Practice Essentials
Inborn errors of metabolism (IEMs) are a large group of rare genetic diseases that generally result from 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. Often the central nervous system (CNS) is affected, leading to neurological disease.
The incidence of IEMs, collectively, is estimated to be as high as 1 in 800 live births,
but it varies greatly and depends on the population. Phenylketonuria (PKU) and medium-chain acyl-CoA dehydrogenase (MCAD) deficiency with respective incidences of 1 in 10,000 and 1 in 20,000 are among the most prevelant.
The incidence within different racial and ethnic groups varies with predominance of certain 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).
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.
Goals of treatment for patients with IEMs are prevention of further accumulation of harmful substances, correction of metabolic abnormalities, and elimination of toxic metabolites. Even the apparently stable patient with mild symptoms may deteriorate rapidly with progression to death within hours. With appropriate therapy, patients may completely recover without sequelae.
For patients with suspected or known IEMs, 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.
Provide education regarding disease and patient care (manifestations, course of disease, treatment, psychosocial support) and genetic counseling to discuss recurrence risks, screening of other family members, and prenatal diagnosis.
Professional and peer support groups exist for many IEMs. The National Organization of Rare Diseases (NORD) can direct families to resources for more than 1000 IEMs.