Prevalent mutations in fatty acid oxidation disorders: diagnostic considerations

The mutational spectrum in a given disease-associated gene is often comprised of a large number of different mutations, of which a single or a few are present in a large proportion of diseased individuals. Such prevalent mutations are known in four genes of the fatty acid oxidation: the medium-chain acyl-CoA dehydrogenase (MCAD) gene; the short-chain acyl-CoA dehydrogenase (SCAD) gene; the long-chain 3-hydroxy acyl-CoA dehydrogenase (LCHAD) gene and the carnitine-palmitoyl-CoA transferase II (CPT II) gene. In MCAD deficiency the analysis confirms the conventional wisdom that individuals carrying the prevalent 985A > G mutation are at risk of developing life-threatening attacks. In SCAD/ethylmalonic aciduria, on the other hand, the presence of the prevalent susceptibility variations, 625A and 511T, in the SCAD gene seems to require additional genetic and cellular factors to be present in order to result in a phenotype. For the prevalent mutations in the LCHAD and CPT II genes further data are needed to evaluate the penetrance and risk of manifest disease when carrying these mutations.

Assessment of the prevalence of a prevalent mutation in the mutation spectrum of the disease in question and determination of the carrier frequency in the general population may help in elucidating the penetrance of the genotype. This is exemplified in disorders of mitochondrial fatty acid oxidation.