neoreviews 2001 enns e183 91

Diagnosing Inborn Errors ofMetabolism in the Newborn:Clinical FeaturesGregory M. Enns, MB, ChB*

and Seymour Packman, MD†Objectives After completing this article, readers should be able to:

1. Delineate features of a medical history that should raise suspicion for an inborn errorof metabolism.

2. Describe common ocular findings associated with inborn errors of metabolism.3. List the primary clinical findings of inborn errors of metabolism associated with

encephalopathy without metabolic acidosis.4. Delineate the categories of inborn errors of metabolism associated with

encephalopathy and metabolic acidosis.

IntroductionThe rapid deterioration of a previously healthy-appearing neonate is one of the moststressful scenarios in medicine. Unless appropriate therapy is initiated without delay, thereis a high risk of morbidity or mortality, regardless of the etiology of the acute illness. Anyinfant who presents with feeding difficulties, vomiting, jaundice, failure to thrive, apnea ortachypnea, hypotonia or hypertonia, seizures, lethargy, or coma should be considered assuffering from diseases in one of two broad categories: 1) disorders resulting from causessuch as infection, cardiopulmonary dysfunction or other causes of hypoxemia, toxins,trauma, or congenital structural brain abnormalities or 2) disorders caused by an inbornerror of metabolism. Because metabolic diseases are individually rare, there is a tendency toconsider them only after excluding more common causes of neonatal distress. However,the aggregate incidence of inborn errors of metabolism is relatively high, with as many asone child in every 1,000 births being affected. The clinician must consider these disordersin all neonates who have nonspecific features of distress upon initial presentation. In manycases, only rapid diagnosis and management can prevent death or significant morbidity.Appropriate laboratory investigations should be obtained immediately. Even simple testssuch as measurement of blood gases, glucose, electrolytes, lactate, and ammonia and theevaluation of urine for ketones may provide valuable clues to the underlying diagnosis.

InheritanceMost inborn errors of metabolism are inherited as autosomal recessive traits or, as in thecase of ornithine transcarbamylase deficiency, are X-linked. A detailed family history mayreveal an affected relative who has a similar illness, which is of great diagnostic importance.The affected relative typically is a sibling of either gender in the case of an autosomalrecessive condition, but can be a maternal uncle, a brother, or a mildly affected mother orother female in X-linked disease. Some disorders are caused by mitochondrial DNAmutations, and maternal transmission to all children in a sibship is observed. Specialattention should be given to stillbirths, unexplained deaths, and neurologic diseases ordelayed development of any degree or severity. Maternal illness in pregnancy also has beenassociated with specific metabolic disorders and may yield a clue to the presence of aninborn error of metabolism in a neonate. For example, acute fatty liver of pregnancy andhypertension, elevated liver enzymes, low platelets (HELLP) syndrome may occur in aheterozygous mother carrying a fetus that has long-chain 3-hydroxyacyl-CoA dehydroge-nase (LCHAD) deficiency.

*Assistant Professor of Pediatrics; Director, Biochemical Genetics Program, Division of Medical Genetics, Stanford UniversitySchool of Medicine, Stanford, CA.†Professor of Pediatrics, Division of Medical Genetics, Department of Pediatrics, University of California, San Francisco, CA.

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Signs and SymptomsSymptoms of metabolic disease generally occur post-natally, appearing after an interval period of apparentgood health and following a normal pregnancy. Theinterval may be as short as a few hours or be several daysor even longer. The infant may do well until subjected toa catabolic insult (infection, fasting, dehydration) or anexcessive protein or carbohydrate load. Following expo-sure to a stressor, the child may become strikingly ill verysuddenly and can present as sudden infant death ofunexplained etiology. On the other hand, the absence ofa normal period does not exclude an inborn error fromdiagnostic consideration. Neonatal distress from as-phyxia or complications of prematurity may constitutethe environmental stress that unmasks an underlyingmetabolic disease.

Irritability and feeding difficulties may be associatedwith uncoordinated sucking and swallowing or abnormalmuscle tone. Persistent and severe vomiting and convul-sions may occur. In mildly affected neonates, symptomscan disappear, only to recur in days or weeks. Moreseverely affected infants have inexorable progressionfrom lethargy to coma to episodic apnea and death. Morelimited symptoms, often in the form of generalized orpartial seizures, may occur in some instances. These caninclude staring spells, eye rolling or myoclonus, andvarious combinations of tone abnormalities, tremulous-ness, lethargy, and a weak cry. Electroencephalographymay suggest nonspecific diffuse encephalopathy. Unlessan inborn error is suspected, the child may be misdiag-nosed as having hypoxic-ischemic encephalopathy, intra-ventricular hemorrhage, sepsis, heart failure, or a gastro-intestinal illness, such as pyloric stenosis or intestinalobstruction.

A concomitant acquired disorder may confound thediagnosis of an inherited metabolic disease. For example,neutropenia may occur in an organic acidemia that has aneonatal presentation, but sepsis with leukocytosis (orneutropenia) also may be present because of an increasedsusceptibility to bacterial infection. Escherichia coli sepsisis frequent in infants who have galactosemia, and theinanition and jaundice of that disorder might be ascribedincorrectly solely to sepsis. Other examples of acquiredconditions that may complicate the presentation of ametabolic disorder include pulmonary hemorrhage orprimary respiratory alkalosis in urea cycle defects.

Physical FindingsA paucity of abnormal physical findings is the general rulein heritable metabolic diseases. Nevertheless, certaincomponents of the physical examination should be em-

phasized. A detailed ocular examination is essential; cor-neal clouding, cataracts, optic nerve abnormalities, andmacular or retinal pigmentary changes may be helpful inestablishing a diagnosis (Table 1). Hepatomegaly canoccur in carbohydrate disorders (galactosemia, glycogen

Table 1. Ocular Findings in InfantsWho Have Inborn Errors ofMetabolism

Finding Disorder

Neonatal cataracts GalactosemiaGalactokinase deficiencyTyrosinemia type IIPeroxisomal disordersGlucose-6-phosphate

dehydrogenase deficiencySorbitol dehydrogenase

deficiencyLowe syndrome*Cockayne syndrome†

Infantile cataracts Mitochondrial respiratory chaindefects

SialidosisAlpha-mannosidosisMevalonic aciduria

Retinitis pigmentosa Peroxisomal disordersSjogren-Larsson syndromeCobalamin C diseaseAbetalipoproteinemiaNeuronal ceroid lipofuscinosisCongenital disorders of

glycosylationMitochondrial respiratory chain

disordersLong-chain 3-hydroxyacyl-CoA

dehydrogenase (LCHAD)deficiency‡

Mucopolysaccharidoses types I,II, III, IV‡

Cherry red spot GM1 and GM2 gangliosidosisGalactosialidosisMetachromatic leukodystrophyNiemann-Pick diseaseWolman disease

Optic atrophy 3-Methylglutaconic aciduriaMitochondrial disordersCanavan disease (aspartoacylase

deficiency)Krabbe disease

Lens dislocation Sulfite oxidase deficiencyMolybdenum cofactor deficiency

*Phosphatidylinositol 4,5-bisphosphate 5-phosphatase deficiency.†This disorder of DNA repair usually is not categorized as an inbornerror, but it is an important cause of congenital cataracts.‡Pigmentary retinopathy tends to develop later in childhood.

inborn errors of metabolism clinical features

e184 NeoReviews Vol.2 No.8 August 2001



storage disease, hereditary fructose intolerance), peroxi-somal disorders, tyrosinemia, Niemann-Pick disease,Gaucher disease, inborn errors of bile acid metabolism,neonatal hemochromatosis, some forms of congenitallactic acidosis (mitochondrial respiratory chain defects),and other organic acidemias and fatty acid oxidationdefects that may have a Reye syndrome-like presenta-tion. Abnormal, brittle hair may be seen in some ureacycle defects (argininosuccinic aciduria, citrullinemia),holocarboxylase synthetase deficiency, and Menkes syn-drome (pili torti). An unusual body or urine odor hasbeen associated with several organic acidemias, in-cluding branched-chain ketoaciduria (maple syrup), iso-valeric acidemia or multiple acyl-CoA dehydrogenasedeficiency (sweaty feet), and 3-methylcrotonyl-CoA carboxylasedeficiency (cat-like) (Table 2). Ke-tosis accompanies many of theseconditions and will cause the sweetodor of ketone bodies in the urine.An unusual urine color also maysignal some inborn errors (Table 3).

Encephalopathy WithoutMetabolic AcidosisA number of inborn errors of me-tabolism are associated with en-cephalopathic findings or isolated

seizures in the newborn period (Ta-ble 4). The nonspecific features ofthese conditions are similar to thoseof hypoxic-ischemic encephalopa-thy. However, unlike acute as-phyxia, generally there is no historyof birth trauma, and patients appearnormal for at least a short time. Ifthe degree of encephalopathy ap-pears greater than would be ex-pected from careful review of theperinatal history, an inborn errorshould be considered strongly.

Maple Syrup Urine Disease(MSUD)

Infants who have MSUD typicallydevelop symptoms in the first fewdays to weeks of life after appearingnormal at birth. Poor feeding andvomiting may be the initial symp-toms, but lethargy and progressive

neurologic deterioration supervene. The child may behypotonic or appear markedly hypertonic with opistho-tonus. Not all infants develop a “maple syrup” smell.Although ketosis is prominent, metabolic acidosis is notoften present until later in the course of disease.

Mevalonic AciduriaMevalonic aciduria is a disorder of cholesterol biosynthe-sis that usually is not associated with metabolic acidosis.Severe neurologic involvement may occur in neonates,but patients often have other findings, such as dysmor-phic features, hepatosplenomegaly, recurrent fevers, andanemia.

Table 2. Urine Odors Associated With Inborn Errorsof Metabolism

Odor Compound Disorder

Musty, mousy Phenylacetate Classic phenylketonuriaMaple syrup 2-Oxoisocaproic acid Maple syrup urine diseaseSweaty feet Isovaleric acid Isovaleric acidemia

Multiple acyl-CoAdehydrogenase deficiency(glutaric aciduria type II)

3-Hydroxy-3-methylglutaricaciduria

Cat urine 3-Hydroxyisovaleric acid 3-Methylcrotonyl-CoAcarboxylase deficiency

Multiple carboxylase deficiencyCabbage-like 2-Hydroxybutyric acid Tyrosinemia type 1

Methionine malabsorptionRancid butter 2-Oxo-4-methiolbutyric acid Tyrosinemia type 1Acid smell Methylmalonic acid Methylmalonic acidemiaSulfurous Hydrogen sulfide CystinuriaFish market Trimethylamine Trimethylaminuria

Adapted with permission from Blau et al, 1996.

Table 3. Unusual Urine Colors Associated withInborn Errors of Metabolism

Color Compound Disorder

Blue Indican Hartnup disorderBlue/brown Homogentisic acid AlkaptonuriaBrown Methemoglobin MyoglobinuriaRed/brown Hemoglobin/methemoglobin HemoglobinuriaLight red Urates HyperuricosuriaRed Erythrocytes Hematuria

Porphyrins Porphyria

Adapted with permission from Blau et al, 1996.





Urea Cycle DefectsThe early clinical course of patients who have urea cycledefects is similar to that in MSUD, except that hypotoniatypically is more severe, and a respiratory alkalosis iscommon. Severe hyperammonemia is the hallmark ofthese conditions. However, sepsis often is suspected ini-tially, and unless an ammonia level is evaluated, theseinfants may die of unknown cause early in the newbornperiod. Aside from the X-linked ornithine transcarbamy-lase deficiency, these are autosomal recessive disorders.

Transient hyperammonemia of the newborn (THAN)is an important consideration in the differential diagnosisof these conditions. THAN tends to occur in the first dayof life; urea cycle disorders typically present after 1 or2 days. Other inborn errors, including pyruvate carbox-ylase deficiency, organic acidemias, fatty acid oxidationdefects, lysinuric protein intolerance, and the hyper-ammonemia-hyperornithinemia-homocitrullinuria syn-drome, can cause marked hyperammonemia by second-ary inhibition of urea cycle function. Standard metabolic

investigations are usually sufficient to diagnose theseconditions.

Peroxisomal DisordersInfants who have peroxisomal disorders (Zellweger syn-drome, neonatal adrenoleukodystrophy) often exhibitsevere neonatal features, including craniofacial dysmor-phism, neuronal migration defects, pigmentary retinop-athy, profound hypotonia, seizures, hepatomegaly, jaun-dice, and renal cysts. Short limbs, joint contractures, andepiphyseal stippling are characteristic of rhizomelic chon-

Table 4. Inborn Errors ofMetabolism Associated WithEncephalopathy WithoutMetabolic AcidosisLethargy Without Hyperammonemia

Maple syrup urine diseaseMevalonic aciduria

Lethargy With Hyperammonemia

Urea cycle defectsHyperammonemia-Hyperornithinemia-Homocitrullinuria

syndromeLysinuric protein intoleranceHyperinsulinism-Hyperammonemia syndrome

Encephalopathy With Dysmorphic Features andCongenital Anomalies

Peroxisomal disorders

Seizures Without Abnormal Metabolites on RoutineBiochemical Screening

Nonketotic hyperglycinemiaSulfite oxidase/molybdenum cofactor deficiencyPyridoxine-responsive seizures4-Aminobutyrate amino transferase (GABA

transaminase) deficiencyFolinic acid-responsive seizuresGuanidinoacetate methyltransferase (GAMT) deficiencyGlucose transporter (GLUT-1) deficiency

Table 5. Inborn Errors ofMetabolism Associated WithEncephalopathy WithMetabolic AcidosisOrganic Acidemias With Ketosis

Propionic acidemiaIsovaleric acidemiaMethylmalonic acidemiaHolocarboxylase synthetase deficiencyMultiple acyl-CoA dehydrogenase deficiency (Glutaric

acidemia type II)*3-Hydroxyisobutyric acidemia*

Organic Acidemias Without Ketosis

3-Hydroxy-3-methylglutaryl-CoA (HMG-CoA) lyasedeficiency

Fatty Acid Oxidation Defects†

Short-chain acyl-CoA dehydrogenase (SCAD) deficiencyMedium-chain acyl-CoA dehydrogenase (MCAD)

deficiencyLong-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD)

deficiencyTrifunctional protein deficiencyVery long-chain acyl-CoA dehydrogenase (VLCAD)

deficiencyCarnitine uptake deficiencyCarnitine-acylcarnitine translocase (CAT) deficiencyCarnitine palmitoyltransferase 2 (CPT-2) deficiency

Congenital Lactic Acidoses

Pyruvate dehydrogenase deficiencyPyruvate carboxylase deficiencyMitochondrial respiratory chain disordersGluconeogenesis disorders

Phosphoenolpyruvate carboxykinase deficiencyFructose-1,6-bisphosphatase deficiency

*Dysmorphic features and congenital anomalies may be present.†Cardiomyopathy is common, except in SCAD and MCADdeficiencies.





drodysplasia punctata. Evidence of hepatocellular dys-function is common.

Isolated SeizuresA growing list of metabolic disorders are associated withisolated seizures or progressive encephalopathy withoutobvious biochemical abnormalities on routine metabolicscreening (Table 4). It is important to save a sample ofcerebrospinal fluid (CSF) for specialized testing in case acommon cause for neonatal seizures is not identified.

Approximately two thirds of patients who have non-ketotic hyperglycinemia exhibit symptoms within48 hours of delivery. Infants typically present with leth-argy, apnea, profound hypotonia, feeding difficulty, hic-cups, and intractable seizures. The only consistent ab-normalities are elevated urine, plasma, and CSF glycinelevels. A CSF-to-plasma glycine ratio of greater than 0.08confirms the diagnosis. CSF and blood samples for gly-cine analysis must be obtained as near to simultaneouslyas possible for accurate calculation of the glycine ratio.

Sulfite oxidase deficiency may occur in isolation orcombined with xanthine oxidase deficiency. The com-

bined defects are secondary to molybdenum cofactordeficiency. Patients have seizures that are recalcitrant totherapy starting in the first few days of life. A low uric acidlevel may be noted in molybdenum cofactor deficiency,but other laboratory findings are normal. A specific assayfor elevation of plasma or urine S-sulfocysteine is re-quired to make the diagnosis.

Infants who have pyridoxine-dependent seizures maypresent as early as the first day of life with flaccidity,abnormal eye movements, and irritability. The diagnosisis clinical and is based on documented response of sei-zures to intravenous pyridoxine (vitamin B6).

The enzyme 4-aminobutyrate aminotransferase(GABA transaminase) catalyzes the initial step in theconversion of GABA, a central nervous system inhibitoryneurotransmitter, to succinic acid. Elevated GABA con-centrations in the central nervous system result in neo-natal seizures, lethargy, hypotonia, hyperreflexia, and ahigh-pitched cry.

Folinic acid-responsive seizures is a newly described

Table 6. Inborn Errors ofMetabolism Associated WithNeonatal CardiomyopathyFatty Acid Oxidation Defects

Long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD)deficiency

Trifunctional protein deficiencyVery long-chain acyl-CoA dehydrogenase (VLCAD)

deficiencyCarnitine uptake deficiencyCarnitine-acylcarnitine translocase (CAT) deficiencyCarnitine palmitoyltransferase 2 (CPT-2) deficiency

Mitochondrial Respiratory Chain Disorders

Tricarboxylic Acid Cycle Defects

Alpha-ketoglutarate dehydrogenase deficiency

Glycogen Storage Disorders

Pompe diseasePhosphorylase b kinase deficiency

Lysosomal Storage Disorders

I-cell disease

Cardiomyopathy may be present in other inborn errors of metabolism,including organic acidemias, tyrosinemia, congenital disorders of gly-cosylation, and other lysosomal storage disorders, but tends to occurafter the newborn period.

Table 7. Liver Disease in NeonatalInborn Errors of MetabolismHepatomegaly With Hepatocellular Disease

GalactosemiaHereditary fructose intoleranceTyrosinemiaNeonatal hemochromatosisWolman diseaseMitochondrial respiratory chain disordersMitochondrial DNA depletion syndromeLong-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD)

deficiencyGlycogen storage disease type IV (Brancher enzyme

deficiency)

Hepatomegaly With Cholestasis

Alpha-1-antitrypsin deficiencyByler disease (progressive familial intrahepatic

cholestasis)Bile acid synthesis disordersNiemann-Pick disease, type CPeroxisomal disordersNeonatal hemochromatosisGalactosemia (rare)Hereditary fructose intolerance (rare)Cystic fibrosis (rare)

Hepatomegaly Without Hepatocellular Disease orCholestasis

Glycogen storage disease, type 1Fructose-1,6-bisphosphatase deficiency





disease of unknown etiology. Sei-zures occur as early as 2 hours afterbirth. High-performance liquidchromatography documents a char-acteristic peak. Infants respond tofolinic acid supplementation.

Patients who have guanidino-acetate methyltransferase defi-ciency, a recently identified disor-der of creatine metabolism, usuallypresent in infancy with seizures, de-velopmental delay, and extrapyra-midal signs, but symptoms havebeen described in neonates. Lowplasma creatinine levels and ele-vated guanidinoacetate are charac-teristic.

A reduced CSF glucose concen-tration (hypoglycorrhachia) ispresent in the GLUT-1 deficiencysyndrome (glucose transporter de-fect). This autosomal dominant dis-order causes severe clinical symp-toms, including seizures, acquiredmicrocephaly, and developmentaldelay. Patients have become symp-tomatic as early as the third week oflife, but it is unclear whether symp-toms may occur earlier because ofthe paucity of reported cases.

Encephalopathy WithMetabolic AcidosisInborn errors of metabolism thatare characterized by a nonspecific encephalopathy withassociated metabolic acidosis include organic acidemias,fatty acid oxidation defects, and primary congential lacticacidoses (Table 5). Distinctive clinical features are oftenabsent.

Organic acidemias that present in the newborn periodwith encephalopathy and severe metabolic acidosis arevirtually indistinguishable clinically. Hyperammonemiamay be severe, with ammonia levels similar to thoseencountered in urea cycle disorders. In addition, neutro-penia and thrombocytopenia are common, and sepsis ora bleeding diathesis may supervene. Distinctive odorsmay be present in some of these conditions (Table 2), butoften only the nonspecific sweet smell of ketone bodies isnoticeable.

Fatty acid oxidation disorders may have a Reyesyndrome-like presentation. Approximately 5% to 10% of

unexplained sudden infant deaths may be attributed tothese conditions. Although encephalopathy may domi-nate the clinical picture, multiorgan system involvementis common, with infants showing various degrees ofcardiac, skeletal muscle, ophthalmologic, and hepaticinvolvement. Hyperammonemia and lactic acidosis mayoccur. Cardiomyopathy is particularly common in long-chain defects (Table 6). Hepatomegaly and hepatocellu-lar dysfunction are typical of these conditions when theyoccur in neonates. A pigmentary retinopathy is oftenpresent in long-chain 3-hydroxyacyl-CoA dehydroge-nase deficiency, but it tends to develop later in child-hood.

Disorders of pyruvate metabolism and mitochondrialdisorders may cause congenital lactic acidosis. Manyinfants who have pyruvate dehydrogenase deficiency ex-hibit dysmorphic features. Brain abnormalities, including

Table 8. Inborn Errors of Metabolism AssociatedWith Dysmorphic Features

Disorder Features

Peroxisomal disordersZellweger syndrome Large fontanelle, high, prominent

forehead, hypoplastic supraorbitalridges, epicanthic folds, flat nasalbridge

Rhizomelic chondrodysplasia punctata Dysmorphic facial features, rhizomeliclimb shortening, epiphyseal stippling

Pyruvate dehydrogenase deficiency Epicanthic folds, flat nasal bridge, smallnose with anteverted flared alae nasi,long philtrum

Mitochondrial disorders Epicanthic folds, flat nasal bridgeMultiple acyl-CoA dehydrogenase

deficiency (glutaric aciduria type II)Macrocephaly, high forehead, flat nasal

bridge, short anteverted nose, earanomalies, hypospadias, rocker-bottom feet

D-2-Hydroxyglutaric aciduria Epicanthic folds, asymmetric ears, coarsefeatures

3-Hydroxyisobutyric aciduria “Myopathic” face, sloping forehead,midface hypoplasia, long prominentphiltrum, micrognathia, clinodactyly

Cholesterol biosynthetic defectsSmith-Lemli-Opitz syndrome Epicanthic folds, flat nasal bridge, toe 2/

3 syndactyly, abnormal genitaliaMevalonic aciduria Large fontanelle, high forehead,

hypertelorism, epicanthic folds, low-set ears, long philtrum

Congenital disorders of glycosylation* LipodystrophyLysosomal storage disorders

GM1 gangliosidosis Fetal hydropsI-cell disease Hurler-like phenotype

*Formerly carbohydrate deficient glycoprotein syndrome.





cerebral and cerebellar atrophy, agenesis of the corpuscallosum, and Leigh syndrome, may be present. Patientswho have the neonatal form of pyruvate carboxylasedeficiency have hepatomegaly, hyperammonemia, citrul-linemia, and ketosis. Infants who have mitochondrialdisease often have lactic acidosis with an elevated lactate-to-pyruvate ratio. Virtually any organ system may beaffected, either in isolation or in any combination, inpatients who have mitochondrial disease. However, in-volvement of the neuromuscular systems is especiallycommon.

CardiomyopathyLong-chain fatty acid oxidation defects are a significantcause of neonatal cardiomyopathy. Although cardiomy-opathy may occur in mitochondrial disorders, onset isoften in early infancy. The infantile form of Pompedisease presents between birth and 6 months of age withmuscle weakness and a rapidly progressive cardiomyopa-thy. Electrocardiography may show very large QRS com-plexes and a short PR interval due to the electricalconductive properties of glycogen. Phosphorylase b ki-nase deficiency is another glycogen storage disorder thatrarely causes cardiomyopathy. Several of the lysosomalstorage disorders may be associated with cardiomyopa-thy, but this tends to develop after the newborn period(Table 6).

Liver DiseaseNeonates who have classic galactosemia often have ahistory of persistent hyperbilirubinemia, hepatomegaly,and hepatocellular dysfunction. The hyperbilirubinemiatends to be unconjugated initially, but it becomes mostlyconjugated in later untreated disease. Patients who havealpha-1-antitrypsin deficiency also may exhibit persistentneonatal jaundice that may progress to cirrhosis overseveral months.

Severe hepatocellular dysfunction is common in fattyacid oxidation defects and is characteristic of hereditarytyrosinemia type I and neonatal hemochromatosis. He-reditary fructose intolerance may present in the newbornperiod with acute liver dysfunction if an affected infant isexposed to fructose. Hepatomegaly associated with hy-poglycemia (without encephalopathy) is characteristic ofglycogen storage disease type I and some disorders ofgluconeogenesis. Causes of neonatal liver disease areshown in Table 7.

Dysmorphic FeaturesAn increasing number of inborn errors are being recog-nized that may be associated with dysmorphic features

(Table 8). Infants who have peroxisomal disorders mayhave striking facial dysmorphism and structural anoma-lies. Pyruvate dehydrogenase deficiency, cholesterol bio-synthetic disorders (mevalonic aciduria, Smith-Lemli-Opitz syndrome), 3-hydroxyisobutyric aciduria, multipleacyl-CoA dehydrogenase deficiency (glutaric aciduriatype II), D-2-hydroxyglutaric aciduria, and mitochon-drial disorders also may be associated with dysmorphicfeatures. Children who have congenital disorders of gly-cosylation (formerly carbohydrate deficient glycoproteinsyndrome) typically exhibit inverted nipples and an un-usual distribution of fat, often with suprailiac fat pads andbuttock lipodystrophy. The coarse features characteristicof lysosomal storage disorders usually evolve in infancyand early childhood, but some of these conditions maypresent in the neonatal period with hydrops. Therefore,the presence of dysmorphic features does not exclude aninborn error of metabolism from diagnostic consider-ation.

Table 9. Inborn Errors ofMetabolism Associated WithNonimmune Fetal HydropsHematologic Disorders

Glucose-6-phosphate dehydrogenase deficiencyPyruvate kinase deficiencyGlucose phosphate isomerase deficiency

Lysosomal Storage Disorders

GM1 gangliosidosisGaucher diseaseNiemann-Pick diseaseFarber lipogranulomatosisSialidosisGalactosialidosisInfantile sialic acid storage diseaseI-cell diseaseMucopolysaccharidosis type I (Hurler syndrome)Mucopolysaccharidosis type IVA (Morquio syndrome)Mucopolysaccharidosis type VII (Sly syndrome)

Mitochondrial Disorders

Pearson marrow-pancreas syndrome

Other Disorders

Congenital disorders of glycosylation*Nemaline myopathyGlycogen storage disorder type IV (Brancher enzyme

deficiency)

*Formerly carbohydrate deficient glycoprotein syndrome





Nonimmune Fetal HydropsInborn errors of metabolism may be associated withnonimmune fetal hydrops (Table 9). Although the asso-ciation of metabolic disorders that cause anemia withfetal hydrops is clear, the cause of the massive generalizededema that may accompany many of these conditionsremains obscure.

SummaryIn aggregate, inborn errors of metabolism are a signifi-cant cause of neonatal distress. A presumptive diagnosis,or at least a narrow differential diagnosis, may be appar-ent after taking into account family history, clinical fea-tures, and results of basic laboratory studies. The consid-eration of these conditions in any infant who hasnonspecific signs of distress may lead to rapid diagnosisand provide the best chance of decreasing the morbidityand mortality associated with metabolic diseases.

Suggested ReadingBlau N, Duran M, Blaskovics ME, eds. Physician’s Guide to the

Laboratory Diagnosis of Metabolic Diseases. London, England:Chapman and Hall; 1996

Burlina AB, Bonafe L, Zacchello. Clinical and biochemical ap-proach to the neonate with a suspected inborn error of aminoacid and organic acid metabolism. Semin Perinatol. 1999;23:162–173

Clarke JTR. Acute metabolic illness in the newborn. In: A ClinicalGuide to Inherited Metabolic Diseases. New York, NY: Cam-bridge University Press; 1996:176–204

Greene CL, Goodman SI. Catastrophic metabolic encephalopathiesin the newborn period: evaluation and management. Clin Peri-natol. 1997;24:773–786

Packman S. Metabolic encephalopathies. In: Berg B, ed. ChildNeurology: A Clinical Manual. Philadelphia, Pa: JB LippincottCo; 1994:51–59

Packman S. Approach to inherited metabolic disorders that presentin the newborn period and infancy. In: Rudolph AM, HoffmanJIE, Rudolph CD, eds. Rudolph’s Pediatrics. Stamford, Conn:Appleton and Lange; 1996:291–294

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. NewYork, NY: McGraw-Hill; 2001:1327–1403

Sue CM, Hirano M, DiMauro S, De Vivo DC. Neonatal presenta-tions of mitochondrial metabolic disorders. Semin Perinatol.1999;23:113–124

Ward JC. Inborn errors of metabolism of acute onset in infancy.Pediatr Rev. 1990;11:205–216





NeoReviews Quiz

1. You are examining a newborn delivered at term gestation. His mother is concerned about the risk of ametabolic disorder because of the history of early neonatal deaths involving her two brothers. Of thefollowing, this pattern of inheritance is most consistent with:

A. Glycogen storage disease.B. Hereditary fructose intolerance.C. Mitochondrial respiratory chain disorder.D. Ornithine transcarbamylase deficiency.E. Propionic acidemia

2. A newborn in whom an inborn error of metabolism is suspected should receive a careful eye examination.Conversely, a newborn in whom ophthalmic findings are unusual should receive a detailed metabolicevaluation. Of the following, a cherry red spot observed on retinal examination of a neonate is most likelyto indicate:

A. Aspartoacyclase deficiency.B. Galactosemia.C. GM1 gangliosidosis.D. Peroxisomal disorder.E. Sulfite oxidase deficiency.

3. Several inborn errors of metabolism are characterized by unusual odors. The odor may be appreciated bestin a urine specimen. Of the following, the odor of sweaty feet is most associated with:

A. Isovaleric acidemia.B. Methylmalonic acidemia.C. Phenylketonuria.D. Trimethylaminuria.E. Tyrosinemia.

4. A 10-day-old female infant is lethargic and feeding poorly. She has a weak cry, rolling of the eyes, andpoor muscle tone. Electroencephalographic findings are consistent with nonspecific diffuse encephalopathy.During the metabolic evaluation of this infant, an arterial blood gas reveals a pH of 7.38 and bicarbonateconcentration of 24 mEq/L. Of the following, these blood gas results are most compatible with:

A. Carnitine-acylcarnitine translocase deficiency.B. Maple syrup urine disease.C. Mitochondrial respiratory chain disorder.D. Propionic acidemia.E. Pyruvate dehydrogenase deficiency.





DOI: 10.1542/neo.2-8-e1832001;2;e183NeoReviews

Gregory M. Enns and Seymour PackmanDiagnosing Inborn Errors of Metabolism in the Newborn: Clinical Features

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DOI: 10.1542/neo.2-8-e1832001;2;e183NeoReviews

Gregory M. Enns and Seymour PackmanDiagnosing Inborn Errors of Metabolism in the Newborn: Clinical Features

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http://neoreviews.aappublications.org/content/suppl/2005/01/27/2.8.e183.DC1.htmlData Supplement at:

ISSN: 1526-9906. 60007. Copyright © 2001 by the American Academy of Pediatrics. All rights reserved. Online the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois,it has been published continuously since . Neoreviews is owned, published, and trademarked by Neoreviews is the official journal of the American Academy of Pediatrics. A monthly publication,


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