Inborn Errors of Metabolism

Updated: Sep 20, 2017
  • Author: Debra L Weiner, MD, PhD; Chief Editor: Robert P Hoffman, MD  more...
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Overview

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. [1, 2, 3, 4, 5]  

The incidence of IEMs, collectively, is estimated to be as high as 1 in 800 live births, [1] 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. [6]  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. 

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Pathophysiology

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.

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Etiology

Inborn errors of metabolism describes a class of over 1000 inherited disorders caused by mutations in genes coding for proteins that function in metabolism. Most of the disorders are inherited as autosomal recessive, whereas autosomal dominant and X-linked disorders are also present. IEMs were initially thought to be caused by single-gene mutations, but their presentation is as a spectrum of disease phenotypes in which a clear correlation between the severity of mutation at the affected locus and the phenotype (genotype-phenotype correlation) is lacking and impacts the ability to predict disease course. For example, PKU was originally thought to be caused by mutations at the human phenylalanine hydroxylase locus (PAH) but was subsequently found to arise from different genetic defects (eg, tetrahydrobiopterin homeostasis) and to be influenced by dietary protein intake. The PAH genotype alone failed to consistently predict the extent of cognitive and metabolic phenotypes in PKU. Thus, environmental, epigenetic, and microbiome factors as well as additional genes are potential modifying etiologic factors in individual IEMs. [6]

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Epidemiology

Frequency

United States

Individual IEMs are very rare diseases, with incidence ranging 1:10,000 (PKU) to 1:250,000 or less (GAMT deficiency). [7]  The prevalence of lysosomal storage disorders (approximately 60 diseases and growing) is significant when the group is considered as a whole, varying from 1 case in every 4000 to 13,000 births across different studies and projected to increase as data emerging from newborn screening programs is reported. [8] The incidence of IEMs, collectively, is estimated to be as high as 1 in 800 live births. [1]

 International

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. [9] Overall rates are in a range similar to that of the United States.

Race

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). In addition to Tay-Sachs disease, Gaucher disease type 1, Niemann-Pick disease type A, and mucolipidosis IV all have a higher prevelance in the Ashkenazi Jewish population, and patients of Finnish descent have been reported to have an increased frequency of infantile neuronal ceroid lipofuscinosis, Salla disease, and aspartylglucosaminuria . [8]

Sex

The mode of inheritance determines the male-to-female ratio of affected individuals.

Many 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

Age for presentation of clinical symptoms varies for individual IEMs 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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Prognosis

Prognosis varies based on the individual inborn error of metabolism and may differ for different forms of a particular IEM. A high index of suspicion is critical for early diagnosis and treatment of IEM. Rapid treatment may be lifesaving and often results in full recovery.

Mortality can be very high for certain IEMs, particularly those that present in neonates, but initial presentation of an IEM even in adults may result in death. Prompt treatment of acute decompensation can be lifesaving and is critical to optimizing outcome.

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. Diet or stress (ie, from intercurrent illness, trauma, surgery, or immunization) may precipitate episodic decompensation.

 

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