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.
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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
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
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
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
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
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
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–S285
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
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
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
Menkes JH, Hurst PL, Craig JM (1954) A new syndrome: progressive familial infantile cerebral dysfunction associated with an unusual urinary substance. Pediatrics 14(5):462–467
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
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
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
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
Stoddard JL, Niemela JE, Fleisher TA, Rosenzweig SD (2014) Targeted NGS: a cost-effective approach to molecular diagnosis of PIDs. Front Immunol 5:531
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
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):827–829
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
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
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
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.
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Li, X., Yang, Y., Gao, Q. et al. Clinical characteristics and mutation analysis of five Chinese patients with maple syrup urine disease. Metab Brain Dis 33, 741–751 (2018). https://doi.org/10.1007/s11011-017-0168-0
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DOI: https://doi.org/10.1007/s11011-017-0168-0