Inborn Errors of Metabolism
- Author: Debra L Weiner, MD, PhD; Chief Editor: Stephen Kemp, MD, PhD more...
Inborn errors of metabolism (IEMs) individually are rare but collectively are common. Presentation is usually in the neonatal period or infancy but can occur at any time, even in adulthood. Diagnosis does not require extensive knowledge of biochemical pathways or individual metabolic diseases. An understanding of the major clinical manifestations of inborn errors of metabolism provides the basis for knowing when to consider the diagnosis. A high index of suspicion is most important in making the diagnosis.
For patients with suspected or known inborn errors of metabolism, successful emergency treatment depends on prompt institution of therapy aimed at metabolic stabilization. Asymptomatic neonates with newborn screening results positive for an inborn error of metabolism may require emergent evaluation including confirmatory testing, and as appropriate, initiation of disease-specific management.
Single gene defects result in abnormalities in the synthesis or catabolism of proteins, carbohydrates, fats, or complex molecules. Most are due to a defect in an enzyme or transport protein, which results in a block in a metabolic pathway. Effects are due to toxic accumulations of substrates before the block, intermediates from alternative metabolic pathways, defects in energy production and use caused by a deficiency of products beyond the block, or a combination of these metabolic deviations. Nearly every metabolic disease has several forms that vary in age of onset, clinical severity, and, often, mode of inheritance.
Categories of inborn errors of metabolism, or IEMs, are as follows:
Disorders that result in toxic accumulation
- Disorders of protein metabolism (eg, amino acidopathies, organic acidopathies, urea cycle defects)
- Disorders of carbohydrate intolerance
- Lysosomal storage disorders
Disorders of energy production, utilization
- Fatty acid oxidation defects
- Disorders of carbohydrate utilization, production (ie, glycogen storage disorders, disorders of gluconeogenesis and glycogenolysis)
- Mitochondrial disorders
- Peroxisomal disorders
For more information, see the articles in the Genetic and Metabolic Disease section of the Medscape Reference Pediatrics volume.
The incidence, collectively, is estimated to be as high as 1 in 800 live births. The frequencies for each individual inborn error of metabolism vary, but most are very rare. Of term infants who develop symptoms of sepsis without known risk factors, as many as 20% may have an inborn error of metabolism.
The overall incidence and the frequency for individual diseases varies based on racial and ethnic composition of the population and on extent of screening programs. Overall rates are in a range similar to that of the United States.
Mortality can be very high for certain inborn errors of metabolism (IEMs), particularly those that present in neonates, but initial presentation of IEM even in adults may result in death. Prompt treatment of acute decompensation can be life-saving and is critical to optimizing outcome.
Inborn errors of metabolism (IEMs) can affect any organ system and usually affect multiple organ systems resulting in morbidity due to acute and/or chronic organ dysfunction.
Progression may be unrelenting with rapid life-threatening deterioration over hours, episodic with intermittent decompensations and asymptomatic intervals, or insidious with slow degeneration over decades.
Consider IEMs in all neonates and young infants with unexplained death. Obtain specimens immediately postmortem in children with unexplained death.
The incidence within different racial and ethnic groups varies with predominance of certain inborn errors of metabolism (IEMs) within particular groups (eg, cystic fibrosis, 1 per 1600 people of European descent; sickle cell anemia, 1 per 600 people of African descent; Tay-Sachs, 1 per 3500 Ashkenazi Jews).
The mode of inheritance determines the male-to-female ratio of affected individuals.
Many inborn errors of metabolism (IEMs) have multiple forms that differ in their mode of inheritance.
The male-to-female ratio is 1:1 for autosomal dominant and autosomal recessive transmission. It is also 1:1 for X-linked dominant if transmission is from mother to child.
Age for presentation of clinical symptoms varies for individual inborn errors of metabolism (IEM) and variant forms within the IEM with presentation from within hours of life to very late in adulthood. The timing of presentation depends on significant accumulation of toxic metabolites or on the deficiency of substrate.
The onset and severity may be exacerbated by environmental factors such as diet and intercurrent illness.
Disorders of protein or carbohydrate intolerance and disorders of energy production tend to present in the neonatal period or early infancy and tend to be unrelenting and rapidly progressive. Less severe variants of these diseases usually present later in infancy or childhood and tend to be episodic.
Fatty acid oxidation defects, glycogen storage, and lysosomal storage disorders tend to present in infancy or childhood. Disorders manifested by subtle neurologic or psychiatric features often go undiagnosed until adulthood.
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|Poor feeding, vomiting, failure to thrive||X||+||++||+||X||X||+||+||+|
|Dysmorphic features and/or skeletal or organ malformations||X||X||-||-||X||X||+||X||X|
|Abnormal hair and/or dermatitis||-||X||X||-||-||-||-||-||-|
|Cardiomegaly and/or arrhythmias||-||X||-||-||X||X||+||-||X|
|Hepatosplenomegaly and/or splenomegaly||X||+||+||+||+||+||+||X||X|
|Developmental delay +/- neuroregression||+||+||+||X||X||X||++||+||+|
|Lethargy or coma||X||++||++||+||X||++||-||-||X|
|Hypotonia or hypertonia||+||+||+||+||X||+||X||+||X|
|Primary metabolic acidosis||X||++||+||+||X||+||-||-||X|
|Primary respiratory alkalosis||-||-||+||-||-||-||-||-||-|
|*Within disease categories, not all diseases have all findings. For disorders with episodic decompensation, clinical and laboratory findings may be present only during acute crisis. For progressive disorders, findings may not be present early in the course of disease.
AA = Amino acidopathy
OA = Organic acidopathy
UCD = Urea cycle defect
CD = Carbohydrate disorder
GSD = Glycogen storage disorder
FAD = Fatty acid oxidation defect
LSD = Lysosomal storage disease
PD = Peroxisomal disorder
MD = Mitochondrial disorder
++ = Always present
+ = Usually present
X = Sometimes present
- = Absent
H = Inappropriately high
L = Inappropriately low
A = Appropriate