Isolated 3-methylcrotonyl-CoA carboxylase (MCC) deficiency is an autosomal recessive disorder of leucine catabolism. MCC is a heteromeric mitochondrial enzyme comprised of biotin-containing alpha-subunits and smaller beta-subunits. The recent introduction of neonatal screening programs based on tandem mass spectrometry has revealed an unexpectedly high frequency of this disorder, which appears to be the most common organic aciduria in some populations. The phenotype is variable, ranging from neonatal onset with severe neurological involvement to asymptomatic adults. Most symptomatic patients have normal growth and development until presenting with an acute metabolic crisis between 2 and 33 months of age. Such an episode usually follows a minor infection or introduction of a protein-rich diet. Symptoms include vomiting, opisthotonus, involuntary movements, seizures, coma and apnoea, and are often accompanied by severe hypoglycemia, ketoacidosis and mild hyperammonemia. The major abnormal metabolites are 3-methylcrotonylglycine and 3-hydroxyisovaleric acid in urine, and 3-hydroxisovalerylcarnitine in blood. The patients usually respond to intravenous fluids and cessation of protein feeding and are asymptomatic between acute episodes. Some children have been placed on a leucine-restricted diet supplemented with oral L-carnitine, but the efficacy of this approach is unproven. Recent studies provide evidence that the missense mutation MCCA-R385S in the presence of the wild type allele has a dominant negative effect that may lead to biochemical and clinical abnormalities in heterozygous individuals. Moreover, in such subjects biotin therapy appears to counteract the dominant negative effect in vivo.
Last update: February 2005