MYOT基因新发杂合变异致肌原纤维肌病一家系报道并文献复习  

Myofibrillar myopathies caused by a de novo heterozygous mutation in MYOT gene: a family report and literature review

作　　者：胡聪 郑献召 瞿千千 马晓丽 崔文豪 周亚光 王佳璇 吕海东 Hu Cong;Zheng Xianzhao;Qu Qianqian;Ma Xiaoli;Cui Wenhao;Zhou Yaguang;Wang Jiaxuan;Lyu Haidong(Department of Neurology,Jiaozuo People's Hospital Affiliated to Xinxiang Medical University,Jiaozuo 454002,China)

机构地区：[1]新乡医学院附属焦作市人民医院神经内科,焦作454002

出　　处：《中华神经医学杂志》2024年第12期1234-1241,共8页Chinese Journal of Neuromedicine

基　　金：河南省医学科技攻关计划(LHGJ20240705)。

摘　　要：目的探讨MYOT基因变异致肌原纤维肌病(MFMs)的临床表型、肌肉MRI和病理改变、基因变异特点。方法(1)收集新乡医学院附属焦作市人民医院神经内科2021年2月收治的MYOT基因变异致MFMs一家系患者的临床资料,应用肌电图、肌肉MRI、病理检查明确先证者肌肉病变情况,采用第二代测序(NGS)、Sanger测序分别检测先证者和其他家系成员MYOT基因的变异,采用AlphaFold3及pymol3对基因变异前后myotilin蛋白的3D结构模型进行预测和分析。(2)应用计算机在Pubmed数据库和中国知网中检索自建库至2024年7月报道的MYOT基因变异致MFMs的相关文献,总结文献中报道的MYOT基因变异致MFMs患者的临床、基因变异特点。结果(1)本家系中9例患者,其中8例患者在青少年期(16~20岁)发病,多以单侧或双侧手部肌无力为首发症状,后逐渐出现手部肌肉萎缩,并向肢体近端缓慢进展。肌电图示肌源性损害。肌肉MRI示双侧胫前肌组织内斑片状长T1、长T2信号影。肌肉病理染色显示部分肌纤维内有典型镶边空泡、胞浆体、涂擦样肌纤维和结蛋白异常沉积,电镜下可见肌原纤维结构紊乱、局灶性肌原纤维溶解、Z带流动、肌膜下或肌原纤维间线粒体堆积。8例患者及先证者女儿均存在MYOT基因c.680_683del(p.Val227GlufsTer10)位点杂合变异。MYOT基因c.680_683del位点变异可导致myotilin蛋白的翻译提前终止、截短蛋白产生,使其丧失原有的正常结构及功能。(2)既往文献中89例MYOT基因变异致MFMs患者的临床表现主要为慢性进行性肢体远端或近端肌无力,部分可伴有心肌、呼吸肌和周围神经受累。共报道12个MYOT基因变异位点,其中p.Ser60Phe为最常见的变异位点。除p.Tyr4_His9del为框内变异外,其余位点均为错义变异。结论MYOT基因变异致MFMs患者具有较强的临床异质性,肌无力症状进展十分缓慢。MYOT基因位点c.680_683del(p.Val227GlufsTer10)变异为�ObjectiveTo investigate the clinical phenotypes,muscle magnetic resonance imaging(MRI)and pathological changes,and genetic characteristics of myfibrillar myopathies(MFMs)cuased by MYOT gene mutation.Methods(1)The clinical data of a MFMs family caused by a de novo frameshift mutation in MYOT gene admitted to Department of Neurology,Jiaozuo People's Hospital Affiliated to Xinxiang Medical University in February 2021 were collected.Electromyography,muscle MRI,and pathological examination were used to confirm the changes of the muscle lesions.MYOT gene mutation in the proband and other patients was detected by next generation sequencing(NGS)and Sanger sequencing,respectively.The 3D structure models of myotilin protein before and after gene mutation were predicted by AlphaFold3 and pymol3.(2)Literature on MFMs caused by MYOT gene mutation was searched from Pubmed and China National Knowledge Infrastructure from the establishment of these databases to July 2024;clinical and genetic characteristics of MFMs caused by MYOT gene mutation were summarized.Results(1)In the 9 patients from this family,8 had onset in adolescence(16-20 years old).Unilateral or bilateral hand muscle weakness as the first symptoms appeared in most patients,and then,hand muscle atrophy gradually appeared and slowly progressed to the proximal limbs.Electromyography showed myogenic damage.Muscle MRI showed patchy long T1 and long T2 signal intensity in the bilateral anterior tibial muscles.Muscle pathological staining showed typical rimbed vacuoles,cytoplasm,smear-like muscle fibers and desmin abnormal deposition in some muscle fibers;electron microscopy revealed disorganized myofibril structures,focal myofibril lysis,Z-band streaming,and subsarcolemmal or myofibril mitochondrial accumulation.Heterozygous mutation in MYOT gene c.680_683del(p.Val227GlufsTer10)locus was noted in 8 patients and daughter of the proband.Bioinformatics analysis suggested that MYOT gene c.680_683del mutation could cause premature termination of myotilin translation,leading

关 键 词：肌原纤维肌病 MYOT基因 临床特点 肌肉MRI 肌肉病理 

分 类 号：R73[医药卫生—肿瘤]