title: Description of the mutations in 15 subjects with variant forms of maple syrup urine disease.
abstract: BACKGROUND
  In maple syrup urine disease (MSUD), disease-causing mutations can affect the BCKDHA, BCKDHB or DBT genes encoding for the E1 alpha, E1 beta and E2 subunits of the multienzyme branched-chain 2-keto acid dehydrogenase (BCKD) complex.
  
  
  OBJECTIVE
  The aim of this study was to screen DNA samples of 15 subjects with distinct well-characterized variant MSUD phenotypes for mutations in the three genes in order to demonstrate a potential correlation between specific nucleotide changes and particular variant phenotypes.
  
  
  METHODS
  The exonic coding sequences of all three genes were studied using genomic DNA and cellular RNA derived from peripheral blood leukocytes.
  
  
  RESULTS
  In 37% of the cases (total 30 alleles), disease-causing mutations were located in the BCKDHA, in 46% in the BCKDHB, and in 13% in the DBT gene. Novel mutations occurring homozygously were p.Ala328Thr in the BCKDHA gene and p.Gly249_Lys257del in the DBT gene. Both are associated with a mild MSUD variant. The same holds true for the novel mutations p.Pro200Ala in BCKDHB and p.Phe307Ser in DBT which were identified in heterozygous fashion. Among the known mutant alleles, p.Gly278Ser in the BCKDHB gene was relatively frequent and also associated with a mild MSUD variant.
  
  
  CONCLUSIONS
  The results of this study indicate that genotyping may be predictive of clinical severity of variant MSUD phenotypes and might be of prognostic value particularly in subjects with variant MSUD identified in newborn screening in whom early treatment fortunately slows the natural course of the disease.
authors.affiliation: Department of General Paediatrics, University Children's Hospital, Heinrich-Heine-University, Düsseldorf, Germany.
authors.forename: N
authors.initials: N
authors.lastname: Flaschker
authors.forename: O
authors.initials: O
authors.lastname: Feyen
authors.forename: S
authors.initials: S
authors.lastname: Fend
authors.forename: E
authors.initials: E
authors.lastname: Simon
authors.forename: P
authors.initials: P
authors.lastname: Schadewaldt
authors.forename: U
authors.initials: U
authors.lastname: Wendel
mesh_terms: D042942:3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide) / Q000235:genetics*; D000483:Alleles; D004252:DNA Mutational Analysis; D005091:Exons; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007962:Leukocytes / Q000378:metabolism; D008297:Male; D008375:Maple Syrup Urine Disease / Q000235:genetics*; D009154:Mutation; D010641:Phenotype; D011379:Prognosis
chemical_list: D042942:3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)