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Home , GM1, Hepatomegaly, Hyperammonemia, Metabolic disorder

Inborn Errors of in Infancy: A Guide to Diagnosis

Barbara K. Burton, MD

ABSTRACT. Recent advances in the diagnosis and 102/6/e69; inborn errors of metabolism, inherited metabolic treatment of inborn errors of metabolism have improved disorders. substantially the prognosis for many of these conditions. This makes it essential that the practicing pediatrician be familiar with the clinical presentation of these disorders. ABBREVIATIONS. CNS, central nervous system; THAN, transient A practical clinical approach to the recognition of inborn hyperammonemia of the newborn; OTC, ornithine transcarbamy- lase; CoA, co- A; PDH, ; GSD, errors of metabolism in the young infant is presented in glycogen storage . this review. Indications for specific laboratory studies are discussed. Guidelines are provided for the stabilization and emergency treatment of critically ill infants. This he number, complexity, and varied clinical approach will identify those infants who will benefit presentation of inborn errors of metabolism from additional evaluation and specific treatment. present a formidable challenge to the practic- Many of the inborn errors of metabolism, including T ing pediatrician. Yet, in many cases, prevention of cycle defects, organic acidemias, and certain disor- death or permanent neurologic sequelae in patients ders of amino acid metabolism, present in the young infant with symptoms of an acute or chronic metabolic with these disorders is dependent on early diagnosis . Typical symptoms include lethargy, and institution of appropriate . It is therefore poor feeding, apnea or tachypnea, and recurrent vomit- incumbent on the pediatrician to be familiar with the ing. Metabolic acidosis and/or hyperammonemia are ob- major of inborn errors of me- served in many of these conditions, but there are notable tabolism and with the basic laboratory studies nec- exceptions, including nonketotic hyperglycinemia and essary to arrive at an initial diagnosis. Although the molybdenum co-factor deficiency. Therefore, appropri- pediatrician may rarely be called on to be the sole ate laboratory testing for metabolic disorders should be provider of long-term care to patients with these performed in any infant who exhibits these findings. complex disorders, he or she will be responsible for Although sepsis may be the initial consideration in a the emergency care and stabilization of the infants neonate with these symptoms, inborn errors of metabo- lism should always be in the differential diagnosis, par- and children affected and should be familiar with the ticularly in a full-term infant with no specific risk factors. fundamental aspects of such care. Hypoglycemia may be the predominant finding in a It is the purpose of this review to define the con- number of inborn errors of metabolism, including glyco- stellation of findings in the young infant that should gen storage disorders, defects in gluconeogenesis, and alert the pediatrician to the possibility of inherited fatty acid oxidation defects. The latter disorders, among metabolic disease. The discussion is confined to the most common encountered, exhibit marked clinical those disorders that typically present in early infancy variability and also may present as a sudden death, a and have potential life-threatening consequences. Reye’s-like episode, or a cardiomyopathy. or The many disorders that typically present in later other evidence of hepatic dysfunction is the mode of childhood, such as most lysosomal storage disorders, presentation of another important group of inborn errors of metabolism including , hereditary ty- are not included. The laboratory tools used to eval- rosinemia, neonatal hemochromatosis, and a number of uate infants suspected of having metabolic disease other conditions. A subset of lysosomal storage disorders are described. Treatment of important groups of met- may present very early with coarse facial features, orga- abolic disorders is addressed, focusing on the stabi- nomegaly, or even hydrops fetalis. Specific patterns of lization and acute management of patients with dysmorphic features and congenital anomalies character- these conditions. A more comprehensive discussion ize yet another group of inherited metabolic disorders, of each of these topics can be found in recent editions such as and the Smith–Lemli–Opitz of reference textbooks.1,2 syndrome. Each of these symptom complexes, and the appropriate evaluation of the affected infants, is dis- cussed in more detail in this review. 1998; CLINICAL MANIFESTATIONS OF INBORN ERRORS 102(6). URL: http://www.pediatrics.org/cgi/content/full/ OF METABOLISM Acute Metabolic Encephalopathy From the Center for Medical , Michael Reese Hospital and Medical Center, Division of Genetics and Metabolism, University of Illinois College Several groups of inherited metabolic disorders, of , Chicago, Illinois. most notably the organic acidemias, de- Received for publication May 15, 1998; accepted Jul 15, 1998. fects, and certain disorders of amino acid metabo- Reprint requests to (B.K.B) Center for , Michael Reese lism, typically present with acute life-threatening Hospital and Medical Center, Division of Genetics and Metabolism, Uni- versity of Illinois College of Medicine, 2929 S Ellis Ave, Chicago, IL 60616. symptoms of an encephalopathy. These symptoms PEDIATRICS (ISSN 0031 4005). Copyright © 1998 by the American Acad- are the result of toxic effects of accumulating metab- emy of Pediatrics. olites on the central nervous system (CNS). Because http://www.pediatrics.org/cgi/content/full/102/6/Downloaded from www.aappublications.org/newse69 PEDIATRICS by guest on September Vol. 102 28, No.2021 6 December 1998 1of9 most of these metabolites cross the placenta and are Hyperammonemia cleared by the mother during gestation, affected in- Among the most important laboratory findings fants usually appear normal at birth. The interval associated with inborn errors of metabolism present- between birth and onset of clinical symptoms ranges ing with an acute encephalopathy is hyperammone- from hours to months. The initial findings are usu- mia. A plasma level should be obtained for ally those of lethargy and poor feeding, as seen in any child with unexplained , lethargy, or almost any sick infant. Although sepsis is often the other evidence of an encephalopathy. Significant hy- first consideration in infants who present in this way, perammonemia is observed in a limited number of these symptoms in a full-term infant with no specific conditions. Inborn errors of metabolism, including risk factors strongly suggest a . urea cycle defects and many of the organic aci- Infants with inborn errors of metabolism may be- demias, are at the top of the list. Also in the differ- come debilitated and septic rather quickly, and it is ential diagnosis in the neonate is a condition referred therefore important that the presence of sepsis not to as transient hyperammonemia of the newborn exclude consideration of other possibilities. If un- (THAN),3 whereas in the older infant, fatty acid ox- treated, the lethargy associated with these conditions idation defects may be considered. Ammonia levels may progress to coma. Other signs of CNS dysfunc- in newborns with these conditions frequently exceed ␮ tion, such as and abnormal muscle tone, also 1000 mol/L. The finding of marked hyperammone- may be noted. Evidence of may be mia provides an important clue to diagnosis and observed, and intracranial hemorrhage occasionally indicates the need for urgent treatment to reduce the occurs. ammonia level. The degree of neurologic impairment An infant with an inborn error of metabolism who and developmental delay observed subsequently in presents more abruptly or in whom the lethargy and affected infants has been shown to be dependent on the duration of the neonatal hyperammonemic coma. poor feeding go unnoticed may first come to atten- A flowchart for the differentiation of conditions tion because of apnea or respiratory distress. The producing significant hyperammonemia in the new- apnea is typically central in origin and a symptom of born is presented in Fig 1. The timing of the onset of the metabolic encephalopathy, but tachypnea may be symptoms may provide an important clue. Patients a symptom of an underlying metabolic acidosis, as with some of the organic acidemias, such as glutaric occurs in the organic acidemias. Infants with urea acidemia type II or with pyruvate carboxylase (PC) cycle defects and evolving hyperammonemic coma deficiency, may exhibit symptomatic hyperammone- initially exhibit central hyperventilation, which leads mia during the first 24 hours. Symptoms in the first to respiratory alkalosis. 24 hours also are characteristic of THAN, a condition Vomiting is a striking feature of many of the in- that is poorly understood but apparently not genet- born errors of metabolism associated with ically determined. The typical patient with this dis- intolerance, although considerably less common in order is a large, premature infant (mean gestational the newborn than in the older infant. If persistent age of 36 weeks) who has symptomatic pulmonary vomiting occurs in the neonatal period, it usually disease, often from birth, and severe hyperammone- signals significant underlying disease. Inborn errors mia. The condition can occur in full-term infants, of metabolism should always be considered in the however, including those without respiratory symp- differential diagnosis. It is common for an infant to toms. Survivors do not have recurrent episodes of be diagnosed as having a metabolic disorder after hyperammonemia and may or may not exhibit neu- having undergone for suspected pyloric ste- rologic sequelae, depending on the extent of the neo- nosis. Formula intolerance is frequently suspected, natal insult. and many affected infants have numerous formula Infants who develop severe hyperammonemia af- changes before a diagnosis is finally established. ter 24 hours of age usually have a urea cycle defect or The basic laboratory studies that should be ob- an ; infants with organic acidemias tained for an infant who has symptoms of a meta- typically exhibit a metabolic acidosis as well. bolic encephalopathy consistent with an inborn error organic acid analysis should always be obtained, of metabolism are listed in Table 1. regardless of whether acidosis is present. Metabolic acidosis is not a typical feature of the urea cycle defects. Plasma amino acid analysis is helpful in the TABLE 1. Laboratory Studies For an Infant Suspected of differentiation of the specific defects in this group. In Having an Inborn Error of Metabolism addition, carbamyl phosphate synthetase deficiency and ornithine transcarbamylase (OTC) deficiency Complete count with differential Urinalysis may be differentiated by measuring urine orotic acid, Blood gases which is low in the former and elevated in the latter. Serum electrolytes Although the family history is often negative, a pos- Blood itive history of early male deaths or females with Plasma ammonia Urine reducing substances episodic illness in the family of a male infant with Urine ketones if acidosis or hypoglycemia present hyperammonemia suggests ornithine transcarbamy- Plasma and urine amino acids, quantitative lase deficiency, the only one of the urea cycle defects Urine organic acids with a sex-linked mode of inheritance. Plasma lactate Less significant elevations of plasma ammonia

2of9 INBORN ERRORSDownloaded OF METABOLISM from www.aappublications.org/news IN INFANCY by guest on September 28, 2021 Fig 1. Flowchart for differentiation of conditions associated with neonatal hyperammonemia. ASA, indicates argininosuccinic acid; CPS, carbamyl phosphate synthetase. than those associated with inborn errors of metabo- born errors of metabolism and in most other condi- lism and THAN can be observed in a variety of other tions producing metabolic acidosis in the neonate. In conditions associated with dysfunction, includ- contrast, the differential diagnosis of metabolic aci- ing sepsis, generalized herpes simplex , and dosis with a normal anion gap is essentially limited perinatal asphyxia. Liver function studies should be to two conditions, and . obtained in evaluating the significance of moderate Among the inborn errors, the largest group typically elevations of plasma ammonia. However, even in associated with overwhelming metabolic acidosis in cases of severe hepatic necrosis, it is rare for ammo- infancy is the group of organic acidemias, including nia levels to exceed 500 ␮mol/L.4 Mild transient such entities as , propionic hyperammonemia with ammonia levels as high as acidemia, and . twice normal is relatively common in the newborn, In addition to specific organic acid intermediates, especially in the premature infant, and is usually plasma lactate often is elevated in organic acidemias asymptomatic. It appears to be of no clinical signifi- as a result of secondary interference with co-enzyme cance, and there are no long-term neurologic se- A (CoA) metabolism. Neutropenia and thrombo- quelae. cytopenia are commonly observed and further un- derscore the clinical similarity of these disorders to Metabolic Acidosis neonatal sepsis. Hyperammonemia, sometimes as The second important laboratory feature of many dramatic as that associated with urea cycle defects, is of the inborn errors of metabolism during acute commonly but not uniformly seen in clinically ill episodes of illness is metabolic acidosis with an infants with organic acidemias. increased anion gap, readily demonstrable by mea- Defects in pyruvate metabolism or in the respira- surement of arterial blood gases or serum electro- tory chain may lead to primary lactic acidosis pre- lytes and bicarbonate. A flowchart for the evaluation senting as severe metabolic acidosis in infancy.5 Un- of infants with this finding is presented in Fig 2. An like most of the other conditions presenting acutely increased anion gap (Ն16) is observed in many in- in the newborn, clinical features of these disorders

Downloaded from www.aappublications.org/newshttp://www.pediatrics.org/cgi/content/full/102/6/ by guest on September 28, 2021 e69 3of9 Fig 2. Flowchart for evaluation of metabolic acidosis in the young infant. Fructose-1,6-DP indicates fructose-1,6–diphosphatase; L/P, lactate/pyruvate. are unrelated to protein intake. Disorders in this medical center genetics units. It is important to insist group should be considered in patients with lactic that any reference laboratory used for this purpose acidosis who have normal urine organic acids. Dif- provide prompt test results and reference ranges and ferentiation of the various disorders in this group can provide interpretation of abnormal results. be facilitated by measuring plasma pyruvate and A summary of the inborn errors of metabolism calculating the lactate/pyruvate ratio. A normal ratio most likely to be associated with symptoms of an (Յ25) suggests a defect in pyruvate dehydrogenase acute encephalopathy is presented in Table 2. The (PDH) or in gluconeogenesis, and an elevated ratio typical laboratory findings in each condition or (Ն25) suggests PC deficiency, a respiratory chain group of conditions are also listed. defect, or a mitochondrial myopathy. Not all infants with life-threatening metabolic dis- Emergency Treatment of the Infant With an Acute ease have metabolic acidosis or hyperammonemia. Metabolic Encephalopathy For example, nonketotic hyperglycinemia typically When an inborn error of metabolism, such as an presents in the neonatal period with evidence of organic acidemia or urea cycle defect, is suspected in severe and progressive CNS dysfunction, but with a critically ill infant, immediate treatment should be neither metabolic acidosis nor hyperammonemia. initiated, even if a definitive diagnosis may not yet The same is true of molybdenum co-factor de- be established. Within 48 to 72 hours, the results of ficiency, which on the surface may be virtually amino acid and organic acid analysis should be avail- indistinguishable from hypoxic–ischemic encepha- able, allowing diagnostic confirmation in most cases. lopathy. Even patients with galactosemia may rarely Appropriate and aggressive treatment before the present with symptoms of CNS toxicity, which may confirmation of a diagnosis may be life-saving and progress to cerebral edema, when galactose-1-phos- may avert or reduce the neurologic sequelae of some phate levels rise precipitously. Therefore, the series of these disorders. The immediate treatment of in- of laboratory studies listed in Table 1 should be fants with disorders in this group has two primary obtained for any infant with clinical findings sug- goals. The first is the removal of accumulating me- gesting an inborn error of metabolism, even if met- tabolites such as organic acid intermediates or am- abolic acidosis and hyperammonemia are not monia. At the first suspicion of a disorder associated present. Most of the tests on this list are self-explan- with protein intolerance, protein intake should be atory. Although not available in many hospital lab- discontinued immediately. In critically ill infants oratories, amino acid and organic acid analysis can with hyperammonemia, arrangements should be be obtained in any part of the country through ref- made for . Although peritoneal dialysis, erence laboratories or through referral of samples to continuous arteriovenous hemoperfusion, and ex-

4of9 INBORN ERRORSDownloaded OF METABOLISM from www.aappublications.org/news IN INFANCY by guest on September 28, 2021 TABLE 2. Major Inborn Errors of Metabolism Presenting in the Neonate as an Acute Encephalopathy Disorders Characteristic Laboratory Findings References Organic acidemias (includes MMA, PA, Metabolic acidosis with increased anion gap; elevated plasma and 6–8 IVA, MCD and many less common urine ketones; variably elevated plasma ammonia and lactate; conditions) abnormal urine organic acids Urea cycle defects Variable respiratory alkalosis; no metabolic acidosis; markedly 9 elevated plasma ammonia; elevated orotic acid in OTCD; abnormal plasma amino acids Maple syrup urine disease Metabolic acidosis with increased anion gap; elevated plasma and 10 urine ketones; positive ferric chloride test; abnormal plasma amino acids Nonketotic hyperglycinemia No acid-base or electrolyte abnormalities; normal ammonia; 11 abnormal plasma amino acids Molybdenum co-factor deficiency No acid-base or electrolyte abnormalities; normal ammonia; 12 normal amino and organic acids; low serum uric acid; elevated sulfites in urine Abbreviations: MMA, methylmalonic acidemia; PA, ; IVA, isovaleric acidemia; MCD, multiple carboxylase deficiency; OTCD, ornithine transcarbamylase deficiency. change transfusion all have been used in the past to of complete protein restriction. Essential amino acids lower plasma ammonia levels, all are substantially or total protein can be provided orally or intrave- less effective than hemodialysis. In infants who are nously at an initial dose of 0.5 g protein/kg/24 comatose or ventilator-dependent, or who exhibit hours. This should be increased incrementally to 1.0 evidence of cerebral edema, dialysis should be insti- g/kg/24 hours and held at that level until the diag- tuted immediately without waiting to determine nostic evaluation is complete and plans can be made whether there is a response to dietary manipulation, for definitive long-term therapy. Therapy should be medication, or other less aggressive therapy. Maxi- planned in conjunction with a geneticist or specialist mal supportive care should be provided simulta- in metabolic disease. Until then, supplemental calo- neously. In patients suspected of having a urea cycle ries and nutrients can be provided orally using pro- defect because of significant hyperammonemia with- tein-free diet powder (product 80056, Mead Johnson, out acidosis, an infusion of 6 mL/kg of 10% Evansville, IN or Prophree, Ross Laboratories, Co- HCL (0.6 g/kg) can be given intravenously over 90 lumbus, OH). Once a definitive diagnosis is estab- minutes. In patients with and arginino- lished, commercial products formulated for individ- succinic aciduria, this often results in a precipitous ual can be instituted. drop in the plasma ammonia level. An intravenous arginine preparation is available commercially and Hypoglycemia should be readily accessible to any hospital phar- Hypoglycemia and its associated symptoms occa- macy. sionally may be seen in infants with disorders of If an organic acidemia is suspected, vitamin B12 (1 protein intolerance, but it is seen more commonly in mg) should be given intramuscularly in case the disorders of or fatty acid patient turns out to have a B12-responsive form of oxidation. Among the best known inborn errors of methylmalonic acidemia. (10 mg) should be metabolism associated with hypoglycemia are the given orally or by nasogastric tube, because some hepatic glycogen storage diseases (GSD). The hypo- patients with multiple carboxylase deficiency are glycemia in these disorders is related to the inability biotin-responsive. If acidosis exists, intravenous bi- of the liver to release glucose from glycogen, and it is carbonate should be administered liberally. Calcula- most profound during periods of fasting. Hypogly- tions of bicarbonate requirements appropriate for the cemia, , and lactic acidosis are promi- treatment of other conditions are rarely adequate in nent features of these disorders. Hypoglycemia is not these disorders because of ongoing production of a feature of GSD type II (Pompe disease) because organic acids or lactate. The acid-base status should cytoplasmic glycogen metabolism and release are be monitored frequently, with therapy adjusted ac- normal in this disorder in which glycogen accumu- cordingly. Dialysis should be considered for severely lates within lysosomes as a result of deficiency of the acidotic neonates with organic acidemias, regardless enzyme acid maltase. Clinical manifestations of this of whether hyperammonemia is present. disorder include macroglossia, , cardio- After removing toxic metabolites, the second ma- megaly with congestive , and hepato- jor goal of therapy in infants with inborn errors of megaly. Cardiomegaly is the most striking feature metabolism should be to prevent . Intra- and may be apparent in the neonatal period. Con- venous glucose should be administered liberally to gestive heart failure is the cause of death in most provide as many calories as possible. Intravenous cases. Hypoglycemia may be a prominent feature of can be given to infants with urea cycle defects both galactosemia and hereditary fructose intoler- and other disorders in which dietary fat plays no ance, although symptoms of the latter disorder occur role. Protein should not be withheld indefinitely. If only after fructose (sucrose) has been introduced in clinical improvement is observed and a final diagno- the diet. sis has not been established, some amino acid intake A number of inherited defects in fatty acid oxida- should be provided after a maximum of 2 to 3 days tion have been identified in infants presenting with

Downloaded from www.aappublications.org/newshttp://www.pediatrics.org/cgi/content/full/102/6/ by guest on September 28, 2021 e69 5of9 hypoglycemia. These disorders are important be- definitive diagnosis of some of the fatty acid oxida- cause of their apparent frequency and because of the tion defects. As is true for the defects in carbohydrate variability of the initial presentation. Infants affected metabolism leading to hypoglycemia, treatment of have an impaired capacity to use stored fat for fuel the fatty acid oxidation defects involves avoidance of during periods of fasting and readily deplete their fasting and provision of adequate glucose. Restric- glycogen stores. Despite the development of hypo- tion of dietary fat intake and supplemental l-carni- glycemia, acetyl CoA production is diminished, and tine therapy are recommended. ketone production is impaired. The hypoglycemia occurring in these conditions is typically character- Jaundice and Liver Dysfunction ized as nonketotic, although small amounts of ke- Jaundice or other evidence of liver dysfunction tones may be produced. Hypoglycemia may occur as may be the presenting finding in a number of inher- an isolated finding or may be accompanied by many ited metabolic disorders in infancy. These are listed of the other biochemical derangements typically in Table 3, along with the laboratory studies useful in associated with , such as hyperam- diagnosis. For most of the inborn errors of metabo- monemia, metabolic acidosis, and elevated transami- lism associated with jaundice, the elevated serum nases. Hepatomegaly may or may not be present. bilirubin is of the direct-reacting type. This general- Any infant presenting with findings suggesting Reye ization does not include those inborn errors of eryth- syndrome should be evaluated for fatty acid oxida- rocyte metabolism, such as glucose-6-phosphate tion defects. Because the incidence of true Reye syn- dehydrogenase deficiency or pyruvate kinase de- drome has decreased, most children presenting at ficiency, that are occasionally responsible for he- any age with this constellation of findings have an molytic disease in the newborn. The best known inherited metabolic disorder. metabolic disease associated with jaundice is The most common of the fatty acid oxidation de- galactosemia, in which deficiency of the enzyme ga- fects is medium-chain acyl CoA dehydrogenase lactose-1-phosphate uridyl transferase results in an deficiency. In addition to presenting as nonketotic accumulation of galactose-1-phosphate and other hypoglycemia or a Reye’s-like syndrome, it may metabolites such as galactitol that are thought to present as sudden death or an acute life-threatening have a direct toxic effect on the liver and on other event. Many reports of infants diagnosed as having organs. Jaundice and liver dysfunction in this disor- medium-chain acyl CoA dehydrogenase deficiency der are progressive and usually appear at the end of have described a history of a sibling who died of the first or during the second week of life with vom- SIDS. Fat accumulation in the liver or muscle of any iting, diarrhea, poor weight gain, and eventually infant dying unexpectedly should suggest strongly formation. Hypoglycemia may be observed. the possibility of this or a related disorder of fatty The disease may present initially with indirect hy- acid oxidation. Very long-chain fatty acyl CoA dehy- perbilirubinemia resulting from hemolysis second- drogenase deficiency is associated with similar clin- ary to high levels of galactose-1-phosphate in ical findings, although there also may be evidence of erythrocytes. Alternatively, the effects of acute galac- a cardiomyopathy. Infants with this and several tose toxicity on the may rarely cause the CNS other fatty acid oxidation defects may present with symptoms to predominate. cardiac arrhythmias or unexplained cardiac arrest. If galactosemia is suspected, the urine should be The accumulation of fatty acyl CoAs in patients tested simultaneously with Benedict’s reagent and with fatty acid oxidation defects leads to a secondary with a glucose oxidase method. The glucose oxidase deficiency, probably as a result of method is specific for glucose, and Benedict’s reagent of excess acylcarnitines in the urine. Urine organic can detect any reducing substance. A negative dip- acid analysis, measurement of serum carnitine, and stick result for glucose with a positive Benedict’s analysis of the plasma acylcarnitine profile are the reaction means that a nonglucose reducing substance most helpful laboratory studies in the initial screen- is present. With appropriate clinical findings, this is ing for defects in fatty acid oxidation. These studies most likely to be galactose. If a child with galac- are sufficient to establish the diagnosis of medium- tosemia has been on intravenous fluids and has not chain acyl CoA dehydrogenase deficiency, which is recently been receiving galactose in the diet, galac- associated with the presence of a characteristic tose may not be present in the urine. metabolite, octanoylcarnitine, on the acylcarnitine If the diagnosis of galactosemia is suspected, profile. Enzymatic assays may be necessary for the whether or not reducing substances are found in the

TABLE 3. Inborn Errors of Metabolism Associated With Neonatal Liver Disease and Laboratory Studies Useful in Diagnosis Disorder Laboratory Studies References Galactosemia Urine reducing substances; RBC galactose-1-phosphate uridyl transferase 13 Hereditary Plasma quantitative amino acids; urine succinylacetone 14 ␣ ␣ 1-Antitrypsin deficiency Quantitative serum 1-antitrypsin; protease inhibitor typing 15 Neonatal hemochromatosis Serum ferritin; liver biopsy 16 Zellweger syndrome Plasma very long-chain fatty acids 17 Niemann–Pick disease type C Skin biopsy for fibroblast culture; studies of cholesterol esterification and 18 accumulation GSD type IV (brancher deficiency) Liver biopsy for histology and biochemical analysis or skin biopsy with assay 19 of branching enzyme in cultured fibroblasts

6of9 INBORN ERRORSDownloaded OF METABOLISM from www.aappublications.org/news IN INFANCY by guest on September 28, 2021 urine, galactose-containing feedings should be dis- oxisome assembly disorders and is associated with continued immediately and replaced by soy formula generalized peroxisomal dysfunction. or other lactose-free formula pending the results of In contrast to disorders in which there is an eleva- an appropriate enzyme assay on erythrocytes to con- tion of the direct-reacting bilirubin, a persistent ele- firm the diagnosis. Untreated infants with galac- vation of indirect bilirubin beyond the limits of tosemia, if they survive the neonatal period, have physiologic jaundice, without evidence of hemolysis, persistent liver disease, , and severe mental suggests the diagnosis of Crigler–Najjar syndrome. retardation. Many affected infants die of Escherichia The hyperbilirubinemia in this disorder is related to coli sepsis in the neonatal period, and the early onset a partial or complete deficiency of glucuronyl trans- of sepsis may alter the presentation of the disorder. ferase, the liver enzyme responsible for the normal Although many states have newborn screening pro- conjugation of bilirubin to bilirubin diglucuronide. grams for galactosemia, clinical manifestations of the In patients with this disorder, the standard modali- disorder may appear before the results of screening ties of phototherapy and exchange transfusion may studies are available, and it is therefore critical that prevent the development of kernicterus in the neo- remain alert to this possibility. natal period. Another disorder that may be associated with neo- ␣ Finding Suggestive of a Storage Disease natal jaundice is 1-antitrypsin deficiency, a common condition with clinical manifestations that may be Many of the well-known storage diseases identical to those of traditional neonatal or giant cell do not typically present in early infancy. Among ␣ . A determination of serum 1-antitrypsin those that occasionally may be associated with hepa- should be a part of the initial evaluation of all chil- tosplenomegaly in the first few months of life dren presenting with this syndrome. Hereditary ty- are GM1- type I, Gaucher disease, rosinemia also should be considered in any child Niemann–Pick disease, and Wolman disease. The who presents with liver disease in early infancy. The GSDs may be associated with hepatomegaly in the biochemical hallmarks of this disorder include newborn period. Infants with the most common mu- marked elevations of plasma and methio- copolysaccharidoses, such as the Hurler and Hunter nine and generalized with a dispro- syndromes, uncommonly exhibit clinical abnormali- portionate increase in the excretion of tyrosine. ties in the first few months of life. Newborns with the However, these findings are relatively nonspecific typical features of these syndromes, such as coarse and may be observed as a secondary phenomenon in facial features, , skeletal abnor- other forms of liver disease. Determination of succi- malities, and , are more likely to have GM1- nylacetone in the urine is a helpful diagnostic test for gangliosidosis or a , such as I-cell the disorder. disease. ␤-Glucuronidase deficiency, classified as A recently described and poorly understood dis- type VII, may present in the order, neonatal hemochromatosis, may be the most neonatal period with features virtually indistinguish- common cause of congenital . Its fulminat- able clinically from those seen later in Hurler and ing course distinguishes it from many of the other Hunter syndromes. An infantile form of is metabolic disorders associated with neonatal liver typically associated with findings at birth. Indeed, disease. In addition to being associated with severe the clinical manifestations of several of these condi- from birth, the disorder is characterized tions may be so severe in utero that fetal hydrops by distinctive hepatic morphology and hepatic and develops. extrahepatic parenchymal iron deposition. Serum If one of these disorders is suspected, urine screen- ferritin and iron are typically elevated, whereas total ing tests for mucopolysaccharides and oligosaccha- transferrin is low, but these findings are not diagnos- rides should be performed. These can be helpful tic. The definitive diagnosis is established by liver diagnostically, but negative results do not rule out biopsy or autopsy. Most infants affected succumb to the possibility of a storage disorder. In addition, the disorder during the early weeks of life. false-positive mucopolysaccharide test results are Less common metabolic causes of neonatal liver commonly observed in neonates. The definitive di- dysfunction include Niemann–Pick disease type C agnosis of most lysosomal storage disorders is made and GSD type IV. Infants with Niemann–Pick dis- by appropriate biochemical studies on leukocytes or ease type C exhibit cholestatic jaundice that typically cultured skin fibroblasts. resolves by several months of age. They are then clinically normal for a period of months to years Abnormal Odor before developing findings of a degenerative neuro- Abnormal body or urinary odor, more commonly logic disorder. Infants with GSD type IV accumulate observed by nurses or mothers rather than by phy- an abnormal form of glycogen in the liver as a result sicians, is an important but often overlooked clue to of a deficiency of the glycogen branching enzyme. the diagnosis of several of the inborn errors of me- This leads to progressive cirrhosis and generalized tabolism and may be the most specific clinical find- hepatic dysfunction. Hypoglycemia is not a promi- ing in these patients. In the acutely ill infant with an nent feature as it is in some other forms of GSD. abnormal odor, isovaleric acidemia, glutaric aci- Zellweger syndrome, another cause of neonatal jaun- demia type II, and maple syrup urine disease are the dice and hepatic dysfunction, is usually recognizable most likely entities to be encountered. In maple clinically because of the associated hypotonia and syrup urine disease, the urine has a distinctive sweet dysmorphic features. It is the prototype of the per- odor, said to be reminiscent of maple syrup or burnt

Downloaded from www.aappublications.org/newshttp://www.pediatrics.org/cgi/content/full/102/6/ by guest on September 28, 2021 e69 7of9 sugar. The odor associated with isovaleric acidemia exhibit one or more dysmorphic features or anoma- and glutaric acidemia type II is pungent and un- lies that are nonspecific. The observation of dysmor- pleasant and similar to that of sweaty feet. phic features in an infant should in no way preclude consideration of an inherited metabolic disorder. In Dysmorphic Features selected circumstances, it may heighten the clinical There formerly appeared to be a clear distinction suspicion. between inborn errors of metabolism and dysmor- Abnormal eye findings typically are associated phic syndromes, both of which may be inherited in a with many of the inborn errors of metabolism, al- similar manner. Infants with inherited metabolic dis- though they are not always found at the time of ease were thought to be phenotypically normal at initial presentation. Cataracts may be observed in birth, with no evidence of major or minor structural galactosemia, Zellweger syndrome, Lowe syndrome, anomalies. It is now apparent, however, that inher- and a number of other conditions. Dislocated lenses, ited metabolic disorders may be associated with con- seen in , molybdenum co-factor defi- sistent patterns of birth defects, suggesting that ciency, and sulfite oxidase deficiency, may be found metabolic derangements in utero may disrupt the as early as the first month of life and are an impor- normal process of fetal development. tant clue to the diagnosis. Retinal degenerative This phenomenon is illustrated clearly by the changes are typical of the peroxisomal disorders and group of disorders associated with multiple defects are observed in several other conditions as well. in peroxisomal , including those involved in Other abnormalities that may be associated with in- fatty acid oxidation and plasmalogen synthesis. born errors of metabolism include corneal clouding These include Zellweger syndrome and neonatal ad- and congenital glaucoma. A careful eye examination renoleukodystrophy and several variant conditions, by an ophthalmologist should be performed when- all of which are associated with congenital hypotonia ever an inherited metabolic disorder is suspected. and dysmorphic features such as epicanthal folds, Brushfield spots, large fontanels, simian creases, and Samples to Obtain From a Dying Child With a renal cysts. Patients with glutaric acidemia type II Suspected Inborn Error of Metabolism have a characteristic phenotype including a high If death appears imminent in a child suspected of forehead, hypertelorism, low set ears, abdominal having an inborn error of metabolism, it is important wall defects, enlarged kidneys, hypospadias, and to obtain the appropriate samples for postmortem rocker bottom feet. An energy-deficient mechanism, analysis. This is critical for resolution of the cause of similar to that postulated for maternal mel- death and is essential for subsequent genetic coun- litus, has been suggested to explain these findings. seling and prenatal diagnosis. The following samples Several of the other organic acidemias, such as me- should be collected and stored: urine, frozen; plasma, valonic aciduria and 3-OH-isobutyric aciduria, as separated from whole blood and frozen; and a small well as PDH deficiency, have been associated with snip of skin obtained using sterile technique and multiple dysmorphic features. The dysmorphic find- stored at room temperature or 37°C in tissue culture ings in PDH deficiency may strongly resemble those medium, if available, or sterile saline. If an autopsy is observed in fetal syndrome, and it has been performed, a sample of unfixed liver tissue should be suggested that this resemblance is explained by a obtained as soon as possible after death and frozen at common mechanism in the two disorders. It has been Ϫ20°C for subsequent biochemical studies. Addi- postulated that in fetal alcohol syndrome, acetalde- tional tissue should be preserved for electron micros- hyde from the maternal circulation may inhibit fetal copy. If consent for autopsy is denied, consent for a PDH, thus leading to malformations. postmortem needle biopsy of the liver can be re- The Smith–Lemli–Opitz syndrome is an autosomal quested. The liver tissue should be frozen in total or recessive disorder associated with a wide range of in part if histologic studies appear to be indicated. As malformations including dysmorphic facies, cleft soon as possible after death, the case should be re- palate, congenital heart disease, hypospadias, poly- viewed with a metabolic specialist and plans made dactyly, and syndactyly. Recent observations have for the transport of samples to the appropriate labo- revealed that this disorder is an inborn error of cho- ratory. lesterol biosynthesis associated with decreased levels of plasma cholesterol and markedly elevated levels SUMMARY of the cholesterol precursor 7-dehydrocholesterol. Recent advances in diagnosis and treatment have The defect in cholesterol synthesis associated with improved significantly the prognosis for many in- this condition presumably leads to abnormal devel- fants with inborn errors of metabolism. Early clinical opment in many different organ systems. diagnosis is essential in ensuring that affected infants Isolated malformations may be even more com- will receive the benefits of these advances. It is hoped monly associated with inherited metabolic disorders that the guidelines presented in this review will as- than are specific malformation patterns. Patients sist the in the recognition of infants who with nonketotic hyperglycinemia frequently have may have an inborn error of metabolism and in the agenesis of the corpus callosum and may have gyral initial evaluation and stabilization of these patients. malformations related to defects in neuronal migra- tion. Agenesis of the corpus callosum also is seen in REFERENCES PDH deficiency. It is not uncommon for patients 1. Scriver CR, Beaudet AL, Sly WS, eds. The Metabolic and Molecular Bases with almost any of the inborn errors of metabolism to of Inherited Disease. 6th ed. New York, NY: McGraw-Hill; 1995

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Downloaded from www.aappublications.org/news by guest on September 28, 2021 Inborn Errors of Metabolism in Infancy: A Guide to Diagnosis Barbara K. Burton Pediatrics 1998;102;e69 DOI: 10.1542/peds.102.6.e69

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