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摘要: 先天性肌无力综合征(CMS)是一组以神经肌肉接头信号传递功能障碍为主要特征的可部分治疗的罕见遗传性疾病。近年来，随着高通量测序的普及及对疾病认识的深入，已发现30余种CMS致病基因，且基因型与临床表型之间存在一定关联。CMS在临床上易误诊和漏诊，为了加强临床工作者对该类疾病的认识，本文对CMS主要亚型的分子机制、临床特征、电生理检测、病理特征及治疗予以归纳并总结。Abstract: Congenital Myasthenic syndrome (CMS) is a group of partially treatable genetic disorders characterized by dysfunction of neuromuscular junction signaling.With the popularization of high-throughput sequencing and in-depth understanding of the disease in recent years, more than thirty pathogenic genes have been discovered and there is a correlation between genotype and clinical phenotype.Misdiagnosis and missed diagnosis are common in clinical practice. This paper summarized the molecular mechanisms, clinical features, electrophysiologic, pathological features and treatment of main subtypes of CMS to deepen the understanding of the disease.
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图 1 神经肌肉接头结构及已知的CMS相关蛋白分布示意图
Figure 1. Scheme of NMJ structure and distribution of the proteins leading to CMS
表 1 CMS亚型的分子机制、表型特点和药物选择
Table 1. The molecular mechanism, phenotype and therapy choice of various CMS subtypes
分型 基因 遗传 分子机制 表型特点 治疗 突触前膜相关CMS 高亲和力胆碱转运体1 (ChT)缺陷 SLC5A7 AR 胆碱再摄取障碍 呼吸暂停发作，可有中枢神经系统症状，关节挛缩 AChEI有效 胆碱乙酰基转移酶(ChaT)缺陷 CHAT AR 缺陷时ACh合成和囊泡充填障碍 呼吸功能不全和窒息发作，眼外肌无明显受累，自发缓解倾向，可仅在持续运动后发生重频递减，寒冷加重 AChEI、沙丁胺醇有效 突触小体相关蛋白25B缺陷 SNAP25B AD 囊泡释放过程障碍 关节挛缩、小脑性共济失调、皮质过度兴奋和智力残疾 3, 4-DAP有效 突触结合蛋白2(synapto- tagmin-2)缺陷 SYT2 AD 钙离子感受器，与SNAP25B相互作用，影响囊泡释放的启动 CMAP波幅下降伴易化现象(突触前膜综合征)，运动神经病，足部畸形 3, 4-DAP有效 囊泡乙酰胆碱转运体(VAChT)缺陷 SLC18A3 AR ACh进入囊泡过程障碍 呼吸暂停发作，寒冷加重，学习困难，左心室功能不全，小头畸形，肌张力下降 AChEI有效 肌球蛋白9a缺陷 MYO9A AR 在突触发育中起神经元分支和轴突引导作用 婴儿起病，肌张力低，呼吸肌和球部受累，眼球震颤，眼肌麻痹 AChEI有效 MUNC13-1缺陷 MUNC13-1 AR 影响囊泡释放 呼吸功能不全，严重肌张力减退 3, 4-DAP、AChEI有效 囊泡相关膜蛋白1缺陷 VAMP1 AR 影响囊泡释放 肌张力下降，喂养困难 AChEI有效 PREPL缺陷 PREPL AR 乙酰胆碱转运至囊泡过程障碍 近端肌无力，肌张力低，喂养困难 AChEI有效 突触间隙相关CMS AChE缺陷 COLQ AR AChE缺陷，延长突触间隙内ACh的寿命 瞳孔对光反射延迟R-CMAP 沙丁胺醇或麻黄碱有效; AChEI和3, 4-DAP有害 层粘连蛋白β2缺陷 LAMB2 AR 神经末梢成熟和突触分化障碍 呼吸困难，近端肌无力，Pierson综合征 麻黄碱有效; AChEI无效或有害 层粘连蛋白α5缺陷 LAMA5 AR 影响突触后区域发育成熟 面部抽搐，近视 AChEI、3, 4-DAP有效 胶原蛋白13A1缺陷 COL13A1 AR 影响终板的发育成熟和突触前后区的黏附 出生时起病，伴有呼吸和喂养困难、面部特征轻微畸形和明显上睑下垂，眼球运动正常 3，4-DAP、沙丁胺醇有效 突触后膜相关CMS AChR缺陷 CHRNE
CHRNA
CHRNB
CHRNDAR AChR表达减少 眼外肌麻痹明显 AChEI、3, 4-DAP、沙丁胺醇有效 慢通道综合征 CHRNE
CHRNA
CHRNB
CHRNDAD AChR中央阳离子孔道开放时间延长 R-CMAP选择性颈肌、上肢远端肌肉受累 氟西汀或奎尼丁有效; AChEI及3, 4- DAP加重 快通道综合征 CHRNE
CHRNA
CHRNB
CHRNDAR AChR阳离子孔道开放时间缩短 眼外肌麻痹，呼吸危象 AChEI、3, 4-DAP、沙丁胺醇有效 Escobar综合征 CHRNG AR 影响运动突触的形成和定位 胎动减少，关节挛缩，脊柱侧凸，呼吸窘迫，颅面畸形，隐睾 AChEI有效 钠通道型肌无力 SCN4A AR NaV1.4通道动力学异常 婴儿期肌张力减退，发育迟滞，吞咽、吸吮困难，呼吸暂停发作 AChEI有效 网蛋白1缺陷 PLEC1 AR 细胞骨架成分的连接剂 单纯大疱性表皮松解症肌营养不良 AChEI有效 rapsyn缺陷 RAPSN AR Agrin-LRP4-MuSK-Dok7-rapsyn通路与AChR聚集障碍和终板发育维持有关 早期肌张力减退，呼吸肌无力，关节挛缩或畸形，呼吸暂停发作，眼睑下垂常见，眼外肌麻痹罕见 AChEI、3, 4-DAP、沙丁胺醇有效; 氟西汀可能有害 Dok7缺陷 DOK7 AR 以近端肌和中轴肌无力为主，面肌无力轻微，眼外肌多不受累，可出现严重的球部肌肉无力，可出现夜间喘鸣，舌肌萎缩 麻黄碱或沙丁胺醇有效; AChEI无效或有害 agrin缺陷 AGRN AR 远端肌无力和萎缩，眼外肌受累轻 沙丁胺醇有效; AChEI有害 LRP4缺陷 LRP4 AR 呼吸肌、近端肌受累 沙丁胺醇有效; AChEI有害 MuSK缺陷型 MUSK AR 肢带肌无力，呼吸肌受累 沙丁胺醇有效; AChEI无效或有害 糖基化缺陷 GFPT1缺陷
DPAGT1缺陷
ALG2缺陷
ALG14缺陷
GMPPB缺陷GFPT1
DPAGT1
ALG2
ALG14
GMPPBAR GMPPB涉及N-糖基化和O-糖基化; 其余涉及N-糖基化 肢带型肌无力，眼外肌和颅面肌保留，可伴先天畸形或学习认知功能障碍，肌活检可见管聚集和自噬空泡，GMPPB缺陷合并肌营养不良改变 AChEI、3, 4-DAP、沙丁胺醇有效 其他类型 线粒体柠檬酸转运体缺陷 SLC25A1 AR 不明确 呼吸暂停、视神经萎缩、癫痫发作、认知障碍、延髓功能障碍、羟基戊二酸尿症 3, 4-DAP、AChEI有效 核纤层蛋白相关蛋白1(LAP1) 缺陷 TOR1AIP1 AR 与细胞核和细胞质之间的通讯、染色质稳定性和转录控制有关。 肢带型肌无力，眼外肌和咽喉肌未受累，轻度近端肌萎缩，轻度踝关节挛缩 AChEI有效 SNAP25B:突触小体相关蛋白; CMAP:复合肌肉动作电位; AChEI:乙酰胆碱酯酶抑制剂; 3 ，4-DAP:3 ，4-二氨基吡啶; R-CMAP:重复复合肌肉动作电位; AChR:乙酰胆碱受体; AD:常染色体显性遗传; AR:常染色体隐性遗传 
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