Four novel mutations of the BCKDHA, BCKDHB and DBT genes in Iranian patients with maple syrup urine disease

J Pediatr Endocrinol Metab. 2018 Jan 26;31(2):205-212. doi: 10.1515/jpem-2017-0305.


Background: Maple syrup urine disease (MSUD) is a rare metabolic autosomal recessive disorder caused by dysfunction of the branched-chain α-ketoacid dehydrogenase (BCKDH) complex. Mutations in the BCKDHA, BCKDHB and DBT genes are responsible for MSUD. The current study analyzed seven Iranian MSUD patients genetically and explored probable correlations between their genotype and phenotype.

Methods: The panel of genes, including BCKDHA, BCKDHB and DBT, was evaluated, using routine the polymerase chain reaction (PCR)-sequencing method. In addition, protein modeling (homology and threading modeling) of the deduced novel mutations was performed. The resulting structures were then analyzed, using state-of-the-art bioinformatics tools to better understand the structural and functional effects caused by mutations.

Results: Seven mutations were detected in seven patients, including four novel pathogenic mutations in BCKDHA (c.1198delA, c.629C>T), BCKDHB (c.652C>T) and DBT (c.1150A>G) genes. Molecular modeling of the novel mutations revealed clear changes in the molecular energy levels and stereochemical traits of the modeled proteins, which may be indicative of strong correlations with the functional modifications of the genes. Structural deficiencies were compatible with the observed phenotypes.

Conclusions: Any type of MSUD can show heterogeneous clinical manifestations in different ethnic groups. Comprehensive molecular investigations would be necessary for differential diagnosis.

Keywords: BCCAs; BCKDH; MSUD; molecular genetic tests.

MeSH terms

  • 3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide) / chemistry
  • 3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide) / genetics*
  • 3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide) / metabolism
  • Acyltransferases / chemistry
  • Acyltransferases / genetics*
  • Acyltransferases / metabolism
  • Amino Acid Substitution
  • Child, Preschool
  • Computational Biology
  • Consanguinity
  • Exons
  • Expert Systems
  • Female
  • Frameshift Mutation*
  • Humans
  • Infant
  • Infant, Newborn
  • Iran
  • Male
  • Maple Syrup Urine Disease / blood
  • Maple Syrup Urine Disease / genetics*
  • Maple Syrup Urine Disease / metabolism
  • Maple Syrup Urine Disease / physiopathology
  • Models, Molecular*
  • Mutation, Missense*
  • Protein Subunits / chemistry
  • Protein Subunits / genetics*
  • Protein Subunits / metabolism
  • Severity of Illness Index
  • Structural Homology, Protein


  • Protein Subunits
  • 3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)
  • Acyltransferases
  • dihydrolipoamide acyltransferase