Veterinary Department, University of Cambridge, Cambridge.
Nuffield Department fo Clinical Neuroscience, Neurosciences Group, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK.
Curr Opin Neurol. 2019 Oct;32(5):696-703. doi: 10.1097/WCO.0000000000000736.
Congenital myasthenic syndromes (CMS) are a group of heterogeneous inherited disorders caused by mutations in genes encoding proteins whose function is essential for the integrity of neuromuscular transmission. This review updates the reader on the expanding phenotypic spectrum and suggested improved treatment strategies.
As next-generation sequencing is taken into the clinic, its use is both continuing to unearth new causative genes in which mutations underlie CMS and also broadening the phenotypic spectrum for known CMS genes. The number of genes in which mutations may cause neuromuscular transmission defects has now passed 30. The defective transmission may be part of an overall more complex phenotype in which there may be muscle, central nervous system or other involvement. Notably, mutations in series of genes encoding proteins located in the presynatic motor bouton have been identified. Rare cases of mutations in basal laminar proteins of the synaptic cleft are coming to light and additional mutations/phenotypic features have been located in some of the larger neuromuscular junction proteins such as AGRN and MUSK, where previously mutation screening by sanger sequencing was time consuming and costly. Finally, there are more reports of the beneficial effects of treatment with β2-adrenergic receptor agonists in patients, and the study of their action in disease models.
Recent studies of the CMS illustrate the increasing complexity of the genetics and pathophysiological mechanisms involved. With therapy tailored for the underlying disease mechanism treatment, although incomplete, is usually life-transforming. However, treatment for newly identified conditions in which myasthenia is only one component within complex multisystem disorder will prove challenging.
先天性肌无力综合征（CMS）是一组异质性遗传性疾病，由编码蛋白质的基因突变引起，这些蛋白质的功能对于神经肌肉传递的完整性至关重要。本篇综述更新了读者对不断扩大的表型谱和建议的改进治疗策略的认识。
随着下一代测序技术进入临床，它不仅继续发现导致 CMS 的突变的新致病基因，而且还拓宽了已知 CMS 基因的表型谱。突变可能导致神经肌肉传递缺陷的基因数量现已超过 30 个。传递缺陷可能是更复杂的整体表型的一部分，其中可能存在肌肉、中枢神经系统或其他方面的受累。值得注意的是，现已鉴定出一系列位于突触前运动终板的编码蛋白质的基因突变。突触间隙基底膜蛋白的罕见突变也逐渐被发现，并且在一些较大的神经肌肉接头蛋白中，如 AGRN 和 MUSK，也发现了其他突变/表型特征，以前通过桑格测序进行突变筛选既耗时又昂贵。最后，有更多关于β2-肾上腺素能受体激动剂在患者中的治疗效果的报道，以及对其在疾病模型中的作用的研究。
CMS 的最新研究说明了所涉及的遗传学和病理生理学机制日益复杂。针对潜在疾病机制的治疗虽然不完整，但通常可以改变生活。然而，对于新发现的仅在复杂多系统疾病中有肌无力表现的疾病，治疗将具有挑战性。
