Three Korean patients with maple syrup urine disease: four novel mutations in the BCKDHA gene

Maple syrup urine disease (MSUD) is a rare, autosomal recessive disorder of branched-chain amino acid (BCAA) metabolism caused by dysfunction of the multienzyme branched-chain alpha-ketoacid dehydrogenase (BCKDH) complex. Although a few cases of MSUD have been reported in the Korean population, the genetic background of MSUD is not well understood. In this study, we investigated three newborn males who were diagnosed with MSUD using a standard newborn screening test and amino acid analysis. We screened all coding regions of the BCKDHA, BCKDHB and DBT genes for abnormalities using direct sequencing. Changes in these genes are associated with MSUD. For one patient with complex deletion/duplication mutations, we also performed TOPO TA cloning sequencing. Amino acid analysis showed elevated levels of all branched chain amino acids (BCAAs) in all patients. Three patients were either homozygous or compound heterozygous for the BCKDHA mutations. Patient 1 was homozygous for c.1036C>T (p.R346C); patient 2 was heterozygous, with c.632C>T (p.T211M) and c.659C>T (p.A220V); and patient 3 had c.1204_1209dupAAACCC (p.L402_P403dup) and c.1280_1282delTGG (p.L427_A428delinsP). Among these mutations, c.1036C>T, c.632C>T, c.1204_1209dup and c.1280_1282del were novel. These patients had no mutations in either the BCKDHB or the DBT gene. Although this study included only three patients, the five different mutations in these patients may indicate mutational heterogeneity in Korean patients with MSUD. In addition, the BCHDHA gene may present a primary target for clinical genetic analysis. To the best of our knowledge, this is the first report of genetically confirmed MSUD in Korea.