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Inborn Errors of in Infancy and Early Childhood: An Update TALKAD S. RAGHUVEER, M.D., University of Kansas Medical Center, Kansas City, Kansas UTTAM GARG, PH.D., and WILLIAM D. GRAF, M.D., Children’s Mercy Hospitals and Clinics, Kansas City, Missouri

Recent innovations in medical technology have changed newborn screening programs in the United States. The widespread use of tandem mass spectrometry is helping to identify more inborn errors of metabolism. Primary care physicians often are the first to be contacted by state and reference laboratories when neonatal screening detects the possibility of an inborn error of metabolism. Physicians must take immediate steps to evaluate the infant and should be able to access a regional subspecialty center. Detailed knowledge of biochemical pathways is not necessary to treat patients during the initial evaluation. Nonspecific metabolic abnormalities (e.g., hypoglycemia, meta- bolic , ) must be treated urgently even if the specific underlying metabolic disorder is not yet known. Similarly, physicians still must recognize inborn errors of metabolism that are not detected reliably by tandem mass spectrometry and know when to pursue additional diagnostic testing. The early and specific diagnosis of inborn errors of metabolism and prompt initiation of appropriate therapy are still the best determinants of outcome for these patients. (Am Fam Physician 2006;73:1981-90. Copyright © 2006 American Academy of Family Physicians.)

This article exem- he topic of inborn errors of metab- prevent progression are well estab- plifies the AAFP 2006 olism is challenging for most phy- lished. Screening tests must be timely and Annual Clinical Focus on sicians. The number of known effective with a high predictive value. Cur- caring for children and adolescents. metabolic disorders is probably as rent approaches to detecting inborn errors Tlarge as the number of presenting symptoms of metabolism revolve around laboratory that may indicate metabolic disturbances screening for certain disorders in asymptom- (Table 11-3). Furthermore, physicians know atic newborns, follow-up and verification of they may not encounter certain rare inborn abnormal laboratory results, prompt physi- errors of metabolism during a lifetime of cian recognition of unscreened disorders in practice. Nonetheless, with a collective inci- symptomatic persons, and rapid implementa- dence of one in 1,500 persons, at least one of tion of appropriate therapies. these disorders will be encountered by almost The increasing application of new tech- all practicing physicians.1-3 nologies such as electrospray ionization– Improvements in medical technology and tandem mass spectrometry to newborn greater knowledge of the human genome screening4 in asymptomatic persons allows are resulting in significant changes in the earlier identification of clearly defined diagnosis, classification, and treatment of inborn errors of metabolism. It also detects inherited metabolic disorders. Many known some conditions of uncertain clinical sig- inborn errors of metabolism will be recog- nificance.5 The inborn errors of metabolism nized earlier or treated differently because detected by tandem mass spectrometry gen- of these changes. It is important for primary erally include aminoacidemias, care physicians to recognize the clinical signs disorders, organic acidurias, and fatty acid of inborn errors of metabolism and to know oxidation disorders. Earlier recognition of when to pursue advanced laboratory testing these inborn errors of metabolism has the or referral to a children’s subspecialty center. potential to reduce morbidity and mortality rates in these infants.6 Early Diagnosis and Screening Tandem mass spectrometry has been in Asymptomatic Infants introduced or mandated in many states, The principles of population screening with some states testing for up to seven to identify persons with biologic markers conditions and others screening for up to of disease and to apply interventions to 40 conditions. Therefore, physicians must

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SORT: KEY RECOMMENDATIONS FOR PRACTICE

Evidence Clinical recommendation rating References

Tandem mass spectrometry in newborn screening allows earlier identification A4 of inborn errors of metabolism in asymptomatic persons. Earlier recognition of inborn errors of metabolism has the potential to reduce A6 morbidity and mortality rates in affected infants. Special consideration for pregnant women with includes A12 constant monitoring of concentrations to prevent intrauterine fetal malformation.

A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evi- dence; C = consensus, disease-oriented evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, see page 1874 or http://www.aafp.org/afpsort.xml.

TABLE 1 Inborn Errors of Metabolism and Associated Symptoms*

Diarrhea Peripheral neuropathy Lactase deficiency (common) Mitochondrial disorders (1:30,000) Mitochondrial disorders (1:30,000; e.g., Pearson’s syndrome [rare]) Peroxisomal disorders (1:50,000; e.g., Zellweger syndrome, Abetalipoproteinemia (rare) neonatal adrenoleukodystrophy, Refsum’s disease) Enteropeptidase deficiency (rare) Metachromatic leukodystrophy (1:100,000) Lysinuric protein intolerance (rare) Congenital disorders of glycosylation (rare) Sucrase-isomaltase deficiency (rare) Recurrent emesis Exercise intolerance (1:40,000) Fatty acid oxidation disorders (1:10,000) 3-oxothiolase deficiency (1:100,000) Glycogenolysis disorders (1:20,000) D-2-hydroxyglutaricaciduria (rare) Mitochondrial disorders (1:30,000; e.g., lipoamide dehydrogenase Symptoms of pancreatitis deficiency [rare]) Mitochondrial disorders (1:30,000; e.g., cytochrome-c oxidase Myoadenylate deaminase deficiency (1:100,000) deficiency; MELAS syndrome; Pearson’s syndrome [all rare]) Familial myocardial infarct/stroke Glycogenosis, type I (1:70,000) 5,10-methylenetetrahydrofolate reductase deficiency (common) Hyperlipoproteinemia, types I and IV (rare) Familial hypercholesterolemia (1:500) Lipoprotein lipase deficiency (rare) Fabry’s disease (1:80,000 to 1:117,000) Lysinuric protein intolerance (rare) (1:200,000) Upward gaze paralysis Muscle cramps/spasticity Mitochondrial disorders (1:30,000; e.g., Leigh disease, Multiple carboxylase deficiency (e.g., holocarboxylase synthetase Kearns-Sayre syndrome [rare]) [rare]) and biotinidase deficiencies (1:60,000) Niemann-Pick disease, type C (rare) Metachromatic leukodystrophy (1:100,000) HHH syndrome (rare)

NOTE: Disorders are listed as possible diagnostic considerations in order of descending incidence. Incidence in the general U.S. population is compa- rable to international estimates; however, disorders may occur more often in select ethnic populations. Rare is defined as an estimated incidence of fewer than 1:250,000 persons. HHH = hyperornithinemia-hyperammonemia-homocitrullinuria; MELAS = mitochondrial , lactic acidosis, and stroke-like episodes. *—Inborn errors of metabolism can induce disease manifestations in any organ at various stages of life, from newborn to adulthood. Whereas advanced newborn screening programs using tandem mass spectrometry will detect some inherited metabolic disorders before clinical signs appear, most of these disorders will be detected by the primary care physician before the diagnosis is made. Reliable determination of certain metabolic disorders varies between laboratories. Changes in screening reflect a growing field. Information from references 1 through 3.

1982 American Family Physician www.aafp.org/afp Volume 73, Number 11 U June 1, 2006 Inborn Errors of Metabolism

be aware of variability in newborn screening ciated with dysfunction of the central ner- among individual hospitals and states. Cur- vous system (CNS), liver, , eye, , rent state-by-state information on newborn blood, muscle, gastrointestinal tract, and screening programs can be obtained through integument. Infants with symptoms of acute the Internet resource -R-US (Genetic or chronic encephalopathy usually require a and Newborn Screening Resource Center of focused but systematic evalua- the United States; http://genes-r-us.uthscsa. tion by a children’s neurologist Within a few days or weeks 7 edu/). Primary care physicians are most and appropriate testing (e.g., afterbirth,apreviously likely to be the first to inform parents of an magnetic resonance imaging, healthy neonate may begin abnormal result from a newborn screening additional genetic or metabolic to show signs of an under- program. In many instances, primary care analysis). Subspecialty refer- lying metabolic disorder. physicians may need to clarify preliminary ral is likewise necessary for laboratory results or explain the possibility infants or children presenting of a false-positive result.6 with hepatic, renal, or cardiac syndromes; dysmorphic syndromes; ocular findings; or Early Diagnosis in Symptomatic Infants significant orthopedic abnormalities. Within a few days or weeks after birth, a pre- A “pattern recognition” approach helps viously healthy neonate may begin to show guide the physician toward a differential signs of an underlying metabolic disorder. diagnosis and targeted biochemical and Although the clinical picture may vary, infants molecular testing.9 However, this approach with metabolic disorders typically present is not to be confused with the identification with lethargy, decreased feeding, vomiting, of congenital malformations, particularly tachypnea (from acidosis), decreased perfu- those related to chromosomal disorders. sion, and . As the metabolic illness Patients generally have a normal appearance progresses, there may be increasing stupor or in the early stages of most inborn metabolic coma associated with progressive abnormali- disorders. Because most inborn errors of ties of tone (, hypertonia), pos- metabolism are single- disorders, chro- ture (fisting, opisthotonos), and movements mosomal testing usually is not indicated. (tongue-thrusting, lip-smacking, myoclonic jerks), and with sleep apnea.8 Metabolic Considerations in Older screening tests should be initiated. Elevated Infants and Children plasma ammonia levels, hypoglycemia, and Older infants with inborn errors of metabo- metabolic acidosis, if present, are suggestive lism may demonstrate paroxysmal stupor, of inborn errors of metabolism (Table 21-3). lethargy, emesis, , or organo- In addition, the parent or physician may megaly. Neurologic findings of neurometa- notice an unusual odor in an infant with cer- bolic disorders are acquired macrocephaly or tain inborn errors of metabolism (e.g., maple microcephaly (CNS storage, dysmyelination, syrup disease, phenylketonuria [PKU], atrophy), hypotonia, hypertonia/spasticity, sei- hepatorenal type 1, isovaleric zures, or other movement disorders. General acidemia). A disorder similar to Reye’s syn- nonneurologic manifestations of neurometa- drome (i.e., nonspecific hepatic encepha- bolic disorders include skeletal abnormalities lopathy, possibly with hypoglycemia) may be and coarse facial features (e.g., with muco- present secondary to abnormalities of gluco- polysaccharidoses), macular or retinal changes neogenesis, fatty acid oxidation, the electron (e.g., with leukodystrophies, poliodystrophies, transport chain, or organic acids. mitochondrial disorders), corneal clouding Table 31-3 shows a partial list of meta- (e.g., with Hurler’s syndrome, galactosemia), bolic disorders associated with organ system skin changes (e.g., angiokeratomas in Fabry’s manifestations. Most of these disorders are disease), or hepatosplenomegaly (with various not detected by tandem mass spectrometry storage ; Table 21-3). screening. These highly diverse presentations Consistent features of metabolic disor- of inborn errors of metabolism may be asso- ders in toddlers and preschool-age children

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include stagnation or loss of cognitive mile- may lead to the identification of clinically stones; loss of expressive language skills; recognizable genetic disorders. Referral to a progressive deficits in attention, focus, geneticist often is indicated to further evalu- and concentration; and other behavioral ate physical findings of primary genetic changes. The physician should attempt to determinants. make fundamental distinctions between Initial laboratory investigations for older primary-genetic and secondary-acquired children are the same as for infants. Infants causes of conditions that present as develop- and children presenting with acute metabolic mental delay or failure to thrive. Clues can decompensation precipitated by periods of be extracted through careful family, social, prolonged fasting should be evaluated further environmental, and nutritional history-tak- for those organic acid, fatty acid oxidation, or ing. Syndromes with metabolic disturbances peroxisomal disorders that are not detected

TABLE 2 Inborn Errors of Metabolism and Associated Laboratory Findings*

Abnormal liver function tests (e.g., elevated transaminase or hyperbilirubinemia levels) (1:7,000; e.g., ) Hemochromatosis (1:300) X-linked hypophosphatemic (1:20,000) G1-antitrypsin deficiency (1:8,000) Hereditary fructose intolerance (1:20,000 to 1:50,000) Fanconi syndrome (1:7,000; e.g., cystinosis) Mitochondrial disorders (1:30,000; e.g., mitochondrial DNA Xanthine oxidase deficiency (1:45,000) depletion syndromes) Molybdenum cofactor deficiency (rare) Galactosemia (1:40,000) Purine-nucleoside phosphorylase deficiency (rare) Wilson’s disease (1:50,000) Increased CSF protein Gaucher’s disease (1:60,000; type 1–1:900 in Ashkenazi Jews) Mitochondrial disorders (1:30,000; e.g., MELAS syndrome [rare], (1:160,000) MERRF syndrome, Kearns-Sayre syndrome [rare]) Cholesteryl ester storage disease (rare) Peroxisomal disorders (1:50,000; e.g., Zellweger syndrome, , type IV (rare) neonatal adrenoleukodystrophy, Refsum’s disease) Niemann-Pick disease, types A and B (both rare) Leukodystrophies (e.g., Krabbe’s disease; metachromatic Type 1 tyrosinemia (rare) leukodystrophy [1:100,000]; multiple sulfatase deficiency [rare]) Wolman’s disease (rare) L-2-hydroxyglutaricaciduria (rare) Hypoglycemia Congenital disorders of glycosylation (rare) Carbohydrate metabolism disorders (>1:10,000) Ketosis Fatty acid oxidation disorders (1:10,000) Aminoacidopathies (1:40,000) Hereditary fructose intolerance (1:20,000 to 1:50,000) Organic acidurias (1:50,000) Glycogen storage diseases (1:25,000) Metabolic acidosis Galactosemia (1:40,000) Aminoacidopathies (1:40,000) Organic acidemias (1:50,000) Organic acidurias (1:50,000) Phosphoenolpyruvate carboxykinase deficiency (rare) Primary lactic acidosis (rare) Primary lactic acidosis (rare) (rare)

NOTE: Disorders are listed as possible diagnostic considerations in order of decreasing incidence. Incidence in the general U.S. population is compa- rable to international estimates; however, disorders may occur more often in select ethnic populations. Rare is defined as an estimated incidence of fewer than 1:250,000 persons. CSF = cerebrospinal fluid; MELAS = mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes; MERRF = myoclonus with epilepsy and with ragged red fibers. *—Inborn errors of metabolism can induce disease manifestations in any organ at various stages of life, from newborn to adulthood. Whereas advanced newborn screening programs using tandem mass spectrometry will detect some inherited metabolic disorders before clinical signs appear, most of these disorders will be detected by the primary care physician before diagnosis is made. Reliable determination of certain metabolic disorders varies among laboratories. Changes in screening reflect a growing field. Information from references 1 through 3.

1984 American Family Physician www.aafp.org/afp Volume 73, Number 11 U June 1, 2006 Inborn Errors of Metabolism

by tandem mass spectrometry or certain recommended that strict dietary therapy be regional neonatal screening programs. continued for life. Special considerations for Cerebrospinal fluid (CSF) may be help- pregnant women with PKU include constant ful in the evaluation of certain metabolic monitoring of phenylalanine concentrations disorders after neuroimaging studies and to prevent intrauterine fetal malformation.12 basic blood and urine analyses have been completed. Common CSF studies include ORNITHINE TRANSCARBAMYLASE DEFICIENCY cells (to rule out inflammatory disorders), Ornithine transcarbamylase deficiency is the (plus plasma glucose to evaluate for most common urea cycle disorder. Signs blood-brain barrier or glucose transporter of ornithine transcarbamylase deficiency in disorders), lactate (as a marker of energy infant boys include severe emesis, hyperam- metabolism or mitochondrial disorders), monemia, and progressive encephalopathy. total protein, and quantitative amino acids. Heterozygous girls, who demonstrate par- Nuclear magnetic resonance spectroscopy tial expression of the X-linked ornithine can provide a noninvasive, in vivo evalua- transcarbamylase deficiency disorder, may tion of proton-containing metabolites and present with symptoms such as mild hyper- can lead to the diagnosis of certain rare, ammonemia and notable avoidance of dietary but potentially treatable, neurometabolic protein. Acute treatment options include disorders.10 Electron microscopic evalua- sodium benzoate, sodium phenylacetate, and tion of a skin biopsy is a highly sensitive . Certain persons may benefit from screening tool that provides valuable clues liver transplantation. to stored membrane material or ultrastruc- tural organelle changes.11 METHYLMALONICACIDURIA DISORDERS Table 4 lists some of the more common The most common genetic causes of meth- inborn errors of metabolism, classified by ylmalonicaciduria are deficiencies in methyl- type of metabolic disorder. Such prototypi- malonyl-CoA mutase activity and in enzymatic cal inborn errors of metabolism include synthesis of cobalamin. Pernicious anemia and PKU, ornithine transcarbamylase deficiency, dietary cobalamin deficiency also can result methylmalonicaciduria, medium-chain acyl- in abnormal methylmalonicacid metabolism. CoA dehydrogenase (MCAD) deficiency, Metabolic ketoacidosis is the clinical hallmark galactosemia, and Gaucher’s disease. of methylmalonicaciduria in infants. Therapy consists of protein restriction, restriction of PKU methylmalonate precursors, and pharmaco- PKU is an autosomal-recessive disorder most logic doses of vitamin B12. commonly caused by a mutation in the gene coding for phenylalanine hydroxylase, an MCAD DEFICIENCY responsible for the conversion of The most common fatty acid oxidation dis- phenylalanine to . Sustained phenyl- order is MCAD deficiency. The majority of alanine concentrations higher than 20 mg per infants diagnosed with MCAD deficiency dL (1,211 Rmol per L) usually correlate with are homozygous for the A985G missense classic symptoms of PKU, such as impaired mutation and have northwestern European head circumference growth, poor cognitive ancestry. Infants with MCAD deficiency function, irritability, and lighter skin pig- appear to develop normally but present with mentation. Infants diagnosed with PKU are rapidly progressive hypoglycemia, lethargy, treated with a special low-phenylalanine for- and seizures, typically secondary to acute mula. Tyrosine is given at approximately vomiting or fasting. Treatment of MCAD 25 mg per kg of weight per day; amino acids deficiency includes frequent cornstarch feeds are given at about 3 g per kg per day in infancy and avoidance of fasting. Parents must have and 2 g per kg per day in childhood. Infants a basic understanding of the metabolic deficit and children must be monitored regularly in their child and should carry a letter from during the developmental period, and it is their treating physicians to alert emergency

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caregivers about the need for urgent atten- uridyltransferase (GALT). Clinical manifesta- tion in a crisis situation. tions of galactosemia include lethargy, hypo- tonia, jaundice, hypoglycemia, elevated liver GALACTOSEMIA , and coagulopathy. It is important to There are three known enzymatic errors in distinguish the galactosemia disease genotype galactose metabolism. The most common (G/G) from asymptomatic variant genotypes defect is confirmed by measuring decreased (e.g., G/D, G/N, D/D), which can be picked up activity of erythrocyte galactose 1-phosphate as “positive” in newborn screening.

TABLE 3 InbornErrorsofMetabolismandAssociatedOrganSystemManifestations*

Central nervous system Central nervous system (continued) Skin/eye (continued) Acute encephalopathy Macrocephaly (continued) Cataracts—lenticular (continued) Mitochondrial disorders (1:30,000) L-2-hydroxyglutaricaciduria (rare) Cerebrotendinous xanthomatosis CPS deficiency (1:70,000 to 1:100,000) 3-hydroxy-3-methylglutaricaciduriayl (rare) (rare) Acute stroke Canavan disease (rare) Galactokinase deficiency (rare) 5,10-methylene tetrahydrofolate Krabbe’s disease (rare) Hyperornithinemia (ornithine reductase deficiency (common) Mannosidosis (rare) aminotransferase deficiency; rare) Fabry’s disease (1:80,000 to 1:117,000) Multiple sulfatase deficiency (rare) Lowe syndrome (rare) Ethylmalonic-adipicaciduria (rare) Stroke-like episodes Lysinuric protein intolerance (rare) Agenesis of the corpus callosum Ornithine transcarbamylase deficiency Mannosidosis (rare) Mitochondrial disorders (1:30,000; (1:70,000) Mevalonicaciduria (rare) e.g., PDH deficiency [1:200,000]) Chédiak-Higashi syndrome (rare) Cherry red macula Peroxisomal disorders (1:50,000; e.g., Zellweger MELAS syndrome (rare) Tay-Sachs disease (1:222,000) syndrome, neonatal adrenoleukodystrophy, Subacute necrotizing encephalomyelopathy Galactosialidosis (rare) Refsum’s disease) (Leigh disease) GM1 gangliosidosis (rare) Maternal PKU (1:35,000 pregnancies) ETC disorders (e.g., complex I deficiency) Mucolipidosis I (rare) Nonketotic hyperglycinemia Multiple carboxylase deficiency (e.g., Multiple sulfatase deficiency (1:250,000 in United States) holocarboxylase synthetase [rare]) (rare) Pyruvate carboxylase deficiency (rare) and biotinidase deficiencies (1:60,000) Niemann-Pick disease, types A and B Cerebral calcifications PDH deficiency (1:200,000) (rare) Adrenoleukodystrophy (1:15,000) 3-methylglutaconicaciduria (rare) Sandhoff’s disease (rare) Mitochondrial disorders (1:30,000) deficiency (rare) Sialidosis (rare) GM2 gangliosidosis (rare) Pyruvate carboxylase deficiency (rare) Corneal opacity Encephalopathy (rapidly progressive) Skin/eye Fabry’s disease (1:80,000 to Adenylosuccinate lyase deficiency (rare) Angiokeratomas 1:117,000) Atypical PKU (e.g., biopterin defects [rare]) Fabry’s disease (1:117,000) Hurler’s syndrome (MPS I; Molybdenum cofactor deficiency or Fucosidosis (rare) 1:100,000) sulfite oxidase deficiency (both rare) Cystinosis (1:100,000 to 1:200,000) GM1 gangliosidosis (rare) Macrocephaly Sialidosis (rare) I-cell disease (mucolipidosis II or Hurler’s syndrome (MPS I; 1:100,000) mucolipidosis III [rare]) Cataracts—lenticular Neonatal adrenoleukodystrophy (1:100,000) Galactosialidosis (rare) Mitochondrial disorders (1:30,000) Tay-Sachs disease (1:222,000) GM1 gangliosidosis (rare) Galactosemia (1:40,000) 4-hydroxybutyricaciduria (rare) Mannosidosis (rare) Fabry’s disease (1:80,000 to 1:117,000) Glutaricaciduria, type II (rare) Multiple sulfatase deficiency (rare)

NOTE: Disorders are listed as possible diagnostic considerations in order of decreasing incidence. Incidence in the general U.S. population is comparable to international estimates; however, disorders may occur more often in select ethnic populations. Rare is defined as an estimated incidence of fewer than 1:250,000 persons. CPS = carbamoyl phosphate synthetase; ETC = ; HPRT = hypoxanthine phosphoribosyltransferase; MELAS = mitochondrial encepha- lopathy, lactic acidosis, and stroke-like episodes; MPS = mucopolysaccharidosis; PDH = pyruvate dehydrogenase; PKU = phenylketonuria.

1986 American Family Physician www.aafp.org/afp Volume 73, Number 11 U June 1, 2006 Inborn Errors of Metabolism

The main treatment for infants with the and adequate intervention, some children G/G mutation or very low GALT activity still may develop milder signs of these is lactose-free formula followed by dietary clinical manifestations. restriction of all lactose-containing foods later in life. Untreated infants who survive GAUCHER’S DISEASE the neonatal period may have severe growth Type 1 Gaucher’s disease, the most common failure, mental retardation, cataracts, ovar- lysosomal storage disorder, typically presents ian failure, and liver cirrhosis. Despite early with hepatosplenomegaly, pancytopenia, and

Skin/eye (continued) Muscle/bone/kidney Muscle/bone/kidney (continued) Dermatosis Arthrosis Osteoporosis Acrodermatitis enteropathica (rare) Farber’s disease (acid ceramidase Xanthine oxidase deficiency (1:45,000) Multiple carboxylase deficiency (e.g., deficiency; < 1:40,000) Gaucher’s disease, (1:60,000; type holocarboxylase synthetase [rare]) and Gaucher’s disease (1:60,000; 1–1:900 in Ashkenazi Jews) biotinidase deficiencies (1:60,000) type 1–1:900 in Ashkenazi Jews) Glycogenosis (1:70,000) Hair abnormalities HPRT deficiency (Lesch-Nyhan syndrome; Adenosine deaminase Menkes syndrome (rare; e.g., pili torti, 1:100,000) deficiency (1:100,000) trichorrhexis nodosa, monilethrix) Homocystinuria (1:200,000) I-cell disease (mucolipidosis II or Ichthyosis (rare) mucolipidosis III [rare]) Sjögren-Larsson syndrome (fatty aldehyde Cardiomyopathy Refsum’s disease dehydrogenase deficiency, <1:100,000) Hemochromatosis (1:300) Lysinuric protein intolerance (rare) X-linked ichthyosis (1:6,000 boys and men; Fatty acid oxidation disorders (1:10,000) Menkes syndrome (rare) e.g., steryl-sulfatase deficiency) Mitochondrial disorders (1:30,000) Renal calculi Inverted nipples Pompe’s disease (1:40,000) (1:7,000) Congenital disorders of glycosylation (rare) MPS (1:50,000) HPRT deficiency (Lesch-Nyhan syndrome; Tetrahydrobiopterin synthesis disorders Glycogenosis, type III (1:125,000) 1:100,000) (rare) D-2-hydroxyglutaricaciduria (rare) Adenine phosphoribosyltransferase Lens dislocation (ectopia lentis) 3-methylglutaconicaciduria deficiency (rare) Marfan syndrome (1:10,000) (Barth syndrome; rare) Oxaluria (rare) Homocystinuria (1:200,000) Dysostosis multiplex Phosphoribosylpyrophosphate synthetase Molybdenum cofactor deficiency or MPS (e.g., Hurler’s syndrome [MPS I; deficiency (rare) sulfite oxidase deficiency (both rare) 1:100,000], Hunter’s syndrome Renal Fanconi syndrome Optic atrophy [MPS II; 1:70,000], Sanfilippo’s syndrome Hereditary fructose intolerance Peroxisomal disorders (1:50,000; [MPS III; 1:24,000 in Netherlands, (1:20,000 to 1:50,000) Zellweger syndrome, neonatal 1:66,000 in United States]; Maroteaux- Mitochondrial disorders adrenoleukodystrophy, Refsum’s Lamy syndrome [MPS VI; rare]; Sly’s (1:30,000; e.g., ETC disorders) disease) syndrome [MPS VII; rare]) Galactosemia (1:40,000) Xanthomas I-cell disease (mucolipidosis II or Wilson’s disease (1:50,000) mucolipidosis III [rare]) Familial hypercholesterolemia (1:500) Cystinosis (1:100,000 to 1:200,000) Multiple sulfatase deficiency (rare) Lipoprotein lipase deficiency (rare) Type 1 tyrosinemia (rare) Galactosialidosis (rare) Niemann-Pick disease, types A and B Lowe syndrome (rare) (both rare) GM1 gangliosidosis (rare) Cerebrotendinous xanthomatosis (rare)

*—Inborn errors of metabolism can induce disease manifestations in any organ at various stages of life from newborn to adulthood. Whereas advanced newborn screening programs using tandem mass spectrometry will detect some inherited metabolic disorders before clinical signs appear, most of these disorders will be detected by the primary care physician before the diagnosis is made. Reliable determination of certain metabolic disorders varies between laboratories. Changes in screening reflect a growing field. Information from references 1 through 3.

June 1, 2006 U Volume 73, Number 11 www.aafp.org/afp American Family Physician 1987 TABLE 4 Examples of Inborn Errors of Metabolism by Disorder

Disorder ~Incidence Inheritance Metabolic error

Amino acid metabolism Phenylketonuria 1:15,000 Autosomal Phenylalanine hydroxylase recessive (>98 percent) Biopterin metabolic defects (<2 percent) Maple syrup urine disease 1:150,000 Autosomal Branched-chain G-keto acid (1:1,000 in recessive dehydrogenase Mennonites) Carbohydrate metabolism Galactosemia 1:40,000 Autosomal Galactose 1-phosphate recessive uridyltransferase (most common); galactokinase; epimerase Glycogen storage disease, 1:100,000 Autosomal Glucose-6-phosphatase type Ia (von Gierke’s disease) recessive Fatty acid oxidation Medium-chain acyl-CoA 1:15,000 Autosomal Medium-chain acyl-CoA dehydrogenase deficiency recessive dehydrogenase

Lactic acidemia

Pyruvate dehydrogenase 1:200,000 X-linked E1 subunit defect deficiency most common

Lysosomal storage Gaucher’s disease 1:60,000; type Autosomal H-glucocerebrosidase 1–1:900 in recessive Ashkenazi Jews Fabry’s disease 1:80,000 to X-linked G-galactosidase A 1:117,000

Hurler’s syndrome 1:100,000 Autosomal G-L-iduronidase recessive Organic aciduria Methylmalonicaciduria 1:20,000 Autosomal Methylmalonyl-CoA mutase, recessive cobalamin metabolism

Propionic aciduria 1:50,000 Autosomal Propionyl-CoA carboxylase recessive

Peroxisomes Zellweger syndrome 1:50,000 Autosomal Peroxisome membrane protein recessive Urea cycle Ornithine transcarbamylase 1:70,000 X-linked Ornithine transcarbamylase deficiency

destructive bone disease. Types 2 and 3 Gau- Importance of Early Treatment cher’s disease present with strabismus, bulbar Often, empiric therapeutic measures are needed signs, progressive cognitive deterioration, and before a definitive diagnosis is available. In a myoclonic seizures. Treatment options for type critically ill infant, aggressive treatment before 1 Gaucher’s disease include regular infusions the definitive confirmation of diagnosis is with recombinant human acid H-glucosidase. lifesaving and may reduce neurologic sequelae.

1988 American Family Physician www.aafp.org/afp Volume 73, Number 11 U June 1, 2006 Key manifestation Key laboratory test Therapy approach

Mental retardation, acquired Plasma phenylalanine concentration Diet low in phenylalanine microcephaly hydroxylase

Acute encephalopathy, metabolic Plasma amino acids and urine Restriction of dietary branched- acidosis, mental retardation organic acids chain amino acids Dinitrophenylhydrazine for ketones

Hepatocellular dysfunction, Enzyme assays, galactose and Lactose-free diet cataracts galactose 1-phosphate assay, molecular assay

Hypoglycemia, lactic acidosis, Liver biopsy enzyme assay Corn starch and continuous ketosis overnight feeds

Nonketotic hypoglycemia, acute Urine organic acids, acylcarnitines, Avoid hypoglycemia, encephalopathy, coma, sudden gene test avoid fasting infant death

Hypotonia, psychomotor Plasma lactate Correct acidosis; high-fat, retardation, failure to thrive, Skin fibroblast culture for enzyme low-carbohydrate diet seizures, lactic acidosis assay

Coarse facial features, Leukocyte H-glucocere-brosidase Enzyme therapy, bone hepatosplenomegaly assay marrow transplant

Acroparesthesias, angiokeratomas Leukocyte G-galactosidase A assay Enzyme replacement therapy hypohidrosis, corneal opacities, renal insufficiency Coarse facial features, Urine mucopolysaccharides Bone marrow transplant hepatosplenomegaly Leukocyte G-L-iduronidase assay

Acute encephalopathy, metabolic Urine organic acids Sodium bicarbonate, carnitine,

acidosis, hyperammonemia Skin fibroblasts for enzyme assay vitamin B12, low-protein diet, liver transplant Metabolic acidosis, Urine organic acids Dialysis, bicarbonate, sodium hyperammonemia benzoate, carnitine, low- protein diet, liver transplant

Hypotonia, seizures, liver Plasma very-long-chain No specific treatment available dysfunction fatty acids

Acute encephalopathy Plasma ammonia, plasma amino Sodium benzoate, arginine, low- acids protein diet, essential amino Urine orotic acid acids; dialysis in acute stage Liver (biopsy) enzyme concentration

Infants with a treatable (e.g., drugs, but patients with rare inborn errors of methylmalonicacidemia) may respond to 1 mg metabolism may respond to other treatments of intramuscular vitamin B12. Metabolic acido- (e.g., oral pyridoxine in a dosage of 5 mg per kg sis should be treated aggressively with sodium per day) if rare disorders such as pyridoxine- bicarbonate. Seizures in infancy should be dependent epilepsy are clinically suspected by treated initially with traditional antiepileptic the consulting neurologist.

June 1, 2006 U Volume 73, Number 11 www.aafp.org/afp American Family Physician 1989 Inborn Errors of Metabolism

Long-term Treatment of Kansas Medical Center, 3901 Rainbow Blvd., Traditional therapies for metabolic diseases Kansas City, KS 66160. Reprints are not available from the authors. include dietary therapy such as protein restriction, avoidance of fasting, or cofactor The authors thank Amy E. Wolf for her assistance in manu- supplements (Table 4). Evolving therapies script preparation. include organ transplantation and enzyme Author disclosure: Nothing to disclose. replacement. Efforts to provide treatment through somatic gene therapy are in early REFERENCES stages, but there is hope that this approach 1. Beaudet AL, Scriver CR, Sly WS, Valle D. Molecular will provide additional therapeutic possibili- bases of variant human phenotypes. In: Scriver CR, ties. Even when no effective therapy exists or ed. The Metabolic and Molecular Bases of Inherited when an infant dies from a metabolic disor- Disease. 8th ed. New York: McGraw-Hill, 2001:3-51. der, the family still needs an accurate diag- 2. Applegarth DA, Toone JR, Lowry RB. Incidence of inborn errors of metabolism in British Columbia, 1969- nosis for clarification, reassurance, genetic 1996. 2000;105:e10. counseling, and potential prenatal screening. 3. Meikle PJ, Hopwood JJ, Clague AE, Carey WF. Additional resources, including information Prevalence of lysosomal storage disorders. JAMA about regional biochemical genetic consulta- 1999;281:249-54. 13-15 4. Wilcken B, Wiley V, Hammond J, Carpenter K. Screening tion services, are available online. newborns for inborn errors of metabolism by tandem mass spectrometry. N Engl J Med 2003;348:2304-12. The Authors 5. Holtzman NA. Expanding newborn screening: how good is the evidence? JAMA 2003;290:2606-8. TALKAD S. RAGHUVEER, M.D., is assistant professor of 6. Waisbren SE, Albers S, Amato S, Ampola M, Brew- pediatrics in the division of neonatology at the University ster TG, Demmer L, et al. Effect of expanded new- of Kansas Medical Center, Kansas City. Dr. Raghuveer born screening for biochemical genetic disorders on received his medical degree from Karnatak Medical child outcomes and parental stress. JAMA 2003;290: College, Hubli, India, and completed a pediatric resi- 2564-72. dency at Albert Einstein College of Medicine of Yeshiva 7. University of Texas Health Science Center at San University, Bronx, N.Y., and a fellowship in neonatal- Antonio. National Newborn Screening and Genetics perinatal medicine at the University of Iowa Hospitals and Resource Center. Accessed online January 10, 2006, at: Clinics, Iowa City. http://genes-r-us.uthscsa.edu. 8. Clarke JT. A Clinical Guide to Inherited Metabolic Dis- UTTAM GARG, PH.D., is director of biochemical genet- eases. 2nd ed. New York: Cambridge University Press, ics, clinical chemistry, and toxicology laboratories at 2002. Children’s Mercy Hospitals and Clinics, Kansas City, 9. Blau N, Duran M, Blaskovics ME, Gibson KM. Physician’s Mo., and professor of pediatrics and pathology at the Guide to the Laboratory Diagnosis of Metabolic Dis- University of Missouri–Kansas City School of Medicine. Dr. eases. 2nd ed. New York: Springer, 2003. Garg received his doctorate degree from the Postgraduate 10. Novotny E, Ashwal S, Shevell M. Proton magnetic reso- Institute of Medical Education and Research, Chandigarh, nance spectroscopy: an emerging technology in pediat- India, and completed his postdoctoral training at New ric neurology research. Pediatr Res 1998;44:1-10. York Medical College, Valhalla, and the University of 11. Prasad A, Kaye EM, Alroy J. Electron microscopic exami- Minnesota Medical School, Minneapolis. nation of skin biopsy as a cost-effective tool in the diagnosis of lysosomal storage diseases. J Child Neurol WILLIAM D. GRAF, M.D., is chief of the section of neurol- 1996;11:301-8. ogy at Children’s Mercy Hospitals and Clinics and professor of pediatrics at the University of Missouri–Kansas City 12. Levy HL, Ghavami M. Maternal phenylketonuria: a meta- School of Medicine. Dr. Graf completed a residency bolic teratogen. Teratology 1996;53:176-84. in pediatrics at Albert Einstein College of Medicine of 13. GeneTests. National Institutes of Health. Accessed Yeshiva University, a fellowship in neurodevelopmental online January 10, 2006, at: http://www.genetests. disabilities at New York Medical College, and a residency org. in neurology at the University of Washington School of 14. National Human Genome Research Institute. National Medicine, Seattle. Institutes of Health. Accessed online January 10, 2006, at: http://www.genome.gov/. Address correspondence to Talkad S. Raghuveer, M.D., 15. American Society of Human Genetics. Accessed online Division of Neonatology, 3043 Wescoe Bldg., University January 10, 2006, at: http://www.ashg.org.

1990 American Family Physician www.aafp.org/afp Volume 73, Number 11 U June 1, 2006