Mutational spectrum of maple syrup urine disease in Spain.

Mutations in any of the three different genes BCKDHA, BCKDHB, and DBT encoding for the E1alpha, E1beta, and E2 catalytic components of the branched-chain alpha-ketoacid dehydrogenase (BCKD) complex can cause maple syrup urine disease (MSUD). The disease presents heterogeneous clinical and molecular phenotypes. Severity of the disease ranges from the classical to the mildest variant types. Here, we describe the MSUD genotypes and related phenotypes in a cohort of 33 Spanish patients. Based on complementation testing, we selected 15 patients as defective in E1beta, 10 in E1alpha, seven in E2l; one remains unclassified. 92.5% of alleles have been characterized, and the mutational spectrum includes 36 different sequence variations presumably leading to loss-of-function, 15 changes in the BCKDHA, 14 in the BCKDHB, and seven in the DBT genes. Twenty-four changes are novel. The mutational profile is heterogeneous with no prevalent sequence variations detected, except for the E1beta mutation, c.487G>T (p.Glu163X), which appears on six out of 30 disease alleles analyzed. Approximately 30% of the patients included in this study showed a variant MSUD phenotype. That included 50% of the patients identified as EIa and at least four out of seven of those selected as EII. Precise genotypes as c.[647C>T]+[889C>T] for the EIa and c.[827T>G ]+[1349C>A] for the EII appeared associated to the mildest presentations of the disease.