Premium
Description of the mutations in 15 subjects with variant forms of maple syrup urine disease
Author(s) -
Flaschker N.,
Feyen O.,
Fend S.,
Simon E.,
Schadewaldt P.,
Wendel U.
Publication year - 2007
Publication title -
journal of inherited metabolic disease
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.462
H-Index - 102
eISSN - 1573-2665
pISSN - 0141-8955
DOI - 10.1007/s10545-007-0579-x
Subject(s) - maple syrup urine disease , genetics , gene , biology , allele , phenotype , mutation , amino acid , leucine
Summary Background: In maple syrup urine disease (MSUD), disease‐causing mutations can affect the BCKDHA , BCKDHB or DBT genes encoding for the E1α, E1β and E2 subunits of the multienzyme branched‐chain 2‐keto acid dehydrogenase (BCKD) complex. Aim: 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. Conclusion: 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.