Mutational spectrum of maple syrup urine disease in Spain

Abstract

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.

Pleuroparenchymal fibroelastosis: the prevalence of secondary forms in hematopoietic stem cell and lung transplantation recipients

“…A total of 15 mutations were identified in BCKDHA, BCKDHB, and DBT genes in our MSUD patients. BCKDHB mutations were most common in neonates with the more severe classical form of MSUD in our study, which is in agreement with previous findings (21). However, other studies have reported contradictory findings: one study identified BCKDHB mutations in patients with the intermediate and thiamine-responsive forms of MSUD (22), while another observed BCKDHB mutations in patients with the intermittent or asymptomatic forms of MSUD (11).…”

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

“…At least homozygous p.Gly290Arg and p.Val412Met were associated with very low (2-4%) residual BCKD activity in cultured fibroblasts. Thus, for the homoallelic p.Gly290Arg genotype the prediction of a severe variant MSUD phenotype with neonatal manifestation (Chuang et al 1995;Rodriguez-Pombo et al 2006) is verified. The same holds true for the previously described p.Ala253Thr mutation (Nobukuni et al 1993) and the p.Val412Met mutation (Henneke et al 2003) in the BCKDHA gene.…”

“…and two E1" subunits. The genomic changes that impair BCKD activity can occur in any of the catalytic components of the complex, but both alleles at a single gene locus must harbour nucleotide changes (Aevarsson et al 2000;Chuang and Shih 2001;Nellis and Danner 2001;Rodriguez-Pombo et al 2006). Based on the affected loci of the BCKD complex, three molecular MSUD genotypes are known so far: subtype Ia for mutations affecting the E1!…”

Targeted comparative genomic hybridization array for the detection of single- and multiexon gene deletions and duplications

“…For example, intragenic deletion and duplication mutations had not been documented in MSUD patients previously. Molecular characterization of MSUD alleles has a ϳ95% mutation detection rate with a mutation spectrum of ϳ95% point mutations; the remaining 5% were considered uncharacterized mutations, 35,36 and large and single-exon deletions and duplications had not been seen before. Here we present for the first time two cases of multiexon deletion and duplication mutations in the BCKDHB gene, identified in patient T6 and T5, respectively.…”