Advertisement

Metabolic Brain Disease

, Volume 33, Issue 3, pp 741–751 | Cite as

Clinical characteristics and mutation analysis of five Chinese patients with maple syrup urine disease

  • Xiaomei Li
  • Yali Yang
  • Qing Gao
  • Min Gao
  • Yvqiang Lv
  • Rui Dong
  • Yi Liu
  • Kaihui Zhang
  • Zhongtao Gai
Original Article
  • 272 Downloads

Abstract

Maple syrup urine disease (MSUD) is an autosomal recessive disorder affecting branched-chain amino acids (BCAAs) metabolism and caused by a defect in the thiamine-dependent enzyme branched chain α-ketoacid dehydrogenase (BCKD) with subsequent accumulation of BCAAs and corresponding branched-chain keto acids (BCKAs) metabolites. Presently, at least 4 genes of BCKDHA, BCKDHB, DLD and DBT have been reported to cause MSUD. Furthermore, more than 265 mutations have been identified as the cause across different populations worldwide. Some studies have reported the data of gene mutations in Chinese people with MSUD. In this study, we present clinical characteristics and mutational analyses in five Chinese Han child with MSUD, which had been screened out by tandem mass spectrometry detection of amino acids in blood samples. High-throughput sequencing, Sanger sequence and real-time qualitative PCR were performed to detect and verify the genetic mutations. Six different novel genetic variants were validated in BCKDHB gene and BCKDHA gene, including c.523 T > C, c.659delA, c.550delT, c.863G > A and two gross deletions. Interestingly, 3 cases had identical mutation of BCKDHB gene (c.659delA). We predicted the pathogenicity and analyzed the clinical characteristics. The identification of these mutations in this study further expands the mutation spectrum of MSUD and contributes to prenatal molecular diagnosis of MSUD.

Keywords

Maple syrup urine disease BCKDHA BCKDHB Mutation 

Notes

Acknowledgments

This work was financially supported by The Natural Science Training Foundation of Shandong Province (ZR2014HP051) and Jinan Excellent Science and Technology Innovation Team Project (20150515). The authors are grateful to the patients and their parents for their contribution to the study. We would like to thank SinoPath (Beijing) Medical Laboratory for technical support.

Compliance with ethical standards

Conflicts of interests

There are no conflicts of interest.

References

  1. Abiri M, Karamzadeh R, Karimipoor M, Ghadami S, Alaei MR, Bagheri SD, Bagherian H, Setoodeh A, Noori-Daloii MR, Sirous Z (2016) Identification of six novel mutations in Iranian patients with maple syrup urine disease and their in silico analysis. Mutat Res 786:34–40.  https://doi.org/10.1016/j.mrfmmm.2016.01.005 CrossRefPubMedGoogle Scholar
  2. Abiri M, Karamzadeh R, Mojbafan M, Alaei MR, Jodaki A, Safi M, Kianfar S, Bandehi Sarhaddi A, Noori-Daloii MR, Karimipoor M, Zeinali S (2017) In silico analysis of novel mutations in maple syrup urine disease patients from Iran. Metab Brain Dis 32(1):105–113.  https://doi.org/10.1007/s11011-016-9867-1 CrossRefPubMedGoogle Scholar
  3. Al-Shamsi A, Baker A, Dhawan A, Hertecant J (2016) Acute metabolic crises in maple syrup urine disease after liver transplantation from a related heterozygous living donor. JIMD Rep 30:59–62.  https://doi.org/10.1007/8904_2016_532 CrossRefPubMedPubMedCentralGoogle Scholar
  4. Burrage LC, Nagamani SC, Campeau PM, Lee BH (2014) Branched-chain amino acid metabolism: from rare Mendelian diseases to more common disorders. Hum Mol Genet 23(R1):R1–R8.  https://doi.org/10.1093/hmg/ddu123 CrossRefPubMedPubMedCentralGoogle Scholar
  5. 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(6):1395–1400.  https://doi.org/10.1007/s11011-015-9711-z CrossRefPubMedGoogle Scholar
  6. Hou JW, Hwang TL (2014) Different gene preferences of maple syrup urine disease in the aboriginal tribes of Taiwan. Pediatr Neonatol 55(3):213–217.  https://doi.org/10.1016/j.pedneo.2013.09.009 CrossRefPubMedGoogle Scholar
  7. Lee JY, Chiong MA, Estrada SC, Cutiongco-De la Paz EM, Silao CL, Padilla CD (2008) Maple syrup urine disease (MSUD)--clinical profile of 47 Filipino patients. J Inherit Metab Dis 31(Suppl 2):S281–S285CrossRefPubMedGoogle Scholar
  8. Li X, Ding Y, Liu Y, Ma Y, Song J, Wang Q, Li M, Qin Y, Yang Y (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(11):617–623.  https://doi.org/10.1016/j.ejmg.2015.10.002 CrossRefPubMedGoogle Scholar
  9. Lin N, Ye J, Qiu W, Han L, Zhang H, Gu X (2013) Application of liquid chromatography -tandem mass spectrometry in the diagnosis and follow-up of maple syrup urine disease in a Chinese population. J Pediatr Endocrinol Metab 26(5–6):433–439.  https://doi.org/10.1515/jpem-2012-0343 PubMedCrossRefGoogle Scholar
  10. Lu G, Sun H, She P, Youn JY, Warburton S, Ping P, Vondriska TM, Cai H, Lynch CJ, Wang Y (2009) Protein phosphatase 2Cm is a critical regulator of branched-chain amino acid catabolism in mice and cultured cells. J Clin Invest 119(6):1678–1687.  https://doi.org/10.1172/JCI38151 CrossRefPubMedPubMedCentralGoogle Scholar
  11. Menkes JH, Hurst PL, Craig JM (1954) A new syndrome: progressive familial infantile cerebral dysfunction associated with an unusual urinary substance. Pediatrics 14(5):462–467PubMedGoogle Scholar
  12. 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 28(5–6):673–675.  https://doi.org/10.1515/jpem-2014-0341 PubMedCrossRefGoogle Scholar
  13. Oyarzabal A, Martínez-Pardo M, Merinero B, Navarrete R, Desviat LR, Ugarte M, Rodríguez-Pombo P (2013) A novel regulatory defect in the branched-chain α-keto acid dehydrogenase complex due to a mutation in the PPM1K gene causes a mild variant phenotype of maple syrup urine disease. Hum Mutat 34(2):355–362.  https://doi.org/10.1002/humu.22242 CrossRefPubMedGoogle Scholar
  14. Puffenberger EG (2003) Genetic heritage of the old order Mennonites of southeastern Pennsylvania. Am J Med Genet C: Semin Med Genet 121C(1):18–31.  https://doi.org/10.1002/ajmg.c.20003 CrossRefGoogle Scholar
  15. Ribas GS, Vargas CR, Wajner M (2014) L-carnitine supplementation as a potential antioxidant therapy for inherited neurometabolic disorders. Gene 533(2):469–476.  https://doi.org/10.1016/j.gene.2013.10.017 CrossRefPubMedGoogle Scholar
  16. Stoddard JL, Niemela JE, Fleisher TA, Rosenzweig SD (2014) Targeted NGS: a cost-effective approach to molecular diagnosis of PIDs. Front Immunol 5:531CrossRefPubMedPubMedCentralGoogle Scholar
  17. Taylor J, Robinson BH, Sherwood WG (1978) A defect in branched-chain amino acid metabolism in a patient with congenital lactic acidosis due to dihydrolipoyl dehydrogenase deficiency. Pediatr Res 12(1):60–62.  https://doi.org/10.1203/00006450-197801000-00018 CrossRefPubMedGoogle Scholar
  18. Wang J, Liu H, Chen G, Tsuei SH, Yu T, Fu Q (2011) Identification of two novel BCKDHA mutations in a Chinese patient with maple syrup urine disease. J Pediatr Endocrinol Metab 24(9–10):827–829PubMedGoogle Scholar
  19. 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(1):112–115.  https://doi.org/10.1016/j.gene.2012.01.082 CrossRefPubMedGoogle Scholar
  20. Yang N, Han L, Gu X, Ye J, Qiu W, Zhang H, Gong Z, Zhang Y (2012) Analysis of gene mutations in Chinese patients with maple syrup urine disease. Mol Genet Metab 106(4):412–418.  https://doi.org/10.1016/j.ymgme.2012.05.023 CrossRefPubMedGoogle Scholar
  21. Zeltner NA, Huemer M, Baumgartner MR, Landolt MA (2014) Quality of life, psychological adjustment, and adaptive functioning of patients with intoxication-type inborn errors of metabolism - a systematic review. Orphanet J Rare Dis 9(1):159.  https://doi.org/10.1186/s13023-014-0159-8 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2017

Authors and Affiliations

  • Xiaomei Li
    • 1
  • Yali Yang
    • 2
  • Qing Gao
    • 3
  • Min Gao
    • 4
  • Yvqiang Lv
    • 4
  • Rui Dong
    • 4
  • Yi Liu
    • 4
  • Kaihui Zhang
    • 4
  • Zhongtao Gai
    • 4
  1. 1.Department of NeonatologyQilu Children’s Hospital of Shandong UniversityJinanChina
  2. 2.Department of RehabilitationQilu Children’s Hospital of Shandong UniversityJinanChina
  3. 3.Department of GeneticsJinan Maternity and Child Care HospitalJinanChina
  4. 4.Pediatric Research InstituteQilu Children’s Hospital of Shandong UniversityJinanChina

Personalised recommendations