Metabolic Brain Disease

, Volume 32, Issue 3, pp 765–772 | Cite as

Two homozygous mutations in the exon 5 of BCKDHB gene that may cause the classic form of maple syrup urine disease

  • Ling Su
  • Zhikun Lu
  • Fatao Li
  • Yongxian Shao
  • Huiying Sheng
  • Yanna Cai
  • Li LiuEmail author
Original Article


Maple syrup urine disease (MSUD) is a rare autosomal recessive genetic disorder caused by defects in the catabolism of the branched-chain amino acids (BCAAs). Classic form of MSUD (CMSUD) is caused by mutations in BCKDHA, BCKDHB, DBT genes mostly. In this study, we analyzed the clinical and genetic characteristics of two patients with CMSUD. Two homozygous mutations, c.517G > T (p.Asp173Tyr) and c.503G > A (p.Arg168His), both in the exon 5 of BCKDHB were detected respectively. The novel mutation p.Asp173Tyr of patient A, inherited from his parents, is predicted to affect conformation of protein by computer analysis. The reported mutation p.Arg168His observed in patient B seemed to occur in a maternal uniparental disomy inheritance manner. Review of related literature revealed that most missense mutations in exon 5 of BCKDHB in homozygous genotype often result in CMSUD because of its incorrect conformation, and exon 5 of BCKDHB might be a susceptible region. Thus the novel homozygous mutation p.Asp173Tyr and the founder homozygous mutation p.Arg168His may be responsible for the clinical presentation of the two CMSUD patients, facilitating the future genetic counselling and prenatal diagnosis.


Maple syrup urine disease (MSUD) Branched-chain amino acids (BCAAs) BCKDHB gene 



The study was supported by National “Twelfth Five-Year” Plan for Science and Technology Support (2012BAI09B04), China, and Health and Family planning Commission of Guangzhou Municipality Grant (20151A010048). Thank Dr. Lian Zhang and his team for the clinical data management.

Compliance with ethical standards

Conflict of interest statement

The authors declared that they have no conflicts of interest to this work.


  1. Axler O, Holmquist P (2014) Intermittent maple syrup urine disease: two case reports. Pediatrics 133:e458–e460. doi: 10.1542/peds.2013-0427 CrossRefPubMedGoogle Scholar
  2. Bashyam MD et al. (2012) Molecular genetic analysis of MSUD from India reveals mutations causing altered protein truncation affecting the C-termini of E1alpha and E1beta. J Cell Biochem 113:3122–3132 doi: 10.1002/jcb.24189
  3. Chuang JL et al (2004) Structural and biochemical basis for novel mutations in homozygous Israeli maple syrup urine disease patients: a proposed mechanism for the thiamin-responsive phenotype. J Biol Chem 279:17792–17800. doi: 10.1074/jbc.M313879200 CrossRefPubMedGoogle Scholar
  4. Couce ML et al (2015) Evolution of maple syrup urine disease in patients diagnosed by newborn screening versus late diagnosis. Eur J Paediatr Neurol: EJPN: official journal of the European Paediatric Neurology Society 19:652–659. doi: 10.1016/j.ejpn.2015.07.009 CrossRefGoogle Scholar
  5. Edelmann L, Wasserstein MP, Kornreich R, Sansaricq C, Snyderman SE, Diaz GA (2001) Maple syrup urine disease: identification and carrier-frequency determination of a novel founder mutation in the Ashkenazi Jewish population. Am J Hum Genet 69:863–868. doi: 10.1086/323677 CrossRefPubMedPubMedCentralGoogle Scholar
  6. Flaschker N, Feyen O, Fend S, Simon E, Schadewaldt P, Wendel U (2007) Description of the mutations in 15 subjects with variant forms of maple syrup urine disease. J Inherit Metab Dis 30:903–909. doi: 10.1007/s10545-007-0579-x
  7. Funchal C, Tramontina F, Quincozes dos Santos A, Fraga de Souza D, Goncalves CA, Pessoa-Pureur R, Wajner M (2007) Effect of the branched-chain alpha-keto acids accumulating in maple syrup urine disease on S100B release from glial cells. J Neurol Sci 260:87–94. doi: 10.1016/j.jns.2007.04.011 CrossRefPubMedGoogle Scholar
  8. Gorzelany K et al (2009) Molecular genetics of maple syrup urine disease in the Turkish population. Turk J Pediatr 51:97–102PubMedGoogle Scholar
  9. Grafakou O et al (2003) Leigh syndrome due to compound heterozygosity of dihydrolipoamide dehydrogenase gene mutations. Description of the first E3 splice site mutation. Eur J Pediatr 162:714–718. doi: 10.1007/s00431-003-1282-z CrossRefPubMedGoogle Scholar
  10. Guo Y, Liming L, Jiang L (2015) Two novel compound heterozygous mutations in the BCKDHB gene that cause the intermittent form of maple syrup urine disease. Metab Brain Dis 30:1395–1400. doi: 10.1007/s11011-015-9711-z CrossRefPubMedGoogle Scholar
  11. Gupta D et al (2015) Identification of mutations, genotype-phenotype correlation and prenatal diagnosis of maple syrup urine disease in Indian patients. Eur J Med Genet 58:471–478. doi: 10.1016/j.ejmg.2015.08.002 CrossRefPubMedGoogle Scholar
  12. Hou JW, Hwang TL (2014) Different gene preferences of maple syrup urine disease in the aboriginal tribes of Taiwan. Pediatr Neonatol 55:213–217. doi: 10.1016/j.pedneo.2013.09.009 CrossRefPubMedGoogle Scholar
  13. Li X et al (2015) Eleven novel mutations of the BCKDHA, BCKDHB and DBT genes associated with maple syrup urine disease in the Chinese population: Report on eight cases. Eur J Med Genet 58:617–623. doi: 10.1016/j.ejmg.2015.10.002 CrossRefPubMedGoogle Scholar
  14. McConnell BB, Burkholder B, Danner DJ (1997) Two new mutations in the human E1 beta subunit of branched chain alpha-ketoacid dehydrogenase associated with maple syrup urine disease. Biochim Biophys Acta 1361:263–271CrossRefPubMedGoogle Scholar
  15. Miryounesi M, Ghafouri-Fard S, Goodarzi H, Fardaei M (2015) A new missense mutation in the BCKDHB gene causes the classic form of maple syrup urine disease (MSUD). J Pediatr Endocrinol Metab: JPEM 28:673–675. doi: 10.1515/jpem-2014-0341 CrossRefPubMedGoogle Scholar
  16. Morton DH, Strauss KA, Robinson DL, Puffenberger EG, Kelley RI (2002) Diagnosis and treatment of maple syrup disease: a study of 36 patients. Pediatrics 109:999–1008CrossRefPubMedGoogle Scholar
  17. Muelly ER, Moore GJ, Bunce SC, Mack J, Bigler DC, Morton DH, Strauss KA (2013) Biochemical correlates of neuropsychiatric illness in maple syrup urine disease. J Clin Invest 123:1809–1820. doi: 10.1172/JCI67217 CrossRefPubMedPubMedCentralGoogle Scholar
  18. Narayanan MP, Menon KN, Vasudevan DM (2013) Analysis of gene mutations among South Indian patients with maple syrup urine disease: identification of four novel mutations. Indian J Biochem Biophys 50:442–446PubMedGoogle Scholar
  19. Nellis MM, Kasinski A, Carlson M, Allen R, Schaefer AM, Schwartz EM, Danner DJ (2003) Relationship of causative genetic mutations in maple syrup urine disease with their clinical expression Mol Genet Metab 80:189–195Google Scholar
  20. Rodriguez-Pombo P, Navarrete R, Merinero B, Gomez-Puertas P, Ugarte M (2006) Mutational spectrum of maple syrup urine disease in Spain. Hum Mutat 27:715. doi: 10.1002/humu.9428 CrossRefPubMedGoogle Scholar
  21. Shen Y, Gong X, Yan J, Qin L, Qiu G (2015) [Maple syrup urine disease caused by two novel BCKDHB gene mutations in a Chinese neonate]. Zhonghua er ke za zhi = Chinese journal of pediatrics 53:66–70Google Scholar
  22. Simon E, Flaschker N, Schadewaldt P, Langenbeck U, Wendel U (2006) Variant maple syrup urine disease (MSUD)--the entire spectrum. J Inherit Metab Dis 29:716–724. doi: 10.1007/s10545-006-0276-1
  23. Strauss KA et al (2010) Classical maple syrup urine disease and brain development: principles of management and formula design. Mol Genet Metab 99:333–345. doi: 10.1016/j.ymgme.2009.12.007 CrossRefPubMedPubMedCentralGoogle Scholar
  24. Wang YP, Qi ML, Li TT, Zhao YJ (2012) Two novel mutations in the BCKDHB gene (R170H, Q346R) cause the classic form of maple syrup urine disease (MSUD). Gene 498:112–115. doi: 10.1016/j.gene.2012.01.082
  25. Yang N et al (2012) Analysis of gene mutations in Chinese patients with maple syrup urine disease. Mol Genet Metab 106:412–418. doi: 10.1016/j.ymgme.2012.05.023 CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Ling Su
    • 1
  • Zhikun Lu
    • 1
  • Fatao Li
    • 2
  • Yongxian Shao
    • 1
  • Huiying Sheng
    • 1
  • Yanna Cai
    • 1
  • Li Liu
    • 1
    Email author
  1. 1.Department of Genetics and Endocrinology, Guangzhou women and children’s medical centerGuangzhou Medical UniversityGuangzhouChina
  2. 2.Prenatal Diagnostic Center, Guangzhou women and children’s medical centerGuangzhou Medical UniversityGuangzhouChina

Personalised recommendations