Maple Syrup Urine Disease: 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 below) 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, many mutations in all of these 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 (BCAA) is the standard therapy to reduce the risk of metabolic decompensation. Liver transplantation has become an effective approach to control BCAA levels. Small-molecule inhibitors of the regulatory kinase may hold promise for reactivation of the BCKDC activity in some patients with low to intermediate enzyme activity. Naturally occurring and knockout animal models with classic and intermediate MSUD phenotypes, respectively, are available. Transplanted human amniotic epithelial cells significantly increased BCKDC enzyme activity in a mouse model of intermediate MSUD. The treatment resulted in prolonged animal survival, increased body weight and decreased circulating BCAA. Taken together, these advances will impact our approaches to developing effective therapies to mitigate the disease manifestations.