Newborn screening for metabolic disorders began in 1962 when the Guthrie bacterial inhibition assay for phenylalanine quantitation1 was first used in a mass screening program for the identification of patients with phenylketonuria (PKU). Because of the success of neonatal screening for PKU, screening tests have been developed for other disorders, including metabolic diseases (eg, galactosemia, maple syrup urine disease, homocystinuria, and biotinidase deficiency), endocrinopathies (eg, congenital hypothyroidism and congenital adrenal hyperplasia), infectious diseases (eg, congenital toxoplasmosis), hemoglobinopathies, and cystic fibrosis.2
The more recent development of tandem mass spectrometry (MS /MS)3 and its modification to facilitate the testing of large numbers of blood filter paper specimens now enable newborn screening for more inherited metabolic disorders, including disorders of amino acid metabolism, organic acidemias, and fatty acid oxidation defects (Table 1). A blood spot on a filter paper serves as the specimen. Metabolically important compounds within the blood specimen undergo ionization, producing characteristic daughter ions that are then subjected to mass spectrometry. With the use of stable isotopelabeled internal standards, amino acid analytes and acylcarnitine derivatives of metabolites characteristic of organic acid and fatty acid oxidation disorders are identified accurately, at low concentrations, and more rapidly than other conventional modes of analysis. Which disorders are screened for is determined on a stateby-state basis.
Screening for these disorders not only facilitates early identification of affected patients, but also provides an opportunity for effective therapy to commence. In addition, it increases awareness about metabolic diseases among primary care physicians, who are generally unfamiliar with this group of treatable disorders.
In this article, the many metabolic disorders amenable to screening are grouped into broad clinical categories, and their presenting phenotypes and biochemical abnormalities are summarized. Although MS/MS can identify most of these disorders, it does not screen for galactosemia and biotinidase deficiency. However, these disorders are included in this review to be complete. Finally, the role of the primary provider when an abnormal screening result is reported and during follow-up is also discussed.
Available Newborn Screening for Metabolic Disorders*
Classification of Screened Metabolic Disorders
CLASSIFICATION OF SCREENED METABOLIC DISORDERS
Metabolic disorders identified by MS/MS can be classified into three groupings, according to the age of symptom onset and whether they are associated with "metabolic crises" (ie, acute episodes of clinical decompensation, biochemical decompensation, or both).
Clinical Features of All Disorders
Group I (Table 2) includes those disorders in which the onset of symptoms can occur in the neonatal period, or later, often in association with an intercurrent febrile illness. These disorders are frequently associated with severe, recurrent episodes of clinical and biochemical decompensation. Patients who show their first symptoms beyond the newborn period generally have a milder variant of the illness (perhaps due to increased residual enzyme activity). However, all metabolic crises, whether they occur in the neonatal period or later in childhood, are potentially lethal.
Biochemical Features of Group I and Group II Disorders
Group II (Table 2) includes those disorders that are generally associated with an onset of symptoms later in infancy, again, usually in association with an intercurrent infection. These disorders may also be associated with severe, recurrent metabolic crises, although, in some, the course progresses in a slower, less dramatic fashion.
Disorders not associated with metabolic crises are listed under group III (Table 2). Their onset is more subtle and occurs sometime during infancy or beyond.
CLINICAL AND BIOCHEMICAL FEATURES
The clinical phenotypes discussed in this section describe patients who have "typical" presentations. However, patients with both classic and variant forms of a disorder are likely identified by the MS/MS newborn screening process.
Therefore, patients with variant disease may be completely asymptomatic at the time of laboratory identification; "presymptomatic" may better describe these patients. It is also likely that screening will detect patients who will never go on to develop symptoms, as PKU screening does when patients with only mild elevations in phenylalanine are identified (benign hyperphenylalaninemia). Currently, however, it is not possible to determine who will ultimately remain free of symptoms. The clinical and biochemical phenotypes of all disorders are summarized in Tables 3 and 4.
Group I Disorders
Patients with group I disorders tend to present with vomiting and feeding difficulties, and, as a result, may not gain weight or grow well. Their acute metabolic crises are generally associated with lethargy or irritability and muscle tone that is frequently diminished but which can also be increased. In severe cases, coma may result. Jaundice can be exacerbated, prolonged, or both in galactosemia and tyrosinemia type I. Seizures may occur as a result of the acute biochemical derangements (eg, metabolic acidosis, hypoglycemia, hyperammonemia, or all three, depending on the disorder), the neurotoxic effects of accumulated metabolites specific for a particular disorder, other intracellular pathobiochemical processes, or all three. Infants with propionic acidemia and methylmalonic acidemia are also at risk for basal ganglial injury during acute metabolic crises.4 Although affected infants may appear "septic," they are generally not at risk for infection. However, approximately 20% of newborns with untreated galactosemia can have gram-negative infections,5 and patients who have certain organic acidemias (eg, propionic, methylmalonic, and isovaleric acidemia) can have neutropenia (and thrombocytopenia) during severe crises. Metabolic crises occurring beyond infancy may resemble Reye syndrome (with hyperammonemia).6 Sudden death has been reported in patients with urea cycle disorders, organic acidemias, and fatty acid oxidation defects.6
Biochemically, all patients in group I may show hypoglycemia. The organic acidemias and fatty acid oxidation defects are often associated with a primary metabolic acidosis (low blood pH, low HCO3) and an increased anion gap. Defects in the urea cycle may show a primary respiratory alkalosis and secondary metabolic acidosis (high blood pH, low HCO3), often associated with tachypnea. A high blood pH is a rare occurrence in children and necessitates measurement of the blood ammonia level.
Hyperammonemia is not only present in children with urea cycle defects and in advanced liver failure (due to galactosemia or tyrosinemia type I), but can also occur in children acutely ill with certain organic acidemias (eg, propionic acidemia and methylmalonic acidemia) and fatty acid oxidation defects. Indeed, when ammonia levels are extremely high, a respiratory alkalosis can also occur even in the organic acidemias.
Liver dysfunction occurs with metabolic liver disease (eg, galactosemia and tyrosinemia type I), but may also occur transiently in urea cycle defects, organic acidemias, and fatty acid oxidation defects during periods of decompensation. A septic work-up needs to be considered for patients with galactosemia or the organic acidemias (eg, propionic, methylmalonic, or isovaleric acidemia) who are symptomatic. Given the significant coagulopathy that can go along with metabolic liver disease, caution is necessary when performing a lumbar puncture in patients acutely ill with galactosemia.
Group II Disorders
Although the metabolic crises characteristic of group II disorders almost never occur in the neonatal period, patients show many of the same signs and symptoms as those with group I disorders, including vomiting, lethargy or irritability, occasionally seizures, and potentially coma. Altered muscle tone is also noted, particularly during a metabolic crisis. Infants with glutaric acidemia type I can initially show hypotonia, then become strikingly dystonic, secondary to basal ganglial injury.7 The metabolic crises of patients with fatty acid oxidation defects can resemble Reye syndrome (with hyperammonemia).6 Patients with biotinidase deficiency who are acutely sick may be immunologically compromised.8 Sudden death has been reported as the presenting phenotype in approximately 20% of cases of medium-chain acyl coenzyme A (CoA) dehydrogenase deficiency9 (the most common fatty acid oxidation disorder), and rarely occurs in cases where the diagnosis is known.
Prior to the occurrence of a metabolic crisis, children with glutaric acidemia type I may also show asymptomatic, nonfamilial macrocephaly with abnormal fluid collections on brain imaging anterior to the frontal and temporal horns.7 Infants with biotinidase deficiency may demonstrate chronic hypotonia, seizures, alopecia, and a skin rash.10 In a number of fatty acid oxidation defects associated with cardiomyopathy (deficiencies in very-long-chain acyl CoA dehydrogenase, long-chain hydroxy acyl CoA dehydrogenase, carnitine palmitoyl transferase II, and glutaric acidemia type II), heart failure can be the initial presentation with a more chronic, less dramatic encephalopathy.11
Biochemically, group II disorders may all cause a primary metabolic acidosis (low pH, low HCO3) with an increased anion gap, and some degree of hypoglycemia. Hypoglycemia is normally associated with a significant ketonuria. Because defects in fatty acid oxidation impair ketone production, most cases in which hypoglycemia occurs show a hypoketotic hypoglycemia12 (ie, inappropriately low ketonuria associated with low blood glucose levels); short-chain acyl CoA dehydrogenase deficiency is an exception, showing significant ketosis. Patients acutely symptomatic with a defect in fatty acid oxidation may also show some elevation in blood ammonia owing to a chemical inhibition of the urea cycle by some toxic intermediate.
Group III Disorders
Finally, group III disorders have symptoms that develop over time during infancy or childhood. Patients with PKU present with developmental delay in their first year and occasionally have seizures. They are fair in coloring and may have eczema. Children with homocystinuria have developmental delays and a Marfanoid habitus with tall stature, long limbs, and long digits. They may have a pectus deformity and scoliosis, and their bones are osteoporotic. They are at risk for lens dislocation, and later for thromboembolism.
Tyrosinemia type II and hyperornithinemia with gyrate atrophy are both exceedingly rare. The former is characterized by developmental delays, painful hyperkeratotic lesions on palms and soles, and keratoconjunctivitis. With the latter, patients have (usually isolated) progressive ocular disease and visual impairment.
Group III disorders are not associated with episodic biochemical decompensation, or perturbations of simple blood and urine tests.
Available treatment for these disorders varies with the disorder. For the amino acid disorders, urea cycle defects, and organic acidemias, nutritional therapy represents the mainstay of managing the disease. The dietary intake of specific amino acids is restricted according to the disorder, and care is taken to ensure the patient's overall protein and calorie needs are met. In treating patients with a fatty acid oxidation defect, the goals include avoiding prolonged fasts (to minimize the need to oxidize endogenous fatty acids as a source of energy) and providing frequent feedings when sick (or intravenous dextrose if the patient cannot tolerate anything by mouth). Children with urea cycle defects and organic acidemias are frequently anorexic and are generally unable to support themselves for the long term without the assistance of gastrostomy feedings. Supplementation with specific vitamins, cofactors, or both can help by stimulating residual enzyme activity (eg, vitamin B12 in methylmalonic acidemia), or by binding toxic intermediates and facilitating their excretion from the body (eg, carnitine in propionic acidemia). Special medications also exist for clearing waste nitrogen from the body (eg, sodium phenylbutyrate in citrullinemia).
In all cases, the parents and involved family members need to be educated thoroughly about the disease and its management because few, if any, nonmetabolic professionals involved in the child's care will have any background knowledge about the disorder. For families with children who have disorders associated with recurrent crises, this process should provide caregivers with the skill to assess for early signs and symptoms of metabolic instability. The administration of simple tests in the home (eg, blood glucose in hydroxymethylglutaryl CoA lyase deficiency and urinary ketones in propionic and methylmalonic acidemia) can be useful to help gauge the patient's clinical status. Finally, the patient's developmental progress needs to be closely monitored and community-based therapy begun if any concerns arise.
THE ROLE OF THE PEDIATRICIAN
What to Do on Receiving Notification of an Abnormal Result
The pediatrician should discuss the case with a metabolic specialist to better understand the medical ramifications associated with the diagnosis. Decisions regarding further testing, the need for a metabolic evaluation, and the timing of such an evaluation depend on the diagnosis and the status of the patient. The specialist can also provide the pediatrician with up-to-date information about the disorder, as the information in general pediatric textbooks is often outdated and can be misleading.
If there are any significant concerns about the patient's clinical state, he or she should be referred for evaluation in a metabolic clinic or emergency department. Biochemical evaluation may include the following (according to the particular disorder of concern): blood gases, electrolytes, bicarbonate, ammonia, glucose, liver function, if appropriate (including bilirubin, prothrombin time, and partial thromboplastin time), complete blood cell count with differential white blood cell count and platelets, and urinalysis (including ketones). Extra plasma (2 cc) and urine (5 to 10 cc) should be collected for additional testing, and should be kept refrigerated. Also, a follow-up blood filter paper specimen should be sent to the newborn screening laboratory, which can usually expedite a result.
Pending the outcome of these screening tests, feedings should be discontinued, and, if necessary, an intravenous catheter placed for providing 10% dextrose with electrolytes. The higher glucose administration not only prevents hypoglycemia, but provides additional calories that are necessary to diminish flux through catabolic pathways, which are generally the site of involvement in these metabolic disorders. Acute hypoglycemia, primary metabolic acidosis, or both are treated conventionally.
Patients with group III disorders are not at risk for complications during the newborn period, but need to be evaluated in a metabolic center for confirmation of the diagnosis, family counseling, and initiation of therapy.
Once the diagnosis of a metabolic disorder is made, it is unfortunately common for the role of the pediatrician in the patient's overall care to diminish. Sometimes this occurs because of concern by an uncomfortable primary care physician that any medical issue may somehow be related to the underlying metabolic disorder. At times, it is a matter of convenience. Because the family is in touch with the metabolic specialist on a regular basis, it seems easier to have him or her deal with any nonmetabolic issues that arise.
However, when a pediatrician's involvement is reduced, the patient's overall care suffers. The subspecialist has the patient's metabolic issues as the prime focus, whereas the pediatrician views the whole patient. When the latter is minimized, it is too often the parents who fill the role of the primary care physician, an unhealthy and medically impossible situation for all involved.
Ideally, the pediatrician and the metabolic specialist work out a complementary relationship over time. The pediatrician continues to manage all general health issues, and should be educated by the specialist regarding all medical complications that can occur as a result of the diagnosis. Acting as a resource for both the family and the pediatrician, the metabolic specialist needs to actively support and nurture this therapeutic bond. The pediatrician should help guide the parents in monitoring the patient at home for metabolic instability, and be able to take part in assessing the patient's clinical status. The degree of involvement varies with the disorder. It is the responsibility of the metabolic specialist to provide instruction and clinical backup when necessary. Certain issues (eg, nutritional therapy) are still managed best by the metabolic professionals who have the expertise. Because frequent correspondence around these issues will occur with the patient or family, direct communication with the metabolic clinic can help prevent errors and can serve as a basis for educating the parents about managing their child's disorder.
Because metabolic centers often service large regions, the pediatrician, as the professional based in the patient's community, is frequently in a better position to help secure community services that the patient and family may need to maintain metabolic stability and to ensure the patient's maximal development. Support and guidance are provided by the metabolic clinic, but should be tailored to the patient's individual needs by the pediatrician. In addition, as the physician closest with the family, the pediatrician may need to assume the role of patient advocate in other local matters, including educational planning, medical referrals, and insurance problems.
1. Guthrie R, Susi A. A simple phenylalanine method for detecting phenylketonuria in large populations of newborn infants. Pediatrics. 1963;32:338-343.
2. American Academy of Pediatrics, Committee on Genetics. Newborn screening fact sheets. Pediatrics. 1996;98:473-501.
3. Millington DM, Chase DH, Hillman SL, et al, Diagnosis of metabolic disease. In: Matsuo T, Caprioli RM, Gross ML, Seyama Y, eds. Biological Mass Spectrometry: Present and Future. New York: John Wiley & Sons; 1994:559-579.
4. de Sousa C, Piesowicz AT, Brett EM, et al. Focal changes in the globi pallidi associated with neurological dysfunction in methylmalonic acidemia. Neuropediatrics. 1989;20: 199-201.
5. Korson MS, Irons M, Levy HL. The neonatal phenotype of galactosemia. Am J Hum Genet. 1987;41(suppl):A10.
6. Saudubray J-M, Charpentier C. Clinical phenotypes: diagnosis/ algorithms. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease, 7th ed. New York: McGraw-Hill; 1995: 327-400.
7. Hoffman GF. Glutaric aciduria type I and related cerebral organic acid disorders. In: Fernandes J, Saudubray J-M, van den Berghe G, eds. Inborn Metabolic Diseases: Diagnosis and Treatment, 2nd ed. Berlin: Springer; 1996:229-236.
8. Cowan MJ, Wana DW, Packman S, et al. Multiple biotindependent carboxylase deficiencies associated with defects in T-cell and B-cell immunity. Lancet. 1979;2:115118.
9. Iafolla AK, Millington DS, Chen YT, et al. Natural course of medium chain acyl-CoA dehydrogenase deficiency. Am J Hum Genet. 1991;49(suppl):A475.
10. Wolf B, Heard GS, Weissbecker BA, et al. Biotinidase deficiency: initial clinical features and rapid diagnosis. Ann Neurol. 1985;18:614-617.
11. Pollitt RJ. Disorders of mitochondrial long-chain fatty acid oxidation. J Inherit Metab Dis. 1975;18:473-490.
12. Hale DE, Bennett MJ. Fatty acid oxidation disorders: a new class of metabolic diseases. J Pediatr. 1992;121:1-11.
Available Newborn Screening for Metabolic Disorders*
Classification of Screened Metabolic Disorders
Clinical Features of All Disorders
Biochemical Features of Group I and Group II Disorders