Molecular characterization of methylmalonate semialdehyde dehydrogenase deficiency

Three patients have been reported with (putative) methylmalonic semialdehyd e dehydrogenase (MMSDH) deficiency. The urine metabolic pattern was strikin gly different in all, including beta-alanine, 3-hydroxypropionic acid, both isomers of 3-amino- and 3-hydroxyisobutyric acids in one and 3-hydroxyisob utyric and lactic acids in a second, and mild methylmalonic aciduria in a t hird patient. In an effort to clarify these disparate metabolite patterns, we completed the cDNA structure, and characterized the genomic structure of human MMSDH gene in order to undertake molecular analysis. Only the first patient had alterations in the MMSDH coding region, revealing homozygosity for a 1336G > A transversion, which leads to substitution of arginine for h ighly conserved glycine at amino acid 446. No abnormalities of the MMSDH cD NA were detected in the other patients. These data provide the first molecu lar characterization of an inborn error of metabolism specific to the L-val ine catabolic pathway.