Maple syrup urine disease: Biochemical, clinical and therapeutic considerations

Maple syrup urine disease (MSUD) is an autosomal-recessive disorder caused by a deficiency of the branched-chain α-ketoacid dehydrogenase complex (BCKDC). Patients with MSUD show variable degrees of enzyme deficiency leading to several distinct phenotypes. Classic MSUD patients exhibit pronounced branched-chain ketoacidosis, marked cerebral edema, and severe neurological impairments. Intermittent and intermediate forms of MSUD show lesser degrees of metabolic and clinical derangements. A thiamine-responsive form responding to the vitamin supplement and an E3-deficient form (see later) have also been described. Levels of residual BCKDC activity present in the patients guide regimens for dietary therapy. MSUD is genetically heterogeneous since the BCKDC is encoded by six different genetic loci. Using the tools of molecular biology, several mutations in these six loci have been identified. A tight association of genetic lesions in the E2 locus with the thiamine-responsive MSUD phenotype was demonstrated. Restriction in the intake of branched-chain amino acids (BCAAs) is the standard therapy to reduce the risk of metabolic decompensation. Domino liver transplantation has become an effective approach to control BCAA levels. Small-molecule inhibitors of the regulatory kinase may hold promise for reactivation of residual BCKDC activity in patients with various forms of MSUD. Naturally occurring and knock-out animal models with classic and intermediate MSUD phenotypes, respectively, are available. Taken together, these advances will impact our approaches to developing effective therapies to mitigate the disease manifestations.