Key points

Newborn screening has been among the most successful public health programs of the 21st century. The year 2013 was the 50th anniversary of newborn screening. Approximately 4 million infants are screened per year under newborn screening programs that are mandated in most states. About 12,500 infants are identified each year with heritable disorders. Many of these are associated with severe effects if not identified before the onset of symptoms. Therefore, the goal of newborn screening programs is to detect these disorders that cause harm to life or threaten long-term health before they become symptomatic. Conditions like endocrine disorders, hemoglobinopathies, immunodeficiencies, cystic fibrosis, and critical congenital heart defects, as well as inborn errors of metabolism are among those that can be screened for. Early treatment may significantly improve outcome and improve survival.

Although individual metabolic diseases are relatively uncommon, inherited metabolic diseases collectively represent a more common cause of disease in the neonatal period than is generally appreciated. For example, the estimated incidence of inherited metabolic disease in the general population varies from 1 per 10,000 live births for phenylketonuria to as few as 1 per 200,000 live births with homocystinuria. Currently, there are approximately 100 such inheritable disorders that can be diagnosed in the neonatal period. The overall incidence for metabolic disease is about 1 per 2000 persons. Newborn screening programs have found an incidence of about 1 in 4000 for a subset of these diseases. It is also possible that this is an underestimate of the incidence of these disorders, because many with metabolic disease go undiagnosed.

New technologies have expanded the capabilities of newborn screening programs. Presently, 31 conditions are recommended to be screened on state newborn screening panels by the Discretionary Advisory Committee of Heritable Disorders in Newborns and Children. It all began in 1960 when Robert Guthrie developed a bacterial inhibition assay that detected elevated levels of phenylalanine after birth from infant’s blood. Population studies for screening for phenylketonuria began in 1963 when Massachusetts became the first state to actually mandate newborn screening. This same technique, where a blood specimen contains greater than normal quantities of an amino acid or metabolite is associated with a large growth of bacteria, has been used to detect other conditions, including maple syrup urine disease, homocystinuria, tryosinemia, and histidinemia.

The new technologies that have expanded newborn screening included a radioimmunoassay for thyroxine, making possible screening for congenital hypothyroidism. Isoelectric focusing and liquid chromatography have allowed for hemoglobinopathy screening. The polymerase chain reaction allowed screening for mutations in hemoglobin genes in DNA extracted from dried blood samples. Tandem mass spectrometry (also known as MS/MS) as well as some other techniques now allow expanded possibilities for mass screening of many disorders. This spectrometry detects molecules by measuring their weight and is a series of 2 mass spectrometers. They sort the samples and identify and weigh the molecules of interest in screening. It is best suited for inborn errors of organic acid, fatty acid, and amino acid metabolism. Newer methods have allowed this technique to also be used to detect lysosomal storage disorders. New biochemical and genetic tests have recently allowed screening for cystic fibrosis and severe combined immunodeficiency. Tandem mass spectrometry because of its availability and its cost effectiveness has allowed expansion of newborn screening that can be provided and remains the strategy used to detect the majority of conditions that are screened for today.

Principles of screening

Newborn screening tests are administered to healthy populations to detect infants who may have a serious disorder. They do not always provide definitive results, but they identify which infants require further testing. The medical requirements of an acceptable mass screening program for a particular disease include the following, which are reviewed by Zinn :

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  The availability of a reliable screening test with a low false-negative rate;

  
  
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  A test that is simple and inexpensive, because many tests will be performed for each case identified;

  
  
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  A rapid screening test that can provide results quickly enough to permit effective intervention;

  
  
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  A definitive follow-up test that is available for unambiguous identification of true positive results and elimination of false-positive results;

  
  
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  A disorder of a sufficiently deleterious nature that, if untreated, would result in significant morbidity or death; and

  
  
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  An effective therapy that significantly alters the natural history of the disease.

Unfortunately, few metabolic diseases satisfy all of these requirements. Certain principles also apply to all newborn screening programs and include the following :

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  Genetic heterogeneity, biologic variation, and error lead to false-positive results in any screening test. Thus, a definitive method must be available to confirm a positive screening result.

  
  
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  Positive results must be acted upon on an emergent basis so that timely testing and intervention can be accomplished.

  
  
• •
  

  Patients with positive screening tests should be referred to a pediatric specialist experienced in the diagnosis and management of the specific condition for definitive diagnosis and treatment, if needed.

Principles of screening

Newborn screening tests are administered to healthy populations to detect infants who may have a serious disorder. They do not always provide definitive results, but they identify which infants require further testing. The medical requirements of an acceptable mass screening program for a particular disease include the following, which are reviewed by Zinn :

• •
  

  The availability of a reliable screening test with a low false-negative rate;

  
  
• •
  

  A test that is simple and inexpensive, because many tests will be performed for each case identified;

  
  
• •
  

  A rapid screening test that can provide results quickly enough to permit effective intervention;

  
  
• •
  

  A definitive follow-up test that is available for unambiguous identification of true positive results and elimination of false-positive results;

  
  
• •
  

  A disorder of a sufficiently deleterious nature that, if untreated, would result in significant morbidity or death; and

  
  
• •
  

  An effective therapy that significantly alters the natural history of the disease.

Unfortunately, few metabolic diseases satisfy all of these requirements. Certain principles also apply to all newborn screening programs and include the following :

• •
  

  Genetic heterogeneity, biologic variation, and error lead to false-positive results in any screening test. Thus, a definitive method must be available to confirm a positive screening result.

  
  
• •
  

  Positive results must be acted upon on an emergent basis so that timely testing and intervention can be accomplished.

  
  
• •
  

  Patients with positive screening tests should be referred to a pediatric specialist experienced in the diagnosis and management of the specific condition for definitive diagnosis and treatment, if needed.

Tandem mass spectrometry

The current MS/MS techniques allow analysis of large numbers of metabolites that may belong to a particular category of disease. Therefore, many disorders can be screened in every sample. Literally, hundreds of samples can be analyzed and studied each day. These devices are sensitive, accurate, and allow multiple metabolites to be identified simultaneously. Computerization allows pattern recognition using several related metabolites and thereby increases the reliability of the testing.

Normal ranges must be determined for the MS/MS screening programs for the different metabolites that are studied. Cut-offs are set, and values above or below those levels identify a potential case as an at-risk situation. It is important for these values to be accurate; if a cut-off is set too high, then there may be inordinately great number of false-negative results. Conversely, if cut-offs are set too low, there is an unacceptable rate of false-positive results. The onus is on the practitioner to decide whether a particular result is truly positive or is false positive as quickly as is possible. As mentioned, newborn screening programs have found that about 1 in 4000 newborns have a diagnosable error of metabolism.

It should also be appreciated that most programs do not screen for inborn errors that are associated with low concentrations of the specific amino acids. The organic acidemias and fatty acid oxidation disorders are detected by analyzing for increased blood concentrations of specific acylcarnitines, namely, the esters formed between carnitine and the acids that accumulate with the organic acidemias and fatty acid oxidation disorders. However, screening for the plasma membrane carnitine uptake defect looks for a reduced (rather than increased) concentration of free carnitine.

Table 1 provides the basics about inborn errors of metabolism that can be diagnosed by MS/MS used in newborn screening programs. The table from Zinn names each disorder and provides information about the underlying enzymatic defect and the clinical features and natural history of the disorder. There is also an approach to treatment and what the prognosis may be. As discussed, some 4 million infants are screened each year in the United States and approximately 12,500 are diagnosed with 1 of the 29 core conditions on the screening panel. This means that 1 in 4000 live births are detected. The top 5 diagnosed conditions are:

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  Hearing loss,

  
  
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  Primary congenital hypothyroidism,

  
  
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  Cystic fibrosis,

  
  
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  Sickle cell disease, and

  
  
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  Medium-chain acyl-coenzyme A dehydrogenase deficiency.

Table 1

Inborn errors of metabolism diagnosable by tandem mass spectrometry

Disorder	Defect	Clinical Features and Natural History	Treatment	Prognosis with Treatment
Homocystinuria	Cystathionine β-synthetase deficiency	Generally asymptomatic at birth Developmental delay, dislocated lens, skeletal deformities, and thromboembolic episodes	Dietary protein restriction Selective amino acid restriction (methionine) vitamin B 6 supplementation plus betaine, folate, and vitamin B 12	Patients with vitamin B 6 -responsive form of disease have fewer complications and later age onset of complications than do patients with vitamin B 6 -nonresponsive form
Maple syrup urine disease	Branched-chain α-keto acid dehydrogenase deficiency	Patients might present before newborn screening results are available Difficulty feeding, vomiting, lethargy progressing to coma, opisthotonic posturing, and possibly death Ketoacidosis	Emergent treatment might be indicated for symptomatic neonates Chronic care includes dietary protein restriction, selective branched-chain amino acid restriction (leucine, isoleucine, valine), and thiamine supplementation for thiamine-responsive patients	Improved intellectual outcome can be expected if treatment is initiated before first crisis, but there is developmental delay in severe cases Recurrent episodes of ketoacidosis
Nonketotic hyperglycinemia	Glycine cleavage enzyme deficiency	Patients might present before newborn screening results are available Hypotonia, apnea, intractable seizures, and lethargy progressing to coma Burst-suppression electroencephalograph pattern Hiccups (characteristic) Transient forms very rare	Various drugs can lower plasma glycine, but none lower CSF glycine or improve clinical outcome Dextromethorphan for seizures	Intractable seizures and poor intellectual development in patients who survive the neonatal period, except in rare instances
Phenylketonuria	Phenylalanine hydroxylase deficiency	Generally asymptomatic at birth After a few months, microcephaly, seizures, and pale pigmentation develop, followed in later years by abnormal posturing, mental retardation, and behavioral or psychiatric disturbances	Dietary protein restriction Selective amino acid restriction (phenylalanine)	Normal development can be expected (although a mild decrease in IQ and behavioral difficulties relative to nonaffected siblings might be seen) if diet is instituted early
	BH 4 biosynthesis or recycling defect	Patients with BH 4 defects have additional problems secondary to dopamine and serotonin deficiency	Biopterin defects require special care	Patients with biopterin defects have a more guarded prognosis
Tyrosinemia type I	Fumarylacetoacetate hydrolase deficiency	Patients might present before newborn screening results are available Severe liver failure associated with jaundice, ascites, and bleeding diathesis Peripheral neuropathy and seizures can develop Renal Fanconi syndrome leading to rickets Survivors develop chronic liver disease with increased risk of HCC	Emergency treatment might be indicated for symptomatic neonates Chronic care includes dietary protein restriction, selective amino acid restriction (phenylalanine and tyrosine), administration of selective enzyme inhibitor (NTBC), and liver transplantation when indicated to prevent HCC	Liver disease could progress despite dietary treatment NTBC treatment improves liver, kidney, and neurologic function, but it does not eliminate risk for HCC Liver transplantation might still be required
Tyrosinemia type II	Tyrosine aminotransferase	Corneal lesions and hyperkeratosis of the soles and palms	Selective amino acid restriction (tyrosine)	Good
Urea cycle disorders
Argininosuccinic acidemia	Argininosuccinic acid lyase deficiency	Patients might present before newborn screening results are available Anorexia, vomiting, lethargy, seizures, and coma, possibly leading to death Hyperammonemia	Emergency treatment might be indicated for symptomatic neonates Chronic care includes dietary protein restriction, essential amino acid supplementation, arginine or citrulline supplementation, and alternative pathway drugs for removing NH 3 (sodium benzoate and phenylbutyrate)	Improved intellectual outcome could be expected if treatment is initiated early, but there is developmental delay in the severe cases Recurrent hyperammonemic episodes
Arginemia	Arginase deficiency	Rarely symptomatic in neonatal period Progressive spastic diplegia or tetraplegia, opisthotonus, seizures Low risk of symptomatic hyperammonemia	Dietary protein restriction Selective amino acid restriction (arginine) Alternative pathway drugs for removing NH 3 (sodium benzoate and phenylbutyrate)	Uncertain but might improve neurologic outcome
Citrullinemia	Argininosuccinate synthetase deficiency	Patients might present before newborn screening results are available Anorexia, vomiting, lethargy, seizures, and coma, possibly leading to death Hyperammonemia	Emergency treatment might be indicated for symptomatic neonates Chronic care includes dietary protein restriction, essential amino acid supplementation, arginine or citrulline supplementation, and alternative pathways drugs for removing NH 3 (sodium benzoate and phenylbutyrate)	Improved intellectual outcome can be expected if treatment is initiated early, but there is developmental delay in the severe cases Recurrent hyperammonemic episodes
Organic acidemias
Glutaric academia type I	Glutaryl-CoA dehydrogenase deficiency	Rarely symptomatic in neonatal period, although macrocephaly may be present Progressive macrocephaly, ataxia, dystonia and choreoathetosis, developmental regression, seizures, and stroke like episodes, possibly exacerbated by infection or fasting	Dietary protein restriction Selective amino acid restriction (lysine, tryptophan) Riboflavin and carnitine supplementation	Improved intellectual outcome if treatment is initiated early, but poor neurologic outcome if treatment is started after acute neurologic injury occurs Treatment might slow neurologic deterioration
Glutaric acidemia type II	ETF deficiency or ETF dehydrogenase deficiency	Commonly manifests in neonatal period Hypotonia, hepatomegaly, abnormal odor, with or without congenital anomalies, including facial dysmorphism and cystic kidney disease Metabolic acidosis and hypoglycemia Generally lethal Late-onset forms variable, rarely have structural birth defects	Emergency treatment might be indicated for symptomatic neonates Chronic care includes dietary protein restriction, selective amino acid restriction (isoleucine, methionine, threonine, and valine), and carnitine supplementation	Treatment for neonatal-onset forms invariably unsuccessful Dietary fat and protein restriction and riboflavin and carnitine supplementation might help patients with late-onset disease
3-Hydroxy-3-methylglutaric aciduria	3-Hydroxy-3-methylglutaryl-CoA lyase deficiency	Generally does not manifest in neonatal period Episodic hypoglycemia leading to developmental delay	Dietary protein restriction Selective amino acid restriction (leucine) Low-fat diet	Improved intellectual outcome may be expected if treatment is initiated early, but there is developmental delay in the severe cases Recurrent hypoglycemic episodes decrease in frequency and severity over time
Isobutyric acidemia	Isobutyryl-CoA dehydrogenase deficiency	Uncertain because number of cases is small	Dietary protein restriction Selective amino acid restriction (valine)	Unknown
Isovaleric acidemia	Isovaleryl-CoA dehydrogenase deficiency	Patients might present before newborn screening results are available Vomiting, lethargy and coma, possibly death Abnormal odor Thrombocytopenia, leukopenia, anemia Ketoacidosis Hyperammonemia	Emergency treatment might be indicated for symptomatic neonates Chronic care includes dietary protein restriction, selective amino acid restriction (leucine), and glycine and carnitine supplementation	Improved intellectual outcome if diagnosed and treated early If treated appropriately, most have normal development Recurrent metabolic episodes
β-Ketothiolase deficiency	Mitochondrial acetoacetyl-CoA thiolase deficiency	Patients might present before newborn screening results are available Vomiting, lethargy, and coma, possibly death Abnormal odor Thrombocytopenia, leukopenia, anemia Possible basal ganglia damage Ketoacidosis Hyperammonemia	Dietary protein restriction Selected amino acid restriction (isoleucine) Avoidance of fasting Bicarbonate therapy and intravenous glucose in acute crises Carnitine supplementation	Highly variable clinical course Improved intellectual outcome if diagnosed and treated early If treated appropriately, some patients have normal development Recurrent metabolic episodes
2-Methylbutyric acidemia	2-Methylbutyryl-CoA dehydrogenase deficiency	Uncertain because number of cases is small	Dietary protein restriction Selected amino acid restriction	Uncertain
3-Methylcrotonyl-glycinuria	3-Methylbutyryrl-CoA-carboxylase deficiency	Neonatal form: Hypoglycemia and metabolic acidosis Maternal form: Transplacental transport of 3-methylcrotonyl glycine form generally asymptomatic mother to fetus	Neonatal form: Dietary protein restriction; selected amino acid restriction (leucine); carnitine and glycine supplementation Maternal form: Mother might benefit from carnitine supplementation if she has carnitine sufficiency	Neonatal form: Generally good Maternal form: Mother might benefit from carnitine supplementation
2-Methyl-3-hydroxybutyric academia	2-Methylbutyryl-CoA dehydrogenase deficiency	Uncertain because number of cases is small	Dietary protein restriction Selected amino acid restriction	Uncertain
Methylmalonic acidemia	Methylmalonyl-CoA mutase deficiency or vitamin B 12 (cobalamin) metabolism defect	Patients might present before newborn screening results are available Vomiting, lethargy and coma, possibly death Seizure and risk of basal ganglia infarcts Thrombocytopenia, leukopenia, anemia Ketoacidosis Hyperammonemia	Emergent treatment might be indicated for symptomatic neonates Chronic care includes dietary protein restriction (isoleucine, methionine, threonine, and valine), carnitine supplementation, antibiotic suppression of gut flora (metronidazole), liver and/or kidney transplantation might be considered Cobalamin defects require special treatment	Improved intellectual outcome if diagnosed and treated early If treated appropriately, most have normal development Recurrent metabolic episodes Renal failure often develops despite appropriate therapy
Propionic acidemia	Propionyl-CoA carboxylase deficiency	Patients might present before newborn screening results are available Vomiting, lethargy and coma, possibly death Seizures and risk of basal ganglia infarcts Thrombocytopenia, leukopenia, anemia Ketoacidosis Hyperammonemia	Emergency treatment might be indicated for symptomatic neonates Chronic care includes dietary protein restriction, selective amino acid restriction (isoleucine, methionine, threonine, and valine), carnitine supplementation, antibiotic suppression of gut flora (metronidazole and neomycin) Liver transplantation might be considered	Improved intellectual outcome if diagnosed and treated early If treated appropriately, most have normal development Recurrent metabolic episodes
Biotinidase deficiency	Biotinidase deficiency	Generally does not manifest in neonatal period Skin rash and alopecia, optic atrophy, hearing loss, seizures, and developmental delay Metabolic ketoacidosis	Biotin supplementation	Excellent if diagnosed and deficiency treated before irreversible neurologic damage occurs
Multiple carboxylase	Holocarboxylase synthetase deficiency	Commonly manifests in neonatal period Lethargy leading to coma and possibly death Skin rash, impaired T-cell immunity, seizures, and developmental delay Metabolic ketoacidosis and hyperammonemia	Biotin supplementation	Most patients respond to some degree to biotin supplemental, but others show poor or no response to biotin supplementation and have significant residual neurologic impairment
Fatty acid oxidation
Carnitine transporter deficiency	Carnitine transporter deficiency	Commonly manifests in neonatal period Cardiomyopathy, skeletal myopathy, and inability to tolerate prolonged fasting	Carnitine supplementation Avoid fasting Low-fat diet	Good response to treatment, often associated with reversal of cardiomyopathic changes
Carnitine/acylcarnitine translocase deficiency	Carnitine/acylcarnitine translocase deficiency	Commonly manifests in neonatal period Lethargy leading to coma, hepatomegaly Cardiomyopathy with ventricular arrhythmia, skeletal myopathy, and early death Hypoketotic hypoglycemia and hyperammonemia	Avoid fasting High-carbohydrate, low-fat diet Nightly cornstarch supplementation Carnitine supplementation	Severe neonatal cases generally have a poor outcome and early death Patients with later onset might respond to treatment, but they often succumb to chronic skeletal-muscle weakness or cardiac arrhythmias
CPT II deficiency	CPT II deficiency	Commonly manifests in neonatal period Coma, cardiomyopathy and ventricular arrhythmias, hepatic disease, and congenital malformation (brain and cystic renal disease) Hypoketotic hypoglycemia Late-onset forms (child or adult) characterized by weakness and exercise-induced rhabdomyolysis	Avoid fasting High-carbohydrate, low-fat diet supplemented with MCT oil Nightly cornstarch supplementation Carnitine supplementation	Severe neonatal cases generally have a poor outcome and early death Patients with late-onset disease generally do well
LCHAD deficiency	LCHAD deficiency	Sometimes manifests in neonatal period Cardiomyopathy, hypotonia, hepatic disease, and hypoketotic hypoglycemia Patients later develop rhabdomyolysis, peripheral neuropathy, and pigmentary retinopathy and are at risk for sudden death Heterozygous pregnant women are at risk for acute fatty liver of pregnancy if they are carrying a homozygous fetus	Avoid fasting High-carbohydrate, low-fat diet supplemented with MCT oil Nightly cornstarch supplementation Carnitine supplementation	Early diagnosis and treatment generally leads to improved outcome, but no change in risk of peripheral neuropathy and visual impairment
MCAD deficiency	MCAD deficiency	Generally does not manifest in neonatal period Recurrent episodes of vomiting, coma, seizures, and possibly sudden death associated with prolonged period of fasting Cardiomyopathy not generally seen Hypoketotic or nonketotic hypoglycemia	Avoid fasting High-carbohydrate, low-fat diet (controversial) Nightly cornstarch supplementation Carnitine supplementation	Excellent intellectual and physical outcome generally seen if treatment is initiated before irreversible neurologic damage occurs
SCAD deficiency	SCAD deficiency	Generally does not manifest in neonatal period Highly variable presentation primarily associated with failure to thrive, developmental delay Hypoglycemia uncommon Many patients detected by newborn screening program have been asymptomatic	Avoid fasting High-carbohydrate, low-fat diet Nightly cornstarch supplementation Carnitine supplementation	Efficacy of treatment is unknown and metabolic acidosis
VLCAD deficiency	VLCAD deficiency	Commonly manifests in neonatal period Lethargy leading to coma, hepatomegaly, cardiomyopathy with ventricular arrhythmia, skeletal myopathy, and early death Hypoketotic hypoglycemia Later-onset forms (childhood or adult) characterized primarily by weakness and exercise-induced rhabdomyolysis	Avoid fasting High-carbohydrate, low-fat diet supplemented with MCT oil Nightly cornstarch supplementation Carnitine supplementation	Severe neonatal cases generally have poor outcome Patients with late-onset disease respond to treatment and do well
Galactosemia	Galactose-1-phosphate uridyltransferase deficiency	Early onset characterized by lethargy, poor feeding, jaundice, and possible sepsis (especially with Escherichia coli ) Chronic problems include growth failure, cirrhosis, cataracts, seizures, mental retardation and (in females) ovarian failure	Strict dietary galactose restriction must be started immediately	Improved intellectual outcome and milder problems if diagnosed and treated early Ovarian failure develops despite appropriate therapy Recurrent metabolic episodes

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