Pediatric emergency medicine trisk 606

TABLE 95.2
CLINICAL AND LABORATORY FINDINGS OF INBORN ERRORS OF METABOLISM

Most IEMs are autosomal recessive in their inheritance, but they may be X-linked, mitochondrial, or,
uncommonly, autosomal dominant. A family history of either known metabolic disease or unusual
medical presentations (e.g., death due to neurologic, cardiac, and/or hepatic dysfunction; sepsis; or
unexplained neonatal or sudden infant deaths in siblings or maternal male relatives) should increase
suspicion for an underlying metabolic disease. Maternal illness during pregnancy, particularly acute fatty
liver of pregnancy or HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome, may be due to
maternal heterozygosity for a fatty acid oxidation defect, specifically 3-hydroxyacyl-CoA dehydrogenase
deficiency. A negative family history and negative NBS do not rule out an IEM. It is important to note
that NBS varies from state-to-state and not all IEMs are part of the screen. For example, several urea
cycle disorders (ornithine transcarbamylase deficiency and carbamoyl phosphate synthetase deficiency)
are not detectable by NBS. It is also worth keeping in mind that the results of the NBS are often not
available in the first several days of life.
Neonate (<30 days of life). Most of the IEMs that are acutely life threatening during the neonatal
period usually present as acute encephalopathy and/or hepatic disease. Among the most common lifethreatening IEMs to present in the neonate are amino acid disorders, organic acidemias, urea cycle
defects, galactosemia, and hereditary fructose intolerance. Manifestations may include poor feeding,
vomiting, diarrhea, dehydration, temperature instability, tachypnea or apnea, cyanosis, respiratory failure,
bradycardia, poor perfusion, hiccups, jaundice, hepatomegaly, pseudoobstruction, irritability, lethargy,
coma, seizures, involuntary movements (e.g., tremors, myoclonic jerks, boxing, pedaling), posturing
(e.g., opisthotonus), and abnormal tone (e.g., hypertonia or central hypotonia). These same symptoms are
seen in an infant with sepsis, congenital viral infections, respiratory illness, cardiac disease,
gastrointestinal obstruction, hepatic dysfunction, renal disease, central nervous system (CNS) problems,
and drug withdrawal. It is worth noting that term infants who develop symptoms of sepsis without known


risk factors are nearly as likely to have metabolic disease as sepsis. Some IEM predispose infants to
sepsis. Escherichia coli sepsis in galactosemia is the classic example. Other IEMs with increased risk of
sepsis are the organic acidemias and glycogen storage disorders.
One of the most important clues to an IEM in the neonate is a history of deterioration after an initial

period of apparent good health. The most common time that symptoms are manifest is between 2 and 5
days, but can range from hours to weeks. For neonates with IEMs of protein metabolism and
carbohydrate intolerance disorders, the onset of symptoms occurs after there has been significant
accumulation of toxic metabolites following the initiation of feeding. Initial symptoms often are poor
feeding, vomiting, irritability, and lethargy. In the neonatal period, jaundice occurs most commonly with
tyrosinemia, galactosemia, and hereditary fructose intolerance. Progression to coma, multisystem organ
failure, and death is usually rapid. Neonates with tyrosinemia may present with intracranial or pulmonary
hemorrhage due to coagulopathy. Patients with organic acidemias may have recurrent or chronic subdural
hemorrhages, sometimes mistakenly attributed to child abuse. Fatty acid oxidation disorders, particularly
very long-chain acyl-CoA dehydrogenase deficiency, may present during the neonatal period. Many of
the peroxisomal disorders and some of the mitochondrial and lysosomal disorders also present in the
neonatal period; these infants are less likely to have coma as an early manifestation and are more likely to
have dysmorphic features, brain abnormalities, skeletal malformations, cardiopulmonary compromise,
organomegaly, hepatic dysfunction, myopathy, and/or severe generalized hypotonia, usually evident at
birth. Intractable seizures due to pyridoxine- or folic acid–responsive disorders usually begin within the
first few days of life.
Infant and young child (1 month to 5 years). Infants and young children with potentially acute lifethreatening IEMs (most commonly partial deficiency of the urea cycle enzyme ornithine
transcarbamylase, fatty acid oxidation defects, disorders of carbohydrate intolerance, and disorders of
gluconeogenesis and glycogenolysis) typically present during infancy with recurrent episodes of
vomiting and lethargy, ataxia, seizures, or coma. Amino and organic acidopathies also present during
infancy, usually with progressive neurologic deterioration. Lysosomal storage disorders, mitochondrial
disorders, and peroxisomal disorders also become apparent in infancy and early childhood, usually
presenting with dysmorphism or coarse features, organomegaly, myopathy, and/or neurodegeneration.
More subtle and/or progressive findings in infants and children with IEMs include failure to thrive,
chronic dermatoses, dilated or hypertrophic cardiomyopathy, liver dysfunction, hepatomegaly,
pancreatitis, musculoskeletal weakness, hypotonia and/or cramping, impairments of hearing and vision,
and developmental delay, sometimes with loss of milestones. With routine illnesses, children with IEMs
may be more symptomatic, develop symptoms more quickly, or take longer than unaffected children to
recover. Children with disorders of protein metabolism may present with dietary changes. Fructose
intolerance often manifests between 4 and 8 months of age when fruits are introduced. Disorders with

decreased tolerance for fasting, particularly fatty acid oxidation defects and defects of gluconeogenesis
and glycogenolysis, often manifest when children have poor intake due to illness or surgery and when
infants begin to have longer overnight fasts, commonly between 7 and 12 months of age. The length of
fasting that produces symptoms may be less than 3 hours for disorders of gluconeogenesis and
glycogenolysis, and 12 to 24 hours for fatty acid oxidation defects. When patients with these disorders
present with vomiting, the severity of illness, particularly lethargy, is usually out of proportion to the
duration of illness and the amount of vomiting. IEMs also explain sudden infant death syndrome (SIDS)
in approximately 5% to 10% of cases, most commonly fatty acid oxidation defects that cause cardiac
arrest due to arrhythmia and/or cardiomyopathy; the most common of these is medium-chain fatty acylCoA dehydrogenase deficiency. Other fatty acid oxidation defects, organic acidemias, and congenital
adrenal hyperplasia account for most of the remainder of SIDS cases attributable to genetic defects.
Child >5 years of age, adolescent, or adult. In the older child, adolescent, or adult, undiagnosed
metabolic disease should be considered in individuals with subtle neurologic or psychiatric abnormalities
which may present with a history waxing/waning symptoms that have been attributed to other causes.


Most typically, these individuals are diagnosed as having birth injury, behavioral problems, attention
deficit hyperactivity disorder, psychiatric disorders, or atypical forms of medical diseases such as
multiple sclerosis, migraines, epilepsy, or stroke. The more common findings include mild to profound
developmental delay, autism, and learning disabilities. Manifestations may be intermittent, precipitated
by the stress of illness or dietary changes or fasting, or may be progressive. For example, partial ornithine
transcarbamylase deficiency can present in as a life-threatening encephalopathy in an adolescent female
who has a history of protein aversion, migraine-like headaches, vomiting, abdominal pain, lethargy, and
behavioral problems, and who has consumed a large amount of protein. Fatty acid oxidation defects may
also present in adolescence with sudden death or life-threatening cardiac arrhythmia, hypoketotic
hypoglycemia, and/or rhabdomyolysis. Glycogen storage disorders often present in adolescents as
exercise intolerance, muscle weakness, cramping, and/or rhabdomyolysis because of their greater
participation in sports during these years. Some mitochondrial disorders present during adolescence or
adulthood with loss of vision and/or hearing, cardiac dysfunction, myopathy, neurologic degeneration,
and endocrine disturbances. Stroke or stroke-like episodes with or without encephalopathy may occur
with aminoacidopathies, in particular homocystinuria, urea cycle defects, organic acidemias, disorders of

carbohydrate metabolism, and mitochondrial disorders, most notably mitochondrial encephalomyopathy,
lactic acidosis, stroke-like episodes (MELAS). Disorders in which psychiatric disturbances may be the
initial presenting manifestation include homocystinuria; urea cycle defects, especially partial ornithine
transcarbamylase deficiency; lysosomal storage disorders; peroxisomal disorders; and Wilson disease, a
disorder of copper metabolism. Patients with phenylketonuria who are no longer on a low-protein diet
may also manifest psychiatric symptoms.
Physical Examination. IEMs can affect any organ system ( Table 95.1 ), and often affect multiple organ
systems, and therefore should be considered in patients who present with altered level of consciousness,
encephalopathy, cardiac failure, hepatic failure, skeletal muscle myopathy, weakness and/or cramping,
and/or neuropsychiatric disturbance. Physical examination may be normal, have subtle and/or nonspecific
findings, or have findings that provide more specific diagnostic information ( Table 95.2 ). Findings tend
to be related to abnormal anatomic proportion (i.e., size and shape), rather than to major structural defects
and usually become more pronounced over time. Some disorders have characteristic facies, short stature,
organomegaly, and/or musculoskeletal abnormalities. IEMs within each major category are listed in
Table 95.3 . Features of specific IEMs can be found in texts referenced at the end of this chapter and on
various websites, including the National Center for Biotechnology Information’s “Online Mendelian
Inheritance in Man” website ( ).


TABLE 95.3
SPECIFIC INBORN ERRORS OF METABOLISM BY CATEGORY a