COMBINED MALONIC, METHYLMALONIC AND ETHYLMALONIC ACID SEMIALDEHYDE DEHYDROGENASE DEFICIENCIES - AN INBORN ERROR OF BETA-ALANINE, L-VALINE AND L-ALLOISOLEUCINE METABOLISM

Defects of branched-chain amino acid metabolism in man unique to the L-valine catabolic pathway are rare. L-Valine aminotransferase (McKusick 277100, EC 2.6.1.32), 3-hydroxyisobutyryl-coenzyme A deacylase (McKusick 277080, EC 3.1.2.4), and methylmalonic acid semialdehyde dehydrogenase (EC 1.2.1.27) deficiencies have each been documented in one patient (Brown et al 1982; Gray et al 1987). Recently six patients have been identified with elevated excretion of 3-hydroxyisobutyric acid, an intermediate of the L-valine catabolic pathway (Mienie and Erasmus 1990; Ko et al 1991; Brewster et al 1991; Chitayat et al 1992). Enzymatic studies were performed on cultured skin cells from two of these patients (twins, gender undisclosed) that failed to demonstrate a defect in the L-valine catabolic pathway (Brewster et al 1991). We performed enzyme analyses on fibroblasts from one (Ko et al 1991) of these six patients in whom L-Valine loading had resulted in enhanced excretion of 3-hydroxyisobutyric and 3-aminoisobutyric acids, suggesting a defect at the level of 3-hydroxyisobutyrate dehydrogenase or methylmalonic acid semialdehyde dehydro-genase (Figure 1). 3-Hydroxyisobutyrate dehydrogenase was normal. We found decreased conversion of [U-C-14]valine and beta-[1-C-14]alanine to (CO2)-C-14 in fibroblasts and persistent 2-ethylhydracrylic aciduria in the patient, suggesting a deficiency of malonic, methylmalonic and ethylmalonic acid semialdehyde dehydrogenases.