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is the process of testing
newborn babies for treatable genetic,
endocrinologic, metabolic and hematologic
diseases. Newborn screening has been
adopted by most countries around the
world, though the lists of screened diseases
vary widely, anywhere from 1 disorder to
more than 100 disorders.


ëhe AIM of population screening of
neonates is to identify individuals with
increased probability of having those
conditions which are not easily detected
clinically, and for which diagnosis and early
initiation of treatment are necessary to
prevent, delay or ameliorate considerable
disability or serious disease.
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ëo be included as a primary target, a condition
should meet the following minimum criteria:
It can be identified at a phase (24 to 48 hours after
birth) at which it would not ordinarily be clinically
Detected
ëhere are demonstrated benefits of early detection,
timely intervention and efficacious treatment of the
condition being tested
A test with appropriate sensitivity and specificity is
available for it
Úommon considerations in determining whether to
screen for disorders:
½ A disease that can be missed clinically at birth
½ A high enough frequency in the population
½ A delay in diagnosis will induce irreversible
damages to the baby
½ A simple and reasonably reliable test exists
½ A treatment or intervention that makes a
difference if the disease is detected early
½ According to the U.S.(ÚDÚ) 3,000 babies with
severe disorders are identified in the United
States each year using newborn screening
programs at current testing rates.
½ ëhe first test to be universally mandated across
the U.S. was the Guthrie test forphenylketonuria
( PKU), and in many areas and hospitals, the
newborn blood test is often erroneously
referred to as a "PKU test
½ All states now universally test for congenital
hypothyroidism, galactosemia, and increasing
numbers of other diseases as well.
½ ndocrine disorders: Úongenital adrenal
hyperplasia (ÚAH), Úongenital hypothyroidism
½ Blood cell disorders: sickle-cell disease (SS)
½ Inborn errors of carbohydrate metabolism:
Galactosemia
½ Inborn errors of amino acid metabolism:
Phenylketonuria (PKU), Maple syrup urine
disease (MSUD), Homocystinuria
½ Inborn errors of organic acid metabolism:
Biotinidase deficiency
ëhe only tests mandated in every state are
the following:
½ ÚH - Úongenital hypothyroidism
½ H-HP - Benign hyperphenylalaninemia
½ PKU:
Phenylketonuria/hyperphenylalaninemia
½ HAR - Hearing
½ GALë - ëransferase deficient
galactosemia
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½ Phenylketonuria (PKU) (1:20,000)
½ Biotinidase deficiency (1:90,000)
½ Galactosemia (1:60,000)
½ Úongenital hypothyroidism (ÚH) (1:3,350)
½ Úongenital adrenal hyperplasia (ÚAH)
(1:13,500)
½ Úystic fibrosis (Ú ) (1:4500)
½ Hemoglobin variants (S disease: 1:400 AA)
½ Medium chain acyl-ÚoA dehydrogenase
½ deficiency (MÚADD) (1:17,000)
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½ ilter paper Dzbloodspotdz samples are used
½ Bloodspots are used for screening test
½ Úollection timing is important for some analytes
½ 24-hour sample is standard collection
½ Úonfirmation testing is required for positives
½ for positive identification
½ for possible false positives
½ for possible partial deficiencies
½ Úutoffs are conservative Ȃ favoring sensitivity
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½ Autosomal recessive disorder caused by the
lack of phenylalanine hydroxylase, the
enzyme that converts the amino acid
phenylalanine to tyrosine
½ Prevalence: 1:20,000
½ Without early diagnosis and strict adherence
to a
½ special diet, brain damage and mental
retardation can occur
½ Phenylalanine is present in almost all foods
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½ Screening: measure PH after 24 hours

measured by mass spectrometry
elevated PH presumed positive
½ ëreatment: diet restricted in PH
restricted diet maintained through adolescence
important also to restrict PH during PKU
pregnancy
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½ Biotin (Vitamin H) is a molecule needed for

activation of four carboxylases
e.g., pyruvate-oxaloacetate carboxylase needed
for gluconeogenesis
½ Biotin comes from diet
½ Biotinidase is an enzyme necessary to recycle
biotin
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½ Inherited disorder
½ Prevalence: 1:90,000
½ Symptoms:
two weeks to two years of age
seizures, low muscle tone, developmental delay,
hearing loss, vision problems and recurrent
infections.
½ arly treatment with biotin supplementation
results in normal growth and development
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½ Screen: measure biotinidase activity

substrate to product reaction coupled to color
change
low product = presumed positive
½ ëreatment: biotin supplementation
simple, successful treatment




½ Autosomal recessive disorder

½ Primary form is a deficiency of GALë
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enzyme needed to break down the milk sugar


½ Prevalence: 1:60,000
½ Life-threatening galactosemia, mental
retardation, and blindness can occur
½ Úlinical symptoms may present as early as
the first week of life.




½ Screening test: substrate to product reaction

requiring GALë, coupled to fluorescent
endpoint
non-fluorescence = presumed positive
½ ëreatment: eliminate dietary lactose,
galactose
no breastfeeding
simple, effective treatment
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½ Deficiency in the production of thyroid

hormone
½ Prevalence: 1:3,350
½ Poor growth, mental retardation, deafness
and neurological abnormalities can result
without prompt identification and treatment.
½ arly diagnosis and adequate treatment with
thyroxine within the first weeks of life results
in normal growth and intelligence.
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½ Screening test
½ Immunoassays for ë4, ëSH
½ low ë4, elevated ëSH = presumed positive
½ positive is with respect to primary
hypothyroidism
½ ëreatment
ëhyroxine replacement
 

 

 
½ A group of inherited disorders caused by
abnormalities in specific enzymes of the adrenal
gland
½ Ninety percent of congenital adrenal hyperplasia
cases arecaused by the lack of the enzyme steroid
21-hydroxylase
½ Prevalence: 1:13,500
½ Babies with untreated congenital adrenal
hyperplasia may develop vomiting and severe
dehydration (aldosterone deficient, salt-wasting
ÚAH), which can be life threatening
½ Increased production of androgens can result in
ambiguous genitalia in infants
 

 

 

½ Screening test
immunoassay for 17-OH-progesterone
elevated 17-OH-P = presumed positive
½ ëreatment
androgen suppression
cortisol replacement/endocrine monitoring
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½ Inherited red blood cell disorders caused by

abnormalities in the structure or production of
hemoglobins
½ Sickle cell anemia (S disease) is one of the most
common hemoglobinopathies
Prevalence: 1:400 in African-Americans
red blood cells sickle and clog small vessels, disrupting the
delivery of oxygen to the body tissues.
Sickle cell anemia can cause pain, infection, lung
complications, gallstones, stroke and other medical
problems.
½ Antibiotics can minimize life-threatening
complications.

 

½ Autosomal recessive disorder characterized by

pulmonary obstruction and/or exocrine
pancreatic dysfunction
½ Prevalence: 1:4500
½ Mutations are of Úystic ibrosis ëransmembrane
Regulator (Ú ëR) gene (chloride ion channel)
½ ëhe major (70%) and most severe genetic
mutation is a three-basepair deletion (ȟ 508)
gene product does not reach membrane
nonfunctional
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½ Immunorective trypsinogen (IRë)

½ produced in the pancreas and transported to the
intestine, where it is activated to form the enzyme
trypsin.
½ In Ú , thick mucus plugs can obstruct pancreatic ducts
and prevent trypsinogen from reaching the intestine.
½ IRë will be elevated in newborns with Ú , but positive
results must be followed by confirmatory testing as there
is a high rate of false positive IRës (positives due to
conditions other than Ú and/or temporary elevations)
½ Úonfirmation may involve a sweat test for elevated
chloride
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½ Screening test
immunoassay for IRë
elevated IRë = presumed positive
PÚR check for ȟ 508 deletion mutation
expanded PÚR mutation panel (99% sensitivity)
½ ëreatment
medical care for nutrition, pancreatic enzyme
replacement, infections
outcomes? stateǯs interest?
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½ Inherited disorder of fatty acid oxidation

( AO)
enzyme required to convert fat into energy
AO provides acetyl-ÚoA to Krebs cycle
½ Prevalence: 1:17,000
½ free fatty acids mobilized by hormonal
activity during fasting
½ defects present as acute, life-threatening
episodes of hypoketotic, hypoglycemic coma
induced by fasting
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½ Screening test
by mass spectrometry
measure acylcarnitine profile
elevated Ú8-acylcarnitine = presumed positive
½ ëreatment
careful, critical avoidance of prolonged fasting
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½ Úarnitine Palmitoyl ëransferase Deficiency ëype l (ÚPë-1)
½ Úarnitine Palmitoyl ëransferase Deficiency ëype ll (ÚPë-2)
½ Úarnitine/Acylcarnitine ëranslocase Deficiency (ÚAë)
½ Long-Úhain hydroxy Acyl-ÚoA Dehydrogenase Def (LÚHAD)
½ Multiple Acyl-ÚoA Dehydrogenase Deficiency GA-II
½ Short-Úhain Acyl-ÚoA Dehydrogenase Def. (SÚAD)
½ Short-Úhain Hydroxy Acyl-ÚoA Dehydr. Def. (SÚHAD)
½ J     
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½ ërifunctional Protein Deficiency
½ Very Long-Úhain Acyl-ÚoA Dehydrogenase Def. (VLÚAD)
½ Long-Úhain Acyl-ÚoA Dehydrogenase Def. (LÚAD)
½ 2,4 Dienoyl-ÚoA Reductase Deficiency
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½ Glutaric Aciduria ëype I (GA-1)
½ 3-Hydroxy-3-Methylglutaryl-ÚoA Lyase Deficiency (HMG)
½ Isobutyryl-ÚoA Dehydrogenase Deficiency
½ Isovaleric Acidemia (IVA)
½ Malonic Aciduria
½ GJ    GJ
½ Methylmalonic Acidemia (MMA)
½ Mitochondrial Acetoacetyl-ÚoA ëhiolase Def (3-
Ketothiolase)
½ Propionic Acidemia (PA)
½ 2-Methylbutyrl-ÚoA Dehydrogenase Deficiency
½ Multiple ÚoA Úarboxylase Deficiency
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½ Argininemia
½ Argininosuccinate Lyase Deficiency (ASA)
½ Úarbamoylphosphate Synthetase Deficiency
(ÚPS)
½ Úitrullinemia
½ Hyperammonemia, Hyperornithinemia,
Homocitrullinuria (HHH)
½ Nonketotic hyperglycinemia
½ 5-oxoprolinuria
½ ëyrosinemia type I
½ ëyrosinemia type II
 
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½ if already in place, MS/MS alters criteria for

panel inclusion
prevalence not a consideration
treatment not a consideration
cost not a consideration
½ requires large capital investment
½ requires uncommon technical and clinical
expertise


 


  

½ ëest panel is not uniform

½ Advocacy is for uniform panel
 


 
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Ë ensure high technical and clinical expertise
Ë cost-effective LÚ-MS/MS is very expensive
½ Note that newborn screening is genetic
testing Ȃ laws concerning dissent vary
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½ Success is testimony to:

basic science
medical science
technology
public policy



 
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½ NIHǯs DzOnline Mendelian Inheritance in Mandz

(OMIM)
½ National Newborn Screening and Genetics
Resource Úenter
½ State screening program websites
½ Public advocacy websites
½ MS/MS websites