Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.
Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
Am J Med Genet A. 2020 Oct;182(10):2272-2283. doi: 10.1002/ajmg.a.61765. Epub 2020 Aug 10.
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.
突触结合蛋白是整合突触囊泡膜蛋白，作为钙传感器，调节神经递质在突触前神经末梢的释放。突触结合蛋白-2（SYT2）是在神经肌肉接头表达的主要同工型。最近，SYT2 中的显性错义变异被报道为一种罕见的远端运动神经病和肌无力综合征的原因，表现为稳定或缓慢进展的远端肌无力，严重程度不同，同时伴有突触前 NMJ 损伤。这些变异被认为对突触囊泡胞吐具有显性负效应，尽管确切的发病机制仍有待阐明。在这里，我们报告了五个家系的七名患者，SYT2 存在双等位基因功能丧失变异，临床上表现为严重先天性发作性张力减退和无力，伴有不同程度的呼吸受累。一些患者的电诊断结果与先天性肌无力综合征（CMS）的突触前表现一致。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，表现为力量和功能增加。这一系列进一步确立了 SYT2 为 CMS 疾病基因，并扩展了其临床和遗传谱，包括隐性功能丧失变异，表现为严重先天性发作的突触前 CMS，具有潜在的治疗意义。
