Molecular analysis of maple syrup urine disease in Jordanian families

Abstract

Maple syrup urine disease (MSUD) is an autosomal-recessive inborn error of amino acid metabolism characterized by the accumulation of three branched-chain amino acids (BCAAs) in patients' cells due to reduced activity of the branched-chain α-ketoacid dehydrogenase complex (BCKD). In this study, we aimed to sequence the coding exons of the BCKDHA, BCKDHB, and DBT genes in five Jordanian families with MSUD and one family from Iraq with MSUD. BCAA levels were measured in probands initially presenting with developmental delay and encephalopathy. All of the coding exons and flanking intronic sequences of the BCKDHA, BCKDHB, and DBT genes were amplified and subjected to direct DNA sequencing. Four different mutations in the BCKDHA gene were identified, including a novel frame-shift mutation, c.908_909delTG, in family 4. Two novel missense mutations at residues Met263 and Gly353 in the DBT gene were also found to be cosegregated with the MSUD phenotype in families 5 and 6, respectively. Structural analyses suggested that these two mutations may affect the assembly of the intermediate E2 trimer. No BCKDHB gene mutations were found in Jordanian patients. The mutation profiles described in this study provide a basis for the early detection of MSUD disease. To our knowledge, this is the first molecular study of MSUD in Jordan and Middle Eastern Arabic countries.