isovaleric acidemia diagnosed prenatally has been reported (47). At
birth, this infant was breastfed ad libitum and 250 mg GLY/kg/day was administered. In spite of low
protein intake from human milk and the GLY supplement, the patient became acidotic and began to
vomit and hyperventilate at 3 days of age. Breastfeeding was discontinued and a LEU-free diet
providing 125 kcal/kg supplemented with 380 mg GLY/kg/day was begun. His clinical status improved
rapidly. Dietary LEU at 45 mg/kg/day with GLY at 250 mg/kg/day and protein at 2.0 g/kg was
introduced at 5 days of age. At 2 years of age, the patient was developmentally normal and was
> 95th percentile for height and weight. Diet at 2 years of age supplied per kg: 46 mg LEU, 1.7 g
protein and 72 kcal. Only one hospitalization for vomiting and dehydration was required during the
2-year period.
Outcomes in 9 patients with isovaleric acidemia managed by protein restriction (1.5-2.0 g/kg in
infancy, 0.8-1.5 g/kg thereafter) and 250 mg GLY/kg/day have been reported (12). Since all patients
had secondary carnitine deficiency (total serum carnitine 19 ± 3 µmol/L), 4 children were
supplemented with 50 mg/kg/day L-carnitine. In these patients serum carnitine returned to normal
(51 ± 5 µmol). Actual height, weight, and head circumference of patients were not reported although
growth velocities were stated to be normal after diet initiation. Developmental quotients or IQ scores
of 5 subjects in whom diet was initiated during the neonatal period ranged from 49 to 115.
Food refusal has been reported in a patient with isovaleric acidemia (35). Both physiologic and
behavioral components to feeding problems were reported. The physiologic component involved
altered serotonin metabolism. Any factor such as hyperammonemia or a high-carbohydrate, low-
protein diet that stimulates the transport of tryptophan, a precursor of serotonin, into the brain, could
lead to anorexia. A low-tryptophan diet was suggested as one alternative to treatment of anorexia.
Of 11 reported French cases of isovaleric acidemia, 8 were alive after the neonatal period. LEU
restriction and GLY supplementation were used to manage patients. Six of 8 surviving patients had
normal development (58).

III. Establish Diagnosis


A. Isovaleric Acidemia Resulting From Isovaleryl-CoA Dehydrogenase Deficiency
1. Diagnostic studies should be conducted in any infant or child with poor feeding, vomiting,
metabolic acidosis, hyperammonemia, hypocalcemia, coma, seizures, neutropenia,
thrombocytopenia, pancytopenia, ± alloisoleucine in plasma, ± tachypnea and/or sweaty-feet
or aged-cheese odor (4, 5, 13, 39, 54, 68).
2. See reference 68 for methods of diagnosis.

© 2001 Ross Products Division Disorders of Leucine Catabolism 105


B. 3-Methylcrotonylglycinuria Resulting From 3-Methylcrotonyl-CoA Carboxylase Deficiency
1. Diagnostic studies should be conducted in any infant or child who has hypotonia and lethargy
progressing to coma, or symptoms resembling Reye's syndrome (hypoglycemia,
hyperammonemia, metabolic acidosis, elevated transaminases, and seizures or
incoordination) (8, 9, 27, 42, 51, 57, 58).
2. See references 8 and 68 for methods of diagnosis.
C. 3-Methylglutaconic Aciduria Resulting From 3-Methylglutaconyl-CoA Hydratase Deficiency.
1. Diagnostic studies should be conducted in any infant or child who presents with mental
retardation, retarded speech, or fasting hypoglycemia with metabolic acidosis (15, 18, 25, 26
33, 34, 48).
2. See references 48 and 68 for methods of diagnosis.
D. 3-Hydroxy-3-Methylglutaric Aciduria Resulting From HMG-CoA Lyase Deficiency
1. Diagnostic studies should be conducted in any infant who has convulsions, coma, cyanosis,
dehydration, dyspnea, hyperpnea, hypotonia, lethargy, myoclonic jerks, opisthotonos, stroke-
like encephalopathy, respiratory distress, vomiting, hypoglycemia, metabolic acidosis, and
absent ketonuria, ± hyperammonemia, ± elevated transaminases, ± hepatomegaly (19, 22,
24, 28, 31, 34, 40, 43, 62, 67).
2. See reference 68 for methods of diagnosis.

IV. Rationale for Nutrition Support


A. Correct Primary Imbalance in Metabolic Relationships
1. Restrict dietary LEU to amount tolerated by patient to maintain treatment plasma LEU
concentration (12, 44).
2. For patients with HMG-CoA lyase deficiency, also restrict fat to between 20% and 25% of
energy and avoid fasting (6, 11).
B. Provide Alternative Metabolic Pathways
1. Prescribe adequate L-carnitine and GLY to decrease accumulated toxic compounds formed in
blocked reaction sequences (12, 14, 16, 17, 23, 37, 56).

V. Nutrition Support During Acute Illness


A. Initiation of Nutrition Support
1. Initiate nutrition support immediately. Do not wait for confirmation of diagnosis.
2. Evaluate plasma LEU concentrations and urine organic acid concentrations daily.
B. Medical Care
1. For medical management during diagnosis and acute illness, see references 4, 5, 16, 17, 23,
39, 41, 55, 74.
C. Patients Without Severe Neurologic Involvement
1. Begin high-energy LEU-free feeds (120-150 kcal/kg for infants and young children,
80-100 kcal/kg for children, and 40-50 kcal/kg for adults) that supply adequate water
(Table 6-1, p 115).
a. Depending on clinical status and age of patient, feed orally or by nipple, nasogastric tube,
intravenous infusion, or combine these methods.
1) For nipple or nasogastric feeds:
i. Use I-Valex (Table 6-2, p 116), L-carnitine (100-300 mg/kg), and GLY
(150-300 mg/kg (7) (Appendix 26, p A-28).
2) For intravenous feeds via central line:
i. Use hypertonic D-glucose, LEU-free parenteral amino acid solution (Appendix 26,
p A-28), L-carnitine (100-300 mg/kg) (14, 54, 69), and GLY (150-300 mg/kg)
(6, 16, 17, 36, 41, 46, 47, 59, 60, 70, 71).
ii. Add Liposyn ® II (Appendix 26, p A-28) after 2 to 3 days, when response to
glucose is seen. For 3-hydroxy-3 methylglutaric aciduria, Liposyn II should be
restricted to between 20% and 25% of energy (11, 24).

106 Disorders of Leucine Catabolism © 2001 Ross Products Division


3) For intravenous feeds via peripheral line:
i. Use isotonic D-glucose, LEU-free parenteral amino acid solution, L-carnitine
(100-300 mg/kg) (55, 70) and GLY (150-300 mg/kg). Add Liposyn II (Appendix 26,
p A-28) when response to glucose is seen. For 3-hydroxy-3-methylglutaric
aciduria, Liposyn II should be restricted to between 20% and 25% of energy (11,
24).
2. Introduce nutrition support with I-Valex orally or by nasogastric tube as soon as possible.
a. See Table 6-1, p 115, for Recommended LEU, Protein, Energy, and Fluid intakes.
b. See Table 6-2, p 116 , for composition of I-Valex.
3. Add LEU (Table 6-1, p 115) to I-Valex feeds when plasma LEU concentration drops to upper
limit of treatment range (185 µmol/L).
a. Use Similac ® With Iron Infant Formula to fill LEU prescription for very young infants
(Table 6-3, p 117); Similac and beikost or table foods (Table 6-3, p 117) to fill prescription
for older infants; and whole cow’s milk (Table 6-3, p 117) or table foods to fill LEU
prescription for children and adults.
b. For patients with HMG-CoA lyase deficiency, use ProViMin ® Protein-Vitamin-Mineral
Formula Component With Iron to supply LEU (Table 6-4, p 118).
c. Measure liquid infant formula and whole cow’s milk with disposable syringe. Weigh
powdered infant formula on scale that reads in grams.
D. Comatose Patients
1. For medical management during diagnosis and acute illness, see references 16, 39, 41, 55,
68-74.
2. Begin LEU-free nasogastric feeding of protein and energy (I-Valex) (Tables 6-1 and 6-2,
pp 115 and 116) 36 to 48 hours after beginning dialysis with amino acid-free dialysate.
3. Begin intravenous infusion of 10% D-glucose, L-carnitine (100-300 mg/kg), and GLY
(150-300 mg/kg) during nasogastric feeding. Add L-carnitine and GLY only if amounts
provided by I-Valex are inadequate.
a. GLY is not beneficial in HMG-CoA lyase deficiency.
b. Add Liposyn II (Appendix 26, p A-28) to intravenous infusion in 2 to 3 days when response
to glucose is seen, continuing until major neurologic signs subside.
c. For HMG-CoA lyase deficiency, Liposyn II should provide between 20% and 25% of
energy.
4. Add LEU (Table 6-1, p 115) to I-Valex nasogastric feeding when plasma LEU concentration
drops to upper limit of range (185 µmol/L).
a. Use Similac to fill LEU prescription for infants (Table 6-3, p 117) and whole cow’s milk to
fill LEU prescription for children and adults.
b. For patients with HMG-CoA lyase deficiency, use ProViMin to supply LEU (Table 6-4,
p 118) for infants and skim milk for children and adults.
c. Measure liquid infant formula and whole or skim cow’s milk with disposable syringe.
Weigh powdered infant formula on scale that reads in grams.
5. If parenteral amino acid solutions are indicated, see Appendix 26, p A-28.

VI. Establish Goals of Long-Term Nutrition Support (18)


A. Plasma LEU and GLY Concentrations
1. Maintain 2- to 4-hour postprandial plasma LEU concentrations between 50 and 100 µmol/L
(0.66 to 1.31 mg/dL) when measured by quantitative methods or between 2 and 4 mg/dL when
measured by bacterial inhibition assay.
2. Maintain 2- to 4-hour postprandial plasma GLY concentrations between 200 and 400 µmol/L
(1.5-3.0 mg/dL) when measured by quantitative methods.
3. In practice, obtaining blood 2 to 4 hours postprandially is not always possible. Acceptable local
standards should be developed if plasma amino acids are evaluated at other times (Practical
Aspects of Nutrition Support, p viii).
B. Growth, Development, and Nutrition Status
1. Maintain normal osseous mineralization (41). Osteopenia may occur despite treatment.
2. Support normal growth rate in infants and children and maintain appropriate weight for height
in adults.

© 2001 Ross Products Division Disorders of Leucine Catabolism 107


3. Maintain normal nutrition status.
4. Prevent catabolism (46, 69).
b. Avoid extended periods of fasting in patients with HMG-CoA lyase deficiency (68).
5. Maintain normal blood hemoglobin, leukocyte, and platelet concentrations (39).
6. Maintain normal plasma anion gap.
7. Maintain plasma concentration of free carnitine > 30 µmol/L.
8. Maintain organic acid concentrations in urine in normal range (4).
a. Concentrations of organic acids in urine may be increased somewhat above normal even
when blood organic acids are in normal range.
9. Prevent alopecia.
C. Mental Development and Neurologic Status
1. Prevent developmental delay and mental retardation (12, 18).

VII. Establish Prescription


A. LEU (1)
1. Prescribe LEU intake that promotes goals of nutrition support (Table 6-1, p 115).
2. LEU requirements vary widely:
a. From patient to patient, depending on activity of enzyme involved.
b. In same patient, depending on
1) Age.
2) Growth rate.
3) Adequacy of energy and protein intakes.
4) State of health.
5) GLY and L-carnitine intakes.
3. Values for LEU listed in Table 6-1, p 115, are suggested for initiating therapy.
4. Frequent monitoring of plasma LEU concentration and urinary excretion of organic acids is
essential to assess each patient’s changing requirements.
a. Compare results of plasma and urine monitoring with LEU intake.
b. See Section X, Suggested Evaluation of Nutrition Support, p 110.
Warning: Inadequate LEU intake will result in weight loss or poor weight gain, skin rash
progressing to desquamation, hair loss, below normal plasma LEU
concentration, loss of appetite, irritability, apathy, and increased
concentrations of plasma isoleucine, methionine, serine, threonine, and
valine (66).
B. GLY
1. Prescribe 150-300 mg/kg (47).
C. Protein (2)
1. Prescribe amount greater than Recommended Dietary Allowances (RDAs) (Table 6-1, p 115).
2. Requirements may be greater than RDAs when L-amino acids supply majority of protein
equivalent as result of:
a. Rapid amino acid absorption (29, 30).
b. Early and high peak of plasma amino acids after ingestion of meals where large part of
protein is supplied by L-amino acids (29, 30).
c. Rapid catabolism of amino acids (32, 38, 61, 64).
d. Possible decreased total amino acid absorption (49).
Warning: Inadequate protein intake will result in weight loss or poor weight gain, skin
rash, hair loss, low plasma protein concentration, and decreased tolerance of
LEU.
D. Energy
1. Prescribe amount that should support normal weight gain for infants and children and maintain
appropriate weight for height of adults (Table 6-1, p 115).
2. Requirements vary widely and may be greater than normal when L-amino acids supply
majority of protein equivalent (53).

108 Disorders of Leucine Catabolism © 2001 Ross Products Division


3. At diagnosis and during metabolic acidosis precipitated by infection or trauma, energy needs
may be 25% to 40% greater than values listed in Table 6-1, p 115.
4. Maintenance of adequate energy intake is essential for normal growth and prevention of
catabolism (47, 69).
Warning: Inadequate energy intake results in poor weight gain or weight loss and
depressed tolerance of LEU.
E. L-Carnitine
1. Prescribe amount that will maintain plasma free carnitine concentration > 30 µmol/L. Most
patients require between 100 and 300 mg/kg (17, 23).
F. Fluid
1. Prescribe amount that will supply water requirements (Table 6-1, p 115).
2. Under normal circumstances, offer minimum of 1.5 mL fluid to neonates and 1.0 mL to
children and adults for each kcal ingested (10).
G. Fat
1. Restrict fat to between 20% and 25% of energy in patients with HMG-CoA lyase
deficiency (11, 24).
H. Pantothenic Acid
1. Supplements of 15 to 150 mg/day in three divided doses may be beneficial in
3-methylglutaconic aciduria (50).

VIII. Fill Prescription


A. LEU
1. Calculate amount of infant formula with iron, beikost, whole or skim milk, or table foods
required to fill LEU prescription (Table 6-3, p 117).
a. Low-iron infant formula, whole cow's milk, skim milk, and evaporated milk should not be
used as LEU source for infants because of low iron content.
b. Use ProViMin (Table 6-4, p 118) to supply LEU for infants with HMG-CoA lyase
deficiency.
2. Measure liquid infant formula or whole or skim milk with disposable syringe. Weigh powdered
infant formula on scale that reads in grams.
3. Add beikost or table foods to gradually replace LEU provided by infant formula after infant is
3 to 4 months old or is developmentally ready.
4. Parents or patients may select any food in prescribed Servings Lists for BCAA-Restricted
Diets (Protocol 5, pp 88-99) in specified amounts to fill diet plan.
B. Protein
1. Calculate amount of protein provided by infant formula with iron, beikost, whole or skim milk,
or table foods (Table 6-3, p 117) required to fill LEU prescription.
a. Supplemental GLY is not included in protein calculation.
2. Subtract amount determined above from protein prescription.
3. Provide remaining prescribed protein with I-Valex (Table 6-2, p 116).
a. I-Valex is for infants and toddlers and I-Valex-2 is for children, adolescents, and adults.
b. Weigh I-Valex powder on scale that reads in grams because of variability of household
measuring equipment (Practical Aspects of Nutrition Support, p vii) and changes in
density during shipping.
c. See Table 6-2 (p 116, footnote 3) for approximate packed weight of I-Valex powder in
level, dry US standard household measures.

C. GLY (Appendix 26, p A-28) (7)


1. Supply GLY as pure solution if amount present in I-Valex does not provide amount
prescribed.
a. Add GLY powder to boiled, cooled water to yield 100 mg/mL (eg, 100 g GLY with enough
water to yield 1 liter).
b. Refrigerate in sterilized, closed container until used. Discard unused suspension after
1 week, if not frozen.
© 2001 Ross Products Division Disorders of Leucine Catabolism 109
c. Shake well before using. Measure GLY solution into medical food mixture with disposable
syringe.
D. Energy
1. Calculate energy provided by I-Valex (Table 6-2, p 116) and infant formula with iron, beikost,
whole or skim milk, or table foods (Table 6-3, p 117) required to fill LEU and protein
prescriptions.
2. Subtract amount of energy supplied by these sources from energy prescription.
3. Provide remaining prescribed energy with Polycose ® Glucose Polymers powder
(23 kcal/Tbsp, 3.8 kcal/g) or liquid (2 kcal/mL) (Appendix 9, p A-9); Pro-Phree ® Protein-Free
Energy Module With Iron, Vitamins & Minerals (Appendix 11, p A-10), except for patients with
HMG-CoA lyase deficiency; sugar (48 kcal/Tbsp); or Free Foods B (Table 6-3, p 117).
a. Do not use corn syrup or table sugar for infants because of osmolarity they yield.
b. Do not use honey for infants because it may contain botulinum toxin.
4. Nasogastric or gastrostomy feeds may be required to maintain energy intake.
E. L-Carnitine (Appendix 26, p A-28)
1. If L-carnitine in I-Valex is inadequate to fill prescription, supply as pure solution.
2. Measure L-carnitine solution into medical food mixture with disposable syringe if entire
contents of container are not used.
3. L-carnitine tablets may be used if patient is old enough to swallow them (Appendix 26,
p A-28).
F. Fluid and Mixing Instructions
1. Add sufficient boiled, cooled water to infant formula, GLY solution (if needed), L-carnitine (if
needed), I-Valex, and energy source (if needed) to yield prescribed volume.
2. Mix with sterilized blender at lowest speed for 3 to 4 seconds. Excess mixing may
destabilize emulsion. Medical foods may also be mixed in sterilized, tightly closed container
by shaking vigorously for 10 to 12 seconds.
3. Place in sterilized formula bottles. Cap and store in refrigerator until used. Discard unused
portion 24 hours after mixing because of nutrient loss.
4. Do not use terminal sterilization or boil because of Maillard reaction (Practical Aspects of
Nutrition Support, p viii).
5. Warm or cool medical food mixture to room temperature before feeding to infants. Shake well
before feeding.
6. Do not warm medical food mixture for infants in microwave oven. Unevenly heated formula
can burn infant and steam can make bottles explode.
7. Notify parents or caretakers when they may discontinue using aseptic technique in preparing
medical food mixture for infants.
8. For children and adults, chill I-Valex medical food mixture to improve taste.
G. Diet Guide
1. Provide parents, caretakers, or patient with completed Diet Guide (Appendix 22, p A-24) with
each diet change.
2. Feed infants 6 to 8 times daily (32, 61).
3. Feed children and adults 4 to 6 times daily (32, 61).

IX. Evaluate Adequacy and Safety of Planned Nutrition Support


A. Nutrient Adequacy
1. Determine if diet provides nutrients in amounts prescribed in Section VII, Establish
Prescription, p 107.
a. See Table 6-2, p 116, for composition of I-Valex and Table 6-3, p 117, for nutrient
composition of beikost or table foods, infant formula, and whole or skim milk.
2. Check diet to determine if it supplies Recommended Dietary Intakes (RDIs) for minerals and
vitamins (Appendices 13 and 14, pp A-14 and A-15).
a. See Appendices 4 through 7, pp A-4 to A-7, for composition of infant formulas.
b. Appendix 23, p A-25, may be used to check adequacy of nutrients if computer program is
not available.

110 Disorders of Leucine Catabolism © 2001 Ross Products Division


c. If I-Valex mixture provides < 100% of RDIs for infants and < 75% for children and adults,
supplement diet with needed minerals and vitamins if not provided by beikost or table
foods and laboratory test results indicate need (Appendix 11, p A-10, for composition of
supplements).
B. Osmolarity
1. If concentration of prescribed medical food mixture is > 24 kcal/fl oz, determine if osmolarity
of I-Valex mixture is in acceptable range.
a. Determine osmolarity by laboratory analysis or use mathematical formula given in
Appendix 18, p A-20.
b. Osmolarity per gram of I-Valex is listed in Appendix 19, p A-21.
2. If osmolarity is > 450 mosm/L for infants, > 750 mosm/L for children, > 1,000 mosm/L for
adults, or greater than tolerated by patient, increase water content of prescribed medical food
mixture and recalculate its osmolarity (45, 65).
C. Renal Solute Load
1. Dehydration will result if renal solute load is greater than renal-concentrating ability of patient.
2. If concentration of medical food mixture prescribed is > 24 kcal/fl oz, estimate its potential
renal solute load.
a. This step is important to prevent dehydration of infants who may have renal-
concentrating capacity as low as 600 mosm/L.
b. Upper limit of renal solute load for neonates is approximately 1,100 mosm/L (63).
3. A method for estimating potential renal solute load is given in Appendix 20, p A-22.
4. If potential renal solute load is excessive, increase water content of medical food mixture and
recalculate.

X. Suggested Evaluation of Nutrition Support


A. Plasma LEU Concentration
1. Initial.
a. Evaluate every 2 to 3 days by quantitative methods until plasma concentrations stabilize
and approximate dietary LEU requirement is known.
2. Ongoing.
a. Evaluate weekly until patient is 1 year old if bacterial inhibition assay for LEU is available
in state laboratory.
b. Evaluate at least monthly by quantitative methods if weekly evaluations by bacterial
inhibition assay are conducted.
3. Unacceptable LEU concentrations.
a. If plasma LEU concentration is not detected and patient has ingested full prescription:
1) Increase prescribed LEU by 25% and reevaluate plasma LEU concentration in 3 days.
2) If LEU concentration remains undetected, repeat above process until value is in
treatment range.
b. If plasma LEU concentration is < 50 µmol/L or < 0.66 mg/dL and patient is ingesting full
prescription:
1) Increase prescribed LEU by 5% to 10%, then evaluate plasma LEU concentration in
1 week.
2) If plasma LEU concentration remains low, repeat above process until value is in
treatment range.
c. If plasma LEU concentration is > 100 µmol/L or > 1.31 mg/dL and patient is not ill and is
ingesting full prescription for LEU, protein, and energy:
1) Decrease prescribed LEU by 5% to 10% and reevaluate plasma LEU concentration in
1 week.
2) If plasma LEU concentration remains high, repeat above process until value is in
treatment range.
B. Urinary Organic Acid Excretion
1. Isovaleric acidemia.
a. Assess urinary IVA, 3-OHIVA, and IVG weekly to monthly when patient is well and every
1 to 3 days when patient is ill.

© 2001 Ross Products Division Disorders of Leucine Catabolism 111


2. 3-Methylcrotonylglycinuria.
a. Assess urinary 3-OHIVA and 3-methylcrotonylglycine weekly to monthly when patient is
well and daily or every 2 to 3 days when patient is ill.
3. 3-Methylglutaconic aciduria.
a. Assess urinary 3-OHIVA, 3-methylglutaconic acid, and 3-methylglutaric acid weekly to
monthly when patient is well and daily or every 2 to 3 days when patient is ill.
4. 3-Hydroxy-3-methylglutaric aciduria.
a. Assess urinary 3-OHIVA, 3-methylglutaconic acid, 3-methylglutaric acid and 3-hydroxy-3-
methylglutaric acid weekly to monthly when patient is well and every 1 to 3 days when
patient is ill.
C. Urine Ketoacids by Ketostix ®
1. Evaluate daily for acetoacetic and ß-hydroxybutyric acids when patient is ill.
2. Results for urine ketoacids should be negative at all times.
3. If results for urine ketoacids are positive:
a. Immediately obtain blood sample for evaluation of LEU concentration by bacterial
inhibition assay or quantitative methods.
b. Brief metabolic physician on patient’s illness.
D. Protein Status
1. Evaluate plasma transthyretin concentration every 3 months until patient is 1 year of age and
every 6 months thereafter (Appendix 17, p A-18, for standards).
a. Plasma transthyretin concentrations provide a more reliable and rapid indication of protein
status than plasma albumin concentrations.
b. Plasma albumin concentrations may be in the normal range when plasma transthyretin
concentrations show a clear deficiency (3).
2. If plasma transthyretin concentration is below standard:
a. Increase prescribed protein by 5% to 10% and reevaluate plasma transthyretin
concentration in 1 month. If LEU concentration is in treatment range, use I-Valex to
increase protein.
b. If plasma transthyretin concentration continues below standard, repeat above process until
value is in normal range.

E. Carnitine Status
1. Evaluate plasma free carnitine concentration weekly until amount of L-carnitine required to
maintain concentration > 30 µmol/L is determined, then evaluate every 3 months.
a. If free carnitine concentration in plasma is < 30 µmol/L:
1) Increase prescribed L-carnitine by 5-10%, then evaluate free carnitine concentration
in 1 week.
2) If free carnitine concentration remains low, repeat above process until value is in
treatment range.
F. Iron Status
1. Plasma ferritin concentration.
a. Evaluate at 6, 9, and 12 months of age and every 6 months thereafter (Appendix 17,
p A-18, for standards).
b. If plasma ferritin concentration is below standard:
1) Increase iron intake to 4 mg/kg with supplements (ferrous sulfate).
2) Evaluate plasma ferritin concentration monthly on increased iron intake.
3) Continue iron supplements until plasma ferritin concentration is in normal range.
2. Complete blood count and differential.
a. Hemoglobin and hematocrit concentrations and differential should be evaluated at 6, 9,
and 12 months of age and every 6 months thereafter (Appendix 17, p A-18, for
standards).

112 Disorders of Leucine Catabolism © 2001 Ross Products Division


G. Growth Status
1. Length/height and weight.
a. Measure monthly to 1 year, every 3 months to 4 years, and every 6 months until full
growth is achieved. Plot measurements on NCHS growth charts.
b. Maintain length/height and weight between 10th and 90th percentiles. Some normal
infants, children, and adults will fall above or below these percentiles.
2. If length/height or weight falls below usual growth channel:
a. Increase prescribed protein and energy by 5% to 10% and remeasure after 1 month.
b. If length/height or weight remains low, repeat above process until usual growth channel is
achieved.
H. Bone Mineralization
1. Assess bone age and mineralization and look for signs of osteoporosis via yearly radiographs
of lumbar vertebrae.
I. Nutrient Intake
1. Maintain records of food intake for 3 days immediately before each blood test (Appendices 24
and 25, pp A-26 and A-27).
2. Evaluate intakes of LEU, GLY, carnitine, protein, and energy (plus fat in HMG-CoA lyase
deficiency).
3. Evaluate mineral and vitamin intake after each diet change.
a. Appendix 23, p A-25, may be used to check adequacy of nutrients if computer program is
not available.
b. See Appendix 28, p A-29, for information about ordering software for diet evaluation.
J. Clinical Summary
1. A summary record of growth, laboratory, and nutrient intake data is useful for patient
management (Table 6-5, p 119).

XI. Sample Prescriptions


A. Example 1
Establish and fill prescription for 3-month-old infant weighing 4.5 kg who has isovaleric acidemia,
using Recommended Daily Nutrient Intakes from Table 6-1, p 115, and nutrient contents from
Tables 6-2 and 6-3, pp 116 and 117.
1. Establish prescription.
LEU 80 mg/kg x 4.5 kg = 360 mg/day
GLY 150 mg/kg x 4.5 kg = 675 mg
L-Carnitine 150 mg/kg x 4.5 kg = 675 mg
Protein 3.5 g/kg x 4.5 kg = 15.8 g
Energy 120 kcal/kg x 4.5 kg = 540 kcal
Fluid 150 mL/kg x 4.5 kg = 675 mL
2. Fill prescription.
Medical Food Mixture Measure LEU GLY L-Carnitine Protein Energy
(mg) (mg) (mg) (g) (kcal)
I-Valex-1 81 g 0 810 729 12.2 389
1
Similac With Iron RTF 250 mL 360 70 3 3.5 170
Add water to make 675 mL (23 fl oz).

Total per day 360 880 732 15.7 559


Total per kg 80 196 162 3.5 124
Approximate osmolarity of medical food mixture is < 450 mosm/L. Estimated potential renal solute load
is 100 mosm.
1
RTF = Ready To Feed

© 2001 Ross Products Division Disorders of Leucine Catabolism 113


B. Example 2
Establish and fill prescription for 2-year-old child weighing 13 kg using Recommended Daily
Nutrient Intakes from Table 6-1, p 115, and nutrient contents from Tables 6-2 and 6-3, pp 116
and 117.
1. Establish prescription.
LEU 500 mg/day
GLY 1,300 mg
L-Carnitine 1,300 mg
Protein 30 g
Energy 1,300 kcal
Fluid 1,300 mL
2. Fill prescription.
Medical Food Mixture Measure LEU GLY L-Carnitine Protein Energy
(mg) (mg) (mg) (g) (kcal)
I-Valex-1 140 g 0 1,400 1,260 21.0 672
Add water to make 800 mL (27 fl oz). Offer additional fluid ad libitum daily.

Food List Servings


Breads/Cereals 5 175 0 0 2.5 150
Fats 1 10 0 0 0.1 70
Fruits 4 100 0 0 2.4 300
Vegetables 7 210 0 0 4.2 105
Total per day 495 1,400 1,260 30.2 1,297
Approximate osmolarity of medical food mixture is < 500 mosm/L.

C. Example 3
Establish and fill prescription for 3-year-old child weighing 17 kg who has
3-methylcrotonylglycinuria. Use the Recommended Daily Nutrient Intakes from Table 6-1, p 115,
and nutrient contents from Tables 6-2 and 6-3, pp 116 and 117.
1. Establish prescription.
LEU 600 mg/day
GLY 1,700 mg
L-Carnitine 1,275 mg
Protein 30 g
Energy 1,300 kcal
Fluid 1,300 mL
2. Fill prescription.
Medical Food Mixture Amount LEU GLY L-Carnitine Protein Energy
(mg) (mg) (mg) (g) (kcal)
I-Valex-2 67 g 0 2,023 1,206 20.1 275
Add water to make 710 mL (24 fl oz). Offer additional fluid ad libitum daily.

Food List Servings


Breads/Cereals 8 280 0 0 4.0 240
Fats 4 40 0 0 0.4 280
Fruits 6 150 0 0 3.6 450
Vegetables 4 120 0 0 2.4 60
Total per day 590 2,023 1,206 30.5 1,305
Approximate osmolarity of medical food mixture is < 600 mosm/L.

114 Disorders of Leucine Catabolism © 2001 Ross Products Division


D. Example 4
Establish and fill prescription for 6-month-old child weighing 7 kg who has 3-hydroxy-3-
methylglutaric aciduria. Use Recommended Daily Nutrient Intakes from Table 6-1, p 115, average
nutrient contents from Tables 6-2 through 6-4, pp 116-118.
1. Establish prescription.
LEU 490 mg/day
L-Carnitine 700 mg
Protein 19.2 g
Energy 805 kcal
Fat 18 g
Fluid 910 mL
2. Fill prescription.
Medical Food Mixture Measure LEU L-Carnitine Fat Protein Energy
(mg) (mg) (g) (g) (kcal)
I-Valex-1 81 g 0 729 17.6 12.2 389
ProViMin 2.9 g 196 1 0.0 2.1 9
Sugar 8 g (2 tsp) 0 0 0.0 0.0 32
Add water to make 710 mL (24 fl oz). Offer additional water ad libitum daily.

Food List Servings


Breads/Cereals 3 105 0 0.0 1.5 90
Fruits 3 75 0 0.0 1.8 225
Vegetables 4 120 0 0.0 2.4 60
Total per day 496 730 17.6 20.0 805
Approximate osmolarity of medical food mixture is < 400 mosm/L.

XII. Nutrition Support During Febrile Illness or Following Trauma


A. Rationale
1. In normal persons, febrile illness and trauma are accompanied by catabolism of body protein.
2. Well-nourished patients with disorders of leucine catabolism respond to infection and trauma
as do normal persons.
3. Febrile illness and trauma are life-threatening if not diagnosed and treated promptly.
4. See Section V, Nutrition Support During Acute Illness, p 105.

XIII. Contraindicated Medications


A. Benzoic acid (sodium benzoate) (55).
1. However, benzoic acid may be used for short periods if patient is hyperammonemic.
B. Salicylates (41, 55).

© 2001 Ross Products Division Disorders of Leucine Catabolism 115


TABLE 6-1. Recommended Daily Nutrient Intakes (Average and Range) for Infants, Children and Adults
With Disorders of LEU Catabolism

Age Nutrient
1,2 3,4
LEU Protein Energy 3 Fluid 5
(mg/kg) (g/kg) (kcal/kg) (mL/kg)
Infants
0 to < 3 mo 80 - 150 3.50 - 3.00 120 (145 - 95) 160-125
3 to < 6 mo 70 - 140 3.50 - 3.00 115 (145 - 95) 160-130
6 to < 9 mo 60 - 130 3.00 - 2.50 110 (135 - 80) 145-125
9 to < 12 mo 50 - 120 3.00 - 2.50 105 (135 - 80) 135-120

(mg/day) (g/day) (kcal/day) (mL/day)


Girls and Boys
1 to < 4 yr 500 - 900 > 30.0 1,300 ( 900 - 1800) 900 - 1,800
4 to < 7 yr 600 - 900 > 35.0 1,700 (1300 - 2300) 1,300 - 2,300
7 to < 11 yr 700 - 900 > 40.0 2,400 (1650 - 3300) 1,730 - 3,300

Women
11 to < 15 yr 700 - 900 > 50.0 2,200 (1500 - 3000) 1,500 - 3,000
15 to < 19 yr 620 - 820 > 55.0 2,100 (1200 - 3000) 1,200 - 3,000
> 19 yr 620 - 820 > 60.0 2,100 (1400 - 2500) 1,400 - 2,500

Men
11 to < 15 yr 1,100 - 1500 > 55.0 2,700 (2000 - 3700) 2,000 - 3,700
15 to < 19 yr 1,100 - 1500 > 65.0 2,800 (2100 - 3900) 2,100 - 3,900
> 19 yr 1,000 - 1400 > 70.0 2,900 (2000 - 3300) 2,000 - 3,300
1
Modified from references 1 and 66. Initiate therapy with lowest value for age. Modify prescription based on
frequently obtained blood and/or plasma values and growth in infants and children and frequently obtained
plasma values and weight maintenance in adults.
2
Modified from reference 21.
3
During metabolic acidosis and/or infection following trauma, energy requirements may be 25-40% greater than those
listed. Initiate therapy with energy value outside parentheses.
4
Modified from reference 10. Under normal circumstances, offer minimum of 1.5 mL fluid to neonates and 1.0 mL
fluid to children and adults for each kcal ingested.

116 Disorders of Leucine Catabolism © 2001 Ross Products Division


TABLE 6-2. Nutrient Composition of I-VALEX ®-1 1, 3, and I-VALEX ®-2 2, 3

Nutrient I-Valex-1 I-Valex-2


(per 100 g pwd) (per g protein equiv) (per 100 g pwd) (per g protein equiv)
Energy, kcal 480 32 410 13.7
Protein Equiv, g 15.00 1.000 30.00 1.000
Nitrogen, g 2.40 0.160 4.80 0.160
Amino Acids, g 16.01 1.067 32.02 1.067
Cystine, g 0.15 0.010 0.30 0.010
Glycine, g 1.00 0.067 3.02 0.101
Histidine, g 0.42 0.028 0.84 0.028
Isoleucine, g 0.43 0.029 0.86 0.029
Leucine, g trace 0.000 trace 0.000
Lysine, g 1.00 0.067 2.00 0.067
Methionine, g 0.30 0.020 0.60 0.020
Phenylalanine, g 0.88 0.059 1.76 0.059
Threonine, g 0.70 0.047 1.40 0.047
Tryptophan, g 0.17 0.011 0.34 0.011
Tyrosine, g 0.89 0.059 1.78 0.059
Valine, g 0.48 0.032 0.96 0.032
Other Nitrogen-Containing Compounds
Carnitine, mg 900 60 1,800 60
Taurine, mg 40 2.67 50 1.67
Carbohydrate, g 53.0 3.53 35 1.17
Fat, g 21.7 1.45 13 0.43
4 5
Linoleic acid, g 2.00 0.133 1.50 0.050
α-Linolenic acid, g
6 7
0.36 0.024 0.17 0.006
Minerals
Calcium, mg 575 38 880 29
Chloride, mg/mEq 325/9.17 21.7/0.61 940/26.51 31.33/0.88
Chromium, µg 11 0.73 27 0.90
Copper, mg 1.10 0.073 1.00 0.033
Iodine, µg 65 4.33 100 3.33
Iron, mg 9.0 0.60 13 0.43
Magnesium, mg 50 3.33 225 7.50
Manganese, mg 0.50 0.033 0.80 0.027
Molybdenum, µg 12 0.80 30 1.00
Phosphorus, mg 400 27 760 25
Potassium, mg/mEq 675/17.26 45/1.15 1,370/35.04 45.7/1.17
Selenium, µg 20 1.33 35 1.17
Sodium, mg/mEq 190/8.26 12.7/0.55 880/38.28 29.3/1.28
Zinc, mg 8.0 0.53 13.0 0.43
Vitamins
A, µg RE 420 28 660 22
D, µg 7.50 0.50 7.50 0.25
E, mg α-TE 10.10 0.67 12.10 0.40
K, µg 50 3.33 60 2.00
Ascorbic acid, mg 50 3.33 60 2.00
Biotin, µg 65 4.33 100 3.33
B6, mg 0.75 0.050 1.30 0.043
B12, µg 4.90 0.327 5.00 0.167
Choline, mg 80 5.33 100 3.33
Folate, µg 230 15 430 14.33
Inositol, mg 40 2.67 70 2.33
Niacin equiv, mg 12.80 0.850 21.7 0.72
Pantothenic acid, mg 6.90 0.460 8.00 0.267
Riboflavin, mg 0.90 0.060 1.80 0.060
Thiamin, mg 1.90 0.127 3.25 0.108
1 2
Designed for infants and toddlers. Designed for children, adolescents, and adults.
3
Approximate packed weights of I-Valex in level, dry US standard household measures:
I-Valex-1 I-Valex-2
1 Tbsp = 7g 8g
1/4 cup = 26 g 32 g
1/3 cup = 35 g 41 g
1/2 cup = 53 g 61 g
1 cup = 105 g 117 g
4 5
Analytical data at manufacture = 4.32 g/100 g powder. Analytical data at manufacture = 2.66 g/100 g powder.
6 7
Analytical data at manufacture = 0.40 g/100 g powder. Analytical data at manufacture = 0.28 g/100 g powder.

© 2001 Ross Products Division Disorders of Leucine Catabolism 117


TABLE 6-3. Serving Lists for LEU-Restricted Diets: Approximate LEU, Protein, Fat, and Energy Content per
Serving1

Food List Nutrient


LEU Fat Protein Energy
(mg) (g) (g) (kcal)
Breads/Cereals 35 0.00 0.50 30
Fats 10 8.00 0.10 70
Fruits 25 0.00 0.60 75
Vegetables 30 0.00 0.60 15
Free Foods A 5 varies 0.10 50
Free Foods B 0 varies 0 00 55
Alimentum ® Protein Hydrolysate Formula With Iron, Ready to Feed, 100 mL 2 173 3.74 1.86 68
Isomil ® Soy Formula With Iron, Ready to Feed, 100 mL 2 135 3.70 1.66 68
Similac ® With Iron Infant Formula, Ready to Feed, 100 mL 2 144 3.65 1.40 68
Skim milk, 100 mL 3 346 0.19 3.53 36
3
Whole cow’s milk, 100 mL 332 3.46 3.39 63
1
From reference 20.
2
See Appendices 4 through 7, pp A-4 to A-7, for complete nutrient composition of infant formulas.
3
From reference 52. See Appendix 8, p A-8, for complete nutrient composition.

118 Disorders of Leucine Catabolism © 2001 Ross Products Division


TABLE 6-4. Nutrient Composition of ProViMin ® and Skim Milk
1 2
Nutrient ProViMin Skim Milk
(per 100 g powder) (per 100 mL)
Energy, kcal 312 36
Protein Equiv, g 73.0 3.53
Amino Acids, g 79.59 3.58
Cystine, mg 410 33
Glycine, mg 1,380 75
Histidine, mg 1,950 95
Isoleucine, mg 3,400 213
Leucine, mg 6,750 346
Lysine, mg 5,760 280
Methionine, mg 2,200 89
Phenylalanine, mg 3,630 171
Threonine, mg 3,130 159
Tryptophan, mg 1,000 50
Tyrosine, mg 4,150 171
Valine, mg 4,250 236
Other Nitrogen-Containing Compounds
Carnitine, mg 40 NA
Taurine, mg 110 NA
Carbohydrate, g 2.00 5.02
Fat, g 1.4 0.19
Linoleic acid, g 0 0.005
α-Linolenic acid, g 0 0.002
Minerals
Calcium, mg 2,400 127
Chloride, mg/mEq 2,300/65 104/2.93
Copper, mg 2.10 0.01
Iodine, µg 335 7
Iron, mg 40 0.04
Magnesium, mg 200 11
Manganese, mg 0.20 0.002
Phosphorus, mg 1,700 105
Potassium, mg/mEq 3,300/84 172/4.4
Selenium, µg 70 2.17
Sodium, mg/mEq 1,200/52 54/2.35
Zinc, mg 17 0.41
Vitamins
A, µg RE 2,020 63
D, µg 25 1.06
E, mg α-TE 45 0.04
K, µg 90 NA
Ascorbic acid, mg 200 1.01
Biotin, µg 100 2.00
B6, mg 1.35 0.04
B12, µg 5.6 0.39
Choline, mg 335 NA
Folate, µg 320 5.18
Inositol, mg 105 NA
Niacin equiv, mg 40.6 0.92
Pantothenic acid, mg 10.1 0.34
Riboflavin, mg 2.02 0.14
Thiamin, mg 2.24 0.04
1
Approximate weight in grams of level, dry, US standard household measures:
1 Tbsp = 2.9 g
1/4 cup = 11 g
2/3 cup = 30 g
1 cup = 44 g
2
From reference 52.
NA = Not available.

© 2001 Ross Products Division Disorders of Leucine Catabolism 119


© 2001 Ross Products Division
TABLE 6-5. Isovaleric Acidemia Clinical Summary Sheet

Name: Hospital Number:

Date of Birth: __________/__________/__________


Mo Day Year

Date Age Physical Data Laboratory Data Nutrient Intake Data


1
Length/ Weight Head Free GLY IVA LEU Hgb Hct Ferritin Trans- Urine LEU GLY Carnitine Protein Energy
1 2 3
Height Circum Carnitine thyretin IVA OHIVA IVG
(mo/d/yr)
(yrs/mos) (cm) (kg) (cm) (µmol/L) (µmol/L) (µmol/L) (µmol/L) (g/dL) (%) (ng/mL) (mg/dL) (mg) (mg) (mg) (g) (kcal)
Disorders of Leucine Catabolism 119

1
Isovaleric acid.
2
ß-hydroxyisovaleric acid.
3
Isovalerylglycine
REFERENCES

1. Acosta PB: The contribution of therapy of inherited amino acid disorders to knowledge of amino acid requirements.
In Wapnir RA (ed): Congenital Metabolic Diseases: Diagnosis and Treatment. New York: Marcel Dekker Inc,
1985, 115-135.
2. Acosta PB, Yannicelli S: Protein intake affects phenylalanine requirements and growth of infants with
phenylketonuria. Acta Paediatr 1994;407 (Suppl):66-67.
3. Arnold GL, Vladutiu CJ, Kirby RS: Protein insufficiency and impaired growth in children with PKU. J Inher Metab
Dis 2000;23 (Suppl 1):29A.
4. Arnold WC, Brewster M, Byrne WJ, Booth B: Fanconi syndrome in a patient with a variant of isovaleric acidemia.
Int J Pediatr Nephrol 1986;7:95-98.
5. Attia N, Sakati NAL, Ashwal A, et al: Isovaleric acidemia appearing as diabetic ketoacidosis. J Inher Metab Dis
1996;19:85-87
6. Bakker HD, Wanders RJA, Schutgens RBH, et al: 3-Hydroxy-3-methylglutaryl-CoA lyase deficiency: Absence of
clinical symptoms due to a self-imposed dietary fat and protein restriction. J Inher Metab Dis 1993;16:1061-1062.
7. Bartlett K, Gompertz D: The specificity of glycine-N-acylase and acylglycine excretion in the organic acidaemias.
Biochem Med 1974;10:15-23.
8. Baumgartner R: Isolated biotin-resistant 3-methylcrotonyl-CoA carboxylase deficiency. In Fernandes J, et al (eds):
Inborn Metabolic Diseases: Diagnosis and Treatment. New York: Springer-Verlag, 1990, pp 321-322.
9. Beemer FA, Bartlett K, Duran M, et al: Isolated biotin-resistant 3-methylcrotonyl-CoA carboxylase deficiency in two
sibs. Eur J Pediatr 1982;138:351-354.
10. Behrman RE, Kliegman RM, Arvin AA (eds): Nelson Textbook of Pediatrics, ed 15. Philadelphia: WB Saunders Co,
1996.
11. Berry HK, Suchy F, Hunt M, Norman E: Treatment of 3-hydroxy-3-methylglutaric aciduria in first cousins. In
Walser M, et al (eds): Metabolism and Clinical Implications of Branched Chain Amino and Ketoacids. New York:
Elsevier, 1981, pp 395-400.
12. Berry GT, Yudkoff M, Segal S: Isovaleric acidemia: Medical and neurodevelopmental effects of long-term therapy.
J Pediatr 1988;113:58-64.
13. Budd MA, Tanaka K, Holmes LB, et al: Isovaleric acidemia. Clinical features of a new genetic defect of leucine
metabolism. N Engl J Med 1967;277:321-327.
14. Chalmers RA, Stacey TE, Tracey BM, de Sousa C: L-carnitine insufficiency in disorders of organic acid
metabolism: Response to L-carnitine by patients with methylmalonic aciduria and 3-hydroxy-3-methylglutaric
aciduria. J Inher Metab Dis 1984;7 (Suppl 2):109-110.
15. Chitayat D, Chemke J, Gibson KM, et al: 3-Methylglutaconic aciduria: A marker for as yet unspecified disorders
and the relevance of prenatal diagnosis in a “new” type (type 4). J Inher Metab Dis 1992;15:204-212.
16. Cohn RM, Yudkoff M, Rothman R, Segal S: Isovaleric acidemia: Use of glycine therapy in neonates. N Engl J Med
1978;299:996-999.
17. de Sousa C, Chalmers RA, Stacey TE, et al: The response to L-carnitine and glycine therapy in isovaleric
acidemia. Eur J Pediatr 1986;144:451-456.
18. Duran M, Beemer FA, Tibosch AS, et al: Inherited 3-methylglutaconic aciduria in two brothers — another defect of
leucine metabolism. J Pediatr 1982;101:551-554.
19. Duran M, Schutgens RBH, Ketel A, et al: 3-Hydrox-3-methylglutaryl coenzyme A lyase deficiency: Postnatal
management following prenatal diagnosis by analysis of maternal urine. J Pediatr 1979;95:1004-1007.
20. Elsas LJ, Acosta PB: Nutrition support of inherited metabolic diseases. In Shils ME, et al (eds): Modern Nutrition in
Health and Disease, ed 9. Baltimore: Williams & Wilkins, 1999, pp 1003-1056.
21. Food and Nutrition Board, Committee on Dietary Allowances: Recommended Dietary Allowances, eds 9 and 10.
Washington, DC: National Academy of Sciences, 1980 and 1989.
22. Francois B, Bachmann C, Schutgens RBH: Glucose metabolism in a child with 3-hydroxy-3-methyl-glutaryl-
coenzyme A lyase deficiency. J Inher Metab Dis 1981;4:163-164.
23. Fries MH, Rinaldo P, Schmidt-Sommerfeld E, et al: Isovaleric acidemia: Response to a leucine load after three
weeks of supplementation with glycine, L-carnitine, and combined glycine-carnitine therapy. J Pediatr
1996;129:449-452.
24. Gibson KM, Breuer J, Nyhan WL: 3-Hydroxy-3-methylglutaryl-coenzyme A lyase deficiency: Review of 18 reported
patients. Eur J Pediatr 1988;148:180-186.
25. Gibson KM, Lee CF, Wappner RS: 3-Methylglutaconyl-coenzyme-A hydratase deficiency: A new case. J Inher
Metab Dis 1992;15:363-366.
26. Gibson KM, Sherwood WG, Hoffmann GF, et al: Phenotypic heterogeneity in syndromes of 3-methylglutaconic
aciduria. J Pediatr 1991;118:885-890.
27. Gitzelmann R, Steinmann B, Niederwieser A, et al: Isolated (biotin-resistant) 3-methylcrotonyl-CoA carboxylase
deficiency presenting at age 20 months with sopor, hypoglycaemia, and ketoacidosis. J Inher Metab Dis
1987;10 (Suppl 2):290-292.
28. Greene CL, Cann HM, Robinson BH, et al: 3-Hydroxy-3-methylglutaric aciduria. J Neurogenet 1984;1:165-173.
© 2001 Ross Products Division Disorders of Leucine Catabolism 121
29. Gropper S, Acosta PB: Effect of simultaneous ingestion of L-amino acids and whole protein on plasma amino acid
concentrations and urea nitrogen in humans. JPEN 1991;15:48-53.
30. Gropper SS, Gropper DM, Acosta PB: Plasma amino acid response to ingestion of L-amino acids and whole
protein. J Pediatr Gastroent Nutr 1993;16:143-150.
31. Gunel M, Coskum T, Tokathi A, Ozalp I: 3-Hydroxy-3-methylglutaryl coenzyme A lyase deficiency. J Inher Metab
Dis 1993;16:1062-1063.
32. Herrmann ME, Broesicke HG, Keller M, et al: Dependence of the utilization of a phenylalanine-free amino acid
mixture on different amounts of single dose ingested: A case report. Eur J Pediatr 1994;153:501-503.
33. Hou JW, Wong TR: 3-Methylglutaconic aciduria presenting as Reye syndrome in a Chinese boy. J Inher Metab Dis
1995;18:645-646.
34. Huemer M, Muehl A, Wandl-Vergesslich K, et al: Stroke-like encephalopathy in an infant with 3-hydroxy-3-
methylglutaryl-coenzyme A lyase deficiency. Eur J Pediatr 1998;157:743-746.
35. Hyman SL, Porter CA, Page TJ, et al: Behavior management of feeding disturbances in urea cycle and organic
acid disorders J Pediatr 1987;111:558-562.
36. Ito T, Kidouchi K, Sugiyama N, et al: Liquid chromatographic-atmospheric pressure chemical ionization mass
spectrometric analysis of glycine conjugates and urinary isovalerylglycine in isovaleric acidemia. J Chromat
1995;B670:317-322.
37. Itoh T, Ito T, Ohba S, et al: Effect of carnitine administration on glycine metabolism in patients with isovaleric
acidemia: Significance of acetylcarnitine determination to estimate the proper carnitine dose. Tohoku J Exp Med
1996;179:101-109.
38. Jones BJM, Lees R, Andrews J, et al: Comparison of an elemental and polymeric enteral diet in patients with
normal gastrointestinal function. Gut 1983;24:78-84.
39. Kelleher JF, Yudkoff M, Hutchinson R, et al: The pancytopenia of isovaleric acidemia. Pediatrics
1980;65:1023-1027.
40. Ketel A, Ket JL, Schutgens RBH, et al: Clinical and biochemical observations on a child with a deficiency of
3-hydroxy-3-methylglutaryl coenzyme A lyase. J Inher Metab Dis 1980;3:89-90.
41. Krieger I, Tanaka K: Therapeutic effects of glycine in isovaleric acidemia. Pediatr Res 1976;10:25-29.
42. Lehnert W, Niederhoff H, Suormala T, Baumgartner ER: Isolated biotin-resistant 3-methylcrotonyl-CoA
carboxylase deficiency: Long-term outcome in a case with neonatal onset. Eur J Pediatr 1996;155:568-572.
43. Leupold D, Bojasch M, Jakobs C: 3-Hydroxy-3-methylglutaryl-CoA lyase deficiency in an infant with macrocephaly
and mild metabolic acidosis. Eur J Pediatr 1982;183:73-76.
44. Lott IT, Erickson AM, Levy HL: Dietary treatment of an infant with isovaleric acidemia. Pediatrics 1972;49:616-618.
45. MacLean W, Graham G: Pediatric Nutrition in Clinical Practice. Menlo Park, Calif: Addison-Wesley Publishing Co,
1982.
46. Millington DS, Roe CR, Maltby DA, Inoue F: Endogenous catabolism is the major source of toxic metabolites in
isovaleric acidemia. J Pediatr 1987;110:56-60.
47. Naglak M, Salvo R, Madsen K, et al: The treatment of isovaleric acidemia with glycine supplements. Pediatr Res
1988;24:9-13.
48. Narisawa K, Gibson KM, Sweetman L, et al: Deficiency of 3-methylglutaconyl- coenzyme A hydratase in two
siblings with 3-methylglutaconic aciduria. J Clin Invest 1986;77:1148-1152.
49. Ohkohchi N, Andoh T, Ohi R, Mori S: Defined formula diets alter characteristics of the intestinal transport of amino
acids and peptides in growing rats. J Pediatr Gastroenterol Nutr 1990;10:490-496.
50. Ostmann-Smith I, Brown G, Johnson A, Land JM: Dilated cardiomyopathy due to type II X-linked
3-methylglutaconic aciduria: successful treatment with pantothenic acid. Br Heart J 1994;72:349-53.
51. Pearson MA, Aleck KA, Heidenreich RA: Benign clinical presentation of 3-methylcrotonylglycinuria. J Inher Metab
Dis 1995;18:640-641.
52. Posati LP, Orr ML: Composition of Foods: Dairy and Egg Products, Agriculture Handbook No. 8-1. Washington,
DC: US Dept of Agriculture, Agricultural Research Service, 1976.
53. Pratt EL, Snyderman SE, Cheung MW, et al: The threonine requirement of the normal infant. J Nutr
1955;56:231-251.
54. Riubier D, Parvy P, Bardet J, et al: Alloisoleucine in isovaleric acidemia. J Inher Metab Dis 1992;15:154-155.
55. Roe CR, Millington DS, Maltby DA: Identification of 3-methylglutaryl-carnitine. J Clin Invest 1984;77:1391-1394.
56. Roe CR, Millington DS, Maltby DA, et al: L-carnitine therapy in isovaleric acidemia. J Clin Invest
1984;74:2290-2295.
57. Rolland MD, Divry P, Zabot MT, et al: Isolated 3-methylcrotonyl-CoA carboxylase deficiency in a 16-month-old
child. J Inher Metab Dis 1991;14:838-839.
58. Rousson R, Guidbaud P: Long term outcome of organic acidurias: Survey of 105 French cases (1967-1983).
J Inher Metab Dis 1984;7 (Suppl 1):10-12.
59. Rutledge SL, Berry GT, Stanley CA, et al: Glycine and L-carnitine therapy in 3-methylcrotonyl-CoA carboxylase
deficiency. J Inher Metab Dis 1995;18:229-305.
60. Salamino F, DiLisa F, Burlina AB, et al: Involvement of erythrocyte calpain in glycine- and carnitine-treated
isovaleric acidemia. Pediatr Res 1994;36:182-186.

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61. Schoeffer A, Herrmann ME, Broesicke HG, Moench E: Effect of dosage and timing of amino acid mixtures on
nitrogen retention in patients with phenylketonuria. J Nutr Med 1994;4:415-418.
62. Shilkin R, Wilson G, Owles E: 3-Hydroxy-3-methylglutaryl-coenzyme A lyase deficiency. Acta Paediatr Scand
1981;70:265-268.
63. Smith CA, Nelson NM (eds): The Physiology of the Newborn Infant, ed 4. Springfield, IL: Charles C Thomas
Publisher, 1976.
64. Smith JL, Arteaga C, Heymsfield SB: Increased ureagenesis and impaired nitrogen use during infusion of a
synthetic amino acid formula - A controlled trial. N Engl J Med 1982;306:1013-1018.
65. Smith JL, Heymsfield SB: Enteral nutrition support: Formula preparation from modular ingredients. JPEN
1983;7:280-288.
66. Snyderman SE, Roitman EL, Boyer A, et al: The essential amino acid requirements of infants: Leucine. Am J Dis
Child 1961;102:157-162.
67. Stacey TE, de Sousa C, Tracey BM, et al: Dizygotic twins with 3-hydroxy- 3-methylglutaric aciduria: Unusual
presentation, family studies, and dietary management. Eur J Pediatr 1985;1444:177-181.
68. Sweetman L, Williams JC: Branched chain organic acidurias. In Scriver CR, et al (eds): The Metabolic and
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69. Thompson GN, Chalmers RA, Holliday D: The contribution of protein catabolism to metabolic decompensation in
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70. van Hove JLK, Kahler G, Millington DS, et al: Intravenous L-carnitine and acetyl-L-carnitine in medium-chain-acyl-
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71. van Hove JLK, Rutledge SL, Nada MA, et al: 3-Hydroxyisovalerylcarnitine in 3-methylcrotonyl-CoA carboxylase
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72. Wilson WG, Audenaert SM, Squillaro EJ: Hyperammonemia in a preterm infant with isovaleric acidemia. J Inher
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74. Yudkoff M, Cohn RM, Puschak R, et al: Glycine therapy in isovaleric acidemia. J Pediatr 1978;92:813-817.

© 2001 Ross Products Division Disorders of Leucine Catabolism 123


PROTOCOL 7 — Mitochondrial Acetoacetyl-CoA Thiolase Deficiency (ß-Ketothiolase
Deficiency)

Nutrition Support of Infants, Children, and Adults With


KETONEX ®-1 and KETONEX ®-2 Amino Acid-Modified Medical Foods
I. Introduction
Beta-ketothiolases catalyze the reversible cleavage of ß-ketoacyl-CoA with a-CoA to form an acyl-CoA
with two fewer carbons and acetyl-CoA. Mitochondrial acetoacetyl-CoA thiolase interconverts
α-methylacetoacetyl-CoA to propionyl-CoA plus acetyl-CoA in essential isoleucine (ILE) catabolism
and acetoacetyl-CoA to two acetyl-CoAs in fatty acid oxidation (Figure F) (46).

Figure F. Isoleucine metabolism in mitochondrial acetoacetyl-CoA thiolase deficiency


The clinical features of mitochondrial acetoacetyl-CoA thiolase deficiency range from frequent
severe catabolic crises in infants to asymptomatic adults (46). The most common features are failure
to thrive, intermittent severe metabolic acidosis, and ketosis (9, 10) with hematemesis (6), melena (6,
46), and coma (21, 34) following upper respiratory or gastrointestinal infections or increased protein
intake. The episodes usually begin between 1 and 2 years of age and may occur every few months.
One patient expired with congestive cardiomyopathy at 8 years of age (18). Several siblings of
probands who were presumably affected died during acute episodes. Acute episodes usually resolve
with intravenous glucose and no permanent damage may result, although two patients had
developmental retardation and another is mentally retarded. Most patients are treated with moderate
restriction of ILE intake, avoidance of fasting, and L-carnitine administration, which greatly reduce or
eliminate severe episodes. Several patients have reported severe headaches beginning at 6 to
7 years of age (17) and 2 patients had ataxia (17). The father of 1 patient was shown to have the
same severe deficiency of enzyme activity and never had symptoms (46). In one case, the initial
diagnosis was of salicylate toxicity because of similar symptoms and a positive test for salicylates
(35).

II. Outcome of Nutrition Support


With prompt correction of severe metabolic acidosis and ketosis and treatment with moderate restriction
of essential ILE and L-carnitine administration (7), prognosis and subsequent growth and development
are excellent for patients with mitochondrial acetoacetyl-CoA thiolase deficiency.

124 ß-Ketothiolase Deficiency © 2001 Ross Products Division


III. Establish Diagnosis
A. The Defect
1. Results from deficiency of mitochondrial acetoacetyl-CoA thiolase (3, 10, 11, 20, 21, 26-28,
34, 35).
B. The Disorder
1. Diagnostic studies should be conducted in any infant or child with recurring episodes of severe
ketosis, metabolic acidosis (6), hyperglycinemia (20, 23), ± hematemesis (6), and
± melena (6).
2. Studies should be conducted during acute illness.
C. Laboratory Studies
1. Analysis of urinary organic acids.
a. Elevations of the following metabolites are diagnostic:
1) α-methyl-ß-hyroxybutyric acid (3, 10, 11, 14, 31).
2) α-methylacetoacetic acid (3, 10, 11, 14).
3) Butanone.
4) Tiglylglycine (3, 10, 11).
2. Assay of acetoacetyl-CoA thiolase in fibroblasts (6, 38) or leukocytes (3, 11, 14, 21, 28, 38).
D. Prenatal Diagnosis
1. Measure activity of mitochondrial acetoacetyl-CoA thiolase in cultured amniocytes or chorionic
villus cells (46).

IV. Rationale for Nutrition Support


A. Correct Primary Imbalance in Metabolic Relationships
1. Restrict dietary ILE to amount that maintains normal urinary excretion of organic acids.
B. Provide Conditionally Essential Nutrient
1. Administer L-carnitine to maintain normal plasma free carnitine concentration > 30 µmol/L.

V. Nutrition Support During Acute Illness or at Diagnosis


A. Initiation of Nutrition Support
1. Initiate nutrition support immediately on confirmation of diagnosis and control of metabolic
acidosis and ketosis.
2. Evaluate plasma concentrations of ILE, leucine (LEU), and valine (VAL) daily initially to
prevent deficiency.
B. Patients Without Severe Neurologic Involvement
1. Begin high-energy feeds (120-150 kcal/kg for infants, 80-100 kcal/kg for children, and
40-50 kcal/kg for adults) that supply adequate water (Table 7-1, p 113).
a. Depending on age and clinical status, feed patient by nipple, nasogastric tube,
intravenous infusion, or combine these methods.
1) For nipple or nasogastric feeds, use Ketonex (Table 7-2, p 133).
2) For intravenous feeds via central line, use hypertonic D-glucose and Liposyn ® II
(Appendix 26, p A-28).
3) For intravenous feeds via peripheral line, use isotonic glucose and Liposyn II
(Appendix 26, p A-28).
2. Introduce nutrition support with Ketonex (Table 7-2, p 133) with added source of L-LEU and
L-VAL as rapidly as possible. See Table 7-1, p 133, for Recommended LEU, VAL, Protein,
Energy, and Fluid Intakes.
3. Add ILE (Table 7-1, p 133) to Ketonex feeds when plasma ILE concentration reaches lower
limit of normal (50 µmol/L).
a. Calculate amount of infant formula, beikost, whole cow's milk, or table foods (Table 7-3,
p 133) required to fill ILE prescription.
b. Measure into Ketonex medical food mixture with disposable syringe if liquid infant formula
or cow's milk is used. Weigh powder on scale that reads in grams.

© 2001 Ross Products Division ß-Ketothiolase Deficiency 125


C. Comatose Patients
1. See Reference 34 for medical management.
2. Begin ILE-free parenteral or nasogastric feeding of amino acids and energy within 36 to
48 hours of initiation of dialysis using nitrogen-free (amino acid-free) dialysate.
a. See Table 7-1, p 133, for Recommended LEU, VAL, Protein, and Energy Intakes.
b. See Table7-2, p 133, for Ketonex composition.
3. Begin intravenous infusion of Liposyn II (Appendix 26, p A-28) and 10% D-glucose during
nasogastric feeding, continuing until major neurologic signs subside.
4. When plasma ILE reaches lower limit of normal (50 µmol/L), add L-ILE to Ketonex feeds.
a. See Section VB3, p 124.
5. If parenteral amino acid solutions are indicated, see Appendix 26, p A-28.

VI. Establish Goals of Long-Term Nutrition Support


A. Plasma Amino Acid Concentrations (30)
1. Maintain 2- to 4-hour postprandial plasma BCAA concentrations in ranges noted below when
measured by quantitative methods (modified from reference 30), or near lower limit of normal
range for age established by laboratory used.
Amino Acid µmol/L mg/dL
ILE 50 - 105 0.6 - 1.4
LEU 50 - 185 0.6 - 2.4
VAL 130 - 318 1.5 - 3.7
2. In practice, obtaining blood 2 to 4 hours postprandially is not always possible. Acceptable local
standards should be developed if plasma amino acids are evaluated at other times (Practical
Aspects of Nutrition Support, p viii).
B. Growth, Development, and Nutrition Status
1. Support normal growth rate in infants and children and maintain appropriate weight for height
in adults.
2. Support normal development.
3. Maintain normal nutrition status (8).
4. Prevent catabolism.
5. Avoid prolonged fasting.
6. Maintain urine free of organic acids and ketones.
7. Prevent osteopenia (18).

VII. Establish Prescription for Long-Term Nutrition Support


A. ILE
1. Prescribe ILE intake that promotes goals of nutrition support (1-3, 7, 10, 11, 18, 26, 27, 36).
2. ILE requirements vary widely:
a. From patient to patient, depending on activity of acetoacetyl-CoA thiolase (26, 28).
b. In same patient, depending on:
1) Age.
2) Growth rate.
3) Adequacy of energy and protein intakes.
4) State of health.
3. Lowest values for age for ILE listed in Table 7-1, p 133, are suggested for initiating therapy.
4. Changing requirements of patient are determined by frequent monitoring of:
a. Plasma ILE concentration.
b. Urine concentrations of organic acids.
c. See Section X, Suggested Evaluation of Nutrition Support, p 128.
d. With ILE, LEU, and VAL in normal range, plasma amino acids must be measured
frequently to prevent deficiency.
Warning: ILE, LEU, and VAL deficiencies result in adverse effects:
• ILE deficiency: Weight loss or no weight gain; redness of buccal mucosa;
fissures at corners of mouth; tremors of extremities; decreased plasma
cholesterol and ILE concentrations; increased plasma lysine,

126 ß-Ketothiolase Deficiency © 2001 Ross Products Division


phenylalanine, serine, tyrosine, and VAL concentrations; and skin
desquamation if deficiency is prolonged (42).
• LEU deficiency: Loss of appetite, apathy, irritability; weight loss or poor
weight gain; decreased plasma LEU concentration; and increased plasma
ILE, methionine, serine, threonine, and VAL concentrations (44).
• VAL deficiency: Poor appetite, drowsiness; excess irritability and crying
in infants; weight loss or decrease in weight gain; and decreased plasma
albumin concentration (43).
B. Carnitine
1. Prescribe adequate carnitine to maintain plasma free carnitine concentrations in normal range
(> 30 µmol/L).
2. Between 150 and 300 mg L-carnitine/kg may be required (3).
C. Protein
1. Prescribe, initially, amount greater than Recommended Dietary Allowances (RDAs) (2, 13)
(Table 7-1, p 133).
2. Requirements are greater than RDAs when L-amino acids supply majority of protein
equivalent as a result of:
a. Rapid amino acid absorption (15, 16).
b. Early and high peak of plasma amino acids after ingestion of meals where large part of
protein is supplied by L-amino acids (15, 16).
c. Rapid catabolism of amino acids (19, 22, 37, 40).
d. Possible decreased total amino acid absorption (29).
Warning: Long-term inadequate protein intake will result in failure to thrive in infants,
poor growth in children, weight loss in adults, low plasma transthyretin
concentrations, osteopenia, and hair loss.
D. Energy
1. Prescribe amount that should support normal weight gain in infants and children and maintain
appropriate weight for height in adults (Table 7-1, p 133).
2. Requirements vary widely and may be greater than normal when L-amino acids supply
majority of protein equivalent (33).
3. At diagnosis and during metabolic acidosis resulting from infection, energy needs may be 25%
to 40% higher than values listed in Table 7-1, p 133.
Warning: Inadequate energy intake will result in failure to thrive in infants, poor growth
in children, weight loss in adults, depressed tolerance of ILE, and increased
plasma ILE concentration.
E. Fluid
1. Prescribe amount that will supply water requirements (Table 7-1, p 133) (5). Under normal
circumstances, offer minimum of 1.5 mL fluid to neonates and 1.0 mL fluid to children and
adults for each kcal ingested (5).
F. Sodium Bicarbonate
1. Administer sodium bicarbonate hourly when Acetest is 3+.
2. Administer 1 g hourly until Acetest is negative.

VIII. Fill Prescription


A. ILE
1. Calculate amount of infant formula with iron, beikost, whole cow' milk, or table foods
(Table 7-2, p 133) required to fill ILE prescription.
a. Low-iron infant formula, whole cow's milk, or evaporated milk should not be used as ILE
source for infants because of low iron content.
2. Measure liquid infant formula with disposable syringe. Weigh powdered infant formula on
scale that reads in grams.
3. Add beikost or table foods to gradually displace ILE provided by infant formula after infant is
3 to 4 months old or is developmentally ready.

© 2001 Ross Products Division ß-Ketothiolase Deficiency 127


4. Parents or patients may select any foods in prescribed Servings Lists for BCAA-Restricted
Diets (Protocol 5, pp 88-99) in specified amounts to fill diet prescription.
B. LEU and VAL
1. Calculate approximate amounts of LEU and VAL provided by infant formula with iron, beikost,
whole cow's milk, or table foods (Table 7-2, p 133).
2. Subtract amount determined above from total LEU and VAL prescription.
3. Supply any remaining prescribed LEU and VAL as individual pure solutions. Add supplemental
LEU and VAL (Appendix 26, p A-28) only if plasma concentrations are below normal.
a. Mix weighed amounts of L-LEU and L-VAL powders with boiled, cooled water to make
volume of each that yields 10 mg/mL (eg, 1 g with enough water to yield 100 mL).
b. Refrigerate solutions in separate, sterilized, closed containers until used. Discard unused
suspensions after 1 week, if not frozen.
c. Measure solutions into medical food mixture with disposable syringes.
C. Protein
1. Calculate amount of infant formula with iron, beikost, whole cow's milk, or table foods
(Table 7-2, p 133) required to fill the ILE prescription.
2. Subtract amount determined above from protein prescription
3. Supply remaining prescribed protein with Ketonex (Table 7-2, p 133).
a. Ketonex-1 is for infants and toddlers and Ketonex-2 is for children, adolescents, and
adults.
b. Weigh Ketonex powder on scale that reads in grams because of variability of household
measuring equipment (Practical Aspects of Nutrition Support, p vii) and changes in
density during shipping.
c. See Table 5-2 (p 86, footnote 3) for approximate packed weight of Ketonex powder in
level, dry US standard household measures.
D. Carnitine
1. Calculate amount of carnitine provided by Ketonex (Table 5-2, p 86) and infant formula with
iron (Appendices 4 through 7, pp A-4 to A-7).
2. Supply remaining carnitine prescribed with L-carnitine (Appendix 26, p A-28).
E. Energy
1. Calculate energy provided by infant formula with iron, beikost, whole cow's milk, or table foods
(Table 7-2, p 133) required to fill ILE prescription plus energy provided by Ketonex (Table 7-2,
p 133) required to fill protein prescription.
2. Subtract amount of energy supplied by these sources from energy prescription.
3. Provide remaining prescribed energy with Polycose ® Glucose Polymers powder
(23 kcal/Tbsp, 3.8 kcal/g) or liquid (2 kcal/mL) (Appendix 9, p A-9); Pro-Phree ® Protein-Free
Energy Module With Iron, Vitamins & Minerals (Appendix 11, p A-10); sugar (48 kcal/Tbsp); or
Free Foods B (Table 7-2, p 133).
a. Do not use corn syrup or table sugar for infants because of osmolarity they yield.
b. Do not use honey for infants because it may contain botulinum toxin (45).
F. Fluid and Mixing Instructions
1. Add sufficient boiled, cooled water to infant formula, Ketonex, L-carnitine, and carbohydrate (if
needed) to yield prescribed volume.
2. Mix with sterilized blender at lowest speed for no longer than 3 to 4 seconds. Excess mixing
may destabilize emulsion. May also be mixed in tightly closed container by shaking
vigorously for 10 to 12 seconds.
3. Refrigerate in sterilized, closed containers until used. Discard unused portion 24 hours after
mixing because of nutrient loss.
4. Do not use terminal sterilization because of Maillard reaction (Practical Aspects of Nutrition
Support, p viii).
5. Warm or cool medical food mixture to room temperature before feeding to infants. Shake well
before feeding.
6. Do not warm medical food mixture for infants in microwave oven. Unevenly heated formula
can burn infants, and steam can make bottles explode.
128 ß-Ketothiolase Deficiency © 2001 Ross Products Division
7. Notify parents or caretakers when they may discontinue using aseptic technique in preparing
medical food mixture for infants.
8. For children and adults, chill Ketonex medical food mixture to improve taste.
G. Diet Guide
1. Provide parents, caretakers, or patient with completed Diet Guide (Appendix 22, p A-24) with
each diet change.
2. Feed young infants 6 to 8 times daily (15, 16, 19, 37).
3. Feed children and adults 4 to 6 times daily (15, 16, 19, 37).
4. Avoid prolonged fasting.

IX. Evaluate Adequacy and Safety of Planned Nutrition Support


A. Nutrient Adequacy
1. Determine if diet provides nutrients in amounts prescribed in Section VII, Establish
Prescription, p 125.
a. See Table 7-2, p 133, for composition of Ketonex, infant formulas, and whole cow's milk.
2. Check diet to determine if it supplies Recommended Dietary Intakes (RDIs) for minerals and
vitamins (Table 5-2, p 86, and Appendices 13 and 14, pp A-14 and A-15).
a. See Table 5-2, p 86, and Appendices 4 through 7, pp A-4 to A-7, for complete nutrient
composition of Ketonex and infant formulas.
b. Appendix 23, p A-25, may be used to check adequacy of nutrients if computer program is
not available.
c. If Ketonex mixture provides < 100% of RDIs for infants and < 75% for children and adults,
supplement diet with needed minerals and vitamins if not provided by beikost or table
foods and laboratory tests indicate need.
1) See Appendix 11, p A-10, for composition of supplements.
B. Osmolarity
1. If concentration of prescribed medical food mixture is > 24 kcal/fl oz, determine if osmolarity
is in acceptable range.
a. Determine osmolarity by laboratory analysis or use mathematical formula given in
Appendix 18, p A-20.
b. Osmolarity per gram of Ketonex is listed in Appendix 19, p A-21.
2. If osmolarity is > 450 mosm /kg H2O for neonates, > 750 mosm/L for children, >
1,000 mosm/L for adults, or is greater than tolerated by patient, increase water content of
prescribed medical food mixture and recalculate its osmolarity (25, 41).
C. Potential Renal Solute Load
1. Dehydration will result if renal solute load is greater than renal-concentrating ability of patient.
2. If concentration of medical food mixture prescribed is > 24 kcal/fl oz, estimate its potential
renal solute load.
a. This step is important to prevent dehydration of infants who may have renal-concentrating
capacity as low as 600 mosm/L.
b. Upper limit of renal solute load for neonates is approximately 1,100 mosm/L (39).
3. A method for estimating potential renal solute load is given in Appendix 20, p A-22.
4. If potential renal solute load is excessive, increase water content of medical food mixture and
recalculate.

X. Suggested Evaluation of Nutrition Support


A. Plasma BCAA Concentrations
1. Initial:
a. Evaluate daily by quantitative methods to make sure that concentrations stabilize in low
normal range.
2. Ongoing:
a. Frequent evaluations help ensure adherence to nutrition support plan.
b. Evaluate twice monthly by quantitative methods until patient is 6 months old and monthly
thereafter.

© 2001 Ross Products Division ß-Ketothiolase Deficiency 129


3. Unacceptable amino acid concentrations.
a. If plasma ILE, LEU, or VAL concentration is not detected and patient has ingested full
prescription:
1) Increase prescribed amount of undetected amino acid(s) by 25% and reevaluate
plasma concentrations in 3 days.
2) If plasma ILE, LEU, or VAL concentration continues undetected, repeat above process
until value is in treatment range.
b. If plasma ILE concentration is < 50 µmol/L, plasma LEU concentration is < 50 µmol/L, or
plasma VAL concentration is < 130 µmol/L, and the patient has ingested full prescription:
1) Increase prescribed amount of amino acid that is low by 5% to 10% and reevaluate
plasma concentration in 1 week.
2) If plasma ILE, LEU, or VAL concentration continues to be low, repeat above process
until value is in treatment range.
c. If plasma ILE concentration is > 105 µmol/L, plasma LEU concentration is > 185 µmol/L,
or plasma VAL concentration is > 318 µmol/L, and patient is not ill and has not ingested
more or less protein and energy than prescribed:
1) Decrease prescribed amount of elevated amino acid by 5% to 10% and reevaluate
plasma concentration in 1 week.
2) If plasma ILE, LEU, or VAL concentration continues high, repeat above process until
value is in treatment range.
B. Urine Ketoacids by Ketostix ® (17)
1. Evaluate daily to 6 months of age and twice weekly thereafter.
2. If patient is ill, evaluate daily.
3. Urine should be free of ketoacids at all times (negative Ketostix).
4. If urine contains ketoacids (positive Ketostix):
a. Immediately obtain blood sample for evaluation of ILE concentration by quantitative
methods.
b. Brief metabolic physician immediately on patient's illness.
C. Plasma Carnitine Concentration
1. Analyze plasma free carnitine concentration monthly during first 6 months of life and every
3 months thereafter.
2. If plasma free carnitine concentration is < 30 µmol/L, increase L-carnitine administered by 5%
to 10% and reevaluate in 1 week.
3. If plasma free carnitine concentration remains low, repeat above process until value is in
normal range.
D. Protein Status
1. Evaluate plasma transthyretin every 3 months until patient is 1 year of age and every 6
months thereafter (Appendix 17, p A-18, for standards).
a. Plasma transthyretin concentrations provide a more reliable and rapid indication of protein
status than plasma albumin concentrations.
b. Plasma albumin concentrations may be in the normal range when plasma transthyretin
concentrations show a clear deficiency (4).
2. If plasma transthyretin concentration is below standard:
a. Increase prescribed protein by 5% to 10% and reevaluate plasma transthyretin
concentration in 1 month. If ILE concentration is in treatment range, use Ketonex to
increase protein.
b. If plasma transthyretin concentration remains low, repeat above process until value is in
normal range.
E. Iron Status
1. Plasma ferritin concentration.
a. Evaluate at 6, 9, and 12 months of age and every 6 months thereafter (Appendix 17,
p A-18, for standards).
b. If plasma ferritin concentration is below standard:
1) Increase iron intake to 4 mg/kg body weight with supplements (ferrous sulfate).

130 ß-Ketothiolase Deficiency © 2001 Ross Products Division


2) Evaluate plasma ferritin concentration monthly on increased iron intake.
3) Continue iron supplements until plasma ferritin concentration is in normal range.
2. Complete blood count.
a. Hemoglobin and hematocrit concentrations should be evaluated every 3 months in infants
and every 6 months in toddlers (Appendix 17, p A-18, for standards).
F. Growth Status
1. Length/height and weight.
a. Measure monthly to 1 year and every 3 months thereafter. Plot measurements on NCHS
growth charts.
b. Maintain length/height and weight between 10th and 90th percentiles. Some normal
infants, children, and adults will fall above or below these percentiles.
2. If length/height or weight falls below usual growth channel:
a. Increase protein and energy prescriptions by 5% to 10% and remeasure in 1 month.
b. If length/height or weight remains low, repeat above process until usual growth channel is
achieved.
G. Nutrient Intake
1. Maintain records of food intake for 3 days immediately before each blood test (Appendices 24
and 25, pp A-26 and A-27).
2. Evaluate intakes of BCAAs, protein, and energy before each blood test.
3. Evaluate mineral and vitamin intakes after each diet change.
a. Appendix 23, p A-25, may be used to check adequacy of nutrients if computer program is
not available.
b. See Appendix 28, p A-29, for information about ordering software for diet evaluation.
H. Clinical Summary
1. A summary record of growth, laboratory, and nutrient intake data is useful for patient
management (Table 7-3, p 134).

XI. Sample Prescriptions


A. Example 1
Establish and fill prescription for newborn weighing 3.0 kg using Recommended Daily Nutrient
Intakes from Table 7-1, p 133 and nutrient contents from Table 7-2, p 133.
1. Establish prescription.
ILE 100 mg/kg x 3.0 kg = 300 mg
LEU ≥ 180 mg/kg x 3.0 kg = > 540 mg
VAL ≥ 100 mg/kg x 3.0 kg = > 300 mg
Protein 3.5 g/kg x 3.0 kg = 10.5 g
Energy 140 kcal/kg x 3.0 kg = 420 kcal
Fluid 150 mL/kg x 3.0 kg = 450 mL
2. Fill prescription.
Medical Food Mixture Measure ILE LEU VAL Protein Energy
(mg) (mg) (mg) (g) (kcal)
Ketonex-1 32 g 0 0 0 4.8 154
Similac With Iron RTF 405 mL 304 583 336 5.7 275
Add water to make 450 mL (15 fl oz).

Total per day 304 583 336 10.5 429


Total per kg 101 194 112 3.5 143
Approximate osmolarity of medical food mixture is < 450 mosm/L. Estimated potential renal solute load
is ≤ 100 mosm.

© 2001 Ross Products Division ß-Ketothiolase Deficiency 131


B. Example 2
Establish and fill prescription for 2-year-old child weighing 13 kg using Recommended Daily
Nutrient Intakes from Table 7-1, p 133 and nutrient contents from Table 7-2, p 133.
1. Establish prescription.
ILE 750 mg/day
LEU > 1,000 mg
VAL > 750 mg
Protein 30 g
Energy 1,300 kcal
Fluid 1,300 mL
2. Fill prescription.
Medical Food Mixture Measure ILE LEU VAL Protein Energy
(mg) (mg) (mg) (g) (kcal)
Ketonex-2 42 g 0 0 0 12.6 172
Whole cow's milk 144 mL 295 478 327 4.9 91
Add water to make 710 mL (24 fl oz). Offer additional fluid ad libitum daily.

Food List Servings


Breads/Cereals 14 252 490 350 7.0 420
Fats 4 28 40 28 0.4 280
Fruits 4 68 100 88 2.4 300
Vegetables 5 110 150 120 3.0 75
Total per day 753 1,258 913 30.3 1,338
Approximate osmolarity of medical food mixture is < 400 mosm/L.

C. Example 3
Establish and fill prescription for 15-year-old boy weighing 60 kg using Recommended Daily
Nutrients Intakes from Table 7-1, p 133 and nutrient contents from Table 7-2, p 133.
1. Establish prescription.
ILE 1,300 mg/day
LEU < > 1,650 mg
VAL < > 1,300 mg
Protein 65 g
Energy 2,800 kcal
Fluid 2,800 mL
2. Fill prescription.
Medical Food Mixture Measure ILE LEU VAL Protein Energy
(mg) (mg) (mg) (g) (kcal)
Ketonex-2 122 g 0 0 0 36.6 500
Whole cow's milk 314 mL 644 1,042 713 10.6 198
Add water to make 1,000 mL (34 fl oz). Offer additional fluid ad libitum daily.

Food List Servings


Breads/Cereals 20 360 700 500 10.0 600
Fats 12 84 120 84 1.2 840
Fruits 6 102 150 132 3.6 450
Vegetables 5 110 150 120 3.0 75
Free Foods B 3 0 0 0 0.0 165
Total per day 1,300 2,162 1,549 65.1 2,828
Approximate osmolarity of medical food mixture is < 750 mosm/L.

132 ß-Ketothiolase Deficiency © 2001 Ross Products Division


XII. Nutrition Support During Febrile Illness or Following Trauma
A. Rationale
1. Febrile illness and trauma are life-threatening if not diagnosed and treated promptly (47).
B. Management of Nutrition Support
1. See Section V, Nutrition Support During Acute Illness or at Diagnosis, p 124.

© 2001 Ross Products Division ß-Ketothiolase Deficiency 133


TABLE 7-1. Recommended Daily Nutrient Intakes (Ranges) for Infants, Children, and Adults With
ß-Ketothiolase Deficiency

Age Nutrient
ILE1 LEU1 VAL1 Protein2 Energy2 Fluid3
(mg/kg) (mg/kg) (mg/kg) (g/kg) (kcal/kg) (mL/kg)
Infants
0 to < 3 mo 90 - 140 > 180 > 100 3.50 - 3.00 120 (145 - 95) 150 - 125
3 to < 6 mo 85 - 135 > 160 > 90 3.50 - 3.00 115 (145 - 95) 160 - 130
6 to < 9 mo 80 - 135 > 150 > 80 3.00 - 2.50 110 (135 - 80) 145 - 125
9 to < 12 mo 75 - 125 > 140 > 70 3.00 - 2.50 105 (135 - 80) 135 - 120

(mg/day) (mg/day) (mg/day) (g/day) (kcal/day) (mL/day)


Girls and Boys
1 to < 4 yr 750 - 1,000 > 1,000 > 750 > 30 1,300 ( 900 - 1800) 900 - 1,800
4 to < 7 yr 850 - 1,100 > 1,150 > 850 > 35 1,700 (1300 - 2300) 1,300 - 2,300
7 to < 11 yr 1,000 - 1,300 > 1,300 > 1,000 > 40 2,400 (1650 - 3300) 1,650 - 3,300

Women
11 to < 15 yr 1,200 - 1,500 >1,900 > 1,800 > 50 2,200 (1500 - 3000) 1,500 - 3,000
15 to < 19 yr 1,000 - 1,300 > 1,300 > 1,000 > 55 2,100 (1200 - 3000) 1,200 - 3,000
> 19 yr 1,000 - 1,300 > 1,330 > 1,000 > 60 2,100 (1400 - 2500) 1,400 - 2,500

Men
11 to < 15 yr 1,000 - 1,300 > 1,900 > 1,150 > 55 2,700 (2000 - 3700) 2,000 - 3,700
15 to < 19 yr 1,300 - 1,650 > 1,650 > 1,300 > 65 2,800 (2100 - 3900) 2,100 - 3,900
> 19 yr 1,300 - 1,650 > 1,650 > 1,300 > 70 2,900 (2000 - 3300) 2,000 - 3,300
1
From references 1, 12, and 24. Initiate prescription with lowest recommended intake for age. Modify prescription
based on frequently obtained plasma values and growth in infants and children and frequently obtained plasma
values and weight maintenance in adults.
2
Modified from reference 13.
3
From reference 5. Under normal circumstances, offer minimum of 1.5 mL fluid to neonates and 1.0 mL fluid to
children and adults for each kcal ingested. Fluid intake should be higher during illness to enhance urinary ketoacid
excretion.
1
TABLE 7-2. Serving Lists for ILE-Restricted Diets: Average Nutrient Content per Serving

Food List Nutrient


ILE LEU VAL Protein Energy
(mg) (mg) (mg) (g) (kcal)
Breads/Cereals 18 35 25 0.5 30
Fats 7 10 7 0.1 70
Fruits 17 25 22 0.6 75
Vegetables 22 30 24 0.6 15
Free Foods A 3 5 4 0.1 50
Free Foods B 0 0 0 0.0 55
2
Alimentum ® Protein Hydrolysate Formula With Iron, Ready to Feed, 100 mL 108 173 140 1.86 68
2
Isomil ® Soy Formula With Iron, Ready to Feed, 100 mL 74 135 76 1.66 68
Ketonex®-1 powder, 100 g 0 0 0 15.00 480
Ketonex®-2 powder, 100 g 0 0 0 30.00 410
2
Similac ® With Iron Infant Formula, Ready to Feed, 100 mL 75 144 83 1.40 68
3
Whole cow's milk, 100 mL 205 332 227 3.39 63
1
Reference 12
2
See Appendices 4 through 7, pp A-4 to A-7, for complete nutrient composition of infant formulas.
3
From reference 32. See Appendix 8, p A-8, for complete nutrient composition.

134 ß-Ketothiolase Deficiency © 2001 Ross Products Division


TABLE 7-3. ß- Ketothiolase Deficiency Clinical Summary Sheet
134 ß-Ketothiolase Deficiency

Name: Hospital Number:

Date of Birth: __________/__________/__________


Mo Day Year

Date Age Physical Data Laboratory Data Nutrient Intake Data


1 1 1
Length/ Weight Head ILE LEU VAL Free Carn Hgb Hct Ferritin Transthyretin Ketostix ® ILE LEU VAL CARN Protein Energy
Height Circum or Acetest
(mo/d/yr) (yrs/mos) (cm) (kg) (cm) (µmol/L) (g/dL) (%) (ng/mL) (mg/dL) (mg) (mg) (mg) (mg) (g) (kcal)
© 2001 Ross Products Division

1
Indicate if µmol/L or mg/dL.
REFERENCES
1. Acosta PB: The contribution of therapy of inherited amino acid disorders to knowledge of amino acid requirements.
In Wapnir RA (ed): Congenital Metabolic Diseases: Diagnosis and Treatment. New York: Marcel Dekker Inc,
1985, 115-135.
2. Acosta PB, Yannicelli S: Protein intake affects phenylalanine requirements and growth of infants with
phenylketonuria. Acta Paediatr 1994;407 (Suppl):66-67.
3. Aramaki S, Lehotay D, Sweetman L, et al: Urinary excretion of 2-methylacetoacetate, 2-methyl-3-hydroxybutyrate
and tiglyglycine after isoleucine loading in the diagnosis of 2-methylacetyl-CoA thiolase deficiency. J Inher Metab
Dis 1991;14:63-74.
4. Arnold GL, Vladutiu CJ, Kirby RS: Protein insufficiency and impaired growth in children with PKU. J Inher Metab
Dis 2000;23 (Suppl 1):A29.
5. Behrman RE, Kliegman RM, Arvin AA (eds): Nelson Textbook of Pediatrics, ed 15. Philadelphia: WB Saunders Co,
1996.-
6. Bennett MJ, Littlewood JM, MacDonald A, et al: A case of ß-ketothiolase deficiency. J Inher Metab Dis 1983;6:157.
7. Brown GK, Hunt SM, Mitchell DK, Danks DM: Profound neurological illness, relieved by protein restriction, in a
baby with a transient disturbance in the metabolism of ingested isoleucine. Eur J Pediatr 1987;146:363-369.
8. Calomme MR, Vanderpas JB, Francois B, et al: Thyroid function parameters during a selenium repletion/depletion
study in phenylketonuric subjects. Experientia 1995;51:1208-1215.
9. Cromby CH, Manning NJ, Pollitt, et al: 6-Methyluracil excretion in 2-methylacetoacetyl-CoA thiolase deficiency and
in two children with an unexplained recurrent ketoacidaemia. J Inher Metab Dis 1994;17:81-84.
10. Daum RS, Lamm PH, Mamer OA, Scriver CR: A "new" disorder of isoleucine catabolism. Lancet
1971;2:1289-1290.
11. Daum RS, Scriver CR, Mamer OA, et al: An inherited disorder of isoleucine catabolism causing accumulation of
α-methylacetoacetate and α-methyl-ß-hydroxybutyrate, and intermittent metabolic acidosis. Pediatr Res
1973;7:149-160.
12. Elsas LJ, Acosta PB: Nutrition support of inherited metabolic diseases. In Shils ME, et al (eds): Modern Nutrition in
Health and Disease, ed 9. Baltimore: Williams & Wilkins, 1999, pp 1003-1056.
13. Food and Nutrition Board, Committee on Dietary Allowances: Recommended Dietary Allowances, eds 9 and 10.
Washington, DC: National Academy of Sciences, 1980 and 1989.
14. Gompertz D, Saudubray JM, Charpentier C, et al: A defect in L-isoleucine metabolism associated with α-methyl-ß-
hydroxybutyric acid and α-methylacetoacetic aciduria: Quantitative in vivo and in vitro studies. Clin Chim Acta
1974;57:269-281.
15. Gropper S, Acosta PB: Effect of simultaneous ingestion of L-amino acids and whole protein on plasma amino acid
concentrations and urea nitrogen in humans. JPEN 1991;15:48-53.
16. Gropper SS, Gropper DM, Acosta PB: Plasma amino acid response to ingestion of L-amino acids and whole
protein. J Pediatr Gastroenterol Nutr 1993;16:143-150.
17. Halvorsen S, Stokke O, Jellum E: A variant form of 2-methyl-3-hydroxybutyric and 2-methylacetoacetic aciduria.
Acta Paediatr Scand 1979;68:123-128.
18. Henry CG, Strauss AW, Keating JP, Hillman RE: Congestive cardiomyopathy associated with ß-ketothiolase
deficiency. J Pediatr 1981;99:754-757.
19. Herrmann ME, Broesicke HG, Keller M, et al: Dependence of the utilization of a phenylalanine-free amino acid
mixture on different amounts of single dose ingested. A case report. Eur J Pediatr 1994;153:501-503.
20. Hillman RE, Keating JP: Beta-ketothiolase deficiency as a cause of the "ketotic hyperglycinemia syndrome."
Pediatrics 1974;53:221-225.
21. Hiyama K, Sakura N, Matsumoto T, Kuhara T: Deficient beta-ketothiolase activity in leukocytes from a patient with
2-methylacetoacetic aciduria. Clin Chim Acta 1986;155:189-194.
22. Jones BJM, Lees R, Andrews J, et al: Comparison of an elemental and polymeric enteral diet in patients with
normal gastrointestinal function. Gut 1983;24:78-84.
23. Keating JP, Fergin RD, Tenenbaum SM, Hillman RE: Hyperglycinemia with ketosis due to a defect in isoleucine
metabolism: A preliminary report. Pediatrics 1972;50:890-895.
24. Leverton RM, Johnson N, Dazur J, Ellison J: Amino acid requirements of young adults. In Albanese AA (ed):
Protein and Amino Acid Nutrition. New York: Academic Press, 1959.
25. MacLean W, Graham G: Pediatric Nutrition in Clinical Practice. Menlo Park, Calif: Addison-Wesley Publishing Co,
1982.
26. Merinero B, Perez-Cerda C, Garcia MJ, et al: ß-ketothiolase deficiency: Two siblings with different clinical
conditions. J Inher Metab Dis 1987;10 (Suppl 2):276-278.
27. Middleton B, Bartlett K, Romanos A, et al: 3-Ketothiolase deficiency. Eur J Pediatr 1986;144:586-589.
28. Middleton B, Gray RGF, Bennett MJ: Two cases of ß-ketothiolase deficiency: A comparison. J Inher Metab Dis
1984;7 (Suppl 2):131-132.
29. Ohkohchi N, Andoh T, Ohi R, Mori S: Defined formula diets alter characteristics of the intestinal transport of amino
acids and peptides in growing rats. J Pediatr Gastroenterol Nutr 1990;10:490-496.

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30. Picone TA, Benson JD, Moro G, et al: Growth, serum biochemistries, and amino acids of term infants fed formulas
with amino acid and protein concentrations similar to human milk. J Pediatr Gastroenterol Nutr 1989;9:351-360.
31. Pollitt RJ: The occurrence of substituted 3-methyl-3-hydroxyglutaric acids in urine in propionic acidemia and in
ß-ketothiolase deficiency. Biomed Mass Spec 1983;10:253-257.
32. Posati LP, Orr ML: Composition of Foods: Dairy and Egg Products, Agriculture Handbook No. 8-1. Washington,
DC: US Dept of Agriculture, Agricultural Research Service, 1976.
33. Pratt EL, Snyderman SE, Cheung MW, et al: The threonine requirement of the normal infant. J Nutr
1955;56:231-251.
34. Riudor E, Ribes A, Perez-Cerda C, et al: Metabolic coma with ketoacidosis and hyperglycaemia in
2-methylacetoacetyl-CoA thiolase deficiency. J Inher Metab Dis 1995;18:748-749.
35. Robinson BH, Sherwood WG, Taylor J, et al: Acetoacetyl-CoA thiolase deficiency: A cause of severe ketoacidosis
in infancy simulating salicylism. J Pediatr 1979;95:228-233.
36. Sabetta G, Bachmann C, Giardini O, et al: ß-ketothiolase deficiency with favourable evolution. J Inher Metab Dis
1987;10:405-406.
37. Schoeffer A, Herrmann ME, Broesicke HG, Moench E: Effect of dosage and timing of amino acid mixtures on
nitrogen retention in patients with phenylketonuria. J Nutr Med 1994;4:415-418.
38. Schutgens RBH, Middleton B, Blij JFvd, et al: ß-ketothiolase deficiency in a family confirmed by in vitro enzymatic
assay in fibroblasts. Eur J Pediatr 1982;139:39-42.
39. Smith CA, Nelson NM (eds): The Physiology of the Newborn Infant, ed 4. Springfield, IL: Charles C Thomas
Publisher, 1976.
40. Smith JL, Arteaga C, Heymsfield SB: Increased ureagenesis and impaired nitrogen use during infusion of a
synthetic amino acid formula - A controlled trial. N Engl J Med 1982;306:1013-1018.
41. Smith JL, Heymsfield SB: Enteral nutrition support: Formula preparation from modular ingredients. JPEN
1983;7:280-288.
42. Snyderman SE, Boyer A, Norton PM, et al: The essential amino acid requirements of infants: IX. Isoleucine. Am J
Clin Nutr 1964;15:313-321.
43. Snyderman SE, Holt LE, Smellie F, et al: The essential amino acid requirements of infants: Valine. Am J Dis Child
1959;97:186-191.
44. Snyderman SE, Roitman EL, Boyer A, et al: The essential amino acid requirements of infants: Leucine. Am J Dis
Child 1961;102:157-162.
45. Spika JS, Shaffer N, Hargrett-Bean N, et al: Risk factors for infant botulism in the United States. Am J Dis Child
1989;143:828-832.
46. Sweetman L, Williams JC: Branched-chain-organic acidurias. In Scriver CR, et al (eds): The Metabolic and
Molecular Bases of Inherited Disease, ed 8. New York: McGraw-Hill Medical Publishing Division, 2001,
pp 2125-2164.
47. Wannemacher RW: Key role of various individual amino acids in host response to infection. Am J Clin Nutr
1977;30:1269-1280.

© 2001 Ross Products Division ß-Ketothiolase Deficiency 137


PROTOCOL 8 — Homocystinuria

Nutrition Support of Infants, Children, and Adults With


HOMINEX ®-1 and HOMINEX ®-2 Amino Acid-Modified Medical Foods
I. Introduction (14, 27)

Intact protein contains from 0.3% to 5.0% of the essential amino acid methionine (MET) (33). Some
dietary MET is used by the body for tissue protein synthesis, but most is utilized through the
transsulfuration pathway (Figure G). The first step in the transsulfuration pathway is synthesis of
S-adenosylmethionine (SAM), a reaction catalyzed by methionine-S-adenosyltransferase (MAT).
Impaired MAT activity results in hypermethioninemia and variable clinical expression from sulfurous
breath odor to mental retardation. Biologically important compounds that obtain their methyl group
from SAM include creatine, choline and phosphatidylcholine, methylated DNA and RNA, and
epinephrine. S-adenosylhomocysteine is an intermediary product in the transsulfuration pathway and
is hydrolyzed to homocysteine (27).

Tissue protein catabolism Dietary protein

Glycine Serine Methionine†‡ Tissue protein synthesis

Tetrahydrofolate ATP
5,10-Methylene
5-Methyltetra-
tetrahydrofolate hydrofolate
homocysteine Methionine-S-adenosyltransferase
methyl- Dimethylglycine (MAT)
5,10-Methylene
tetrahydrofolate transferase
reductase CH3-B 12

Betaine-homocysteine
5-Methyltetrahydrofolate methyltransferase

Betaine

S-Adenosylmethionine
Choline
‡ ‡
Homocystine Homocysteine

Cystathionine ß-synthase (CBS), B 6


Serine †
Accumulates in MAT deficiency, if untreated.

Accumulates in CBS deficiency, if untreated
(n) = several steps
Adenosylhomocysteine
= site of enzyme malfunction
Cystathionine
Cystathionase, B 6

Cystine Cysteine + α-Ketobutyrate → Propionyl CoA → Succinyl CoA


(n)
SO4 (n)
Taurine

Figure G. Methionine metabolism in homocystinuria


Four possible pathways are open to homocysteine. It can be remethylated to form MET through two
different enzymatic reactions. In one reaction, the methyl group is derived from betaine and is
catalyzed by betaine-homocysteine methyltransferase. The second reaction requires
5
N -methyltetrahydrofolate as a methyl donor and methylcobalamin (CH3-B12) as coenzyme (Figure G)
(47). The enzyme catalyzing this reaction is 5-methyltetrahydrofolate-homocysteine
methyltransferase. The third pathway open to homocysteine is spontaneous oxidation to homocystine
138 Homocystinuria © 2001 Ross Products Division
(Figure G). This reaction occurs only when homocysteine is present in tissue in abnormal amounts.
Homocystine is not

© 2001 Ross Products Division Homocystinuria 139


further metabolized. Most homocysteine is metabolized by cystathionine ß-synthase (CßS) to
cystathionine using serine as co-substrate and pyridoxal phosphate as coenzyme. Cystathionine is
then hydrolyzed to cysteine and α−ketobutyrate. The enzyme cystathionase, for which pyridoxal
phosphate is coenzyme, is required for this reaction (Figure G). A deficiency of cystathionase results
in cystathioninuria, which has no pathologic consequence. Alpha-ketobutyrate is converted to
propionyl-CoA, which is carboxylated to methylmalonyl-CoA and isomerized to succinyl-CoA, a Krebs-
cycle intermediate. L-Cysteine is catabolized to pyruvate, NH3, and H2S.
Defects in the function of CßS or 5-methyltetrahydrofolate-homocysteine methyltransferase result in
classical homocystinuria. Impaired activity of the latter enzyme may be caused by failure to
synthesize methylcobalamin from vitamin B12 or by a deficiency in 5, 10 methylenetetrahydrofolate
reductase, as well as by mutations in the apoenzyme. Several different defects impair the uptake,
transfer, and conversion of dietary vitamin B12 to methylcobalamin.
The most common form of homocystinuria is caused by a deficiency of CßS. Some forms are
responsive to vitamin B6 while others are not. Severely impaired enzyme function produces
accumulation of plasma homocyst(e)ine and MET and decreased cyst(e)ine in cells and physiologic
fluids. If this disorder is not treated early in life, skeletal changes, dislocated lenses, intravascular
throboses (8), osteoporosis (31), malar flushing, and, in some patients, mental retardation will occur.
In a large survey of patients with homocystinuria due to CßS deficiency, only 13% were vitamin B6
responsive (28). The mechanism involves stabilizing CßS to biological degradation. The more
residual enzyme activity present, the more dramatic the response to vitamin B6. Hypermethioninemia
may not be present in the newborn if the activity of CßS is greater than 15%.
Management of CH3-B12 deficiency or impaired methyl transfer with homocystinuria does not require
MET-restricted diets. Rather, pharmacologic amounts of vitamin B12 (47), folate, choline, or betaine
are added, depending on the primary defect.
Pharmacologic doses of pyridoxine should be tried in all patients with hypermethioninemia and
homocystinemia. In newborns and early childhood, 25 to 100 mg per day should be tried for a 4-week
interval before MET restriction. In older children and adults, oral pyridoxine (1 g daily) should be tried.
Weeks may be required for a biochemical response to occur. If the plasma MET and homocysteine
concentrations are reduced, the amount of pyridoxine should be gradually lowered until the minimum
dose required to maintain biochemical normality is reached. Doses of 25 to 750 mg day have been
required for some patients. Excess vitamin B6 for prolonged periods of time may cause peripheral
neuropathy (5, 36) or rhabdomyolysis (38); consequently, if it is not helpful, vitamin B6 should be
discontinued. Betaine supplements will assist in maintaining postprandial plasma homocysteine
concentrations in the near-normal range in individuals (42, 48).
Patients who do not respond completely to pyridoxine will require a MET-restricted diet supplemented
with L-cysteine. L-cysteine becomes an essential amino acid in homocystinuria (Figure G). If plasma
folate concentrations are below normal owing to excess consumption in remethylating homocysteine
to MET, folate should be added as a supplement.
Prenatal diagnosis may be provided by direct enzyme assay of amniotic fluid cells or by DNA analysis
if the mutations are known.

II. Outcome of Nutrition Support


In a retrospective study of 629 patients with CßS deficiency, MET restriction initiated neonatally
prevented mental retardation, decreased the frequency of lens dislocation, and reduced the incidence
of seizures (28). Newborn screening and treatment of 25 cases in Ireland also supports the efficacy of
nutrition management (49). Pyridoxine treatment of vitamin B6-responsive patients decreased the rate
of thromboembolic events (28). Weight and height in a girl with homocystinuria treated from the 9th
day of life was at the 90th percentile (3). Hispanic male twins born at 38 weeks gestation with
homocystinuria grew well during the entire 1st year of life while on nutrition support. Protein intake of
these two subjects averaged 3.7 g/kg/day during the 1st 6 months of life and 2.6 g/kg/day during the
2nd 6-months of life. Energy intake during the 1st 6 months averaged 131 kcal/kg and 100 kcal/kg
during the 2nd 6 months (2).
Cysteine deficiency manifested as abnormally low plasma cysteine concentrations, elevated plasma
MET concentrations, and weight loss in homocystinuria has been reported (35). Up to
150 mg L-cysteine/kg/day may be required to maintain normal plasma cysteine concentrations.
Elevated plasma copper and ceruloplasmin concentrations were found in patients with homocystinuria
(13, 50). No relationship to plasma homocysteine could be found. The twins described

140 Homocystinuria © 2001 Ross Products Division


above had elevated serum copper concentrations of 151 and 144 µg/dL at about 3 months of age (2).
Low plasma selenium concentration and erythrocyte glutathione peroxidase activity were found in a
child with homocystinuria treated with a medical food free of selenium (45).
Vitamin A absorption tests were carried out in untreated patients with homocystinuria by measuring
the elevation in serum retinol concentration after administration of vitamin A alcohol. The explanation
proposed for the resulting subnormal serum retinol elevation was that retinol was oxidized by -SH
groups excreted into the gut (3). Of the 8 plasma retinol values obtained on the twins studied, 1 was
< 20 µg/dL and 5 were between 20 and 30 µg/dL. According to parental report, vitamin A intake was
always more than adequate (1.20-5.58 times RDA for age). Serum transthyretin concentrations were
all below 20 mg/dL (marginal) and 2 values obtained were below 15 mg/dL (deficient) (2).
Fasting serum folate concentrations in untreated patients with homocystinuria were abnormally low.
Two of these subjects were treated with 20 mg folate daily, which led to a decrease in urinary
homocystine excretion (11). Severe folate deficiency was found in an untreated infant with
homocystinuria who was receiving diluted boiled cow's milk for an episode of gastroenteritis (3).
Excessive utilization of 5-methyltetrahydrofolate in remethylation of homocysteine to form MET is
proposed as a reason for folate deficiency in untreated patients (14). The twins reported had adequate
hemoglobin concentrations after 4 months of age, and mean corpuscular volume was normal (2).
Most clinicians who treat individuals with homocystinuria believe that patients should be kept on diet
indefinitely. Termination of diet after growth is achieved may lead to thromboembolisms and ciliary
muscle laxity with lens dislocation. Where initiation or maintenance of nutrition support is not possible,
acetylsalicylic acid (1 g daily), betaine and dipyridamole (100 mg daily) increase platelet survival time
and decrease thrombotic events. Vitamin B6 in pharmacological doses should be tried and folate
should be given (14).

III. Establish Diagnosis


A. The Defect
1. Homocystinuria without methylmalonic aciduria may result from defect in any of at least
3 enzymes (14, 27).
a. Methylenetetrahydrofolate reductase.
b. 5-Methyltetrahydrofolate-homocysteine methyltransferase.
c. CßS.
1) Abnormalities in this enzyme may respond to pharmacologic doses of vitamin B6
(25-100 mg/day for 1-month trial in neonates).
2) Administer smallest amount of vitamin B6 daily that maintains normal concentrations
of plasma MET and homocyst(e)ine (5, 26, 38).
3) Patients who respond to vitamin B6 therapy usually do not require nutrition support.
B. Clinical Screening
1. MET concentration > 1 mg/dL by bacterial inhibition assay or positive urine nitroprusside-
cyanide test requires differential diagnosis.
C. Differential Diagnosis (14, 27).
1. Differential diagnosis will reveal false-positives and identify specific enzyme defects.
2. Therapy depends on enzyme defect present.
3. This protocol addresses nutrition support of patients with vitamin B6 non-responsive CßS
deficiency.

IV. Rationale for Nutrition Support


A. Correct Primary Imbalance in Metabolic Relationships
1. Restrict dietary MET to amount tolerated by patient to maintain treatment plasma MET
concentration (1, 14).
B. Supply Product of Blocked Primary Pathway
1. Supplement dietary cystine (CYS) as necessary to maintain normal plasma CYS
concentration (35)

© 2001 Ross Products Division Homocystinuria 141


V. Establish Goals of Long Term Nutrition Support (14)
A. Plasma MET Concentration
1. Maintain 2- to 4-hour postprandial plasma MET concentration between 18 and 45 µmol/L
when measured by quantitative methods or within range of normal for age in laboratory used
(14)
a. In practice, obtaining blood 2 to 4 hours postprandially is not always possible. Acceptable
local standards should be developed if plasma amino acids are evaluated at other times
(Practical Aspects of Nutrition Support, p viii).
2. Opinions vary as to best concentration of plasma MET and CYS to support normal growth and
development in infants and children.
a. In this protocol, concentrations as close to normal as possible are recommended.
B. Plasma CYS Concentration
1. Maintain 2- to 4-hour postprandial plasma CYS concentration between 25 and 50 µmol/L, or in
normal range for age as established by laboratory used.
C. Blood Homocystine Concentration
1. Maintain concentration of homocystine in blood at < 12 µmol/L.
D. Growth, Development, and Nutrition Status
1. Support normal growth rate in infants and children; maintain appropriate weight for height in
adults.
2. Support normal development.
3. Maintain normal nutrition status (4, 10, 11).
4. Prevent catabolism.
E. Other Manifestations
1. Prevent dystonia (7, 21), thromboembolic disease (8, 12), gastrointestinal disease (20),
bleeding tendency (29), and pancreatitis (32).

VI. Establish Prescription


A. MET
1. Prescribe MET intake that promotes goals of nutrition support (1, 14, 23).
2. MET requirements vary widely:
a. From patient to patient, depending on activity of CßS.
b. In same patient, depending on:
1) Age.
2) Growth rate.
3) Adequacy of energy and protein intakes.
4) State of health.
3. Lowest values for age listed in Table 8-1, p 148, are suggested for initiating therapy.
4. Frequent monitoring of plasma MET concentration is essential to assess patient's changing
requirements (Section IX, Suggested Evaluation of Nutrition Support, p 144).
Warning: MET deficiency results in adverse effects (43):
Decreased plasma MET concentration.
Increased concentrations of plasma phenylalanine, proline, serine, threonine,
and tyrosine.
Decreased plasma cholesterol concentration.
Failure to thrive in infants and children and weight loss in adults.
B. CYS
1. Prescribe CYS intake that maintains treatment plasma CYS concentration (35).
2. Lowest value for CYS for each age group listed in Table 8-1, p 148, is suggested to start
therapy.
3. Changing requirements of patient are determined by frequent monitoring of plasma CYS
concentration.
a. Prescribe CYS above amount supplied by Hominex and beikost or table foods only if
plasma CYS concentration is below normal.
142 Homocystinuria © 2001 Ross Products Division
Warning: CYS deficiency will result in adverse effects (35):
Elevated plasma MET and homocystine concentrations.
Decreased plasma CYS concentration.
Failure to thrive in infants and children and weight loss in adults.
C. Folate
1. Prescribe amount that maintains plasma or erythrocyte folate concentration in normal
range (11, 18) (Appendix 17, p A-18).
2. Daily supplement of 500 to 1000 µg may be required (11).
D. Protein
1. Prescribe, initially, amount greater than Recommended Dietary Allowances (RDAs) (15)
(Table 8-1, p 148).
2. Requirements may be greater than RDAs when L-amino acids supply majority of protein
equivalent as result of:
a. Rapid amino acid absorption (16, 17).
b. Early and high peak of plasma amino acids after ingestion of meals where large part of
protein is supplied by L-amino acids (16, 17).
c. Rapid catabolism of amino acids (19, 22, 37, 40).
d. Possible decreased total amino acid absorption (30).
Warning: Inadequate protein intake will result in failure to thrive in infants, poor growth
in children, weight loss in adults, low plasma transthyretin concentrations,
osteopenia, hair loss, and decreased MET tolerance.
E. Energy
1. Prescribe amount that should support normal weight gain in infants and children and maintain
appropriate weight for height in adults (Table 8-1, p 148).
2. Requirements vary and may be greater than normal when L-amino acids supply majority of
protein equivalent (34).
Warning: Inadequate energy intake will result in failure to thrive in infants, poor growth
in children, and weight loss in children and adults. Weight loss will result in
elevated plasma MET concentration as result of protein catabolism. Poor
growth will result in lower than expected tolerance of MET.
F. Betaine (Appendix 26, p A-28 — Cystadane™)
1. Prescribe amount that will blunt plasma homocyst(e)ine response to meals (42, 48).
2. 3 g betaine 2 to 3 times daily with meals resulted in significant decline in plasma homocystine
concentration and increase in plasma MET concentrations (48).
G. Fluid
1. Prescribe amount that will supply water requirements (Table 8-1, p 148). Under normal
circumstances, offer minimum of 1.5 mL fluid to neonates and 1.0 mL fluid to children and
adults for each kcal ingested (9).

VII. Fill Prescription


A. MET
1. Calculate amount of infant formula with iron, human milk, beikost, whole cow's milk, or table
foods (Table 8-2, p 148) required to fill MET prescription.
a. Low-iron infant formula, whole cow's milk, or evaporated milk should not be used as MET
source for infants because of low iron content.
2. Measure liquid infant formula, human milk, or whole cow's milk with disposable syringe.
Weigh powdered infant formula on scale that reads in grams.
3. Add beikost or table foods (Table 8-2, p 148) to gradually displace MET provided by infant
formula or human milk after infant is 3 to 4 months old or is developmentally ready.
4. Parents or patients may select any food in prescribed food lists (Table 8-3, pp 149-161) in
specified amounts to fill diet prescription.

© 2001 Ross Products Division Homocystinuria 143


B. Protein
1. Calculate amount of protein provided by infant formula with iron, human milk, beikost, whole
cow's milk, or table foods (Table 8-2, p 148) required to fill MET prescription.
2. Subtract amount determined above from protein prescription.
3. Supply remaining prescribed protein with Hominex (Table 8-2, p 148).
a. Hominex-1 is for infants and toddlers and Hominex-2 is for children, adolescents, and
adults.
b. Weigh Hominex powder on scale that reads in grams because of variability of household
measuring equipment (Practical Aspects of Nutrition Support, p vii) and changes in
density during shipping.
c. See Table 8-4 (p 162, footnote 3) for approximate packed weight of Hominex powder in
level, dry US standard household measures.

C. CYS
1. Calculate approximate amount of CYS provided by infant formula with iron, human milk,
beikost, whole cow's milk, or table foods (Table 8-2, p 148) required to fill MET prescription.
2. Calculate amount of CYS supplied by Hominex (Table 8-2, p 148) required to fill protein
prescription.
3. Added together, values calculated in C1 and C2 should fall within range of CYS intake
recommended in Table 8-1, p 148.
4. Add supplemental L-CYS (Appendix 26, p A-28) only if plasma CYS concentration is below
normal
a. Mix weighed amount of L-CYS with boiled, cooled water to yield 10 mg/100 mL
(eg, 1.0 mg L-CYS with enough water to yield 100 mL).
b. Refrigerate suspension in sterilized, closed container until used. Discard unused
suspension after 1 week, if not frozen.
c. Shake well before using. Measure L-CYS suspension into medical food mixture with
disposable syringe.
1) L-cystine is not very soluble in water (11 mg/100 mL).

D. Folate
1. Administer in 3 equal doses daily.
a. A prescription is required for folic acid when given in excess of 400 µg/day.
2. Crush folic acid tablet and mix prescribed dose with applesauce or other fruit purées.
E. Energy
1. Calculate energy provided by infant formula with iron, human milk, beikost, or table foods and
Hominex (Table 8-2, p 148) required to fill MET and protein prescriptions.
2. Subtract amount determined above from energy prescription.
3. Provide any remaining prescribed energy with Polycose ® Glucose Polymers powder
(23 kcal/Tbsp, 3.8 kcal/g) or liquid (2 kcal/mL) (Appendix 9, p A-9); Pro-Phree ® Protein-Free
Energy Module With Iron, Vitamins & Minerals (Appendix 11, p A-10); sugar (48 kcal/Tbsp); or
Free Foods B (Table 8-2, p 148), depending on age of patient.
a. Do not use corn syrup or table sugar for infants because of osmolarity they yield (25).
b. Do not use honey for infants because it may contain botulinum toxin (44).
F. Betaine (Appendix 26, p A-28)
1. Mix with medical food mixture to administer.
G. Fluid and Mixing Instructions
1. Add sufficient boiled, cooled water to infant formula or human milk, Hominex, carbohydrate (if
needed), and L-CYS suspension (if needed) to yield prescribed volume. Tap water may
replace boiled, cooled water when preparing Hominex for older infants, children, and adults.
2. Mix with sterilized blender at lowest speed for no longer than 3 to 4 seconds. Excess mixing
may destabilize emulsion. May also be mixed in sterilized, tightly closed container by
shaking vigorously for 10 to 12 seconds.
3. Refrigerate in sterilized, closed containers until used. Discard unused portion 24 hours after
mixing because of nutrient loss.

144 Homocystinuria © 2001 Ross Products Division


4. Do not use terminal sterilization or boil because of Maillard reaction (Practical Aspects of
Nutrition Support, p viii).
5. Warm or cool medical food mixture to room temperature before feeding to infants. Shake
mixture well before feeding.
6. Do not warm medical food mixture for infants in microwave oven. Unevenly heated formula
can burn infants, and steam can make bottles explode.
7. Notify parents or caretakers when they may discontinue using aseptic technique in preparing
medical food mixture for infants.
8. For children and adults, chill Hominex medical food mixture to improve taste.
H. Diet Guide
1. Provide parents, caretakers, or patient with completed Diet Guide (Appendix 22, p A-24) with
each diet change.
2. Feed young infants 6 to 8 times daily (16, 17, 19, 37).
3. Feed older infants, children, and adults 4 to 6 times daily (16, 17, 19, 37).

VIII. Evaluate Adequacy and Safety of Planned Nutrition Support


A. Nutrient Adequacy
1. Determine if diet provides nutrients in amounts prescribed in Section VI, Establish
Prescription, p 140.
a. See Table 8-2, p 148, for composition of infant formulas, human milk, whole cow's milk
and Hominex.
b. See Appendix 9, p A-9, for composition of Polycose and Appendix 11, p A-10, for
composition of Pro-Phree.
2. Check diet to determine if it supplies Recommended Dietary Intakes (RDIs) of minerals and
vitamins (Appendices 13 and 14, pp A-14 and A-15).
a. See Table 8-4, p 162, for composition of Hominex and Appendices 4 through 7, pp A-4 to
A-7, for complete nutrient composition of infant formulas.
b. Appendix 23, p A-25, may be used to check adequacy of nutrients if computer program is
not available.
c. If Hominex mixture provides < 100% of RDIs for infants and < 75% for children and
adults, supplement diet with needed minerals and vitamins if not provided by beikost or
table foods and laboratory tests indicate need (Appendix 11, p A-10, for composition of
supplements).

B. Osmolarity
1. If concentration of prescribed medical food mixture is > 24 kcal/fl oz, determine if osmolarity
is in acceptable range.
a. Determine osmolarity by laboratory analysis or use mathematical formula given in
Appendix 18, p A-20.
b. Osmolarity per gram of Hominex is listed in Appendix 19, p A-21.
2. If osmolarity is > 450 mosm/L for infants, > 750 mosm/L for children, > 1,000 mosm/L for
adults, or greater than tolerated by patient, increase water content of prescribed medical food
mixture and recalculate its osmolarity (24, 25, 41).
C. Potential Renal Solute Load
1. Dehydration will result if renal solute load is greater than renal-concentrating ability of patient.
2. If concentration of medical food mixture prescribed is > 24 kcal/fl oz, estimate its potential
renal solute load.
a. This step is important to prevent dehydration of infants who may have renal-concentrating
capacity as low as 600 mosm/L.
b. Upper limit of renal solute load for neonates is approximately 1,100 mosm/L (39).
3. A method for estimating potential renal solute load is given in Appendix 20, p A-22.
4. If potential renal solute load is excessive, increase water content of medical food mixture and
recalculate.

© 2001 Ross Products Division Homocystinuria 145


IX. Suggested Evaluation of Nutrition Support
A. Plasma MET, CYS, and Homocystine Concentrations
1. Initial:
a. Evaluate twice weekly by quantitative methods until plasma concentrations stabilize and
approximate dietary MET and CYS requirements are known (14).
b. Unless plasma samples are immediately deproteinized after drawing, CYS will form
disulfide bridges with protein and be precipitated with protein, resulting in plasma CYS
concentration that appears below normal.
2. Ongoing:
a. Frequent evaluations help ensure adherence to nutrition support plan.
b. Evaluate plasma MET, CYS, and homocystine concentrations by quantitative methods
weekly until 6 months of age and monthly when concentrations are in treatment range
(14).
3. Unacceptable MET concentrations:
a. If plasma MET concentration is not detected and patient has ingested full prescription:
1) Add 20 mg to prescribed MET and reevaluate plasma MET concentration in 7 days.
2) If plasma MET concentration continues undetected, repeat above process until value
is in treatment range.
b. If plasma MET concentration is > 45 µmol/L and patient has ingested full prescription:
1) Subtract 5% to 10% from prescribed MET and reevaluate plasma MET concentration
in 7 days.
2) If plasma MET concentration continues > 45 µmol/L, repeat above process until value
is in treatment range.
B. Protein Status
1. Evaluate plasma transthyretin concentration every 3 months until patient is 1 year of age and
every 6 months thereafter (Appendix 17, p A-18, for standards).
a. Plasma transthyretin concentrations provide a more reliable and rapid indication of protein
status than plasma albumin concentrations.
b. Plasma albumin concentrations may be in the normal range when plasma transthyretin
concentrations show a clear deficiency (6).
2. If plasma transthyretin concentration is below standard:
a. Increase prescribed protein by 5% to 10% and reevaluate plasma transthyretin
concentration in 1 month. If plasma MET, CYS, and homocysteine concentrations are in
treatment range, use Hominex to increase protein.
b. If plasma transthyretin concentration continues below standard, repeat above process until
value is in normal range.
C. Iron Status
1. Plasma ferritin concentration.
a. Evaluate at 6, 9, and 12 months of age and every 6 months thereafter (Appendix 17,
p A-18, for standards).
b. If plasma ferritin concentration is below standard:
1) Increase iron intake to 4 mg/kg with supplements (ferrous sulfate).
2) Evaluate plasma ferritin concentration monthly on increased iron intake.
3) Continue iron supplements until plasma ferritin concentration is in normal range.
2. Complete blood count.
a. Hemoglobin and hematocrit concentrations should be evaluated at 6, 9, and 12 months of
age and every 6 months thereafter (Appendix 17, p A-18, for standards).
D. Erythrocyte Folate Status
1. Evaluate every 3 months in infants and twice yearly thereafter.
a. Maintain concentration in normal range of ≥ 200 ng/mL (18).
b. If erythrocyte folate concentration falls to < 200 ng/mL:
1) Supplement with 500 µg folate/day.
2) Evaluate erythrocyte folate concentration in 1 month.

146 Homocystinuria © 2001 Ross Products Division


E. Growth Status
1. Length/height and weight.
a. Measure monthly to 1 year, every 3 months to 4 years, and every 6 months thereafter.
Plot measurements on NCHS growth charts.
b. Maintain length/height and weight between 10th and 90th percentiles. Some normal
infants, children, and adults will fall above or below these percentiles.
2. If length/height or weight falls below usual growth channel:
a. Increase prescribed protein and energy by 5% to 10% and remeasure in 1 month.
b. If length/height or weight remains low, repeat above process until usual growth channel is
achieved.
F. Nutrient Intake
1. Maintain records of food intake for 3 days immediately before each blood test (Appendices 24
and 25, pp A-26 and A-27).
2. Evaluate intakes of MET, CYS, protein, and energy before each blood test.
3. Evaluate mineral and vitamin intakes after each diet change.
a. Appendix 23, p A-25, may be used to check adequacy of nutrients if computer program is
not available.
b. See Appendix 28, p A-29, for information about ordering software for diet evaluation.
G. Clinical Summary
1. A summary record of growth, laboratory, and nutrient intake data is useful for patient
management (Table 8-5, p 163).

X. Sample Prescriptions
A. Example 1
Establish and fill prescription for 1-month-old infant weighing 4 kg using Recommended Daily
Nutrient Intakes from Table 8-1, p 148 and nutrient contents from Table 8-2, p 148.
1. Establish prescription.
MET 15 mg/kg x 4 kg = 60 mg/day
CYS1 300 mg/kg x 4 kg = 1,200 mg
Folate = 500 µg
Protein 3.5 g/kg x 4 kg = 14 g
Energy 120 kcal/kg x 4 kg = 480 kcal
Fluid 150 mL/kg x 4 kg = 600 mL
Betaine 1g x 4 kg = 4g
1
Add only if plasma CYS concentration is below normal.
2. Fill prescription.
Medical Food Mixture Measure MET CYS Protein Energy
(mg) (mg) (g) (kcal)
Hominex-1 78 g 0 351 11.7 374
Similac With Iron Ready to Feed 171 mL 60 32 2.4 116
1 2
L-Cystine 82 mL 0 820 0.0 0
Add water to make 600 mL (20 fl oz).

Total per day 60 1,203 14.1 490


Total per kg 15 300 3.5 122
Approximate osmolarity of medical food mixture is < 450 mosm/L. Estimated potential renal solute load
is 100 mosm.
1
Suspension is 10 mg/mL (1 g L-cystine with water added to make 100 mL).
2
Add only if plasma CYS concentration is below normal.

© 2001 Ross Products Division Homocystinuria 147


B. Example 2
Establish and fill prescription for 2-year-old child weighing 13 kg using Recommended Daily
Nutrient Intakes from Table 8-1, p 148 and nutrient contents from Table 8-2, p 148.
1. Establish prescription.
MET 130 mg/day
CYS1 1,300 mg
Folate 1 mg
Protein 30 g
Energy 1,300 kcal
Fluid 1,300 mL
Betaine 6g
1
Add only if plasma CYS concentration is below normal.
2. Fill prescription.
Medical Food Mixture Measure MET CYS Protein Energy
(mg) (mg) (g) (kcal)
Hominex-1 150 g 0 675 22.5 720
L-Cystine1 50 mL2 0 500 0.0 0
Add water to make 710 mL (24 fl oz). Offer additional fluid ad libitum daily.

Food List Servings


Breads/Cereals 4 80 80 4.8 220
Fats 3 6 0 0.3 150
Fruits 3 15 15 1.5 180
Vegetables 3 30 24 3.0 40
Total per day 131 1,294 32.1 1,310
Approximate osmolarity of medical food mixture is < 600 mosm/L.
1
Add only if plasma CYS concentration is below normal.
2
Suspension is 10 mg/mL (1 g L-cystine with water added to make 100 mL).

C. Example 3
Establish and fill prescription for 9-year-old child weighing 25 kg using Recommended Daily
Nutrient Intakes from Table 8-1, p 148, and nutrient contents from Table 8-2, p 148.
1. Establish prescription.
MET 150 mg/day
CYS1 2,500 mg (2.5 g)
Folate 1 mg
Protein 40 g
Energy 2,400 kcal
Fluid 2,400 mL
Betaine 8g
1
Add only if plasma CYS concentration is below normal.

148 Homocystinuria © 2001 Ross Products Division


2. Fill prescription.
Medical Food Mixture Measure MET CYS Protein Energy
(mg) (mg) (g) (kcal)
Hominex-2 93 g 0 837 27.9 381
1 2
L-Cystine 152 mL 0 1,520 0.0 0
Sugar 144 g (3/4 cup) 0 0 0.0 576
Add water to make 1000 mL (33 fl oz). Offer additional fluid ad libitum daily.

Food List Servings


Breads/Cereals 4 80 80 4.8 220
Fats 4 8 0 0.4 200
Fruits 7 35 35 3.5 420
Vegetables 2 20 16 2.0 40
Free Foods A 7 7 7 1.4 350
Free Foods B 4 0 0 0.0 220
Total per day 150 2,495 40.0 2,407
Approximate osmolarity of medical food mixture is < 1,000 mosm/L.
1
Add only if plasma CYS concentration is below normal.
2
Suspension is 10 mg/mL (1 g L-cystine with water added to make 100 mL).

XI. Nutrition Support During Febrile Illness or Following Trauma


A. Rationale
1. In normal persons, febrile illness and trauma are accompanied by catabolism of body
protein (46).
2. Well-nourished patients with homocystinuria respond to infection and trauma as do normal
persons.
3. Extent of protein catabolism determines subsequent elevation in blood MET concentration.
B. Objectives of Nutrition Support
1. Maintain hydration and electrolyte balance.
a. Offer infants and toddlers Pedialyte ® Oral Electrolyte Maintenance Solution ad libitum
(Appendix 9, p A-9).
2. Depress catabolism.
a. Enhance energy intake when possible by offering fruit juices ad libitum as tolerated; liquid
Jell-O ®; Polycose powder or liquid (Appendix 9, p A-9) or Pro-Phree (Appendix 11,
p A-10); and caffeine-free soft drinks (not diet drinks).
b. Add 1/3 cup Polycose powder may be added to liquid Pedialyte to yield 8 fl oz.
c. Return patient to Hominex medical food mixture and pre-illness diet as rapidly as
possible.
1) Begin with 1/2 original strength Hominex medical food mixture.
2) Increase to original strength as tolerated.
C. Parenteral Nutrition
1. If parenteral amino acid solutions are indicated, see Appendix 26, p A-28.

© 2001 Ross Products Division Homocystinuria 149


TABLE 8-1. Recommended Daily Nutrient Intakes (Ranges) for Infants, Children, and Adults With
Homocystinuria

Age Nutrient
MET1,2 CYS2 Protein3,4 Energy3,4 Fluid5
(mg/kg) (mg/kg) (g/kg) (kcal/kg) (mL/kg)
Infants
0 to < 3 mo 15 - 30 300 3.50 - 3.00 120 (145 - 95) 150 - 125
3 to < 6 mo 10 - 25 250 3.50 - 3.00 115 (145 - 95) 160 - 130
6 to < 9 mo 10 - 25 200 3.00 - 2.50 110 (135 - 80) 145 - 125
9 to < 12 mo 10 - 20 200 3.00 - 2.50 105 (135 - 80) 135 - 120

(mg/kg) (mg/kg) (g/day) (kcal/day) (mL/day)


Girls and Boys
1 to < 4 yr 10 - 20 100 - 200 > 30.0 1,300 ( 900 - 1800) 900 - 1,800
4 to < 7 yr 8 - 16 100 - 200 > 35.0 1,700 (1300 - 2300) 1,300 - 2,300
7 to < 11 yr 6 - 12 100 - 200 > 40.0 2,400 (1650 -3300) 1,650 - 3,300

Women
11 to < 15 yr 6 - 14 50 - 150 > 50.0 2,200 (1500 - 3000) 1,500 - 3,000
15 to < 19 yr 6 - 12 25 - 125 > 55.0 2,100 (1200 - 3000) 1,200 - 3,000
> 19 yr 4 - 10 25 - 100 > 60.0 2,100 (1400 - 2500) 1,400 - 2,500

Men
11 to < 15 yr 6 - 14 50 - 150 > 55.0 2,700 (2000 - 3700) 2,000 - 3,700
15 to < 19 yr 6 - 16 25 - 125 > 65.0 2,800 (2100 - 3900) 2,100 - 3,900
> 19 yr 6 - 15 25 - 100 > 70.0 2,900 (2000 - 3300) 2,000 - 3,300
1
Initiate prescription with lowest value for patient's age. Modify prescription based on frequently obtained plasma values
and growth in infants and children and frequently obtained plasma values and weight maintenance in adults.
2
From references 1, 14, 23.
3
From reference 15.
4
Based on ideal body weight in kilograms.
5
From reference 9. Under normal circumstances, offer minimum of 1.5 mL fluid to neonates and 1.0 mL fluid to
children and adults for each kcal ingested.

TABLE 8-2. Serving Lists For MET-Restricted Diets: Average Nutrient Content Per Serving1

Food List Nutrient


MET CYS Protein Energy
(mg) (mg) (g) (kcal)
Breads/Cereals 20 20 1.2 55
Fats 2 0 0.1 50
Fruits 5 5 0.5 60
Vegetables 10 8 1.0 20
Free Foods A 1 1 0.2 50
Free Foods B 0 0 0.0 55
2
Alimentum ® Protein-Hydrolysate Formula With Iron, Ready to Feed, 100 mL 54 32 1.86 68
Hominex®-1, powder, 100 g 0 450 15.00 480
Hominex®-2, powder, 100 g 0 900 30.00 410
Human Milk, 100 mL 2 22 20 1.05 72
Isomil Soy Formula With Iron, Ready to Feed, 100 mL 2 42 18 1.66 68
2
Similac With Iron Infant Formula, Ready to Feed, 100 mL 35 19 1.40 68
3
Whole cow's milk , 100 mL 86 31 3.39 63
1
From reference 14.
2
See Appendices 4 through 7, pp A-4 to A-7, for complete nutrient composition of infant formulas.
3
From reference 33. See Appendix 8, p A-8, for complete nutrient composition.

150 Homocystinuria © 2001 Ross Products Division


TABLE 8-3. Serving Lists for MET-Restricted Diets: Gerber ® Baby Foods (Beikost)

Food Weight Approximate MET CYS Protein Energy


(g) Measure (mg) (mg) (g) (kcal)
For greatest accuracy, weigh food on scale that reads in grams. All measures are level.

BREADS AND CEREALS

Baked Finger Snacks


Animal crackers, cinnamon graham 24 6 crackers 19 45 1.4 107
Apple cinnamon cookies 20 2 cookies 24 40 1.6 85
Arrowroot cookies 18 3-2/3 cookies 24 53 1.5 82
Banana cookies 16 2 cookies 21 39 1.1 69
Pretzels 12 4 pretzels 24 47 1.5 47
Strawberry fruit bars 16 1-3/4 bar 20 32 0.9 65
Veggie crackers 21 30 crackers 20 42 1.8 100

Cereals, Dry
Barley 9 2 Tbsp + 1 tsp 20 31 1.1 34
Mixed 9 2 Tbsp + 1 tsp 19 28 0.9 35
Oatmeal 7 1 Tbsp + 2 tsp 20 40 1.1 28
Oatmeal/banana 12 3 Tbsp 20 35 1.4 48
Oateal/mixed fruit 10 2 Tbsp + 2 tsp 20 38 1.1 42
Rice 8 2 Tbsp 19 19 0.7