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.
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References
Aevarsson A, Chuang JL, Wynn RM, Turley S, Chuang DT, Hol WG (2000) Crystal structure of human branched-chain alpha-ketoacid dehydrogenase and the molecular basis of multienzyme complex deficiency in maple syrup urine disease. Structure 18: 277-91.
Chuang DT, Shih VE (2001) Maple syrup urine disease (branched-chain ketoaciduria). In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds; Childs B, Kinzler KW, Vogelstein B, assoc. eds. The Metabolic and Molecular Bases of Inherited Disease, 8th edn. New York: McGraw-Hill 1971–2005.
Chuang JL, Davie JR, Chinsky JM, Wynn RM, Cox RP, Chuang DT (1995) Molecular and biochemical basis of intermediate maple syrup urine disease. Occurrence of homozygous G245R and F364C mutations at the E1α locus of Hispanic-Mexican patients. J Clin Invet 95: 934-63.
Edelmann L, Wasserstein MP, Kornreich R, Sansaricq C, Snyderman SE, Diaz GA (2001) Maple syrup urine disease: identification and carrier-frequency determination of a novel founder mutation in the Ashkenazi Jewish population. Am J Hum Genet 69: 863-68.
Fisher CW, Fisher CR, Chuang JL, Lau KS, Chuang DT, Cox RP (1993) Occurrence of a 2-bp (AT) deletion allele and a nonsense (G-to-T) mutant allele at the E2 (DBT) locus of six patients with maple syrup urine disease: multiple-exon skipping as a secondary effect of the mutations. Am J Hum Genet 52: 414-24.
Henneke M, Flaschker N, Helbling C, et al (2003) Identification of twelve novel mutations in patients with classic and variant forms of maple syrup urine disease. Hum Mutat 22: 417.
Nellis MM, Danner DJ (2001) Gene preference in maple syrup urine disease. Am J Hum Genet 68: 232-37.
Nobukuni Y, Mitsubuchi H, Hayashida Y, et al (1993) Heterogeneity of mutations in maple syrup urine disease (MSUD): screening and identification of affected E1 alpha and E1 beta subunits of the branched-chain alpha-keto-acid dehydrogenase multienzyme complex. Biochim Biophys Acta 1225: 64-0.
Ono K, Hakozaki M, Suzuki T, Mori T, Hata H, Kochi H (2001) cDNA cloning of the chicken branched-chain α-keto acid dehydrogenase complex. Eur J Biochem 268: 727-36.
Pettit FH, Yeaman SJ, Reed LJ (1978) Purification and characterization of branched-chain α-keto acid dehydrogenase complex of bovine kidney. Proc Natl Acad Sci USA 75: 4881-885.
Reed LJ, Damuni Z, Merryfield ML (1985) Regulation of mammalian pyruvate and branched-chain α-keto acid dehydrogenase complexes by phosphorylation-dephosphorylation. Curr Top Cell Regul 27: 41-9.
Rodriguez-Pombo P, Navarette R, Merinero B, Gomez-Puertas P, Ugarte M (2006) Mutational spectrum of maple syrup urine disease in Spain. Hum Mutat 27: 715.
Simon E, Flaschker N, Schadewaldt P, Langenbeck U, Wendel U (2006) Variant maple syrup urine disease (MSUD) — the entire spectrum. J Inherit Metab Dis 29: 532-37.
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Communicating editor: Viktor Kozich
Competing interests: None declared
References to electronic databases: MSUD: OMIM 248600
N.F. and O.F. contributed equally to this work and should be considered as first authors.
This publication contains parts of the doctoral theses of N. Flaschker and S. Fend.
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Flaschker, N., Feyen, O., Fend, S. et al. Description of the mutations in 15 subjects with variant forms of maple syrup urine disease. J Inherit Metab Dis 30, 903–909 (2007). https://doi.org/10.1007/s10545-007-0579-x
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DOI: https://doi.org/10.1007/s10545-007-0579-x