Lessons from genetic disorders of branched-chain amino acid metabolism

David T. Chuang, Jacinta L. Chuang, R. Max Wynn

Research output: Contribution to journalArticlepeer-review

93 Scopus citations


Genetic disorders of BCAA metabolism produce amino acidopathies and various forms of organic aciduria with severe clinical consequences. A metabolic block in the oxidative decarboxylation of BCAA caused by mutations in the mitochondrial branched-chain α-keto acid dehydrogenase complex (BCKDC) results in Maple Syrup Urine Disease (MSUD) or branched-chain ketoaciduria. There are presently .ve known clinical phenotypes for MSUD, i.e., classic, intermediate, intermittent, thiamin-responsive, and dihydrolipoamide dehydrogenase (E3)-deficient, based on severity of the disease, response to thiamin therapy, and the gene locus affected. Reduced glutamate, glutamine, and γ-aminobutyrate concentrations induced by the accumulation of branched-chain α-ketoacids in the brain cortex of affected children and neonatal polled Hereford calves are considered the cause of MSUD encephalopathies. The long-term restriction of BCAA intake in diets and orthotopic liver transplantation have proven effective in controlling plasma BCAA levels and mitigating some of the above neurological manifestations. To date, ∼100 mutations have been identified in four (branched-chain α-ketoacid decarboxylase/dehydrogenaseα [E1α], E1β, dihydrolipoyl transacylase [E2], and E3) of the six genes that encode the human BCKDC catalytic machine. We have documented a strong correlation between the presence of mutant E2 proteins and the thiamin-responsive MSUD phenotype. We show that the normal E1 component possesses residual decarboxylase activity, which is augmented by the binding to a mutant E2 protein in the presence of the E1 cofactor thiamin diphosphate. Our results provide a biochemical model for the effectiveness of thiamin therapy to thiamin-responsive MSUD patients.

Original languageEnglish (US)
Pages (from-to)243S-249S
JournalJournal of Nutrition
Issue number1
StatePublished - Jan 2006


  • Branched-chain amino acid metabolism
  • Branched-chain α-ketoacid dehydrogenase
  • E2 deficiency
  • Maple Syrup Urine Disease
  • Thiamin diphosphate
  • Thiamin supplementation
  • Thiamin-responsive MSUD

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Nutrition and Dietetics


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