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

World Journal of Pediatrics volume 16, pages 401–410 (2020)Cite this article

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.

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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

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

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  1. Wei-Hua Sun
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  10. Min Zhang
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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.

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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.

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The authors have no conflicts of interest to declare.

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

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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

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Keywords

  • Branched-chain amino acids
  • Maple syrup urine disease
  • Mutation
  • Prenatal diagnosis