Inborn Errors of Metabolism

Single-gene defects result in abnormalities in the synthesis or catabolism of proteins, carbohydrates, fats, or complex molecules. As previously stated, 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 IEMs are as follows:

• Disorders that result in toxic accumulation - Disorders of protein metabolism (eg, aminoacidopathies, organic acid disorders, 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
• Disorders of complex molecule storage and/or substrate accumulation in organelles - Lysosomal storage disorders, peroxisomal disorders

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, but some are autosomal dominant or X-linked.

IEMs were initially thought to be caused by a specific single-gene mutation, but genetic characterization of variation in clinical manifestations led to the understanding that IEMs can be caused by different gene mutations that result in the same or similar diagnostic biochemical abnormalities.

The presentation of specific IEMs 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 often lacking and impacts the ability to predict disease course. ^[7] For example, phenylketonuria (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.

Phenotypic variation also results from cofactor defects that may affect multiple enzymes. As an example, biotinidase deficiency, due to a defect in the enzyme that recycles the cofactor biotin, impacts metabolic pathways of four different carboxylase enzymes, but there are also IEMs caused by single-gene defects impacting only one of the carboxylases. Furthermore, defects in different subunits of an enzyme can result in different IEMs.  Additional genes and environmental, epigenetic, and microbiome factors are also potential modifying etiologic factors in individual IEMs. ^[6]

United States data

Individual IEMs are very rare diseases, with incidence ranging 1:10,000 (PKU) to 1:250,000 or less (guanidinoacetate methyltransferase [GAMT] deficiency). ^[8] 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 4000-13,000 births across different studies and projected to increase as data emerging from newborn screening programs is reported. ^[9] The incidence of IEMs, collectively, is estimated to be as high as 1 in 800 live births. ^[1]

International data

The overall incidence and the frequency for individual diseases varies based on racial and ethnic composition of the population and on the extent of screening programs. ^[10] Overall rates are in a range similar to that of the United States.

A report from the Society for the Study of Inborn Errors of Metabolism (SSIEM), which looked at 15 centers specializing in the management of adults with IEMs, found that PKU was the most common disease (19.6%) among the study patients. ^[11]

Race-,ethnicity-, sex-, and age-related data

Race

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 365 people of Black or African descent, with greater than 90% of those having it being of African descent [and with it also being prevalent in the Hispanic population]; 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 prevalence 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 . ^[9]

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 recessive and autosomal dominant transmission. It is also 1:1 for X-linked dominant if transmission is from mother to child. Autosomal recessive X-linked IEMs are more prevalent in males, since they only have one X-linked chromosome.

Age

Age of 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 have a tendency 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 do not present or go undiagnosed until adulthood.

Prognosis varies based on the individual IEM and may differ for different forms of a particular IEM. IEMs can affect any organ system and usually affect multiple organ systems, resulting in morbidity due to acute and/or chronic metabolic derangement and/or organ dysfunction.

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. 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, or it may not manifest even until late in adulthood. Diet or physiologic stress (ie, from intercurrent illness, trauma, surgery, or immunization) may precipitate episodic decompensation. A high index of suspicion is critical for early diagnosis and treatment of IEM.

For IEMs that result in chronic organ dysfunction, interventions that support and ideally preserve organ function to optimize physical and cognitive abilities should be initiated as soon as the IEM is recognized.

 

Education regarding inborn errors should include public education regarding newborn screening, risk factors, and screening based on family history, and if diagnosed, education regarding medical care, genetic counseling, and resources for psychosocial support.