Identification of twelve novel mutations in patients with classic and variant forms of maple syrup urine disease

Abstract

Maple syrup urine disease (MSUD) is an autosomal recessive metabolic disorder of panethnic distribution caused by a deficiency of the activity of branched-chain alpha-ketoacid dehydrogenase (BCKD) complex. Mutations in the human BCKD genes E1alpha (BCKDHA), E1beta (BCKDHB) and E2 (DBT) are known to result in MSUD, referred to as type Ia, Ib and II mutations respectively. In this study 16 patients with the classic severe form of MSUD and three patients with milder variant forms of the disease were investigated for mutations in the E1alpha-, E1beta- and E2-gene by single-strand conformation polymorphism (SSCP) analysis and DNA sequencing. The patients' clinical and biochemical phenotypes were well characterized. One novel type Ia missense mutation, eight novel type Ib (three missense, two nonsense, two small deletions, one small duplication) and three novel type II (two missense, one splice site) mutations were identified in patients. Moreover, eleven previously described mutations were detected: five type Ia (four missense, one nonsense), three type Ib mutations (two missense, one nonsense) and three type II mutations (two missense, one small deletion). Fourteen patients are homozygous for one single mutation, five patients are compound-heterozygous for two different mutations affecting one of the three genes. Thus, in all 19 patients the identified mutations can most probably be considered the molecular basis of the disease.

Mutational spectrum of maple syrup urine disease in Spain

“…Somatic cell complementation studies applied to the cell strains allowed their classification into the genetic subtypes Ia, Ib and II according to the gene presumable harboring the mutant alleles. The distribution observed, 15 /33 in the Ib subtype, 10 /33 in the Ia, 7/ 33 in the II and 1 with an ambiguous result is similar to that found in other studied populations (Henneke, et al, 2003;Nellis and Danner, 2001). No EIII genetic subtype strain has been detected in this cohort (data not shown).…”

“…The c.487G>T change appears in homozygous fashion in three patients without consanguineous pedigree proved but all coming from the same Spanish geographic area. (Henneke, et al, 2003) DNA mutation numbering is based on cDNA reference sequence (GenBank Accession number NM_000056.2) considering nucleotide +1 as the A of the ATG translation initiation codon. Seven different variations have been found in the DBT gene.…”

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

“…Previous imaging studies in MSUD patients have shown signs of both diffuse edema and intense local edema during the acute phase of the disease (12,13). Early diagnosis is essential for the reversal of MSUD encephalopathy and delayed treatment can lead to death (14).…”

On the probability that a novel variant is a disease-causing mutation

“…At present, control group size appears to be arbitrary, with 100 chromosomes being a popular choice (Colomb et al 2003;DiFonzo et al 2003;Eng et al 2003;Henneke et al 2003;Isidro et al 2003;Kramer et al 2003;Njalsson et al 2003;Royer et al 2003). Examination of the "Mutation in Brief" section of two recent issues of Human Mutation (volume 22, issues 6 and 7) revealed that eight of 11 mutation-detection experiments screened 100 or fewer control chromosomes for a putative disease-causing mutation that was initially found in a patient.…”