Newborn screening

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Newborn screening
Intervention

MeSH

D015997

Newborn screening is a public health program designed to screen infants shortly after birth for a list of conditions that are treatable, but not clinically evident in the newborn period. Some of the conditions included in newborn screening programs are only detectable after irreversible damage has been done, in some cases sudden death is the first manifestation of the disease. Screening programs are often run by state or national governing bodies with the goal of screening all infants born in the jurisdiction. The number of diseases screened for is set by each jurisdiction, and can vary greatly. Most newborn screening tests are done by measuring metabolites and enzyme activity in whole blood samples collected on specialized filter paper, however many areas are starting to screen infants for hearing loss using automated auditory brainstem response and congenital heart defects usingpulse oximetry. Infants who screen positive are contacted and undergo further testing to determine if they are truly affected with a disease or if the test result was a false positive. Follow-up testing is typically coordinated between geneticists and the infant's pediatrician or primary care physician.

Newborn screening debuted as a public health program in the United States in the early 1960s, and has expanded to countries around the world, with different testing menus in each country. The first disorder detected by modern newborn screening programs was phenylketonuria, a metabolic condition in which the inability to degrade the essential amino acid phenylalanine can cause irreversible mental retardation unless detected early. With early detection, and dietary management, the negative effects of the disease can be largely eliminated. Robert Guthrie developed a simple method using a bacterial inhibition assay that could detect high levels of phenylalanine in blood shortly after a baby was born. Guthrie also pioneered the collection of blood on filter paper which could be easily transported, recognizing the need for a simple system if the screening was going to be done on a large scale. Newborn screening around the world is still done using similar filter paper.

History
Robert Guthrie is given much of the credit for pioneering the earliest screening for phenylketonuria in the late 1960s using blood samples on filter paper obtained by pricking a newborn baby's heel on the second day of life to get a few drops of blood. [1] Congenital hypothyroidism was the second disease widely added in the 1970s. [2] Guthrie and colleagues also developed bacterial inhibition assays for the detection of maple syrup urine disease and classic galactosemia.[3] The development of tandem mass spectrometry screening in the early 1990s led to a large expansion of potentially detectable congenital metabolic diseases that can be identified by characteristic patterns of amino acids and acylcarnitines.[4] In the United States, the American College of Medical Genetics recommended a uniform panel of diseases that all infants born in every state should be screened for. They also developed an evidence based review process for the addition of conditions in the future. The implementation of this panel across the United States meant all babies born would be screened for the same number of conditions. Prior to this, babies born in different states had received different levels of screening. On April 24, 2008, President George W. Bush signed into law the Newborn Screening Saves Lives Act of 2007. This act was enacted to increase awareness among parents, health professionals, and the public on testing newborns to identify certain disorders. It also sought to improve, expand, and enhance current newborn screening programs at the state level.

[edit]Disease qualification Newborn screening programs initially used screening criteria based largely on criteria established by JMG Wilson and F. Jungner in 1968. [5] Although not specifically about newborn population screening programs, their publication, Principles and practice of screening for disease proposed ten criteria that screening programs should meet before being used as a public health measure. Newborn screening programs are administered in each jurisdiction, with additions and removals from the panel typically reviewed by a panel of experts. The four criteria from the publication that were relied upon when making decisions for early newborn screening programs were:
1. having an acceptable treatment protocol in place that changes the outcome for patients diagnosed early with the disease 2. an understanding of the condition's natural history 3. an understanding about who will be treated as a patient 4. a NBS screening test that is reliable for both affected and unaffected patients and is acceptable to the public[6]

As diagnostic techniques have progressed, debates have arisen as to how screening programs should adapt. Tandem mass spectrometry has greatly expanded the potential number of diseases that can be detected, even without satisfying all of the other criteria used for making screening decisions.[6][7] Duchenne muscular dystrophy is a disease that has been added to screening programs in several jurisdictions around the world, despite the lack of evidence as to whether early detection improves the clinical outcome for a patient.[6] [edit]Techniques [edit]Sample

collection

Newborn screening tests are most commonly done from whole blood samples collected on specially designed filter paper. The filter paper is often attached to a form containing required information about the infant and parents. This includes date and time of birth, date and time of sample collection, the infant's weight and gestational age. The form will also have information about whether the baby has had a blood transfusion and any additional nutrition the baby may have received (total parenteral nutrition). Most newborn screening cards also include contact information for the infant's physician in

cases where follow up screening or treatment is needed. The Canadian province of Quebec performs newborn screening on whole blood samples collected as in most other jurisdictions, and also runs a voluntary urine screening program where parents collect a sample at 21 days of age and submit it to a provincial laboratory for an additional panel of conditions.[8][9] Newborn screening samples are collected from the infant between 24 hours and 7 days after birth, with the requirement that the baby has fed at least once. Samples can be collected at the hospital, or by midwives. If a sample is collected from an infant who is less than 24 hours old, the laboratory will often request a repeat specimen be taken after 24 hours. Samples are mailed daily to the laboratory responsible for testing. In the United States and Canada, newborn screening is mandatory, with an option for parents to opt out of the screening in writing if they desire. [10][11] In most of Europe, newborn screening is done with the consent of the parents. Proponents of mandatory screening claim that the test is for the benefit of the child, and that parents should not be able to opt out on their behalf. In regions that favour informed consent for the procedure, they report no increase in costs, no decrease in the number of children screened and no cases of included diseases in children who did not undergo screening. [12] [edit]Laboratory

testing

Because newborn screening programs test for a number of different conditions, a number of different laboratory methodologies are used, as well as bedside testing for hearing loss using evoked auditory potentials[13] and congenital heart defects using pulse oximetry.[14] Newborn screening started out using simple bacterial inhibition assays to screen for a single disorder, starting withphenylketonuria in the early 1960s.[15] With this testing methodology, newborn screening required one test to detect one condition. As mass spectrometry became more widely available, the technology allowed rapid determination of a number of acylcarnitines and amino acids from a single dried blood spot. This increased the number of conditions that could be detected by newborn screening. Enzyme assays are used to screen for galactosemia and biotinidase deficiency. Immunoassays measure thyroid hormones for the diagnosis of congenital hypothyroidism and 17hydroxyprogesterone for the diagnosis of congenital adrenal hyperplasia. Molecular techniques are used for the diagnosis of cystic fibrosis and severe combined immunodeficiency.

[edit]Reporting

results

The goal is to report the results within a short period of time. If screens are normal, a paper report is sent to the submitting hospital and parents rarely hear about it. If an abnormality is detected, employees of the agency, usually nurses, begin to try to reach the physician, hospital, and/or nursery by telephone. They are persistent until they can arrange an evaluation of the infant by an appropriate specialist physician (depending on the disease). The specialist will attempt to confirm the diagnosis by repeating the tests by a different method or laboratory, or by performing other corroboratory or disproving tests. The confirmatory test varies depending on the positive results on the initial screen. Confirmatory testing can include analyte specific assays to confirm any elevations detected, functional studies to determine enzyme activity, and genetic testing to identify disease-causing mutations. In some cases, a positive newborn screen can also trigger testing on other family members, such as siblings who did not undergo newborn screening for the same condition or the baby's mother, as some maternal conditions can be identified through results on the baby's newborn screen. Depending on the likelihood of the diagnosis and the risk of delay, the specialist will initiate treatment and provide information to the family. Performance of the program is reviewed regularly and strenuous efforts are made to maintain a system that catches every infant with these diagnoses. Guidelines for newborn screening and follow up have been published by the American Academy of Pediatrics[16] and the American College of Medical Genetics.[17] [edit]Targeted disorders
See also: List of disorders included in newborn screening programs

Newborn screening is intended as a public health program to identify infants with treatable conditions before they present clinically, or suffer irreversible damage. Phenylketonuria (PKU) was the first disorder targeted for newborn screening, being implemented in a small number of hospitals and quickly expanding across the United States and the rest of the world.[18] After the success of newborn screening for PKU (39 infants were identified and treated in the first two years of screening, with no false negative results), Guthrie and others looked for other disorders that could be identified and treated in infants, eventually developing bacterial inhibition assays to identify classic galactosemia and maple syrup urine disease.[18][3] Newborn screening has expanded since the introduction of PKU testing in the 1960s, but can vary greatly between countries. In 2011, the United States screened for 54

conditions, Germany for 12, the United Kingdon for 2 (PKU and medium chain acyl-CoA dehydrogenase deficiency (MCADD)), while France and Hong Kong only screened for one condition (PKU and congenital hypothyroidism, respectively). [19] The conditions included in newborn screening programs around the world vary greatly, based on the legal requirements for screening programs, prevalence of certain diseases within a population, political pressure, and the availability of resources for both testing and follow-up of identified patients. [edit]Amino

acid disorders

Newborn screening originated with an amino acid disorder, phenylketonuria (PKU), which can be easily treated by dietary modifications, but causes severe mental retardation if not identified and treated early. Robert Guthrie introduced the newborn screening test for PKU in the early 1960s.[15] With the knowledge that PKU could be detected before symptoms were evident, and treatment initiated, screening was quickly adopted around the world. Austria started screening for PKU in 1966 [20] and England in 1968.[21] [edit]Fatty

acid oxidation disorders

With the advent of tandem mass spectrometry as a screening tool, several fatty acid oxidation disorders were targeted for inclusion in newborn screening programs. Medium chain acyl-CoA dehydrogenase deficiency (MCADD), which had been implicated in several cases of sudden infant death syndrome[22][23][24] was one of the first conditions targeted for inclusion. MCADD was the first condition added when the United Kingdom expanded their screening program from PKU only. [19] Population based studies in Germany, the United States and Australia put the combined incidence of fatty acid oxidation disorders at 1:9300 among Caucasians. The United States screens for all known fatty acid oxidation disorders, either as primary or secondary targets, while other countries screen for a subset of these.[25] The introduction of screening for fatty acid oxidation disorders has been shown to have reduced morbidity and mortality associated with the conditions, particularly MCADD. An Australian study found a 74 % reduction in episodes of severe metabolic decompensation or death among individuals identified by newborn screening as having MCADD versus those who presented clinically prior to screening. Studies in the Netherlands and United Kingdom found improvements in outcome at a reduced cost when infants were identified before presenting clinically. [25]

Newborn screening programs have also expanded the information base available about some rare conditions. Prior to its inclusion in newborn screening, short-chain acyl-CoA dehydrogenase deficiency (SCADD) was thought to be life threatening. Most patients identified via newborn screening as having this enzyme deficiency were asymptomatic, to the extent that SCADD was removed from screening panels in a number of regions. Without the cohort of patients identified by newborn screening, this clinical phenotype would likely not have been identified.[25] [edit]Endocrinopathies The most commonly included disorders of the endocrine system are congenital hypothyroidism (CH) and congenital adrenal hyperplasia (CAH).[26] Testing for both disorders can be done using blood samples collected on the standard newborn screening card. Screening for CH is done by measuring thyroxin (T4), thyrotropin (TSH) or a combination of both analytes. Elevated 17-hydroxyprogesterone (17OHP) is the primary marker used when screening for CAH, most commonly done using enzymelinked immunosorbant assays, with many programs using a second tiertandem mass spectrometry test to reduce the number of false positive results.[26] Careful analysis of screening results for CAH may also identify cases of congenital adrenal hypoplasia, which presents with extremely low levels of 17OHP.[26] CH was added to many newborn screening programs in the 1970s, often as the second condition included after PKU. The most common cause of CH is dysgenesis of the thyroid gland After many years of newborn screening, the incidence of CH worldwide had been estimated at 1:3600 births, with no obvious increases in specific ethnic groups. Recent data from certain regions have showed an increase, with New York reporting an incidence of 1:1700. Reasons for the apparent increase in incidence have been studied, but no explanation has been found. [26] Classic CAH, the disorder targeted by newborn screening programs, is caused by a deficiency of the enzyme steroid 21-hydroxylase, and comes in two forms - simple virilizing and a salt-wasting form. Incidence of CAH can vary greatly between populations. The highest reported incidence rates are among the Yupic Eskimos of Alaska (1:280) and on the French island of La Reunion(1:2100).[26]

[edit]Hemoglobinopathies

Sickle cells in human blood: both normal red blood cells and sickle-shaped cells are present

Any condition that results in the production of abnormal hemoglobin is included under the broad category of hemoglobinopathies. Worldwide, it is estimated that 7% of the population may carry a hemoglobinopathy with clinical significance. [27] The most well known condition in this group is sickle cell disease.[27] Newborn screening for a large number of hemoglobinopathies is done by detecting abnormal patterns using isoelectric focusing, which can detect many different types of abnormal hemoglobins. [27] In the United States, newborn screening for sickle cell disease was recommended for all infants in 1987, however it was not implemented in all 50 states until 2006. [27] Early identification of individuals with sickle cell disease and other hemoglobinopathies allows treatment to be initiated in a timely fashion. Penicillin has been used in children with sickle cell disease, and blood transfusions are used for patients identified with severe thalassemia.[27] [edit]Organic

acidemias

Most jurisdictions did not start screening for any of the organic acidemias before tandem mass spectrometry significantly expanded the list of disorders detectable by newborn screening. Quebec has run a voluntary second-tier screening program since 1971 using urine samples collected at three weeks of age to screen for an expanded list of organic acidemias using a thin layer chromatography method.[9] Newborn screening using tandem mass spectrometry can detect several organic acidemias, including propionic acidemia, methylmalonic acidemia and isovaleric acidemia.

[edit]Cystic

fibrosis

Cystic fibrosis (CF) was first added to newborn screening programs in New Zealand and regions of Australia in 1981, by measuring immunoreactive trypsinogen (IRT) in dried blood spots.[28] After the CFTR gene was identified,, Australia introduced a two tier testing program to reduce the number of false positives. Samples with an elevated IRT value were then analyzed with molecular methods to identify the presence of disease causing mutations before being reported back to parents and health care providers. [29] CF is included in the core panel of conditions recommended for inclusion in all 50 states, Texas was the last state to implement their screening program for CF in 2010. [30] Alberta was the first Canadian province to implement CF screening in 2006. [31] Quebec, New Brunswick, Nova Scotia, Newfoundland and Prince Edward Island do not include CF in their screening programs.[32] The United Kingdom as well as many European Union countries screen for CF as well.[32] Switzerland is one of the latest countries to add CF to their newborn screening menu, doing so in January 2011.
[28]

[edit]Urea

cycle disorders

Disorders of the distal urea cycle, such as citrullinemia, argininosuccinic aciduria and argininemia are included in newborn screening programs in many jurisdictions that using tandem mass spectrometry to identify key amino acids. Proximal urea cycle defects, such as ornithine transcarbamylase deficiency and carbamoyl phosphate synthetase deficiency are not included in newborn screening panels because they are not reliably detected using current technology, and also because severely affected infants will present with clinical symptoms before newborn screening results are available. Some regions claim to screen for HHH syndrome (hyperammonemia, hyperornithinemia, homocitrullinuria) based on the detection of elevated ornithine levels in the newborn screening dried blood spot, but other sources have shown that affected individuals do not have elevated ornithine at birth. [33] [edit]Lysosomal

storage disorders

Lysosomal storage disorders are not included in newborn screening programs with high frequency. As a group, they are heterogenous, with screening only being feasible for a small fraction of the approximately 40 identified disorders. The arguments for their inclusion in newborn screening programs center around the advantage of early treatment (when treatment is available), avoiding a diagnostic odyssey for families and providing information for family planning to couples who have an affected child. [34] The

arguments against including these disorders, as a group or individually center around the difficulties with reliably identifying individuals who will be affected with a severe form of the disorder, the relatively unproven nature of the treatment methods, and the high cost / high risk associated with some treatment options. [34] New York State started a pilot study to screen for Krabbe disease in 2006, largely due to the efforts of Jim Kelly, whose son, Hunter, was affected with the disease. [35] A pilot screening program for four lysosomal storage diseases (Gaucher disease, Pompe disease, Fabry disease and Niemann-Pick disease was undertaken using anonymised dried blood spots was completed in Austria in 2010. Their data showed an increased incidence from what was expected in the population, and also a number of late onset forms of disease, which are not typically the target for newborn screening programs. [36] [edit]Hearing

loss

Undiagnosed hearing loss in a child can have serious effects on many developmental areas, including language, social interactions, emotions, cognitive ability, academic performance and vocational skills, any combination of which can have negative impacts on the quality of life.[37] The serious impacts of a late diagnosis, combined with the high incidence (estimated at 1 - 3 per 1000 live births, and as high as 4% for neonatal intensive care unit patients) have been the driving forces behind screening programs designed to identify infants with hearing loss as early as possible. Early identification allows these patients and their families to access needed resources to help them develop.[37] Newborn hearing testing is done at the bedside using transiently evoked otoacoustic emissions, automated auditory brainstem responses or a combination of both techniques. Hearing screening programs have found the initial testing to cost between $10.20 and $23.37 per baby, depending on the technology used. [37] As these are screening tests only, false positive results will occur. A review of hearing screening programs found varied initial referral rates (screen positive results) from 0.6 % to 16.7 %. The highest overall incidence of hearing loss detection was 0.517%. [37] A significant proportion of screen positive infants were lost to follow-up, before a diagnosis could be confirmed or ruled out in all screening programs. [37] [edit]Congenital

heart defects

Pulse oximetry has been recently added as a bedside screening test for critical congenital heart defects.[14]

[edit]Severe

combined immunodeficiency

Severe combined immunodeficiency (SCID) caused by T-cell deficiency is a disorder that was recently added to newborn screening programs in some regions of the United States. Wisconsin was the first state to add SCID to their mandatory screening panel in 2008, and it was recommended for inclusion in all states' panels in 2010. Identification of infants with SCID is done by detecting T-cell receptor excision circles (TRECs) using real-time quantitative polymerase chain reaction (RT-qPCR). TRECs are decreased in infants affected with SCID.[38] SCID has not been added to newborn screening in a wide scale for several reasons. It requires technology that is not currently used in most newborn screening labs, as PCR is not used for any other assays included in screening programs. Follow-up and treatment of affected infants also requires skilled immunologists, which may not be available in all regions. Treatment for SCID is astem cell transplant, which cannot be done in all centers.[38] [edit]Other

conditions

Duchenne muscular dystrophy (DMD) is an X-linked disorder caused by defective production of dystrophin. Many jurisdictions around the world have screened for, or attempted to screen for DMD using elevated levels of creatine kinase measured in dried blood spots. Because universal newborn screening for DMD has not been undertaken, affected individuals often have a significant delay in diagnosis. As treatment options for DMD become more and more effective, interest in adding a newborn screening test increases. At various times since 1978, DMD has been included (often as a pilot study on a small subset of the population) in newborn screening programs in Edinburgh, Germany, Canada, France, Wales, Cyprus , Belgium and the United States. In 2012, Belgium was the only country that continued to screen for DMD using creatine kinase levels.[39] As treatments improve, newborn screening becomes a possibility for disorders that could benefit from early intervention, but none was previously available. Adrenoleukodystrophy (ALD), a peroxisomal disease that has a variable clinical presentation is one of the disorders that has become a target for those seeking to identify patients early. ALD can present in several different forms, some of which do not present until adulthood, making it a difficult choice for countries to add to screening programs. The most successful treatment option is a stem cell transplant, a procedure that carries a significant risk.[40]

[edit]Laboratory performance Newborn screening programs participate in quality control programs as in any other laboratory, with some notable exceptions. Much of the success of newborn screening programs is dependent on the filter paper used for the collection of the samples. Initial studies using Robert Guthrie's test for PKU reported high false positive rates that were attributed to a poorly selected type of filter paper. [41] This source of variation has been eliminated in most newborn screening programs through standardization of approved sources of filter paper for use in newborn screening programs. In most regions, the newborn screening card (which contains demographic information as well as attached filter paper for blood collection) is supplied by the organization carrying out the testing, to remove variations from this source.[41] [edit]Controversies Newborn screening tests have become a subject of political controversy in the last decade. Two California babies, Zachary Wyvill and Zachary Black, were both born with Glutaric acidemia type I. Wyvill's birth hospital only tested for the four diseases mandated by state law, while Black was born at a hospital that was participating in an expanded testing pilot program. Black's disease was treated with diet and vitamins; Wyvill's disease went undetected for over six months, and during that time the damage from the enzyme deficiency became irreversible.[42] Birth-defects lobbyists pushing for broader and more universal standards for newborn testing cite this as an example of how much of an impact testing can have.[citation needed] Instituting MS/MS screening often requires a sizable up front expenditure. When states choose to run their own programs the initial costs for equipment, training and new staff can be significant. Moreover, MS/MS gives only the screening result and not the confirmatory result. The same has to be further done by higher technologies or procedure like GC/MS, Enzyme Assays or DNA Tests. This in effect adds more cost burden and makes physicians lose precious time. To avoid at least a portion of the up front costs, some states such as Mississippi have chosen to contract with private labs for expanded screening. Others have chosen to form Regional Partnerships sharing both costs and resources. But for many states, screening is an integrated part of the department of health which can not or will not be easily replaced. Thus the initial expenditures can be difficult for states with tight budgets to justify. Screening fees have also increased in recent years as health care costs rise and more states add MS/MS screening to their programs. (See Report of Summation of Fees Charged for Newborn

Screening, 20012005) Dollars spent for these programs may reduce resources available to other potentially lifesaving programs. It has been recommended that one disorder, Short Chain Acyl-coenzyme A Dehydrogenase Deficiency, or SCAD, be eliminated from screening programs, due to a "spurious association between SCAD and symptoms.[43] However, recent studies suggest that expanded screening is cost effective (seeACMG report page 94-95 and articles published in Pediatrics[44]'.[45] Advocates are quick to point out studies such as these when trying to convince state legislatures to mandate expanded screening. Expanded newborn screening is also opposed by among some health care providers who are concerned that effective follow-up and treatment may not be available, that false positive screening tests may cause harm, and issues of informed consent.[46] A recent study by Genetic Alliance and partners suggests that communication between health care providers and parents may be key in minimizing the potential harm when a false positive test occurs. The results from this study also reveal that parents found newborn screening to be a beneficial and necessary tool to prevent treatable diseases. [47] To address the false positive issue, researchers from the University of Maryland, Baltimore and Genetic Alliance established a check-list to assist health care providers communicate with parents about a screen-positive result. [48] Controversy has also erupted in some countries over collection and storage of blood or DNA samples by government agencies during the routine newborn blood screen. It was revealed that in Texas the state had collected and stored blood and DNA samples on millions of newborns without the parents' knowledge or consent. These samples were then used by the state for genetic experiments and to set up a database to catalog all of the samples/newborns. Samples obtained without parents' consent were destroyed. [49]

In many genetic and metabolic disorders, symptoms dont begin until days or weeks after an infant is born. By the time symptoms appear, damage may already have been done to the nervous system, kidneys, vision, hearing, and other body systems. That's why early detection of these serious disorders in all infants is very important. Diagnosis and treatment of these disorders can reduce the risk of disease, disability, and even death.

Beginning of Newborn Screenings The idea of testing all newborn babies for disorders began in the 1960s with the development of a screening test forphenylketonuria, a metabolic disorder. A method of collecting and transporting blood samples on filter paper was developed that made wide scale screening cost effective. Since then many more screening blood tests have been developed, and now an infant can be tested for more than 30 different genetic or metabolic disorders. New technology using tandem mass spectrometry can screen for many disorders using only a few drops of the babys blood. Newborn screening in the United States All 50 states in the US offer newborn screening tests, but not all states require newborn screening by law. Also, although newborns can be screened for as many as 29 disorders, only 13 states and the District of Columbia require all 29 screenings. An additional 27 states require more than 20 screenings. Five states screen for 10 to 20 disorders, and five states screen for fewer than 10 disorders. A list of screening tests provided by each state is available. Each year the March of Dimes issues a Newborn Screening Report Card that analyzes newborn screening requirements in the United States. In 2007, 90 percent of all babies born in the United States lived in states that required screening for at least 21 disorders. The March of Dimes estimates that 6.2 percent of newborns in the United States will get screening for fewer than 10 disorders. The March of Dimes is working to reduce this disparity in newborn screening in the country, with the goal of having all babies screened for 20 or more disorders by 2008. Newborn screening around the world Screening for disorders is part of newborn health care in all developed countries. Most countries screen for phenylketonuria, congenital hypothyroidism, and cystic fibrosis. Many also screen for congenital adrenal hyperplasia, galactosemia, and sickle cell disease, as well as other disorders. The U.S. National Newborn Screening & Genetics Resource Center has links to international programs for more information.

How the tests are done Within the first few days of life (between 24 hours to 7 days after birth), a few drops of blood are taken from an infants heel (see photo) and placed on a special card. The paper is sent to a laboratory for testing. The results of the blood tests are sent to the infants pediatrician. If any of the tests come back positive, further testing is done to make a diagnosis. What disorders can newborns be screened for? The most common disorders newborns are screened for include:

phenylketonuria[/link"> congenital hypothyroidism cystic fibrosis congenital adrenal hyperplasia (CAH) galactosemia sickle cell disease biotinidase deficiency congenital toxoplasmosis homocystinuria maple syrup urine disease (MSUD)

medium-chain acyl-coA dehydrogenase deficiency (MCAD) A full list of the 29 disorders than can be screened for, including information about each disorder, is available.

http://www.marchofdimes.com/peristats/nbsd efinitions.aspx

Newborn Screening: Definitions for 30 Core Conditions

3-Methylcrotonyl-CoA carboxylase deficiency = 3MCC Incidence: greater than 1 in 75,000(1) This defect in processing the amino acid leucine can lead to brain damage, seizures, liver failure and death in infancy or no symptoms at all into adulthood. Symptoms often develop following a childhood illness. Treatment with a low-protein diet and, in some cases, nutritional supplements may be helpful. (An abnormal result by newborn screening could be related to abnormal metabolites in the mother and not the baby. This will be clarified by further diagnostic testing of the infant.) Argininosuccinic acidemia = ASA Incidence: less than 1 in 100,000(1) Most commonly, symptoms begin in the first few days of life, with build-up of argininosuccinic acid and ultimately ammonia resulting in brain swelling, coma and, sometimes, death. Survivors often suffer permanent neurological damage. Other affected children may develop symptoms later in infancy or childhood. Early diagnosis and treatment can be lifesaving; however, in spite of treatment, affected individuals remain susceptible to episodes of ammonia build-up, and most have some degree of brain damage. Treatment consists of a low-protein diet, avoiding fasting, medications to prevent ammonia build-up, nutritional supplements, and in some cases, liver transplant. Beta-Ketothiolase deficiency = BKT Incidence: less than 1 in 100,000(1) Periodic episodes of acid build-up, often triggered by some childhood illness, can progress to coma, brain damage and death. These serious consequences are most often seen in infants. With early diagnosis and prompt intravenous treatment to keep blood sugar levels up and blood acid levels down during an illness, children can develop normally. Parents must be alert to early signs of illness. Additional treatments may vary, but can include avoidance of protein-rich diets and long-term treatment with bicarbonate. Biotinidase deficiency = BIOT Incidence: greater than 1 in 75,000(1)

Biotinidase is the enzyme that recycles the vitamin biotin. An inherited deficiency of this enzyme may cause serious complications, including frequent infections, uncoordinated movement, hearing loss, seizures, and mental retardation. Undiagnosed and untreated, the deficiency can lead to coma and death. If the condition is detected soon after birth, these problems can be completely prevented with daily oral doses of biotin. Carnitine uptake defect = CUD Incidence: less than 1 in 100,000(1) Due to a missing transporter, cells cannot bring in carnitine from the blood. Carnitine is needed for the transfer of fatty acids across the membranes of the mitochondria (cellular organelles that produce energy for the cell). Symptoms include episodes of hypoglycemia (low blood sugar) and sudden unexpected death in infancy. Older children may present with progressive heart failure. Early diagnosis and treatment with carnitine permits normal development. Citrullinemia = CIT Incidence: less than 1 in 100,000(1) Build-up in the body of citrulline and ultimately ammonia can begin during the newborn period or later in infancy. Without treatment, seizures, coma, brain damage and death can result. With early diagnosis and treatment, normal development is possible. Treatment includes a low-protein diet, medications to rid the body of amino groups to prevent ammonia build-up, and nutritional supplements. Classical galactosemia = GALT Incidence: greater than 1 in 50,000(1) Affected babies are missing the liver enzyme needed to convert galactose, a major sugar from the breakdown of lactose in milk, into glucose, another simple sugar that the body can use. Galactose then accumulates in and damages vital organs, leading to blindness, severe mental retardation, infection, and death. Milk and other dairy products must be eliminated from the baby's diet for life. Though treatment dramatically improves the outlook for affected infants, there is still some risk of developmental delays. Congenital adrenal hyperplasia = CAH Incidence: greater than 1 in 25,000(1) CAH refers to a set of inherited disorders resulting from defects in the synthesis of hormones produced by the adrenal gland. In female infants, CAH sometimes results in masculinization of the genitals. Certain severe forms of CAH cause life-threatening salt

loss from the body if undetected and untreated. Treatment includes salt replacement and hormone replacement. Congenital hypothyroidism = CH Incidence: greater than 1 in 5,000(1) This thyroid hormone deficiency severely retards both growth and brain development. If detected soon after birth, the condition can be treated simply with oral doses of thyroid hormone to permit normal development. Cystic fibrosis = CF Incidence: greater than 1 in 5,000(1) Cystic fibrosis is one of the most common inherited disorders in the U.S. Abnormalities in the cystic fibrosis protein result in lung and digestive problems, and death at an average age of 30-35 years. Studies suggest that early diagnosis and treatment improves the growth of babies and children with CF. Treatment varies depending on severity of symptoms, but may include a high-calorie diet supplemented with vitamins and medications to improve digestion, respiratory therapy to help clear mucus from the lungs, and medications to improve breathing and prevent lung infections. Glutaric acidemia type I = GA1 Incidence: greater than 1 in 75,000(1) Babies may develop normally for up to 18 months until something affects a child's health, such as a mild viral illness, which may trigger the onset of symptoms. Without prompt treatment, this can lead to brain damage, seizures, low muscle tone, cerebralpalsy like symptoms and death within the first decade of life. Some affected babies also are born with an enlarged head (macrocephaly). Treatment can vary, but may include dietary protein restriction and supplementation with a nutrient called L-carnitine. With early diagnosis and prompt treatment of illness and fever, brain damage may be prevented. Hb S/Beta-Thalassemia = HBSA Incidence: greater than 1 in 50,000(1) In this form of sickle cell anemia, the child inherits one sickle cell gene and one gene for beta thalassemia, another inherited anemia. Symptoms are often milder than for Hb SS, though severity varies among affected children. Routine treatment with penicillin may not be recommended for all affected children.(3)

Hb S/C disease = HbSC Incidence: greater than 1 in 25,000(1) Another form of sickle cell disease, in which the child inherits one sickle cell gene and one gene for another abnormal type of hemoglobin called HbC. As with Hb S/Th, this form is often milder the Hb SS and routine penicillin treatment may not be recommended.(3) Hearing loss = HEAR Incidence: greater than 1 in 5,000(1); up to 3-4 per 1,000 newborns(4) Without early testing, most babies with hearing loss are not diagnosed until 2 or 3 years of age. By this time, they often have delayed speech and language development. Early diagnosis allows use of hearing aids by 6 months of age, helping prevent serious speech and language problems. Homocystinuria = HCY Incidence: less than 1 in 100,000(1) Individuals with this disorder lack an enzyme responsible for converting the amino acid homocysteine into cystathionine, which is needed for normal brain development. If undetected and untreated, homocystinuria leads to mental retardation, eye problems, skeletal abnormalities, and stroke. Treatment consists of a special diet, one or more vitamins (B6 or B12), and other supplements (betaine). Hydroxymethylglutaric aciduria or HMG-CoA lyase deficiency or 3-OH 3-CH3 glutaric aciduria = HMG Incidence: less than 1 in 100,000(1) An inability to process the amino acid leucine leads to low blood sugar and accumulation of several organic acids, especially following illness or fasting. Without treatment, the disorder can lead to brain damage, mental retardation, coma and death. Avoiding fasting and following a diet low in protein and fat and high in carbohydrates can lead to normal development. Isovaleric acidemia = IVA Incidence: less than 1 in 100,000(1) This disorder is caused by an inability to process the amino acid leucine. The newborn form of the disorder often results in coma, permanent neurological damage, and death. In other cases, symptoms develop later in infancy and childhood, frequently following

an infectious illness. With early diagnosis and treatment, most children have normal development. Treatment includes a low-protein diet and nutritional supplements. Long-chain 3-OH acyl-CoA dehydrogenase deficiency = LCHAD Incidence: greater than 1 in 75,000(1) Symptoms can begin soon after birth, resulting in heart, lung or liver failure and death. In other cases, symptoms such as low muscle tone, developmental delay, heart, lung or liver failure may develop later in infancy or childhood, most likely following an illness. Early diagnosis and treatment effectively prevent life-threatening events, though some children may still develop symptoms. Treatment includes a high-carbohydrate/low-fat diet, nutritional supplements, and avoidance of fasting. Women who are pregnant with fetuses with LCHAD are at increased risk of developing acute fatty liver of pregnancy and other pregnancy complications. Maple syrup urine disease = MSUD Incidence: less than 1 in 100,000(1) This inborn error of metabolism can be lethal if unrecognized and untreated. There is a wide spectrum of clinical presentations, from mild to severe. Affected babies appear normal at birth but soon begin to have neurological symptoms. The disorder gets its name from the fact that the urine smells like maple syrup. Without dietary treatment, severely affected babies do not survive the first month; even those who do receive treatment may have irreversible mental retardation. Rapid diagnosis and treatment are major factors in survival and outcome. Treatment consists of a special low-protein diet, which will vary depending on severity of symptoms, and sometimes, supplementation with a vitamin, thiamin. The diet must be continued indefinitely with frequent monitoring. Medium-chain acyl-CoA dehydrogenase deficiency = MCAD Incidence: greater than 1 in 25,000(1) Seemingly well infants and children can suddenly develop seizures (caused by low blood sugar), liver failure, coma, and death. Identifying affected children before they become ill is vital to preventing a crisis and averting these consequences. Treatment includes avoidance of fasting and nutritional supplements. Methylmalonic acidemia cblA and cblB forms = CBLAB Incidence: less than 1 in 100,000(1) This inherited defect of vitamin metabolism can lead to build-up of acids in the blood and result in brain damage, seizures, paralysis, coma and death. Symptoms can begin as early as the first week of life, though a minority of affected individuals remain

symptom-free. Treatment with vitamin B12 injections and a low-protein diet often prevents serious problems. Methylmalonic acidemia due to mutase deficiency = MUT Incidence: greater than 1 in 75,000(1) A defect in the processing of four essential amino acids and other substances results in illness in the first week of life. Though severity of symptoms varies greatly, death during the first month of life and brain damage in survivors is common. Treatment includes a low-protein diet, vitamin B12 injections, and nutritional supplements. Some children die during the first year of life or develop brain damage despite nutritional intervention. Multiple carboxylase deficiency = MCD Incidence: less than 1 in 100,000(1) This disorder is caused by a defect of an enzyme required to activate several biotindependent enzymes. Without these enzymes, lactic acid and other organic acids build up in the body. Without treatment, brain damage, coma and death can result. Symptoms usually begin between birth and 15 months of age, and may include skin rashes and hair loss. Early diagnosis and treatment with biotin allows normal growth and development. Phenylketonuria = PKU Incidence: greater than 1 in 25,000(1) Affected individuals have an inability to properly process the essential amino acid phenylalanine, which then accumulates and damages the brain. PKU can result in severe mental retardation unless detected soon after birth and treated with a special formula. Affected individuals must be kept on a low-phenylalanine diet at least throughout childhood, adolescence, and for females during pregnancy. Propionic acidemia = PROP Incidence: greater than 1 in 75,000(1) This defect in the processing of four essential amino acids leads to illness during the newborn period. Without treatment, brain damage, coma and death can result. Even with treatment, including a low-protein diet and nutritional supplements, some affected children suffer from developmental delays, seizures, abnormal muscle tone, frequent infections and heart problems.

Sickle cell anemia = HBSS Incidence: greater than 1 in 5,000(1); higher incidence among African-Americans (1 in 400)(2) A blood disease that can cause severe pain, damage to the vital organs, stroke, and sometimes death in childhood. Young children with sickle cell anemia are especially prone to dangerous bacterial infections such as pneumonia and meningitis. Vigilant medical care and treatment with penicillin, beginning in infancy, can dramatically reduce the risk of these adverse effects and the deaths that can result from them. Affected babies should receive all regular childhood vaccinations (including hemophilus influenza B and pneumococcal vaccines) to help prevent serious bacterial infections. Additional treatments may vary according to severity of symptoms, but may include intermittent pain medications and regular blood transfusions. Trifunctional protein deficiency = TFP Incidence: less than 1 in 100,000(1) A seemingly healthy infant can die suddenly of what appears to be sudden infant death syndrome. Other infants may develop low muscle tone, seizures, heart failure and coma, often following an illness. Treatment is based on strict avoidance of fasting, a low-fat diet and nutritional supplements. Tyrosinemia type I = TYR1 Incidence: less than 1 in 100,000(1) Due to absence of an enzyme, byproducts of the amino acid tyrosine, particularly a very toxic compound called succinylacetone, build up in the liver. Without treatment, symptoms generally begin in the first few weeks or months of life and progress to liver or kidney failure, nerve damage and death. Drug treatment, sometimes along with a low-protein diet, is very effective in preventing liver and kidney damage. Very long-chain acyl-CoA dehydrogenase deficiency = VLCAD Incidence: greater than 1 in 75,000(1) Symptoms can first appear at any age from the newborn period through adulthood, but tend to be most severe in infants. Without treatment, affected infants often develop heart and liver failure and die during the first year of life. Treatment includes a highcarbohydrate/low-fat diet, nutritional supplements, avoidance of fasting and prolonged exercise. Severe combined immunodeficiency = SCID Incidence: at least 1 in 100,000(5)

SCID describes a group of rare inherited disorders characterized by defects in two critical immune system cells that are normally mobilized by the body to combat infections. The popular media have referred to SCID as the "bubble boy disease." Without treatment, infants with SCID are more susceptible to and can develop recurrent infections, leading to failure to thrive and oftentimes death. References American College of Medical Genetics. Newborn Screening: Toward a Uniform Screening Panel and System. Final Report, March 8, 2005. General Accounting Office. Newborn Screening: Characteristics of State Programs. Washington, DC: General Accounting Office, 2003. Publication GAO-03-449. Data from the National Newborn Screening and Genetics Resource Center. American Academy of Pediatrics Section on Hematology/Oncology Committee on Genetics. Health Supervision for Children with Sickle Cell Disease, Pediatrics, volume 109, number 3, March 2002, pages 526-535. National Center for Hearing Assessment and Management, Utah State University. Advisory Committee on Heritable Disorders and Genetic Diseases in Newborns and Children, Health Resources Services Administration. Evidence Review: Severe Combined Immunodeficiency.

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