张琼哲;吴世陶;崔明;张敏;石伟伟;刘恒方;

• 1:郑州大学第五附属医院

摘要(Abstract)：

目的分析Bethlem肌病临床表型和基因突变特点。方法报道一家系3例女性患者临床表型、肌电图、肌肉活检、肌肉病理学和基因检测结果,并结合相关文献进行分析。结果先证者于13岁发病,以进行性四肢近端无力为主要临床表现。血清学肌酸激酶水平显著升高,肌电图呈肌源性损害,肌肉病理学显示骨骼肌局灶坏死等非特异性肌源性损害。基因检测显示,先证者及其母、其妹存在相同基因突变,即COL6A3基因错义突变c.4270C>T。结论该家系Bethlem肌病患者为COL6A3基因突变致病,临床通过基因测序手段可提高诊断率,有助于产前诊断,减少遗传病发生率。

关键词(KeyWords)： 遗传性疾病;Bethlem肌病;临床表现;Ⅳ型胶原蛋白;COL6A3基因

Abstract:

Keywords:

基金项目(Foundation): 河南省医学科技攻关计划省部共建项目（编号：SB201901055）

作者(Authors): 张琼哲;吴世陶;崔明;张敏;石伟伟;刘恒方;

参考文献(References)：

• [1]BNNEMANN C G.The collagenⅥ-related myopathies:muscle meets its matrix[J].Nat Rev Neurol,2011,7(7):379-390.DOI:10.1038/nrneurol.2011.81.
• [2]CHOI E,SHIN S,LEE S,et al.Coexistence of digenic mutations in the collagenⅥgenes (COL6A1 and COL6A3)leads to Bethlem myopathy[J].Clin Chim Acta,2020,508:28-32.DOI:10.1016/j.cca.2020.05.011.
• [3]SUREZ B,LOZANO-ARANGO A,ARANEDA D,et al.CollagenⅥrelated myopathies.When to suspect,how to identify.The contribution of muscle magnetic resonance[J].Rev Chil Pediatr,2018,89(3):399-408.DOI:10.4067/S0370-4106201800 5000305.
• [4]SALIM R,DAHLQVIST J R,KHAWAJAZADA T,et al.Characteristic muscle signatures assessed by quantitative MRI in patients with Bethlem myopathy[J].J Neurol,2020,267(8):2432-2442.DOI:10.1007/s00415-020-09860-x.
• [5]SABATELLI P,GUALANDI F,BONALDO P,et al.Detecting CollagenⅥin Bethlem Myopathy[J].J Biol Chem,2015,290(12):8011.DOI:10.1074/jbc.L115.639088.
• [6]SAITO W,IMURA T,MIYAGI M,et al.Cervical Hyperextension Treated by Posterior Spinal Correction and Fusion in A Patient with Ullrich Congenital Muscular Dystrophy:A Case Report[J].JBJS Case Connect,2020,10(2):e0392.DOI:10.2106/JBJS.CC.19.00392.
• [7]何展文，陈启慧，李平甘，等.多重连接探针扩增和二代测序技术检测Duchenne型肌营养不良基因分析[J].中国实用神经疾病杂，2020,23(14):1209-1212.DOI:10.12083/SYSJ.2020.14.274.
• [8]赵爱玲，丁大领，李雪琴，等.婴儿期Duchenne型肌营养不良的临床分析[J].中国实用神经疾病杂志，2019,22(8):842-846.DOI:10.12083/SYSJ.2019.08.104.
• [9]DONKERVOORT S,HU Y,STOJKOVIC T,et al.Mosaicism for Dominant Collagen 6 Mutations as a Cause for Intrafamilial Phenotypic Variability[J].Hum Mutat,2015,36(1):48-56.DOI:10.1002/humu.22691.
• [10]ZANOTELI E,SOARES P S,DA SILVA A M S,et al.Clinical features of collagenⅥ-related dystrophies:A large Brazilian cohort[J].Clin Neurol Neurosurg,2020,192:105734.DOI:10.1016/j.clineuro.2020.105734.
• [11]ALESSANDRA Z,FRANCESCA T,ERIKA R,et al.Melanocytes from Patients Affected by Ullrich Congenital Muscular Dystrophy and Bethlem Myopathy have Dysfunctional Mitochondria That Can be Rescued with Cyclophilin Inhibitors[J].Front Aging Neurosci,2014,6:324.DOI:10.3389/fnagi.2014.00324.
• [12]ANTONIEL M,TRAINA F,MERLINI L,et al.Tendon Extracellular Matrix Remodeling and Defective Cell Polarization in the Presence of CollagenⅥMutations[J].Cells,2020,9(2):409.DOI:10.3390/cells9020409.
• [13]FU J,ZHENG Y M,JIN S Q,et al."Target"and"Sandwich"Signs in Thigh Muscles have High Diagnostic Values for CollagenⅥ-related Myopathies[J].Chin Med J(Engl),2016,129(15):1811-1816.DOI:10.4103/0366-6999.186638.
• [14]SU L,ZHANG J,MENG H,et al.Prevalence of BRCA1/2 large genomic rearrangements in Chinese women with sporadic triple-negative or familial breast cancer[J].Clin Genet,2018,94(1):165-169.DOI:10.1111/cge.13256.
• [15]BAO M,MAO F,ZHAO Z,et al.COL6A1 mutation leading to Bethlem myopathy with recurrent hematuria:a case report[J].BMC Neurol,2019,19(1):32.DOI:10.1186/s12883-019-1263-0.
• [16]WESTRA D,SCHOUTEN M,STUNNENBERG B,et al.Panel-Based Exome Sequencing for Neuromuscular Disorders as a Diagnostic Service[J].J Neuromuscul Dis,2019,6(2):241-258.DOI:10.3233/JND-180376.
• [17]BUTTERFIELD R J,FOLEY A R,DASTGIR J,et al.Position of glycine substitutions in the triple helix of COL6A1,COL6A2,and COL6A3 is correlated with severity and mode of inheritance in collagenⅥmyopathies[J].Hum Mutat,2013,34(11):1558-1567.DOI:10.1002/humu.22429.
• [18]ZHANG Y Z,ZHAO D H,YANG H P,et al.Novel collagenⅥmutations identified in Chinese patients with Ullrich congenital muscular dystrophy[J].World JPediatr,2014,10(2):126-132.DOI:10.1007/s12519-014-0481-1.
• [19]IDOUX R,BRETAUD S,BERTHIER C,et al.Unraveling the pathophysiology of Bethlem Myopathy using a unique zebrafish model for the disease[J].Med Sci(Paris),2019,2:39-42.DOI:10.1051/medsci/2019182.
• [20]BUSHBY K M,COLLINS J,HICKS D.Collagen typeⅥmyopathies[J].Adv Exp Med Biol,2014,802:185-199.DOI:10.1007/978-94-007-7893-1_12.
• [21]MERCURI E,LAMPE A,ALLSOP J,et al.Muscle MRI in Ullrichcongenital muscular dystrophy and Bethlem myopathy[J].Neuromuscul Disord,2005,15(4):303-310.DOI:10.1016/j.nmd.2005.01.004.
• [22]CARIA F,CESCON M,GUALANDI F,et al.Autosomal recessive Bethlem myopathy:A clinical,genetic and functional study[J].Neuromuscul Disord,2019,29(9):657-663.DOI:10.1016/j.nmd.2019.07.007.
• [23]BERNARDI P,BONALDO P.Mitochondrial dysfunction and defective autophagy in the pathogenesis of collagenⅥmuscular dystrophies[J].Cold Spring Harb Perspect Biol,2013,5(5):a011387.DOI:10.1101/cshperspect.a011387.
• [24]FAN Y,LIU A,WEI C,et al.Genetic and clinical findings in a Chinese cohort of patients with collagen VI-related myopathies[J].Clin Genet,2018,93(6):1159-1171.DOI:10.1111/cge.13230.
• [25]PIOTR F J,ANNA M,MARCIN P,et al.Whole-exome sequencing identifies novel pathogenic mutations and putative phenotype-influencing variants in Polish limb-girdle muscular dystrophy patients[J].Hum Genomics,2018,12(1):34.DOI:10.1186/s40246-018-0167-1.
• [26]GADD S,HUFF V,WALZ A L,et al.A Children’s Oncology Group and TARGET initiative exploring the genetic landscape of Wilms tumor[J].Nat Genet,2017,49(10):1487-1494.DOI:10.1038/ng.3940.
• [27]PANADéS-DE OLIVEIRA L,RODRíGUEZ-LóPEZC,CANTERO MONTENEGRO D,et al.Bethlem myopathy:a series of 16 patients and description of seven new associated mutations[J].J Neurol,2019,266(4):934-941.DOI:10.1007/s00415-019-09217-z.
• [28]STAVUSIS J,MICULE I,WRIGHT N T,et al.CollagenⅥ-related limb-girdle syndrome caused by frequent mutation in COL6A3 gene with conflicting reports of pathogenicity[J].Neuromuscul Disord,2020,30(6):483-491.DOI:10.1016/j.nmd.2020.03.010.