Inbor n Errors o f

Metabolism
Ayman W. El-Hattab, MD, FAAP, FACMG

KEYWORDS
 Metabolic  Acidosis  Hypoglycemia  Hyperammonemia  Fatty acid oxidation
 Urea cycle  Organic acidemia

KEY POINTS
 Inborn errors of metabolism (IEMs) are not uncommon; their overall incidence is more than
1:1000.
 Neonates with IEMs usually present with nonspecific signs; therefore, maintaining a high
index of suspicion is extremely important for early diagnosis of IEMs.
 Metabolic acidosis with hyperammonemia is suggestive of organic acidemias.
 Hypoglycemia without ketosis is suggestive of fatty acid oxidation defects.
 Hyperammonemia with respiratory alkalosis is suggestive of urea cycle defects.
 Liver failure can be caused by galactosemia and tyrosinemia type I.
 Cardiomyopathy can be caused by glycogen storage disease type II and fatty acid oxida-
tion defects.
 Adequate caloric intake and early introduction of the appropriate enteral feeding are
important in managing acute metabolic decompensation in neonates with IEMs.

INTRODUCTION

Inborn errors of metabolism (IEMs) are a group of disorders each of which results from
deficient activity of a single enzyme in a metabolic pathway. Although IEMs are individ-
ually rare, they are collectively common, with an overall incidence of more than 1:1000.1
More than 500 IEMs have been recognized, with approximately 25% of them having
manifestations in the neonatal period.2,3 Neonates with IEMs are usually healthy at birth
with signs typically developing in hours to days after birth. The signs are usually nonspe-
cific, and may include decreased activity, poor feeding, respiratory distress, lethargy, or
seizures. These signs are common to several other neonatal conditions, such as sepsis
and cardiopulmonary dysfunction. Therefore, maintaining a high index of suspicion is

Disclosure: None.
Division of Clinical Genetics and Metabolic Disorders, Pediatric Department, Tawam Hospital,
P.O. Box 15258, Al-Ain, United Arab Emirates
E-mail address: [email protected]

Clin Perinatol 42 (2015) 413439

http://dx.doi.org/10.1016/j.clp.2015.02.010 perinatology.theclinics.com
0095-5108/15/$ see front matter 2015 Elsevier Inc. All rights reserved.
414 El-Hattab

important for early diagnosis and the institution of appropriate therapy, which are
mandatory to prevent death and ameliorate complications from many IEMs.3
The vast majority of IEMs are inherited in an autosomal recessive manner. There-
fore, a history of parental consanguinity or a previously affected sibling should raise
the suspicion of IEMs. Some IEMs, such as ornithine transcarbamylase (OTC) defi-
ciency, are X-linked. In X-linked disorder, typically male patients have severe disease,
whereas female patients are either asymptomatic or have milder disease.
Pathophysiologically, IEMs can be divided into three groups. The first includes IEMs
causing intoxication because of defects in the intermediary metabolic pathway, result-
ing in the accumulation of toxic compounds proximal to the metabolic block; examples
are urea cycle defects and maple syrup urine disease (MSUD). The second group in-
cludes IEMs resulting in energy deficiency and includes mitochondrial respiratory chain
defects. The third group is IEMs resulting in defects in the synthesis or the catabolism of
complex molecules in certain cellular organelles, such as lysosomal storage disorders.3

CLINICAL MANIFESTATIONS

After an initial symptom-free period, neonates with IEMs can start deteriorating for no
apparent reasons and do not respond to symptomatic therapies. The interval between
birth and clinical symptoms may range from hours to weeks, depending on the
enzyme deficiency. Neonates with IEMs can present with 1 or more of the following
clinical groups.4,5

Neurologic Manifestations
Deterioration of consciousness is one of the common neonatal manifestations of IEMs that
can occur due to metabolic derangements, including acidosis, hypoglycemia, and hyper-
ammonemia. Neonates with these metabolic derangements typically exhibit poor feeding
and decreased activity that progress to lethargy and coma. Other common neurologic
manifestations of IEMs in the neonatal period are seizures, hypotonia, and apnea (Box 1).

Hepatic Manifestations
Neonates with IEMs can present with hepatomegaly and hypoglycemia, cholestatic
jaundice, or liver failure presenting with jaundice, coagulopathy, elevated transami-
nases, hypoglycemia, and ascites (Box 2).

Cardiac Manifestations
Some IEMs can present predominantly with cardiac diseases, including cardiomyop-
athy, heart failure, and arrhythmias (Box 3).

Abnormal Urine Odor

An abnormal urine odor is present in IEMs in which volatile metabolites accumulate
(Box 4).

Distinctive Facial Features

Several IEMs can present with distinctive facial features (Box 5).

Hydrops Fetalis
Several lysosomal storage diseases can present with hydrops fetalis (Box 6).
 Inborn Errors of Metabolism 415

Box 1
IEMs associated with neurologic manifestations in neonates

 Deterioration in consciousness
 Metabolic acidosis
- Organic acidemias
- Maple syrup urine disease (MSUD)
- Disorders of pyruvate metabolism
- Fatty acid oxidation defects
- Fructose-1,6-bisphosphatase deficiency
- Glycogen storage disease type 1
- Mitochondrial respiratory chain defects
- Disorders of ketolysis
- 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) lyase deficiency
 Hypoglycemia
- Fatty acid oxidation defects
- Fructose-1,6-bisphosphatase deficiency
- Glycogen storage disease type 1
- Organic acidemias
- Mitochondrial respiratory chain defects
- HMG CoA lyase deficiency
 Hyperammonemia
- Urea cycle disorders
- Organic acidemias
- Disorders of pyruvate metabolism
 Seizures
 Biotinidase deficiency
 Pyridoxine-dependent epilepsy
 Pyridoxal phosphate-responsive epilepsy
 Glycine encephalopathy
 Mitochondrial respiratory chain defects
 Zellweger syndrome
 Sulfite oxidase/molybdenum cofactor deficiency
 Disorders of creatine biosynthesis and transport
 Neurotransmitter defects
 Congenital disorders of glycosylation
 Purine metabolism defects
 Hypotonia
 Mitochondrial respiratory chain defects
 Zellweger syndrome
 Glycine encephalopathy
416  Sulfite oxidase/molybdenum cofactor deficiency
 Apnea
 Glycine encephalopathy
 MSUD
 Urea cycle disorders
 Disorders of pyruvate metabolism
 Fatty acid oxidation defects
 Mitochondrial respiratory chain defects

Box 2
IEMs associated with neonatal hepatic manifestations

 Liver failure
 Galactosemia
 Tyrosinemia type I
 Hereditary fructose intolerance
 Mitochondrial respiratory chain defects
 Cholestatic jaundice
 Citrin deficiency
 Zellweger syndrome
 Alpha-1-antitrypsin deficiency
 Niemann-Pick disease type C
 Inborn errors of bile acid metabolism
 Congenital disorders of glycosylation
 Hepatomegaly with hypoglycemia
 Fructose-1,6-bisphosphatase deficiency
 Glycogen storage disease type 1

Box 3
IEMs associated with neonatal cardiomyopathy

 Glycogen storage diseases type II (Pompe disease)

 Fatty acid oxidation defects
 Very long chain acyl-CoA dehydrogenase (VLCAD) deficiency
 Long-chain hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency/Trifunctional protein
deficiency
 Carnitine-acylcarnitine translocase (CAT) deficiency
 Carnitine palmitoyltransferase II (CPT II) deficiency
 Systemic primary carnitine deficiency
 Mitochondrial respiratory chain defects
 Congenital disorders of glycosylations
 Tricarboxylic acid cycle defects: a-Ketoglutarate dehydrogenase deficiency
Box 4
417
IEMs associated with abnormal urine odor

 Maple syrup
 MSUD
 Sweaty feet
 Isovaleric acidemia
 Glutaric acidemia type II
 Sulfur
 Cystinuria
 Tyrosinemia type I
 Boiled cabbage
 Tyrosinemia type I
 Old fish
 Trimethylaminuria
 Dimethylglycine dehydrogenase deficiency
 Cats urine
 Multiple carboxylase deficiency
 Mousy
 Phenylketonuria

Box 5
IEMs associated with distinctive facial features

 Zellweger syndrome: large fontanelle, prominent forehead, flat nasal bridge, epicanthal
folds, hypoplastic supraorbital ridges.
 Pyruvate dehydrogenase deficiency: epicanthal folds, flat nasal bridge, small nose with
anteverted flared alae nasi, long philtrum.
 Glutaric aciduria type II: macrocephaly, high forehead, flat nasal bridge, short anteverted
nose, ear anomalies, hypospadias, rocker-bottom feet.
 Cholesterol biosynthetic defects (Smith-Lemli-Opitz syndrome): epicanthal folds, flat nasal
bridge, toe 2/3 syndactyly, genital abnormalities, cataracts.
 Congenital disorders of glycosylation: inverted nipples, lipodystrophy.

Box 6
IEMs associated with hydrops fetalis

 Lysosomal disorders
 Mucopolysaccharidosis types I, IVA, and VII
 Sphingolipidosis (Gaucher disease, Farber disease, Niemann-Pick disease A, GM1
gangliosidosis, multiple sulfatase deficiency)
 Lipid storage diseases (Wolman and Niemann-Pick disease C)
 Oligosaccharidosis (galactosialidosis), sialic acid storage disease, mucolipidoses I
(sialidosis), mucolipidoses II (I cell disease).
 Zellweger syndrome
 Glycogen storage disease type IV
 Congenital disorders of glycosylation
 Mitochondrial respiratory chain defects
418 El-Hattab

PRINCIPLES OF MANAGEMENT

Early diagnosis and the institution of appropriate therapy are mandatory in IEMs to
prevent death and ameliorate complications. Management of suspected IEMs should
be started even before birth.3,5

Before or During Pregnancy

When a previous sibling has an IEM, the following can be done:
 Prenatal counseling regarding the possibility of having an affected infant.
 Considering intrauterine diagnosis by measurement of abnormal metabolites in
the amniotic fluid or by enzyme assay or molecular genetic analysis of amnio-
cytes or chorionic villus cells.
 Planning for delivery in a facility equipped to handle potential metabolic or other
complications.

Initial Evaluation
If an IEM is suspected in a neonate, initial laboratory studies should be obtained imme-
diately (Box 7). The results of these tests can help to narrow the differential diagnosis
and determine which specialized tests are required.

Box 7
Laboratory evaluation for newborns suspected of having IEMs

 Initial laboratory studies

 Complete blood count
 Blood gas
 Blood glucose and electrolytes
 Plasma ammonia
 Plasma lactate
 Liver function tests: transaminases, total and direct bilirubin, albumin, and coagulation
profile
 Urine reducing substances, pH, and ketones
 Plasma amino acids
 Urine organic acids
 Plasma carnitine and acylcarnitine profile
 Additional laboratory studies considered in neonatal seizures
 Cerebrospinal fluid (CSF) amino acids
 CSF neurotransmitters
 Sulfocysteine in urine
 Very long chain fatty acids

Management of Acute Metabolic Decompensation

Several IEMs can present with acute metabolic decompensation during the neonatal
period, such as urea cycle defects and organic acidemias. The principles of managing
acute metabolic decompensation are as follows:
 Inborn Errors of Metabolism 419

 Decrease production of the toxic intermediates by holding enteral intake for 24 to

48 hours and suppressing catabolism. Reversal of catabolism and promotion of
anabolism can be achieved by:
 Providing adequate caloric intake, which is at least 20% greater than the ordi-
nary maintenance. Adequate calories can be achieved parenterally by intrave-
nous (IV) glucose and intralipid and enterally by giving protein-free formula or
special formula appropriate for the IEM.
 Insulin is a potent anabolic hormone and can be administered as a continuous
infusion (0.050.1 unit/kg/hour) with adjusting the IV glucose to maintain a
normal blood glucose.
 Providing adequate hydration and treating infections aggressively.
 Introducing enteral feeding as early as possible. The period of enteral feed
restriction should not exceed 24 to 48 hours; after that a special formula appro-
priate for the suspected IEM should be introduced if there are no contraindica-
tions for enteral feeding.
 Elimination of toxic metabolites. Toxic metabolites can be eliminated by:
 IV hydration, which can promote renal excretion of toxins.
 The use of specific medications that create alternative pathways. For example,
carnitine can bind organic acid metabolites and enhance their excretion in
urine in organic acidemias. Another example is sodium benzoate, which is
used in glycine encephalopathy and urea cycle defects, because it binds to
glycine forming hippurate, which is excreted in urine.
 Hemodialysis is indicated in cases of unresponsive hyperammonemia
(>500 mg/dL) in urea cycle defects and hyperleucinemia in MSUD.
 Additional treatments include metabolic acidosis correction with sodium bicar-
bonate, which can be given as a bolus followed by a continuous infusion, hypo-
glycemia correction of with IV glucose, and the administration of pharmacologic
doses of appropriate cofactors in cases of vitamin-responsive enzyme
deficiencies (eg, thiamine in MSUD).

Monitoring
Neonates with IEMs should be monitored closely for any mental status changes, fluid
imbalance, evidence of bleeding (if thrombocytopenic), and symptoms of infection (if
neutropenic). Biochemical parameters that need to be followed include electrolytes,
glucose, ammonia, blood gases, complete blood cell count, and urine ketones.

Long-term Management
Several IEMs require dietary restrictions (eg, leucine-restricted diet in isovaleric acid-
emia). If hypoglycemia occurs, then frequent feeding and the use of uncooked corn-
starch is advised. Cofactors are used in vitamin-responsive IEMs (eg, pyridoxine in
pyridoxine-dependent epilepsy). Examples of other oral medications used in chronic
management of IEMs are carnitine for organic acidemias, sodium benzoate for urea
cycle defects, and nitisinone in tyrosinemia type I.

INBORN ERRORS OF METABOLISM WITH METABOLIC ACIDOSIS

Metabolic acidosis is an important feature of many IEMs (see Box 1). The presence or
absence of ketosis in metabolic acidosis can help in guiding the diagnostic workup
(Fig. 1).
 420
El-Hattab
Fig. 1. Approach to neonatal metabolic acidosis. FAO, fatty acid oxidation; FBPase, fructose-1,6-bisphosphatase deficiency; GSD I, glycogen storage dis-
ease type 1; HMG CoA, 3-hydroxy-3-methylglutaryl coenzyme A; MSUD, maple syrup urine disease; PC, pyruvate carboxylase; PDH, pyruvate dehydro-
genase. Note that although a significant elevation in lactate is more associated with mitochondrial respiratory chain defects and pyruvate metabolism
disorders, milder lactate elevations can be seen in organic acidemias and MSUD.
 Inborn Errors of Metabolism
Fig. 2. Branched-chain amino acid metabolic pathways with related IEMs. Note that propionic acid inhibits glycine cleavage enzyme and NAGS result-
ing in elevated glycine and hyperammonemia, respectively in propionic and methylmalonic acidemias.

421
422 El-Hattab

Organic Acidemias
Organic acidemias are characterized by the excretion of organic acids in urine. Isova-
leric acidemia (IVA), propionic acidemia (PPA), and methylmalonic acidemia (MMA)
result from enzymatic defects in the branched-chain amino acids metabolism
(Fig. 2). The organic acid intermediate metabolites are toxic to brain, liver, kidney,
pancreas, retina, and other organs.

Manifestations
Infants with organic acidemias usually present in the neonatal period with poor
feeding, vomiting, decreased activity, truncal hypotonia with limb hypertonia, seizures,
hypothermia, unusual odor (see Box 4), lethargy progressing to coma, and multiorgan
failure.

Diagnosis
In addition to metabolic acidosis and ketosis, initial laboratory evaluation can reveal
hypoglycemia and elevated transaminases. Hyperammonemia and hyperglycinemia
can result from the inhibition of N-acetylglutamate synthase and glycine cleavage
enzyme, respectively by propionic acid (see Fig. 2). Organic acids also can suppress
bone marrow, resulting in neutropenia or pancytopenia. The specific diagnosis can be
reached by performing urine organic acid analysis, serum acylcarnitine profile,
enzyme assay, and molecular genetic testing (Table 1).

Table 1
Enzyme deficiency, genes, and biochemical abnormalities in organic acidemias

Organic Urine Organic Plasma

acidemias Enzymes Genes Acid Analysis Acylcarnitine Profile
Propionic Propionyl-CoA PCCA Elevated Elevated
academia carboxylase and hydroxypropionic propionylcarnitine
(PPA) PCCB acid, methylcitric (C3)
acid, and
propionyl
glycine
Methylmalonic Methylmalonyl- MUT Elevated Elevated
acidemia CoA mutase methylmalonic, propionylcarnitine
(MMA) hydroxypropionic, (C3)
and methylcitric
acids
Isovaleric Isovaleryl-CoA IVD Elevated Elevated
academia dehydrogenase hydroxyisovaleric isovalerylcarnitine
(IVA) acid and (C5)
isovalerylglycine

Management
Management of acute decompensation includes holding protein intake, suppressing
catabolism with glucose and insulin infusions, correcting acidosis with sodium bicar-
bonate infusion, and administering carnitine (100300 mg/kg/d) to enhance the
excretion of organic acids in urine. Hemodialysis may be considered if these mea-
sures fail. Chronic treatment includes oral carnitine and dietary restrictions. A diet
low in amino acids producing propionic acid (isoleucine, valine, methionine, and thre-
onine) is used for PPA and MMA, and a leucine-restricted diet is used for IVA. Biotin
is a cofactor for propionyl-CoA carboxylase and can rarely be beneficial in PPA.
 Inborn Errors of Metabolism 423

Vitamin B12 (adenosylcobalamin) is a cofactor for methylmalonyl-CoA mutase, and

hydroxycobalamin injection (1 mg daily) can be given as a trial in MMA. Glycine
(150250 mg/kg/d) enhances the excretion of isovaleric acid in urine and should
be used in IVA.6,7

Maple Syrup Urine Disease

MSUD is caused by decreased activity of the branched-chain a-ketoacid dehydroge-
nase (BCKAD), which catalyzes the second step in the metabolic pathway of the
branched-chain amino acids (BCAAs) (leucine, isoleucine, and valine) (see Fig. 2).
Decreased activity of BCKAD results in the accumulation of BCAAs and correspond-
ing ketoacids in tissues and plasma. The pathophysiology in MSUD can be explained
by the neurotoxicity of leucine, which interferes with the transport of other large
neutral amino acids across the blood-brain barrier leading to cerebral amino acid
deficiency that has adverse consequences for brain growth and neurotransmitter
synthesis.

Manifestations
Neonates with classic MSUD typically present in the first week of life with poor feeding,
irritability, ketosis, maple syrup odor of urine and cerumen (see Box 4), lethargy, opis-
thotonus, stereotyped movements (fencing and bicycling), coma, and apnea.

Diagnosis
MSUD can be diagnosed biochemically by the identification of elevated plasma alloi-
soleucine and the BCAAs with perturbation of the normal 1:2:3 ratio of isoleucine:leu-
cine:valine. Ketoacids and hydroxyacids can be detected in urine organic acid
analysis or the dinitrophenylhydrazine (DNPH) test. Enzyme activity and molecular
testing for the genes coding BCKAD subunits (BCKDHA, BCKDHB, and DBT) are
available.

Management
Management of acute presentation includes holding protein intake and suppressing
catabolism with glucose and insulin infusions. Isoleucine and valine supplementations
(20120 mg/kg/d) and adequate caloric intake also are needed. Hemodialysis can be
considered for rapid correction of hyperleucinemia. Thiamine, a cofactor for BCKAD,
can be tried for 4 weeks at a dosage of 10 mg/kg/d. Long-term management requires
a BCAA-restricted diet.8

Disorders of Pyruvate Metabolism

Defects in pyruvate metabolism cause the accumulation of pyruvate in plasma, which
is subsequently converted into lactate causing an elevated plasma lactate and meta-
bolic acidosis. Disorders of pyruvate metabolism include pyruvate dehydrogenase
(PDH) and pyruvate carboxylase (PC) deficiencies (Fig. 3).

Pyruvate dehydrogenase deficiency

PDH catalyzes the conversion of pyruvate to acetyl-CoA and is composed of E1a,
E1b, E2, E3, and E3BP subunits (see Fig. 3). PDH deficiency occurs mostly due to de-
fects in E1a, which is encoded by the PDHA1 gene located on chromosome X. There-
fore, PDH deficiency is usually X-linked with the most severe illness occurs in male
infants.

Manifestations Neonates with PDH deficiency typically present with severe lactic
acidosis, hypotonia, seizures, apnea, distinctive facial features (see Box 5), lethargy,
 424
El-Hattab
Fig. 3. Metabolic pathways for urea cycle and pyruvate with the related IEMs. HHH, hyperornithinemia-hyperammonemia-homocitrullinemia.
 Inborn Errors of Metabolism 425

coma, and brain changes, including cerebral atrophy, hydrocephaly, corpus callosum
agenesis, cystic lesions, gliosis, and hypomyelination.

Diagnosis Diagnosis is confirmed by enzyme studies and molecular genetic testing.

Management The prognosis is very poor, and treatment is not effective. Acidosis
correction with bicarbonate and hydration with glucose infusion are needed during
the acute presentation. However, excess administration of glucose may worsen the
acidosis, and a ketogenic diet may reduce the lactic acidosis. Thiamin, a cofactor
for PDH, can be used (10 mg/kg/d).9

Pyruvate carboxylase deficiency

PC catalyzes the conversion of pyruvate to oxaloacetate (see Fig. 3).
Manifestations Neonates with severe form of PC deficiency present with severe lactic
acidosis, seizures, hypotonia, lethargy, and coma.
Diagnosis Biochemical profile of PC deficiency includes lactate acidosis, ketosis,
hyperammonemia, hypercitrullinemia, and low aspartate. Oxaloacetate is the pre-
cursor of aspartate. Therefore, impaired oxaloacetate synthesis in PC deficiency re-
sults in low aspartate leading to urea cycle inhibition (see Fig. 3). Enzyme studies
and molecular gene sequencing for PC gene are necessary for a definitive
diagnosis.

Management The prognosis is poor, and treatment is not effective. Correction of

acidosis with bicarbonate and hydration with glucose infusion are needed during
the acute presentation. Biotin is a cofactor for PC and can be given (5-20 mg/d).9,10

INBORN ERRORS OF METABOLISM WITH HYPOGLYCEMIA

Hypoglycemia is a frequent finding in neonates. The suspicion of an IEM should be

raised if the hypoglycemia is severe and persistent without any other obvious etiology
(see Box 1). The presence or absence of ketosis can help in guiding the diagnostic
workup (Fig. 4).

Fig. 4. Approach to neonatal hypoglycemia. FAO, fatty acid oxidation; FBPase: fructose-1,6-
bisphosphatase; GSD I: glycogen storage disease type 1; HMG CoA, 3-hydroxy-3-methylglu-
taryl coenzyme A.
426 El-Hattab

Fatty Acid Oxidation Defects

Fatty acids are transported into the mitochondria where they are catabolized through
b-oxidation to yield acetyl-CoA units. Disorders of fatty acid oxidation result from
defects in the mitochondrial transfer or b-oxidation. When fat cannot be used, glucose
is consumed, resulting in a hypoketotic hypoglycemia. In addition, the released fat
from adipose tissue accumulates in the liver, skeletal muscle, and heart, resulting in
hepatopathy and skeletal and cardiac myopathy. Diagnosis is based on abnormalities
in acylcarnitine profile, enzyme assay, and molecular testing (Table 2).

Very long chain acyl-CoA dehydrogenase deficiency

Very long chain acyl-CoA dehydrogenase (VLCAD) catalyzes the initial step of b-oxida-
tion of long-chain fatty acids with a chain length of 14 to 20 carbons.

Manifestations Infants with the severe form of VLCAD deficiency typically present in
the first months of life with cardiomyopathy, arrhythmias, hypotonia, hepatomegaly,
and hypoglycemia.

Management Hypoglycemia should be treated with glucose infusion and avoided by

frequent feeding. Diet restrictions with a low-fat formula and supplemental medium-
chain triglycerides should be initiated early. Cardiac dysfunction is reversible with early
intensive supportive care and diet modification.11

Table 2
Acylcarnitine profiles and genes in fatty acid oxidation defects

Fatty Acid Oxidation Defect Genes Acylcarnitine Profile

Very long chain acyl-CoA ACADVL Elevated C16 (hexadecanoylcarnitine),
dehydrogenase (VLCAD) C14 (tetradecanoylcarnitine), C14:1
deficiency (tetradecenoylcarnitine), and C12
(dodecanoylcarnitine).
Medium-chain acyl-CoA ACADM Elevated C6 (hexanoylcarnitine),
dehydrogenase (MCAD) C8 (octanoylcarnitine), C10
deficiency (decanoylcarnitine), and C10:1
(decenoylcarnitine).
Short chain acyl-CoA ACADS Elevated C4 (butyrylcarnitine).
dehydrogenase (SCAD)
deficiency
Long-chain hydroxyacyl-CoA HADHA Elevated C14OH
dehydrogenase (LCHAD) (hydroxytetradecenoylcarnitine), C16OH
deficiency (hydroxyhexadecanoylcarnitine), C18OH
(hydroxystearoylcarnitine), and C18:1OH
(hydroxyoleylcarnitine).
Carnitine palmitoyltransferase I CPT1A Elevated total carnitine; and decreased C16
(CPTI) deficiency (hexadecanoylcarnitine), C18
(octadecanoylcarnitine), and C18:1
(octadecenoylcarnitine).
Carnitine palmitoyltransferase II CPT2 Decreased total carnitine; and elevated C16
(CPTII) deficiency (hexadecanoylcarnitine) and C18:1
(octadecenoylcarnitine).
Systemic primary carnitine SLC22A5 Decreased total carnitine
deficiency
 Inborn Errors of Metabolism 427

Medium-chain acyl-CoA dehydrogenase deficiency

Medium-chain acyl-CoA dehydrogenase (MCAD) is responsible for the initial dehydro-
genation of fatty acids with a chain length between 4 and 12 carbons.

Manifestations Infants with MCAD deficiency usually present between ages 3 and
24 months with hypoketotic hypoglycemia, vomiting, hepatomegaly elevated trans-
aminases, lethargy, and seizures. Sudden and unexplained death can be the first
manifestation of MCAD deficiency.
Management Hypoglycemia should be treated with glucose infusion and avoided by
frequent feeding. Uncooked cornstarch also can be used to prevent the
hypoglycemia.12

Fructose-1,6-Bisphosphatase Deficiency
Deficiency of fructose-1,6-bisphosphatase (FBPase), a key enzyme in gluconeogen-
esis, impairs the formation of glucose from all gluconeogenic precursors, including di-
etary fructose.
Manifestations
Infants with FBPase deficiency can present during the first week of life with lactic
acidosis, hypoglycemia, ketosis, hepatomegaly, seizures, irritability, lethargy, hypoto-
nia, apnea, and coma.
Diagnosis
Diagnosis is confirmed by enzyme assay and FBP1 gene sequencing.
Management
The acute presentation can be treated with glucose infusion and bicarbonate to con-
trol hypoglycemia and acidosis. Maintenance therapy aims at avoiding fasting by
frequent feeding and uncooked starch use. Restriction of fructose and sucrose is
also recommended.13

Glycogen Storage Disease Type 1

Glycogen storage disease type 1 (GSD I) is caused by the deficiency of glucose-6-
phosphatase (G6Pase) activity. The lack of liver G6Pase activity leads to inadequate
conversion of glucose-6-phosphate into glucose through normal glycogenolysis and
gluconeogenesis pathways, resulting in severe hypoglycemia and the accumulation
of glycogen and fat in the liver and kidneys.
Manifestations
Some neonates with GSD I present with severe hypoglycemia; however, the common
age of presentation is 3 to 4 months with hypoglycemia, lactic acidosis, hepatomeg-
aly, hyperuricemia, hyperlipidemia, growth failure, and hypoglycemic seizures. Hypo-
glycemia and lactic acidosis can develop after a short fast (24 hours).
Diagnosis
Diagnosis can be confirmed by enzyme assay and sequencing of the G6PC gene.
Management
The acute presentation should be treated with glucose infusion and bicarbonate to
control the hypoglycemia and the acidosis. Maintenance therapy aims to maintain
normal glucose levels by frequent feeding, the use of uncooked starch, and intragas-
tric continuous feeding if needed. The diet should be low in fat, sucrose, and fructose
and high in complex carbohydrate.14
428 El-Hattab

INBORN ERRORS OF METABOLISM WITH HYPERAMMONEMIA

It is essential to measure ammonia in every sick neonate whenever septic workup is

considered. Hyperammonemia can be caused by IEMs or acquired disorders
(Box 8). The presence of respiratory alkalosis or metabolic acidosis can help in guiding

Box 8
Differential diagnosis of hyperammonemia

 IEM
 Urea cycle enzyme defects
- N-Acetylglutamate synthase (NAGS) deficiency
- Carbamoylphosphate synthase 1 (CPS 1) deficiency
- Ornithine transcarbamoylase (OTC) deficiency
- Argininosuccinate synthase (ASS) deficiency (citrullinemia)
- Argininosuccinate lyase (ASL) deficiency (argininosuccinic aciduria)
- Arginase deficiency
 Transport defects of urea cycle intermediates
- Mitochondrial ornithine transporter (HHH syndrome)
- Aspartate-glutamate shuttle (citrin) deficiency
- Lysinuric protein intolerance
 Organic acidemias
- Propionic acidemia
- Methylmalonic acidemia
 Fatty acid oxidation disorders
- Medium-chain acyl-CoA dehydrogenase deficiency
- Systemic primary carnitine deficiency
- Long-chain fatty acid oxidation defects
 Pyruvate carboxylase deficiency
 Tyrosinemia type 1
 Galactosemia
 Ornithine aminotransferase deficiency
 Hyperinsulinism-hyperammonemia syndrome
 Mitochondrial respirator chain defects
 Acquired disorders
 Transient hyperammonemia of the newborn
 Diseases of the liver and biliary tract
- Herpes simplex virus infection
- Biliary atresia
- Liver failure
 Severe systemic neonatal illness
 Inborn Errors of Metabolism 429

- Neonates sepsis
- Infection with urease-positive bacteria (with urinary tract stasis)
- Reye syndrome
 Medications
- Valproic acid
- Cyclophosphamide
- 5-pentanoic acid
- Asparaginase
 Anatomic variants
 Vascular bypass of the liver (porto-systemic shunt)
 Technical
 Inappropriate sample (eg, capillary blood)
 Sample not immediately analyzed

the evaluation (Fig. 5). Ammonia can cause brain damage through several mechanisms.
The major one is causing cerebral edema by affecting the aquaporin system and water
and potassium homeostasis in brain. Hyperammonemia also can disrupt ion gradients,
neurotransmitters, transport of metabolites, and mitochondrial function in brain.

Urea Cycle Disorders

Urea cycle is the principal mechanism for the clearance of waste nitrogen resulting
from breakdown of protein and other nitrogen-containing molecules through the con-
version of ammonia to urea. Urea cycle disorders (UCDs) result from defects in urea
cycle enzymes leading to the accumulation of ammonia and other precursor metabo-
lites (see Fig. 3). UCDs are among the most common IEMs. They are inherited as auto-
somal recessive conditions, with the exception of OTC deficiency, which is an X-linked
disorder.

Manifestations
Infants with severe forms of UCDs typically present during the first few days of life with
poor feeding, vomiting, hyperventilation, hypothermia, seizures, apnea, hypotonia,
lethargy, and coma.

Diagnosis
In neonatal-onset UCDs, ammonia levels are usually higher than 300 mmol/L and are
often in the range of 5001500 mmol/L. Other laboratory abnormalities include respi-
ratory alkalosis secondary to hyperventilation, low urea, mild elevation of transami-
nases, and coagulopathy. Plasma amino acid profile and urinary orotic acid can
help in reaching the diagnosis (see Fig. 5). The diagnosis is confirmed by enzyme
assay and molecular genetic testing (Table 3).

Acute management
Treatment of acute presentation includes the following:
1. Decreasing the production of ammonia from protein intake and breakdown. Sup-
pression of catabolism can be achieved through the use of glucose infusion, in-
sulin infusion, and intralipid administration. Protein intake can be completely
 430
El-Hattab
Fig. 5. Approach to neonatal hyperammonemia. ASA, argininosuccinic acid; ASL, argininosuccinic acid lyase; ASS, argininosuccinic acid synthetase; CPS,
carbamylphosphate synthase; HHH, hyperornithinemia-hyperammonemia-homocitrullinuria; NAGS, N-acetyl glutamate synthase; OTC, ornithine trans-
carbamylase; PC, pyruvate carboxylase.
 Inborn Errors of Metabolism 431

Table 3
Enzymatic and molecular genetic diagnosis of urea cycle defects

Tissue for Enzyme

Urea Cycle Disorder Gene Assay
N-acetylglutamate synthase (NAGS) deficiency NAGS Liver biopsy
Carbamoylphosphate synthetase I (CPS 1) deficiency CPS1 Liver biopsy
Ornithine transcarbamylase (OTC) deficiency OTC Liver biopsy
Argininosuccinate synthase (ASS) deficiency (citrullinemia) ASS1 Fibroblasts
Argininosuccinate lyase (ASL) deficiency ASL Fibroblasts
(argininosuccinicaciduria)
Arginase deficiency ARG1 Red blood cells

restricted for 24 to 48 hours, followed by introducing an essential amino acid for-

mula to maintain the appropriate levels of essential amino acids, which is
necessary to reverse the catabolic state.
2. Removing ammonia. Ammonia elimination can be enhanced by the use of the
intravenous ammonia-scavenging drug (Ammonul), which contains both sodium
benzoate and sodium phenylacetate and is given as a loading dose of 250 mg/kg
over 60-120 minutes followed by the same dose over 24 hours as a maintenance
infusion. L-arginine hydrochloride is used with Ammonul as loading and mainte-
nance as well. The L-arginine doses are 200 mg/kg for loading and similar dose
for maintenance in carbamoylphosphate synthase (CPS) deficiency and OTC
deficiency; and 600 mg/kg in argininosuccinate synthase (ASS) deficiency and
argininosuccinate lyase (ASL) deficiency. L-arginine hydrochloride is not used
in arginase deficiency. Hemodialysis is the only method for rapid removal of
ammonia from blood and should be considered if ammonia is very high
(>500 mmol/L). However, while preparing for dialysis, the glucose, insulin, and
ammonia scavenger therapy should be maintained.
3. Reduce the risk for neurologic damage by avoiding fluid overload and treating
seizures that can be subclinical.
Long-term management
Maintenance therapy includes the following:
1. Protein-restricted diet. In general, infants require 1.2 to 2.0 g protein/kg with half
of the required protein provided from essential amino acids formula and half from
regular infant formula.
2. Oral ammonia scavenger medications include sodium benzoate (250400 mg/
kg/d) and sodium phenylbutyrate (250500 mg/kg/d).
3. Replacement of arginine (200-600 mg/kg/d for ASS and ASL deficiencies) and
citrulline (100200 mg/kg/d for OTC and CPS deficiencies).
4. Carbamyl glutamate (Carbaglu) is a synthetic analogue for N-acetylglutamate,
which is the natural activator of CPS1. Therefore, Carbaglu is very effective in
N-acetyl glutamate synthase (NAGS) deficiency and can be tried in individuals
with CPS1 deficiency.
5. In children with severe types of UCDs, liver transplantation can be considered.15,16

INBORN ERRORS OF METABOLISM WITH NEONATAL SEIZURE

The possibility of IEMs should always be considered in neonates with unexplained and
refractory seizures (see Box 1).17
432 El-Hattab

Biotinidase Deficiency
Biotinidase is essential for the recycling of the vitamin biotin, which is a cofactor for
several essential carboxylase enzymes.
Manifestations
Untreated children with profound biotinidase deficiency usually present between ages
1 week and 10 years with seizures, hypotonia, metabolic acidosis, elevated lactate,
hyperammonemia, and cutaneous symptoms, including skin rash, alopecia, and
recurrent viral or fungal infections.
Diagnosis
The diagnosis is established by assessing the biotinidase enzyme activity in blood.
Sequencing of BTD, the gene coding biotinidase enzyme, can also be performed.
Management
Acute metabolic decompensation can be treated by glucose and sodium bicarbonate in-
fusions. Symptoms typically improve with biotin (510 mg oral daily) treatment. Children
with biotinidase deficiency who are diagnosed before developing symptoms (eg, by
newborn screening) and who are treated with biotin do not develop any manifestations.18
Pyridoxine-Dependent Epilepsy
Pyridoxine-dependent epilepsy occurs due to the deficiency of antiquitin enzyme in
the lysine metabolism pathway. Antiquitin functions as a piperideine-6-carboxylate
(P6C)/a-aminoadipic semialdehyde (AASA) dehydrogenase, therefore its deficiency
results in the accumulation of AASA and P6C. The latter binds and inactivates pyri-
doxal phosphate, which is a cofactor in neurotransmitters metabolism.
Manifestations
Newborns with pyridoxine-dependent epilepsy present soon after birth with irritability,
lethargy, hypotonia, poor feeding, and seizures that are typically prolonged with recur-
rent episodes of status epilepticus.
Diagnosis
The diagnosis is established clinically by showing a response to pyridoxine. Adminis-
tering 100 mg of pyridoxine IV while monitoring the electroencephalogram (EEG) can
result in cessation of the clinical seizures with corresponding EEG changes generally
over a period of several minutes. If a clinical response is not demonstrated, the dose
can be repeated up to 500 mg. Oral pyridoxine (30 mg/kg/d) can result in cessation of
the seizures within 3 to 5 days. The diagnosis can be confirmed biochemically by
demonstrating high levels of pipecolic acid, ASAA, and P6C, and molecularly by
detecting mutations in ALDH7A1, the gene coding antiquitin.
Management
In general, seizures are controlled with 50 to 100 mg of pyridoxine daily.19
Pyridoxal Phosphate-Responsive Epilepsy
Pyridoxal phosphate-responsive epilepsy results from deficiency of pyridox(am)ine
phosphate oxidase (PNPO), an enzyme that interconverts the phosphorylated forms
of pyridoxine and pyridoxamine to the biologically active pyridoxal phosphate.
Manifestations
Infants with pyridoxal phosphateresponsive epilepsy typically present during the first
day of life with lethargy, hypotonia, and refractory seizures that are not responsive to
pyridoxine.
 Inborn Errors of Metabolism 433

Diagnosis
Diagnosis is established by the demonstration of cessation of seizure with pyridoxal
phosphate administration (50 mg orally) with corresponding EEG changes usually
within an hour. Glycine and threonine are elevated in plasma and cerebrospinal fluid
(CSF), whereas monoamine metabolites and pyridoxal phosphate are low in CSF.
Mutational analysis for PNPO gene is available.

Management
Seizures can usually be controlled with pyridoxal phosphate 30-50 mg/kg/d divided in
four doses.20

Glycine Encephalopathy (Nonketotic Hyperglycinemia)

Glycine encephalopathy occurs due to the deficiency of glycine cleavage enzyme
resulting in glycine accumulation in all tissues including the brain. Glycine increases
neuronal excitability by activating the N-methyl D-aspartate (NMDA) receptors.

Manifestations
Neonates with glycine encephalopathy typically present in the first hours to days of life
with progressive lethargy, poor feeding, hypotonia, seizures, myoclonic jerks, and
apnea.

Diagnosis
Biochemical diagnosis is based on the demonstration of elevated plasma glycine
level and the CSF-toplasma glycine ratio (samples of plasma and CSF should be
obtained at approximately the same time for accurate calculation of the ratio). Molec-
ular genetic testing is available for GLDC, AMT, and GCSH, the 3 genes coding the
glycine cleavage enzyme subunits. Enzymatic activity in liver tissue also can be
measured.

Management
No effective treatment is available. Sodium benzoate (250750 mg/kg/d) can be used
to reduce glycine levels. The NMDA receptor antagonists dextromethorphan, keta-
mine, and felbamate can result in improvement in seizure control. However, these
treatments have been of limited benefit to the ultimate neurodevelopmental
outcome.21

INBORN ERRORS OF METABOLISM WITH HYPOTONIA

Hypotonia is a common symptom in sick neonates. Some IEMs can present predom-
inantly as hypotonia in the neonatal period (see Box 1).

Mitochondrial Disorders
Mitochondria are found in all nucleated human cells and generate most of the cellular
energy in the form of ATP through the respiratory chain complexes. Mitochondria
contain extrachromosomal DNA (mitochondrial DNA [mtDNA]). However, most mito-
chondrial proteins are encoded by the nuclear DNA (nDNA). Mutations in mtDNA or
mitochondria-related nDNA genes can result in mitochondrial diseases that arise as
a result of inadequate energy production required to meet the energy needs of various
organs, particularly those with high energy demand, including the central nervous sys-
tem, skeletal and cardiac muscles, kidneys, liver, and endocrine systems. Defects in
nDNA genes are inherited in autosomal recessive, autosomal dominant, or X-linked
manners, whereas mtDNA is maternally inherited.
434 El-Hattab

Manifestations
Manifestations of mitochondrial diseases can start at any age. Neonates with mito-
chondrial diseases can present with apnea, lethargy, coma, seizures, hypotonia, spas-
ticity, muscle weakness and atrophy, cardiomyopathy, renal tubulopathy,
hepatomegaly, liver dysfunction or failure, lactic acidosis, hypoglycemia, anemia, neu-
tropenia, and pancytopenia. Some infants with mitochondrial diseases display a clus-
ter of clinical features that fall into a discrete clinical syndrome (Box 9). However, there
is often considerable clinical variability, and many affected individuals do not fit into
one particular syndrome.

Diagnosis
Biochemical abnormalities in mitochondrial diseases include lactic acidosis, ketosis,
and elevated tricarboxylic acid cycle intermediates in urine organic acid analysis.
The histology of affected muscles typically shows ragged red fibers that represent pe-
ripheral and intermyofibrillar accumulation of abnormal mitochondria. The enzymatic
activity of respiratory chain complexes can be assessed on skeletal muscle, skin fibro-
blast, or liver tissue. Molecular testing for mtDNA content and sequencing for mtDNA
and known mitochondrial-related nDNA genes also can be performed.

Management
Currently, there are no satisfactory therapies available for the vast majority of mito-
chondrial disorders. Treatment remains largely symptomatic and does not signifi-
cantly alter the course of the disease.22,23

Box 9
Mitochondrial syndromes associated with neonatal presentation

 Pearson syndrome:
 Sideroblastic anemia
 Neutropenia
 Thrombocytopenia
 Exocrine pancreatic dysfunction
 Renal tubular defects
 Barth syndrome:
 Concentric hypertrophic cardiomyopathy
 Skeletal myopathy
 Neutropenia
 Affects male individuals (X-linked)
 Hepatocerebral mitochondrial DNA depletion syndromes
 Hepatic dysfunction or failure
 Hypotonia
 Seizures
 Lactic acidosis
 Hypoglycemia
 Inborn Errors of Metabolism 435

Zellweger Syndrome
Zellweger syndrome is a disorder of peroxisomal biogenesis. Peroxisomes are cell or-
ganelles that possess anabolic and catabolic functions, including synthesizing plas-
malogens, which are important constituents of cell membranes and myelin,
b-oxidation of very long chain fatty acids (VLCFA), oxidation of phytanic acid, and for-
mation of bile acids.

Manifestations
Neonates with Zellweger syndrome typically present with distinctive facial features
(see Box 5), poor feeding, severe weakness and hypotonia, widely split sutures, sei-
zures, hepatomegaly, jaundice, elevated transaminases, short proximal limbs, and
stippled epiphyses.

Diagnosis
Biochemical abnormalities include elevated phytanic acid and VLCFA and low plas-
malogens. Many proteins are involved in peroxisomal biogenesis. Therefore, comple-
mentation analyses allow the determination of which protein is defective and
molecular genetic analysis for the responsible gene can be performed for molecular
confirmation.

Management
There is no effective treatment and management is largely symptomatic.24

INBORN ERRORS OF METABOLISM WITH HEPATIC MANIFESTATIONS

Several IEMs can have hepatic manifestations in the neonatal period (see Box 2).
Galactosemia is the most common metabolic cause of liver disease in neonates.

Galactosemia
Galactosemia occurs due to deficiency of the galactose-1-phosphate uridyltransfer-
ase (GALT) that catalyzes the conversion of galactose-1-phosphate and uridine
diphosphate (UDP)-glucose to UDP-galactose and glucose-1-phosphate. When
GALT enzyme activity is deficient, galactose-1-phosphate and galactose accumulate.
Galactose is converted to galactitol in cells and produces osmotic effects resulting in
cell dysfunction.

Manifestations
Symptoms of classic galactosemia occur in neonates within days of ingestion of
lactose (glucose-galactose disaccharide) through breast milk or standard lactose-
containing formulas. These manifestations include poor feeding, vomiting, diarrhea,
failure to thrive, hypoglycemia, jaundice, hepatomegaly, elevated transaminases, coa-
gulopathy, ascites, liver failure, renal tubulopathy, lethargy, irritability, seizures, cata-
racts, and Escherichia coli neonatal sepsis.

Diagnosis
The biochemical profile of galactosemia includes elevated galactose in plasma,
galactose-1-phosphate in erythrocytes, and galactitol in urine. Diagnosis is confirmed
by measuring GALT enzyme activity in erythrocytes and sequencing the GALT gene.

Management
Lactose-free formula should be started during the first 3 to 10 days of life for the signs
to resolve and the prognosis to be good.25,26
436 El-Hattab

Tyrosinemia Type I
Tyrosinemia type I occurs due to deficiency of fumarylacetoacetate hydrolase (FAH),
which functions in the catalytic pathway of tyrosine. FAH deficiency results in the
accumulation of fumarylacetoacetate and its derivative succinylacetone, both of
which form glutathione adducts thereby rendering cells susceptible to free radical
damage. In addition, fumarylacetoacetate is an alkylating agent that has a widespread
effect on cellular metabolism resulting in cell death.

Manifestations
Children with tyrosinemia type I can present during early infancy with vomiting, diar-
rhea, hepatomegaly, hypoglycemia, sepsis, liver failure with coagulopathy, ascites,
jaundice, renal tubulopathy, and abnormal odor (see Box 4).

Diagnosis
Biochemical abnormalities include elevated urine succinylacetone and tyrosine me-
tabolites (p-hydroxyphenylpyruvate, p-hydroxyphenyllactate, and p-hydroxyphenyla-
cetate) and elevated tyrosine and methionine in plasma. Serum a-fetoprotein is
markedly elevated. Diagnosis can be confirmed by enzyme assay and molecular ge-
netic testing for the FAH gene.

Management
Nitisinone (NTBC) (12 mg/kg/d divided in 2 doses) blocks hydroxyphenylpyruvate
dioxygenase, the second step in the tyrosine degradation pathway, and prevents
the accumulation of fumarylacetoacetate and its derivative succinylacetone. Low tyro-
sine diet is also needed.27

Hereditary Fructose Intolerance

Hereditary fructose intolerance occurs due deficiency of fructose 1,6-biphosphate
aldolase (aldolase B), which is part of the catabolic pathway of fructose. Fructose
intake results in accumulation of fructose-1-phosphate and trapping of phosphate,
leading to diminished ATP regeneration.

Manifestations
Clinical manifestations develop after the exposure to fructose from sucrose (glucose
fructose disaccharide) in soy-based formulas or later at weaning from fruits and veg-
etables. These manifestations include vomiting, hypoglycemia, jaundice, lethargy, ir-
ritability, seizures, coma, hepatomegaly, jaundice, elevated transaminases,
coagulopathy, edema, ascites, liver failure, and renal tubulopathy.

Diagnosis
The diagnosis can be established enzymatically by measuring the aldolase B activity in
liver tissue and molecularly by sequencing the ALDOB gene.

Management
Management is based on eliminating sucrose, fructose, and sorbitol from diet.28

Neonatal Intrahepatic Cholestasis Caused by Citrin Deficiency

Citrin is a mitochondrial aspartate-glutamate carrier that transports aspartate from
mitochondria to cytosol (see Fig. 3). One of the clinical manifestations of citrin defi-
ciency is neonatal intrahepatic cholestasis.
 Inborn Errors of Metabolism 437

Manifestations
Newborn infants with citrin deficiency can present with transient intrahepatic chole-
stasis, prolonged jaundice, hepatomegaly, fatty liver, elevated transaminases, hypo-
proteinemia, coagulopathy, growth failure, hemolytic anemia, and hypoglycemia.
Neonatal intrahepatic cholestasis caused by citrin deficiency is generally not severe,
and symptoms disappear by the age of 1 year with appropriate treatment.

Diagnosis
Biochemical abnormalities include elevated plasma citrulline, arginine, threonine, methi-
onine, and tyrosine. Sequencing the SLC25A13 gene that codes citrin is available.

Management
Management includes the supplementation of fat-soluble vitamins and the use of
lactose-free formula and high medium-chain triglycerides. Subsequently, a diet rich
in lipids and protein and low in carbohydrates is recommended.29

INBORN ERRORS OF METABOLISM WITH CARDIOMYOPATHY

Some metabolic disorders can present predominantly with cardiomyopathy (see

Box 3).

Glycogen Storage Disease Type II (Pompe Disease)

Glycogen storage disease type II (GSD II) is caused by the deficiency of the lysosomal
enzyme acid a-glucosidase (GAA, acid maltase). The enzyme defect results in the
accumulation of glycogen within the lysosomes in different organs.

Manifestations
Infants with the classic infantile-onset GSD II typically present in the first 2 months of life
with hypotonia, muscle weakness, hepatomegaly, hypertrophic cardiomyopathy,
feeding difficulties, failure to thrive, macroglossia, respiratory distress, and hearing loss.

Diagnosis
Nonspecific tests supporting the diagnosis include elevated serum creatinine kinase
level and urinary oligosaccharides. The diagnosis is confirmed enzymatically by
assessing GAA enzyme activity and molecularly by sequencing the GAA gene.

Management
Enzyme replacement therapy using alglucosidase alfa (Myozyme) should be initiated
as soon as the diagnosis is established. The response to enzyme replacement therapy
is better for those in whom the therapy is initiated before age 6 months and before the
need for ventilatory assistance.30

Best Practices

 IEMs are not uncommon, neonates with IEMs usually present with nonspecific signs, and
early diagnosis and institution of therapy are mandatory to prevent death and ameliorate
complications from many IEMs. Therefore, a high index of suspicion for IEMs should be
maintained. Consider metabolic evaluation in sick neonates and those with hypotonia,
seizures, cardiomyopathy, and hepatopathy.
 After performing the initial metabolic workup, you can narrow the differential diagnosis by
the following categorizations:
 In metabolic acidosis with hyperammonemia, consider organic acidemia (or PC deficiency
if lactate is also very high).
438 El-Hattab

 In hypoglycemia without ketosis, consider fatty acid oxidation defects or HMG CoA lyase
deficiency.
 In hypoglycemia with ketosis and elevated lactate, consider fructose-1,6-bisphosphatase
deficiency and glycogen storage disease type 1.
 In hyperammonemia with respiratory alkalosis, consider urea cycle defects.
 In liver failure, galactosemia and tyrosinemia type I should be evaluated.
 In cardiomyopathy, consider glycogen storage disease type II and fatty acid oxidation
defects.
 When managing acute metabolic decompensation, make sure about the following:
 Provide adequate calories, at least 20% above what is normally needed.
 Use insulin infusion to reverse catabolism.
 Limit the enteral feeding restriction to 24 to 48 hours and introduce enteral feeding with
the appropriate formula early (after 2448 hours).

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