Description of the mutations in 15 subjects with variant forms of maple syrup urine disease.

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. 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.

Variant maple syrup urine disease (MSUD)--the entire spectrum.

BACKGROUND: In the rare inborn autosomal recessive disorder maple syrup urine disease (MSUD) the accumulation of the branched-chain amino acids (BCAAs) and their metabolic products results in acute and chronic brain dysfunction. About 20% of the patients suffer from non-classic variant forms of MSUD of different clinical severity. AIM: Up to now variant cases have mostly been published as individual case reports; the aim of this study was to give a comparative description of 16 individuals (aged 6-30 years) with different forms of variant MSUD. METHODS: Laboratory data, information on clinical course and treatment as well as aspects of developmental, intellectual and social outcome were obtained retrospectively. Data from in vitro and in vivo methods measuring the degree of enzyme deficiency were included. RESULTS: In addition to a mild phenotype, which fits well into the so-called intermittent variant, and a more severe phenotype with a wider range from a mild variant to an almost classic form, which fits well into the so-called intermediate variant, we assume the existence of an asymptomatic, non-disease variant of MSUD. These clinical phenotypes are not unambiguously differentiable on the basis of biochemical parameters. CONCLUSION: A continuum of clinical severity from asymptomatic to very severe (border to classic) exists in variant MSUD. Apart from newborns with classic MSUD, also those with variant forms benefit from early diagnosis and start of adequate treatment.