Synaptotagmins are integral synaptic vesicle membrane proteins that function as calcium sensors and regulate neurotransmitter release at the presynaptic nerve terminal. Synaptotagmin‐2 (SYT2), is the major isoform expressed at the neuromuscular junction. Recently, dominant missense variants in SYT2 have been reported as a rare cause of distal motor neuropathy and myasthenic syndrome, manifesting with stable or slowly progressive distal weakness of variable severity along with presynaptic NMJ impairment. These variants are thought to have a dominant‐negative effect on synaptic vesicle exocytosis, although the precise pathomechanism remains to be elucidated. Here we report seven patients of five families, with biallelic loss of function variants in SYT2, clinically manifesting with a remarkably consistent phenotype of severe congenital onset hypotonia and weakness, with variable degrees of respiratory involvement. Electrodiagnostic findings were consistent with a presynaptic congenital myasthenic syndrome (CMS) in some. Treatment with an acetylcholinesterase inhibitor pursued in three patients showed clinical improvement with increased strength and function. This series further establishes SYT2 as a CMS‐disease gene and expands its clinical and genetic spectrum to include recessive loss‐of‐function variants, manifesting as a severe congenital onset presynaptic CMS with potential treatment implications.

中文翻译：

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SYT2 中的双等位基因功能变异导致可治疗的先天性突触前肌无力综合征。

突触结合蛋白是完整的突触囊泡膜蛋白，其功能是钙传感器并调节突触前神经末梢的神经递质释放。Synaptotagmin-2 ( SYT2 ) 是在神经肌肉接头处表达的主要同种型。最近，SYT2的显性错义变异已被报道为远端运动神经病变和肌无力综合征的罕见原因，表现为稳定或缓慢进展的不同严重程度的远端无力以及突触前 NMJ 损伤。这些变体被认为对突触小泡胞吐作用具有显性负作用，尽管确切的发病机制仍有待阐明。在这里，我们报告了 5 个家族的 7 名患者，在SYT2 中具有双等位基因功能变体丧失，临床表现为严重的先天性肌张力减退和虚弱的非常一致的表型，并伴有不同程度的呼吸系统受累。一些电诊断结果与突触前先天性肌无力综合征 (CMS) 一致。在三名患者中进行的乙酰胆碱酯酶抑制剂治疗显示出临床改善，强度和功能增加。该系列进一步将SYT2确立为 CMS 疾病基因，并扩展其临床和遗传谱，包括隐性功能丧失变异，表现为严重的先天性突触前 CMS，具有潜在的治疗意义。