Clear correlation of genotype with disease phenotype in very-long-chain acyl-CoA dehydrogenase deficiency

Very-long-chain acyl-CoA dehydrogenase (VLCAD) catalyzes the initial rate-l imiting step in mitochondrial fatty acid P-oxidation. VLCAD deficiency is c linically heterogenous, with three major phenotypes: a severe childhood for m, with early onset, high mortality, and high incidence of cardiomyopathy; a milder childhood form, with later onset, usually with hypoketotic hypogly cemia as the main presenting feature, low mortality and rare cardiomyopathy ; and an adult form, with isolated skeletal muscle involvement, rhabdomyoly sis, and myoglobinuria, usually triggered by exercise or fasting. To examin e whether these different phenotypes are due to differences in the VLCAD ge notype, we investigated 58 different mutations in 55 unrelated patients rep resenting all known clinical phenotypes and correlated the mutation type wi th the clinical phenotype. Our results show a clear relationship between th e nature of the mutation and the severity of disease. Patients with the sev ere childhood phenotype have mutations that result in no residual enzyme ac tivity, whereas patients with the milder childhood and adult phenotypes hav e mutations that may result in residual enzyme activity. This clear genotyp e-phenotype relationship is in sharp contrast to what has been observed in medium-chain acyl-CoA dehydrogenase deficiency, in which no correlation bet ween genotype and phenotype can be established.