Inborn errors of metabolism

Published on 01/03/2015 by admin

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Last modified 01/03/2015

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Inborn errors of metabolism

The spectrum of genetic disorders is wide and encompasses chromosomal disorders as well as many common diseases in which multiple genes confer susceptibility to the effects of environmental influences. ‘Classical’ genetic diseases result from single gene mutations that result either in reduced synthesis of a particular protein, or the synthesis of a defective protein. In 1909 Garrod first defined the concept of inborn errors of metabolism, where blocks in specific metabolic pathways result from defects in particular enzymes. Certainly, in most inborn errors, the defective or absent protein is an enzyme; exceptions include familial hypercholesterolaemia, cystinuria and Hartnup disease, where the affected proteins are either receptors or are otherwise involved in transport processes.

Patterns of inheritance

Inborn errors can be autosomal (involving a chromosome other than X or Y) or X-linked, and the genetic defect can be either dominant or recessive. In dominant disorders, everyone who carries the gene is affected by the disease, so every affected individual has at least one affected parent. If the defective gene is recessive, it will be silent unless both copies (maternal and paternal) of the gene carry the mutation, i.e. affected individuals must be homozygous; parents carrying only one copy of the affected gene (heterozygotes) are carriers and are not clinically affected. These patterns of inheritance are illustrated in Figure 80.1.

Establishing pedigrees may not be straightforward. One reason for this is that the severity of the disease can vary widely between individuals even within the same family. Sometimes the clinical manifestations may be so mild that the disease cannot be detected, even though the defective gene is present. When this occurs the disease is said to be non-penetrant. Thus, dominant diseases may clinically appear to ‘skip’ generations.

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