Skip to main content
SpringerLink
Log in

Identification of eight novel mutations in 11 Chinese patients with maple syrup urine disease

  • Original Article
  • Published:
World Journal of Pediatrics Aims and scope Submit manuscript

Abstract

Background

Maple syrup urine disease (MSUD) is an autosomal recessive inherited disorder that affects the degradation of branched-chain amino acids and is associated with acute and chronic brain dysfunction. This study presents 11 new patients with MSUD and describes the clinical characteristics and gene mutations reported in Chinese individuals.

Methods

During 2011–2018, 11 pedaitric patients with MSUD from 11 Chinese families were analyzed based on clinical characteristics and mass spectrometry, with confirmation via gene sequencing. Novel mutations affecting protein function were predicted with Mutation-Taster, PolyPhen-2, CADD and SIFT software. 3D models of the mutated proteins were generated by using the SWISS-MODEL online server, and the models were visualized in PyMOL. The characteristics and gene mutations in patients with MSUD were analyzed retrospectively.

Results

Seventeen mutations in the BCKDHA, BCKDHB and DBT genes were found, 8 of which are novel: c.55C>/T, c.349C>T, c.565C>T, c.808G>A, c.859C>G, and c.1270dupC in BCKDHA; c.275-2A>G in BCKDHB; and c.1291C>T in DBT. Eight patients died. Two patients had severe mental retardation and were physically handicapped. One patient with the intermediate type had relatively good prognosis, with mild psychomotor retardation and adiposity. Four mothers underwent amniocentesis for prenatal diagnosis during their second pregnancy; two fetuses were wild type, and two were carriers of one heterozygous mutation.

Conclusions

Eight novel mutations were associated with MSUD in Chinese patients. Prenatal diagnosis was successfully performed by genetic analysis. Mutations in the BCKDHB gene were found in the majority of Chinese patients with MSUD.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Treacy E, Clow CL, Reade TR, Chitayat D, Mamer OA, Scriver CR. Maple syrup urine disease: interrelations between branched-chain amino-, oxo- and hydroxyacids; implications for treatment; associations with CNS dysmyelination. J Inherit Metab Dis. 1992;15:121–35.

    Article  CAS  PubMed  Google Scholar 

  2. Ambrus A, Adam-Vizi V. Human dihydrolipoamide dehydrogenase (E3) deficiency: novel insights into the structural basis and molecular pathomechanism. Neurochem Int. 2018;117:5–14.

    Article  CAS  PubMed  Google Scholar 

  3. Menkes JH, Hurst PL, Craig JM. A new syndrome: progressive familial infantile cerebral dysfunction associated with an unusual urinary substance. Pediatrics. 1954;14:462–7.

    Article  CAS  PubMed  Google Scholar 

  4. Blackburn P, Gass J, Vairo FPE, Farnham KM, Atwal HK, Macklin S, et al. Maple syrup urine disease: mechanisms and management. Appl Clin Genet. 2017;10:57–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Nellis MM, Danner DJ. Gene preference in maple syrup urine disease. Am J Hum Genet. 2001;68:232–7.

    Article  CAS  PubMed  Google Scholar 

  6. Wang XL, Li CJ, Xing Y, Yang YH, Jia JP. Hypervalinemia and hyperleucine–isoleucinemia caused by mutations in the branched-chain-amino-acid aminotransferase gene. J Inherit Metab Dis. 2015;38:855–61.

    Article  CAS  PubMed  Google Scholar 

  7. Knerr I, Colombo R, Urquhart J, Morais A, Merinero B, Oyarzabal A, et al. Expanding the genetic and phenotypic spectrum of branched-chain amino acid transferase 2 deficiency. J Inherit Metab Dis. 2019;42:809–17.

    Article  CAS  PubMed  Google Scholar 

  8. Puffenberger EG. Genetic heritage of the old order mennonites of Southeastern Pennsylvania. Am J Med Genet C Semin Med Genet. 2003;121C:18–311.

    Article  CAS  PubMed  Google Scholar 

  9. Abiri M, Karamzadeh R, Mojbafan M, Alaei MR, Jodaki A, Safi M, et al. In silico analysis of novel mutations in maple syrup urine disease patients from Iran. Metab Brain Dis. 2017;32:105–13.

    Article  CAS  PubMed  Google Scholar 

  10. Sun W, Wang Y, Yang Y, Wang J, Cao Y, Luo F, et al. The screening of inborn errors of metabolism in sick Chinese infants by tandem mass spectrometry and gas chromatography/mass spectrometry. Clin Chim Acta. 2011;412:1270–4.

    Article  CAS  PubMed  Google Scholar 

  11. Yang C, Linpeng S, Cao Y, Wu L. Identification of six novel mutations in five infants with suspected maple syrup urine disease based on blood and urine metabolism screening. Gene. 2019;710:9–16.

    Article  CAS  PubMed  Google Scholar 

  12. Li XY, Ding Y, Liu Y, Ma Y, Song J, Wang Q, et al. 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. 2015;58:617–23.

    Article  PubMed  Google Scholar 

  13. Li X, Yang Y, Gao Q, Gao M, Lv Y, Dong R, et al. Clinical characteristics and mutation analysis of five Chinese patients with maple syrup urine disease. Metab Brain Dis. 2018;33:741–51.

    Article  CAS  PubMed  Google Scholar 

  14. Su L, Lu Z, Li F, Shao Y, Sheng H, Cai Y, et al. Two homozygous mutations in the exon 5 of BCKDHB gene that may cause the classic form of maple syrup urine disease. Metab Brain Dis. 2017;32:765–72.

    Article  CAS  PubMed  Google Scholar 

  15. Han B, Han B, Guo B, Liu Y, Cao Z. Two novel mutations in the BCKDHB gene that cause maple syrup urine disease. Pediatr Neonatol. 2018;59:515–9.

    Article  PubMed  Google Scholar 

  16. Liu G, Ma D, Hu P, Wang W, Luo C, Wang Y, et al. A novel whole gene deletion of BCKDHB by alu-mediated non-allelic recombination in a Chinese patient with maple syrup urine disease. Front Genet. 2018;9:145–54.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Liu Y, Chu X, Liu R, Sun Y, Kong Q, Li Q. Paroxysmal spasticity of lower extremities as the initial symptom in two siblings with maple syrup urine disease. Mol Med Rep. 2019;19:4872–80.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Cox DM, Niewczas-Late V, Riffell MI, Hamerton JL. Chromosomal mosaicism in diagnostic amniotic fluid cell cultures. Pediatr Res. 1974;8:679–83.

    Article  CAS  PubMed  Google Scholar 

  19. Bienert S, Waterhouse A, de Beer TA, Tauriello G, Studer G, Bordoli L, et al. The SWISS-MODEL repository-new features and functionality. Nucleic Acids Res. 2017;45:D313–9.

    Article  CAS  PubMed  Google Scholar 

  20. Waterhouse A, Bertoni M, Bienert S, Studer G, Tauriello G, Gumienny R, et al. SWISS-MODEL: homology modelling of protein structures and complexes. Nucleic Acids Res. 2018;46:W296–303.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Kato M, Wynn RM, Chuang JL, Brautigam CA, Custorio M, Chuang DT. A synchronized substrate-gating mechanism revealed by cubic-core structure of the bovine branched-chain α-ketoacid dehydrogenase complex. EMBO J. 2006;25:5983–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Machius M, Wynn RM, Chuang JL, Li J, Kluger R, Yu D, et al. A versatile conformational switch regulates reactivity in human branched-chain α-ketoacid dehydrogenase. Structure. 2006;14:287–98.

    Article  CAS  PubMed  Google Scholar 

  23. Yang N, Han L, Gu X, Ye J, Qiu W, Zhang H, et al. Analysis of gene mutations in Chinese patients with maple syrup urine disease. Mol Genet Metab. 2012;106:412–8.

    Article  CAS  PubMed  Google Scholar 

  24. Chuang JL, Fisher CR, Cox RP, Chuang DT. Molecular basis of maple syrup urine disease: novel mutations at the E1 alpha locus that impair E1(alpha 2 beta 2) assembly or decrease steady-state E1 alpha mRNA levels of branched-chain alpha-keto acid dehydrogenase complex. Am J Hum Genet. 1994;55:297–304.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Dursun A, Henneke M, Ozgul K, Gartner J, Coşkun T, Tokatli A, et al. Maple syrup urine disease: mutation analysis in Turkish patients. J Inherit Metab Dis. 2002;25:89–97.

    Article  CAS  PubMed  Google Scholar 

  26. Park HD, Lee DH, Hong YH, Kang DH, Lee YK, Song J, et al. Three Korean patients with maple syrup urine disease: four novel mutations in the BCKDHA gene. Ann Clin Lab Sci. 2011;41:167–73.

    CAS  PubMed  Google Scholar 

  27. Henneke M, Flaschker N, Helbling C, Müller M, Schadewaldt P, Gärtner J, et al. Identification of twelve novel mutations in patients with classic and variant forms of maple syrup urine disease. Hum Mutat. 2003;22:417–24.

    Article  PubMed  CAS  Google Scholar 

  28. Flaschker N, Feyen O, Fend S, Simon E, Schadewaldt P, Wendel U. Description of the mutations in 15 subjects with variant forms of maple syrup urine disease. J Inherit Metab Dis. 2007;30:903–9.

    Article  CAS  PubMed  Google Scholar 

  29. Imtiaz F, Al-Mostafa A, Allam R, Ramzan K, Al-Tassan N, Tahir AI, et al. Twenty novel mutations in BCKDHA, BCKDHB and DBT genes in a cohort of 52 Saudi Arabian patients with maple syrup urine disease. Mol Genet Metab Rep. 2017;11:17–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Fisher CW, Fisher CR, Chuang JL, Lau KS, Chuang DT, Cox RP. Occurrence of a 2-bp (AT) deletion allele and a nonsense (G-to-T) mutant allele at the E2 (DBT) locus of six patients with maple syrup urine disease: multiple-exon skipping as a secondary effect of the mutations. Am J Hum Genet. 1993;52:414–24.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Scaini G, Tonon T, Moura de Souza CF, Schuck PF, Ferreira GC, Quevedo J, et al. Evaluation of plasma biomarkers of inflammation in patients with maple syrup urine disease. J Inherit Metab Dis. 2018;41:631–40.

    Article  CAS  Google Scholar 

  32. Venselaar H, Te Beek TA, Kuipers RK, Hekkelman ML, Vriend G. Protein structure analysis of mutations causing inheritable diseases. An e-Science approach with life scientist friendly interfaces. BMC Bioinform. 2010;11:548–57.

    Article  CAS  Google Scholar 

  33. Abi-Wardé MT, Roda C, Arnoux JB, Servais A, Habarou F, Brassier A, et al. Long-term metabolic follow-up and clinical outcome of 35 patients with maple syrup urine disease. J Inherit Metab Dis. 2017;40:783–92.

    Article  PubMed  Google Scholar 

  34. Bouchereau J, Leduc-Leballeur J, Pichard S, Imbard A, Benoist JF, Abi Warde MT, et al. Neurocognitive profiles in MSUD school-age patients. J Inherit Metab Dis. 2017;40:377–83.

    Article  PubMed  Google Scholar 

  35. Servais A, Arnoux JB, Lamy C, Hummel A, Vittoz N, Katerinis I, et al. Treatment of acute decompensation of maple syrup urine disease in adult patients with a new parenteral amino-acid mixture. J Inherit Metab Dis. 2013;36:939–44.

    Article  CAS  PubMed  Google Scholar 

  36. Lee JY, Chiong MA, Estrada SC, Cutiongco-De la Paz EM, Silao CLT, Padilla CD. Maple syrup urine disease (MSUD)-clinical profile of 47 Filipino patients. J Inherit Metab Dis. 2008;31:281–5.

    Article  Google Scholar 

  37. Yoneshiro T, Wang Q, Tajima K, Matsushita M, Maki H, Igarashi K, et al. BCAA catabolism in brown fat controls energy homeostasis through SLC25A44. Nature. 2019;572:614–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Lynch CJ, Adams SH. Branched-chain amino acids in metabolic signalling and insulin resistance. Nat Rev Endocrinol. 2014;10:723–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Frazier DM, Allgeier C, Homer C, Marriage BJ, Ogata B, Rohr F, et al. Nutrition management guideline for maple syrup urine disease: an evidence- and consensus-based approach. Mol Genet Metab. 2014;112:210–7.

    Article  CAS  PubMed  Google Scholar 

  40. Yasui T, Suzuki T, Hara F, Watanabe S, Uga N, Naoe A, et al. Successful living donor liver transplantation for classical maple syrup urine disease. Pediatr Transpl. 2016;20:707–10.

    Article  CAS  Google Scholar 

  41. Ali EZ, Ngu LH. Fourteen new mutations of BCKDHA, BCKDHB and DBT genes associated with maple syrup urine disease (MSUD) in Malaysian population. Mol Genet Metab Rep. 2018;17:22–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

The authors want to thank all patients and their families for their assistance and support. We express our thanks to all those colleagues involved in patient care.

Funding

This work was supported by Grants from the National Key Research and Development Program of China (2016YFC0905100).

Author information

Authors and Affiliations

  1. Institute of Pediatrics, Shanghai Key Laboratory of Birth Defects, Children’s Hospital of Fudan University, Wanyuan Road 399, Shanghai, 201102, China

    Wei-Hua Sun, Bing-Bing Wu, Ya-Qiong Wang, Meng-Yuan Wu, Xin-Ran Dong, Ping Zhang, Hong-Jiang Wu & Wen-Hao Zhou

  2. Key Laboratory of Neonatal Diseases, Ministry of Health, Children’s Hospital of Fudan University, Shanghai, 201102, China

    Bing-Bing Wu & Wen-Hao Zhou

  3. Department of Endocrinology, Children’s Hospital of Fudan University, Shanghai, 201102, China

    Wei Lu

  4. Shanghai Ji-ai Genetics and IVF Institute, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, 200011, China

    Yue-Ping Zhang

  5. Shanghai Key Laboratory of Birth Defects, The Translational Medicine Center of Children Development and Disease of Fudan University, Children’s Hospital of Fudan University, Shanghai, 201102, China

    Wen-Hao Zhou

  6. Department of Radiology, Children’s Hospital of Shanghai, Shanghai, 201102, China

    Bin Yang

  7. Department of Neurology, Children’s Hospital of Fudan University, Shanghai, 201102, China

    Min Zhang

Authors
  1. Wei-Hua Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bing-Bing Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ya-Qiong Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Meng-Yuan Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xin-Ran Dong
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yue-Ping Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Wei Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ping Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Bin Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Min Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Hong-Jiang Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Wen-Hao Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

WHS contributed to the conception and design, collection and assembly of data, data analysis and interpretation, and drafting/revising the manuscript. YQW, YMW, and XRD contributed to in silico analysis. BBW, WL, PZ, YPZ, BY, MZ, and HJW contributed to provision of study materials or patients. WHZ contributed to the conception, design, and the administrative support. All authors approved the final manuscript as submitted.

Corresponding author

Correspondence to Wen-Hao Zhou.

Ethics declarations

Ethical approval

This study was approved by the ethics committee of Children’s Hospital, Fudan University. Informed consent for publication was obtained from all of the families of individual participants included in the study.

Conflict of interest

The authors have no conflicts of interest to declare.

Informed consent

All guardians of the subjects included in this study provided appropriate informed consent.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sun, WH., Wu, BB., Wang, YQ. et al. Identification of eight novel mutations in 11 Chinese patients with maple syrup urine disease. World J Pediatr 16, 401–410 (2020). https://doi.org/10.1007/s12519-020-00349-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12519-020-00349-1

Keywords

Search

Navigation