Dominant versus recessive: molecular mechanisms in metabolic disease

Inborn errors of metabolism used to be regarded as simple monogenic traits, but a closer look at how different alleles of a gene determine different phenotypes shows that the molecular mechanisms in the individual case are often complicated. Most metabolic disorders represent a spectrum of phenotypes from normal via attenuated to severe (and sometimes prenatally fatal), and disease manifestation is often influenced by other specific genetic or exogenous factors. The terms 'dominant' or 'recessive' relate to the functional consequences of differing alleles in the (compound) heterozygous individual; the terms are irrelevant for homozygous individuals and inappropriate for X-linked disorders. Mutations affecting the same amino acid residue may be associated with different inheritance patterns. True dominant inheritance in metabolism is rare; it may be found e.g. in tightly regulated biosynthetic pathways or when minor changes in metabolite concentrations have a functional effect. Some disorders such as erythropoietic protoporphyria show pseudodominant inheritance due to prevalent loss-of-function polymorphisms in the general population and are better acknowledged as recessive traits. The term 'variable expressivity' is not helpful with regard to autosomal recessive disorders when variable phenotypes are explained by different mutations in the respective gene. Clonal unmasking of a heterozygous mutation through somatic loss of the second allele, the main pathomechanism in inherited tumour predisposition syndromes, is rare in metabolic disorders, but focal congenital hyperinsulinism is a notable exception. Somatic mosaicism for an OTC gene mutation is given as an example of an apparently heterozygous mutation pattern in a boy with an X-linked disease.