title: Thiamin-responsive maple syrup urine disease in a patient antigenically missing dihydrolipoamide acyltransferase.
abstract: Maple syrup urine disease results from inherited defects in human nuclear genes for branched chain alpha-ketoacid dehydrogenase, a mitochondrial multienzyme complex. Thiamin pyrophosphate is necessary for complex activity and a thiamin-responsive form of maple syrup urine disease is known. Here we demonstrate the use of [1-13C]leucine oxidation to [13C]O2 quantified in breath samples as a means of assessing whole body leucine oxidation. Analysis of cultured cells from this patient shows the antigenic lack of the E2 subunit, yet she gained branched chain alpha-ketoacid dehydrogenase activity in response to diet supplementation with pharmacologic doses of thiamin. These cultured cells were used to seek a molecular basis for the observed thiamin response. Despite normal thiamin transport in these cells, medium supplementation of up to 1000 thiamin/liter failed to increase complex activity or cause the antigenic appearance of the missing protein. This lack of response in cultured cells suggests that the observed whole body response to thiamin must be a tissue-specific effect in liver, muscle, or kidney. In addition, allele-specific detection of paternal and maternal mutations was used to genotype family members in this pedigree.
authors.affiliation: Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia 30322.
authors.forename: N P
authors.initials: NP
authors.lastname: Ellerine
authors.forename: W J
authors.initials: WJ
authors.lastname: Herring
authors.forename: L J
authors.initials: LJ
authors.lastname: Elsas
authors.forename: M C
authors.initials: MC
authors.lastname: McKean
authors.forename: P D
authors.initials: PD
authors.lastname: Klein
authors.forename: D J
authors.initials: DJ
authors.lastname: Danner
mesh_terms: D000217:Acyltransferases / Q000276:immunology*; D000483:Alleles; D000941:Antigens / Q000032:analysis*; D001483:Base Sequence; D002478:Cells, Cultured; D002648:Child; D005260:Female; D017353:Gene Deletion; D005838:Genotype; D006801:Humans; D007930:Leucine / Q000378:metabolism; D008375:Maple Syrup Urine Disease / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D008969:Molecular Sequence Data; D010084:Oxidation-Reduction; D010375:Pedigree; D010641:Phenotype; D017354:Point Mutation; D013831:Thiamine / Q000627:therapeutic use*
chemical_list: D000941:Antigens; D000217:Acyltransferases; C033588:dihydrolipoamide acyltransferase; D007930:Leucine; D013831:Thiamine