Article

inborn errors of metabolism

Diagnosing Inborn Errors of

Metabolism in the Newborn:
Clinical Features
Gregory 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 error
of 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.

Introduction
The rapid deterioration of a previously healthy-appearing neonate is one of the most
stressful scenarios in medicine. Unless appropriate therapy is initiated without delay, there
is a high risk of morbidity or mortality, regardless of the etiology of the acute illness. Any
infant who presents with feeding difficulties, vomiting, jaundice, failure to thrive, apnea or
tachypnea, hypotonia or hypertonia, seizures, lethargy, or coma should be considered as
suffering from diseases in one of two broad categories: 1) disorders resulting from causes
such as infection, cardiopulmonary dysfunction or other causes of hypoxemia, toxins,
trauma, or congenital structural brain abnormalities or 2) disorders caused by an inborn
error of metabolism. Because metabolic diseases are individually rare, there is a tendency to
consider 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 as
one child in every 1,000 births being affected. The clinician must consider these disorders
in all neonates who have nonspecific features of distress upon initial presentation. In many
cases, only rapid diagnosis and management can prevent death or significant morbidity.
Appropriate laboratory investigations should be obtained immediately. Even simple tests
such as measurement of blood gases, glucose, electrolytes, lactate, and ammonia and the
evaluation of urine for ketones may provide valuable clues to the underlying diagnosis.

Inheritance
Most inborn errors of metabolism are inherited as autosomal recessive traits or, as in the
case of ornithine transcarbamylase deficiency, are X-linked. A detailed family history may
reveal 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 autosomal
recessive condition, but can be a maternal uncle, a brother, or a mildly affected mother or
other female in X-linked disease. Some disorders are caused by mitochondrial DNA
mutations, and maternal transmission to all children in a sibship is observed. Special
attention should be given to stillbirths, unexplained deaths, and neurologic diseases or
delayed development of any degree or severity. Maternal illness in pregnancy also has been
associated with specific metabolic disorders and may yield a clue to the presence of an
inborn error of metabolism in a neonate. For example, acute fatty liver of pregnancy and
hypertension, elevated liver enzymes, low platelets (HELLP) syndrome may occur in a
heterozygous mother carrying a fetus that has long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency.
*Assistant Professor of Pediatrics; Director, Biochemical Genetics Program, Division of Medical Genetics, Stanford University
School of Medicine, Stanford, CA.

Professor of Pediatrics, Division of Medical Genetics, Department of Pediatrics, University of California, San Francisco, CA.
NeoReviews Vol.2 No.8 August 2001 e183

Downloaded from http://neoreviews.aappublications.org/ at Health Internetwork on October 15, 2015

inborn errors of metabolism clinical features

Signs and Symptoms

Symptoms of metabolic disease generally occur postnatally, appearing after an interval period of apparent
good health and following a normal pregnancy. The
interval may be as short as a few hours or be several days
or even longer. The infant may do well until subjected to
a catabolic insult (infection, fasting, dehydration) or an
excessive protein or carbohydrate load. Following exposure to a stressor, the child may become strikingly ill very
suddenly and can present as sudden infant death of
unexplained etiology. On the other hand, the absence of
a normal period does not exclude an inborn error from
diagnostic consideration. Neonatal distress from asphyxia or complications of prematurity may constitute
the environmental stress that unmasks an underlying
metabolic disease.
Irritability and feeding difficulties may be associated
with uncoordinated sucking and swallowing or abnormal
muscle tone. Persistent and severe vomiting and convulsions may occur. In mildly affected neonates, symptoms
can disappear, only to recur in days or weeks. More
severely affected infants have inexorable progression
from lethargy to coma to episodic apnea and death. More
limited symptoms, often in the form of generalized or
partial seizures, may occur in some instances. These can
include staring spells, eye rolling or myoclonus, and
various combinations of tone abnormalities, tremulousness, lethargy, and a weak cry. Electroencephalography
may suggest nonspecific diffuse encephalopathy. Unless
an inborn error is suspected, the child may be misdiagnosed as having hypoxic-ischemic encephalopathy, intraventricular hemorrhage, sepsis, heart failure, or a gastrointestinal illness, such as pyloric stenosis or intestinal
obstruction.
A concomitant acquired disorder may confound the
diagnosis of an inherited metabolic disease. For example,
neutropenia may occur in an organic acidemia that has a
neonatal presentation, but sepsis with leukocytosis (or
neutropenia) also may be present because of an increased
susceptibility to bacterial infection. Escherichia coli sepsis
is frequent in infants who have galactosemia, and the
inanition and jaundice of that disorder might be ascribed
incorrectly solely to sepsis. Other examples of acquired
conditions that may complicate the presentation of a
metabolic disorder include pulmonary hemorrhage or
primary respiratory alkalosis in urea cycle defects.

Physical Findings
A paucity of abnormal physical findings is the general rule
in heritable metabolic diseases. Nevertheless, certain
components of the physical examination should be em-

Ocular Findings in Infants

Who Have Inborn Errors of
Metabolism
Table 1.

Finding

Disorder

Neonatal cataracts

Galactosemia
Galactokinase deficiency
Tyrosinemia type II
Peroxisomal disorders
Glucose-6-phosphate
dehydrogenase deficiency
Sorbitol dehydrogenase
deficiency
Lowe syndrome*
Cockayne syndrome
Mitochondrial respiratory chain
defects
Sialidosis
Alpha-mannosidosis
Mevalonic aciduria
Peroxisomal disorders
Sjogren-Larsson syndrome
Cobalamin C disease
Abetalipoproteinemia
Neuronal ceroid lipofuscinosis
Congenital disorders of
glycosylation
Mitochondrial respiratory chain
disorders
Long-chain 3-hydroxyacyl-CoA
dehydrogenase (LCHAD)
deficiency
Mucopolysaccharidoses types I,
II, III, IV
GM1 and GM2 gangliosidosis
Galactosialidosis
Metachromatic leukodystrophy
Niemann-Pick disease
Wolman disease
3-Methylglutaconic aciduria
Mitochondrial disorders
Canavan disease (aspartoacylase
deficiency)
Krabbe disease
Sulfite oxidase deficiency
Molybdenum cofactor deficiency

Infantile cataracts

Retinitis pigmentosa

Cherry red spot

Optic atrophy

Lens dislocation

*Phosphatidylinositol 4,5-bisphosphate 5-phosphatase deficiency.

This disorder of DNA repair usually is not categorized as an inborn

error, but it is an important cause of congenital cataracts.

Pigmentary retinopathy tends to develop later in childhood.

phasized. A detailed ocular examination is essential; corneal clouding, cataracts, optic nerve abnormalities, and
macular or retinal pigmentary changes may be helpful in
establishing a diagnosis (Table 1). Hepatomegaly can
occur in carbohydrate disorders (galactosemia, glycogen

e184 NeoReviews Vol.2 No.8 August 2001

Downloaded from http://neoreviews.aappublications.org/ at Health Internetwork on October 15, 2015

inborn errors of metabolism clinical features

Urine Odors Associated With Inborn Errors

of Metabolism
Table 2.

Odor

Compound

Disorder

Musty, mousy
Maple syrup
Sweaty feet

Phenylacetate
2-Oxoisocaproic acid
Isovaleric acid

Cat urine

3-Hydroxyisovaleric acid

Cabbage-like

2-Hydroxybutyric acid

Rancid butter
Acid smell
Sulfurous
Fish market

2-Oxo-4-methiolbutyric acid
Methylmalonic acid
Hydrogen sulfide
Trimethylamine

Classic phenylketonuria
Maple syrup urine disease
Isovaleric acidemia
Multiple acyl-CoA
dehydrogenase deficiency
(glutaric aciduria type II)
3-Hydroxy-3-methylglutaric
aciduria
3-Methylcrotonyl-CoA
carboxylase deficiency
Multiple carboxylase deficiency
Tyrosinemia type 1
Methionine malabsorption
Tyrosinemia type 1
Methylmalonic acidemia
Cystinuria
Trimethylaminuria

Adapted with permission from Blau et al, 1996.

storage disease, hereditary fructose intolerance), peroxisomal disorders, tyrosinemia, Niemann-Pick disease,
Gaucher disease, inborn errors of bile acid metabolism,
neonatal hemochromatosis, some forms of congenital
lactic acidosis (mitochondrial respiratory chain defects),
and other organic acidemias and fatty acid oxidation
defects that may have a Reye syndrome-like presentation. Abnormal, brittle hair may be seen in some urea
cycle defects (argininosuccinic aciduria, citrullinemia),
holocarboxylase synthetase deficiency, and Menkes syndrome (pili torti). An unusual body or urine odor has
been associated with several organic acidemias, including branched-chain ketoaciduria (maple syrup), isovaleric acidemia or multiple acyl-CoA dehydrogenase
deficiency (sweaty feet), and 3methylcrotonyl-CoA carboxylase Table 3.
deficiency (cat-like) (Table 2). Ketosis accompanies many of these
conditions and will cause the sweet
Color
odor of ketone bodies in the urine.
Blue
An unusual urine color also may
Blue/brown
signal some inborn errors (Table 3).

seizures in the newborn period (Table 4). The nonspecific features of

these conditions are similar to those
of hypoxic-ischemic encephalopathy. However, unlike acute asphyxia, generally there is no history
of birth trauma, and patients appear
normal for at least a short time. If
the degree of encephalopathy appears greater than would be expected from careful review of the
perinatal history, an inborn error
should be considered strongly.

Maple Syrup Urine Disease

(MSUD)

Infants who have MSUD typically

develop symptoms in the first few
days to weeks of life after appearing
normal at birth. Poor feeding and
vomiting may be the initial symptoms, but lethargy and progressive
neurologic deterioration supervene. The child may be
hypotonic or appear markedly hypertonic with opisthotonus. Not all infants develop a maple syrup smell.
Although ketosis is prominent, metabolic acidosis is not
often present until later in the course of disease.

Mevalonic Aciduria
Mevalonic aciduria is a disorder of cholesterol biosynthesis that usually is not associated with metabolic acidosis.
Severe neurologic involvement may occur in neonates,
but patients often have other findings, such as dysmorphic features, hepatosplenomegaly, recurrent fevers, and
anemia.

Unusual Urine Colors Associated with

Inborn Errors of Metabolism

Encephalopathy Without
Metabolic Acidosis
A number of inborn errors of metabolism are associated with encephalopathic findings or isolated

Brown
Red/brown
Light red
Red

Compound

Disorder

Indican
Homogentisic acid
Methemoglobin
Hemoglobin/methemoglobin
Urates
Erythrocytes
Porphyrins

Hartnup disorder
Alkaptonuria
Myoglobinuria
Hemoglobinuria
Hyperuricosuria
Hematuria
Porphyria

Adapted with permission from Blau et al, 1996.

NeoReviews Vol.2 No.8 August 2001 e185

Downloaded from http://neoreviews.aappublications.org/ at Health Internetwork on October 15, 2015

inborn errors of metabolism clinical features

Inborn Errors of
Metabolism Associated With
Encephalopathy Without
Metabolic Acidosis

Inborn Errors of
Metabolism Associated With
Encephalopathy With
Metabolic Acidosis

Table 4.

Table 5.

Lethargy Without Hyperammonemia

Organic Acidemias With Ketosis

Maple syrup urine disease

Mevalonic aciduria

Propionic acidemia
Isovaleric acidemia
Methylmalonic acidemia
Holocarboxylase synthetase deficiency
Multiple acyl-CoA dehydrogenase deficiency (Glutaric
acidemia type II)*
3-Hydroxyisobutyric acidemia*

Lethargy With Hyperammonemia

Urea cycle defects
Hyperammonemia-Hyperornithinemia-Homocitrullinuria
syndrome
Lysinuric protein intolerance
Hyperinsulinism-Hyperammonemia syndrome
Encephalopathy With Dysmorphic Features and
Congenital Anomalies
Peroxisomal disorders
Seizures Without Abnormal Metabolites on Routine
Biochemical Screening
Nonketotic hyperglycinemia
Sulfite oxidase/molybdenum cofactor deficiency
Pyridoxine-responsive seizures
4-Aminobutyrate amino transferase (GABA
transaminase) deficiency
Folinic acid-responsive seizures
Guanidinoacetate methyltransferase (GAMT) deficiency
Glucose transporter (GLUT-1) deficiency

Organic Acidemias Without Ketosis

3-Hydroxy-3-methylglutaryl-CoA (HMG-CoA) lyase
deficiency
Fatty Acid Oxidation Defects
Short-chain acyl-CoA dehydrogenase (SCAD) deficiency
Medium-chain acyl-CoA dehydrogenase (MCAD)
deficiency
Long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD)
deficiency
Trifunctional protein deficiency
Very long-chain acyl-CoA dehydrogenase (VLCAD)
deficiency
Carnitine uptake deficiency
Carnitine-acylcarnitine translocase (CAT) deficiency
Carnitine palmitoyltransferase 2 (CPT-2) deficiency
Congenital Lactic Acidoses

Urea Cycle Defects

The early clinical course of patients who have urea cycle
defects is similar to that in MSUD, except that hypotonia
typically is more severe, and a respiratory alkalosis is
common. Severe hyperammonemia is the hallmark of
these conditions. However, sepsis often is suspected initially, and unless an ammonia level is evaluated, these
infants may die of unknown cause early in the newborn
period. Aside from the X-linked ornithine transcarbamylase deficiency, these are autosomal recessive disorders.
Transient hyperammonemia of the newborn (THAN)
is an important consideration in the differential diagnosis
of these conditions. THAN tends to occur in the first day
of life; urea cycle disorders typically present after 1 or
2 days. Other inborn errors, including pyruvate carboxylase deficiency, organic acidemias, fatty acid oxidation
defects, lysinuric protein intolerance, and the hyperammonemia-hyperornithinemia-homocitrullinuria syndrome, can cause marked hyperammonemia by secondary inhibition of urea cycle function. Standard metabolic

Pyruvate dehydrogenase deficiency

Pyruvate carboxylase deficiency
Mitochondrial respiratory chain disorders
Gluconeogenesis disorders
Phosphoenolpyruvate carboxykinase deficiency
Fructose-1,6-bisphosphatase deficiency
*Dysmorphic features and congenital anomalies may be present.

Cardiomyopathy is common, except in SCAD and MCAD

deficiencies.

investigations are usually sufficient to diagnose these

conditions.

Peroxisomal Disorders
Infants who have peroxisomal disorders (Zellweger syndrome, neonatal adrenoleukodystrophy) often exhibit
severe neonatal features, including craniofacial dysmorphism, neuronal migration defects, pigmentary retinopathy, profound hypotonia, seizures, hepatomegaly, jaundice, and renal cysts. Short limbs, joint contractures, and
epiphyseal stippling are characteristic of rhizomelic chon-

e186 NeoReviews Vol.2 No.8 August 2001

Downloaded from http://neoreviews.aappublications.org/ at Health Internetwork on October 15, 2015

inborn errors of metabolism clinical features

Inborn Errors of
Metabolism Associated With
Neonatal Cardiomyopathy

Liver Disease in Neonatal

Inborn Errors of Metabolism

Fatty Acid Oxidation Defects

Galactosemia
Hereditary fructose intolerance
Tyrosinemia
Neonatal hemochromatosis
Wolman disease
Mitochondrial respiratory chain disorders
Mitochondrial DNA depletion syndrome
Long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD)
deficiency
Glycogen storage disease type IV (Brancher enzyme
deficiency)

Table 6.

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

deficiency
Trifunctional protein deficiency
Very long-chain acyl-CoA dehydrogenase (VLCAD)
deficiency
Carnitine uptake deficiency
Carnitine-acylcarnitine translocase (CAT) deficiency
Carnitine palmitoyltransferase 2 (CPT-2) deficiency
Mitochondrial Respiratory Chain Disorders
Tricarboxylic Acid Cycle Defects
Alpha-ketoglutarate dehydrogenase deficiency
Glycogen Storage Disorders
Pompe disease
Phosphorylase 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 glycosylation, and other lysosomal storage disorders, but tends to occur
after the newborn period.

Table 7.

Hepatomegaly With Hepatocellular Disease

Hepatomegaly With Cholestasis

Alpha-1-antitrypsin deficiency
Byler disease (progressive familial intrahepatic
cholestasis)
Bile acid synthesis disorders
Niemann-Pick disease, type C
Peroxisomal disorders
Neonatal hemochromatosis
Galactosemia (rare)
Hereditary fructose intolerance (rare)
Cystic fibrosis (rare)
Hepatomegaly Without Hepatocellular Disease or
Cholestasis
Glycogen storage disease, type 1
Fructose-1,6-bisphosphatase deficiency

drodysplasia punctata. Evidence of hepatocellular dysfunction is common.

Isolated Seizures
A growing list of metabolic disorders are associated with
isolated seizures or progressive encephalopathy without
obvious biochemical abnormalities on routine metabolic
screening (Table 4). It is important to save a sample of
cerebrospinal fluid (CSF) for specialized testing in case a
common cause for neonatal seizures is not identified.
Approximately two thirds of patients who have nonketotic hyperglycinemia exhibit symptoms within
48 hours of delivery. Infants typically present with lethargy, apnea, profound hypotonia, feeding difficulty, hiccups, and intractable seizures. The only consistent abnormalities are elevated urine, plasma, and CSF glycine
levels. A CSF-to-plasma glycine ratio of greater than 0.08
confirms the diagnosis. CSF and blood samples for glycine analysis must be obtained as near to simultaneously
as possible for accurate calculation of the glycine ratio.
Sulfite oxidase deficiency may occur in isolation or
combined with xanthine oxidase deficiency. The com-

bined defects are secondary to molybdenum cofactor

deficiency. Patients have seizures that are recalcitrant to
therapy starting in the first few days of life. A low uric acid
level may be noted in molybdenum cofactor deficiency,
but other laboratory findings are normal. A specific assay
for elevation of plasma or urine S-sulfocysteine is required to make the diagnosis.
Infants who have pyridoxine-dependent seizures may
present as early as the first day of life with flaccidity,
abnormal eye movements, and irritability. The diagnosis
is clinical and is based on documented response of seizures to intravenous pyridoxine (vitamin B6).
The enzyme 4-aminobutyrate aminotransferase
(GABA transaminase) catalyzes the initial step in the
conversion of GABA, a central nervous system inhibitory
neurotransmitter, to succinic acid. Elevated GABA concentrations in the central nervous system result in neonatal seizures, lethargy, hypotonia, hyperreflexia, and a
high-pitched cry.
Folinic acid-responsive seizures is a newly described
NeoReviews Vol.2 No.8 August 2001 e187

Downloaded from http://neoreviews.aappublications.org/ at Health Internetwork on October 15, 2015

inborn errors of metabolism clinical features

disease of unknown etiology. Seizures occur as early as 2 hours after

birth. High-performance liquid
chromatography documents a characteristic peak. Infants respond to
folinic acid supplementation.
Patients who have guanidinoacetate methyltransferase deficiency, a recently identified disorder of creatine metabolism, usually
present in infancy with seizures, developmental delay, and extrapyramidal signs, but symptoms have
been described in neonates. Low
plasma creatinine levels and elevated guanidinoacetate are characteristic.
A reduced CSF glucose concentration (hypoglycorrhachia) is
present in the GLUT-1 deficiency
syndrome (glucose transporter defect). This autosomal dominant disorder causes severe clinical symptoms, including seizures, acquired
microcephaly, and developmental
delay. Patients have become symptomatic as early as the third week of
life, but it is unclear whether symptoms may occur earlier because of
the paucity of reported cases.

Encephalopathy With
Metabolic Acidosis

Inborn Errors of Metabolism Associated

With Dysmorphic Features

Table 8.

Disorder

Features

Peroxisomal disorders
Zellweger syndrome

Large fontanelle, high, prominent

forehead, hypoplastic supraorbital
ridges, epicanthic folds, flat nasal
bridge
Rhizomelic chondrodysplasia punctata Dysmorphic facial features, rhizomelic
limb shortening, epiphyseal stippling
Pyruvate dehydrogenase deficiency
Epicanthic folds, flat nasal bridge, small
nose with anteverted flared alae nasi,
long philtrum
Mitochondrial disorders
Epicanthic folds, flat nasal bridge
Multiple acyl-CoA dehydrogenase
Macrocephaly, high forehead, flat nasal
deficiency (glutaric aciduria type II)
bridge, short anteverted nose, ear
anomalies, hypospadias, rockerbottom feet
D-2-Hydroxyglutaric aciduria
Epicanthic folds, asymmetric ears, coarse
features
3-Hydroxyisobutyric aciduria
Myopathic face, sloping forehead,
midface hypoplasia, long prominent
philtrum, micrognathia, clinodactyly
Cholesterol biosynthetic defects
Smith-Lemli-Opitz syndrome
Epicanthic folds, flat nasal bridge, toe 2/
3 syndactyly, abnormal genitalia
Mevalonic aciduria
Large fontanelle, high forehead,
hypertelorism, epicanthic folds, lowset ears, long philtrum
Congenital disorders of glycosylation*
Lipodystrophy
Lysosomal storage disorders
GM1 gangliosidosis
Fetal hydrops
I-cell disease
Hurler-like phenotype
*Formerly carbohydrate deficient glycoprotein syndrome.

Inborn errors of metabolism that

are characterized by a nonspecific encephalopathy with
associated metabolic acidosis include organic acidemias,
fatty acid oxidation defects, and primary congential lactic
acidoses (Table 5). Distinctive clinical features are often
absent.
Organic acidemias that present in the newborn period
with encephalopathy and severe metabolic acidosis are
virtually indistinguishable clinically. Hyperammonemia
may be severe, with ammonia levels similar to those
encountered in urea cycle disorders. In addition, neutropenia and thrombocytopenia are common, and sepsis or
a bleeding diathesis may supervene. Distinctive odors
may be present in some of these conditions (Table 2), but
often only the nonspecific sweet smell of ketone bodies is
noticeable.
Fatty acid oxidation disorders may have a Reye
syndrome-like presentation. Approximately 5% to 10% of

unexplained sudden infant deaths may be attributed to

these conditions. Although encephalopathy may dominate the clinical picture, multiorgan system involvement
is common, with infants showing various degrees of
cardiac, skeletal muscle, ophthalmologic, and hepatic
involvement. Hyperammonemia and lactic acidosis may
occur. Cardiomyopathy is particularly common in longchain defects (Table 6). Hepatomegaly and hepatocellular dysfunction are typical of these conditions when they
occur in neonates. A pigmentary retinopathy is often
present in long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency, but it tends to develop later in childhood.
Disorders of pyruvate metabolism and mitochondrial
disorders may cause congenital lactic acidosis. Many
infants who have pyruvate dehydrogenase deficiency exhibit dysmorphic features. Brain abnormalities, including

e188 NeoReviews Vol.2 No.8 August 2001

Downloaded from http://neoreviews.aappublications.org/ at Health Internetwork on October 15, 2015

inborn errors of metabolism clinical features

cerebral and cerebellar atrophy, agenesis of the corpus

callosum, and Leigh syndrome, may be present. Patients
who have the neonatal form of pyruvate carboxylase
deficiency have hepatomegaly, hyperammonemia, citrullinemia, and ketosis. Infants who have mitochondrial
disease often have lactic acidosis with an elevated lactateto-pyruvate ratio. Virtually any organ system may be
affected, either in isolation or in any combination, in
patients who have mitochondrial disease. However, involvement of the neuromuscular systems is especially
common.

Cardiomyopathy
Long-chain fatty acid oxidation defects are a significant
cause of neonatal cardiomyopathy. Although cardiomyopathy may occur in mitochondrial disorders, onset is
often in early infancy. The infantile form of Pompe
disease presents between birth and 6 months of age with
muscle weakness and a rapidly progressive cardiomyopathy. Electrocardiography may show very large QRS complexes and a short PR interval due to the electrical
conductive properties of glycogen. Phosphorylase b kinase deficiency is another glycogen storage disorder that
rarely causes cardiomyopathy. Several of the lysosomal
storage disorders may be associated with cardiomyopathy, but this tends to develop after the newborn period
(Table 6).

Liver Disease

Inborn Errors of
Metabolism Associated With
Nonimmune Fetal Hydrops

Table 9.

Hematologic Disorders
Glucose-6-phosphate dehydrogenase deficiency
Pyruvate kinase deficiency
Glucose phosphate isomerase deficiency
Lysosomal Storage Disorders
GM1 gangliosidosis
Gaucher disease
Niemann-Pick disease
Farber lipogranulomatosis
Sialidosis
Galactosialidosis
Infantile sialic acid storage disease
I-cell disease
Mucopolysaccharidosis 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 myopathy
Glycogen storage disorder type IV (Brancher enzyme
deficiency)
*Formerly carbohydrate deficient glycoprotein syndrome

Neonates who have classic galactosemia often have a

history of persistent hyperbilirubinemia, hepatomegaly,
and hepatocellular dysfunction. The hyperbilirubinemia
tends to be unconjugated initially, but it becomes mostly
conjugated in later untreated disease. Patients who have
alpha-1-antitrypsin deficiency also may exhibit persistent
neonatal jaundice that may progress to cirrhosis over
several months.
Severe hepatocellular dysfunction is common in fatty
acid oxidation defects and is characteristic of hereditary
tyrosinemia type I and neonatal hemochromatosis. Hereditary fructose intolerance may present in the newborn
period with acute liver dysfunction if an affected infant is
exposed to fructose. Hepatomegaly associated with hypoglycemia (without encephalopathy) is characteristic of
glycogen storage disease type I and some disorders of
gluconeogenesis. Causes of neonatal liver disease are
shown in Table 7.

Dysmorphic Features
An increasing number of inborn errors are being recognized that may be associated with dysmorphic features

(Table 8). Infants who have peroxisomal disorders may

have striking facial dysmorphism and structural anomalies. Pyruvate dehydrogenase deficiency, cholesterol biosynthetic disorders (mevalonic aciduria, Smith-LemliOpitz syndrome), 3-hydroxyisobutyric aciduria, multiple
acyl-CoA dehydrogenase deficiency (glutaric aciduria
type II), D-2-hydroxyglutaric aciduria, and mitochondrial disorders also may be associated with dysmorphic
features. Children who have congenital disorders of glycosylation (formerly carbohydrate deficient glycoprotein
syndrome) typically exhibit inverted nipples and an unusual distribution of fat, often with suprailiac fat pads and
buttock lipodystrophy. The coarse features characteristic
of lysosomal storage disorders usually evolve in infancy
and early childhood, but some of these conditions may
present in the neonatal period with hydrops. Therefore,
the presence of dysmorphic features does not exclude an
inborn error of metabolism from diagnostic consideration.
NeoReviews Vol.2 No.8 August 2001 e189

Downloaded from http://neoreviews.aappublications.org/ at Health Internetwork on October 15, 2015

inborn errors of metabolism clinical features

Nonimmune Fetal Hydrops

Inborn errors of metabolism may be associated with
nonimmune fetal hydrops (Table 9). Although the association of metabolic disorders that cause anemia with
fetal hydrops is clear, the cause of the massive generalized
edema that may accompany many of these conditions
remains obscure.

Summary
In aggregate, inborn errors of metabolism are a significant cause of neonatal distress. A presumptive diagnosis,
or at least a narrow differential diagnosis, may be apparent after taking into account family history, clinical features, and results of basic laboratory studies. The consideration of these conditions in any infant who has
nonspecific signs of distress may lead to rapid diagnosis
and provide the best chance of decreasing the morbidity
and mortality associated with metabolic diseases.

Suggested Reading
Blau N, Duran M, Blaskovics ME, eds. Physicians Guide to the
Laboratory Diagnosis of Metabolic Diseases. London, England:
Chapman and Hall; 1996

Burlina AB, Bonafe L, Zacchello. Clinical and biochemical approach to the neonate with a suspected inborn error of amino
acid and organic acid metabolism. Semin Perinatol. 1999;23:
162173
Clarke JTR. Acute metabolic illness in the newborn. In: A Clinical
Guide to Inherited Metabolic Diseases. New York, NY: Cambridge University Press; 1996:176 204
Greene CL, Goodman SI. Catastrophic metabolic encephalopathies
in the newborn period: evaluation and management. Clin Perinatol. 1997;24:773786
Packman S. Metabolic encephalopathies. In: Berg B, ed. Child
Neurology: A Clinical Manual. Philadelphia, Pa: JB Lippincott
Co; 1994:5159
Packman S. Approach to inherited metabolic disorders that present
in the newborn period and infancy. In: Rudolph AM, Hoffman
JIE, Rudolph CD, eds. Rudolphs Pediatrics. Stamford, Conn:
Appleton and Lange; 1996:291294
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. New
York, NY: McGraw-Hill; 2001:13271403
Sue CM, Hirano M, DiMauro S, De Vivo DC. Neonatal presentations of mitochondrial metabolic disorders. Semin Perinatol.
1999;23:113124
Ward JC. Inborn errors of metabolism of acute onset in infancy.
Pediatr Rev. 1990;11:205216

e190 NeoReviews Vol.2 No.8 August 2001

Downloaded from http://neoreviews.aappublications.org/ at Health Internetwork on October 15, 2015

inborn errors of metabolism clinical features

NeoReviews Quiz
1. You are examining a newborn delivered at term gestation. His mother is concerned about the risk of a
metabolic disorder because of the history of early neonatal deaths involving her two brothers. Of the
following, this pattern of inheritance is most consistent with:
A.
B.
C.
D.
E.

Glycogen storage disease.

Hereditary fructose intolerance.
Mitochondrial respiratory chain disorder.
Ornithine transcarbamylase deficiency.
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 metabolic
evaluation. Of the following, a cherry red spot observed on retinal examination of a neonate is most likely
to indicate:
A.
B.
C.
D.
E.

Aspartoacyclase deficiency.
Galactosemia.
GM1 gangliosidosis.
Peroxisomal disorder.
Sulfite oxidase deficiency.

3. Several inborn errors of metabolism are characterized by unusual odors. The odor may be appreciated best
in a urine specimen. Of the following, the odor of sweaty feet is most associated with:
A.
B.
C.
D.
E.

Isovaleric acidemia.
Methylmalonic acidemia.
Phenylketonuria.
Trimethylaminuria.
Tyrosinemia.

4. A 10-day-old female infant is lethargic and feeding poorly. She has a weak cry, rolling of the eyes, and
poor 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 bicarbonate
concentration of 24 mEq/L. Of the following, these blood gas results are most compatible with:
A.
B.
C.
D.
E.

Carnitine-acylcarnitine translocase deficiency.

Maple syrup urine disease.
Mitochondrial respiratory chain disorder.
Propionic acidemia.
Pyruvate dehydrogenase deficiency.

NeoReviews Vol.2 No.8 August 2001 e191

Downloaded from http://neoreviews.aappublications.org/ at Health Internetwork on October 15, 2015

Diagnosing Inborn Errors of Metabolism in the Newborn: Clinical Features

Gregory M. Enns and Seymour Packman
NeoReviews 2001;2;e183
DOI: 10.1542/neo.2-8-e183

Updated Information &

Services

including high resolution figures, can be found at:

http://neoreviews.aappublications.org/content/2/8/e183

References

This article cites 4 articles, 1 of which you can access for free at:
http://neoreviews.aappublications.org/content/2/8/e183#BIBL

Subspecialty Collections

This article, along with others on similar topics, appears in the

following collection(s):
Endocrinology
http://neoreviews.aappublications.org/cgi/collection/endocrinology_s
ub
Fetus/Newborn Infant
http://neoreviews.aappublications.org/cgi/collection/fetus:newborn_i
nfant_sub
Metabolic Disorders
http://neoreviews.aappublications.org/cgi/collection/metabolic_disor
ders_sub

Permissions & Licensing

Information about reproducing this article in parts (figures, tables) or

in its entirety can be found online at:
http://neoreviews.aappublications.org/site/misc/Permissions.xhtml

Reprints

Information about ordering reprints can be found online:

http://neoreviews.aappublications.org/site/misc/reprints.xhtml

Downloaded from http://neoreviews.aappublications.org/ at Health Internetwork on October 15, 2015

Diagnosing Inborn Errors of Metabolism in the Newborn: Clinical Features

Gregory M. Enns and Seymour Packman
NeoReviews 2001;2;e183
DOI: 10.1542/neo.2-8-e183

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://neoreviews.aappublications.org/content/2/8/e183

Data Supplement at:

http://neoreviews.aappublications.org/content/suppl/2005/01/27/2.8.e183.DC1.html

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

Downloaded from http://neoreviews.aappublications.org/ at Health Internetwork on October 15, 2015