Clinical and genetic features of five unrelated patients with de novo pathogenic variants in the synaptic vesicle‐associated membrane protein 2 (VAMP2) reveal common features of global developmental delay, autistic tendencies, behavioral disturbances, and a higher propensity to develop epilepsy. For one patient, a cognitively impaired adolescent with a de novo stop‐gain VAMP2 mutation, we tested a potential treatment strategy, enhancing neurotransmission by prolonging action potentials with the aminopyridine family of potassium channel blockers, 4‐aminopyridine and 3,4‐diaminopyridine, in vitro and in vivo. Synaptic vesicle recycling and neurotransmission were assayed in neurons expressing three VAMP2 variants by live‐cell imaging and electrophysiology. In cellular models, two variants decrease both the rate of exocytosis and the number of synaptic vesicles released from the recycling pool, compared with wild‐type. Aminopyridine treatment increases the rate and extent of exocytosis and total synaptic charge transfer and desynchronizes GABA release. The clinical response of the patient to 2 years of off‐label aminopyridine treatment includes improved emotional and behavioral regulation by parental report, and objective improvement in standardized cognitive measures. Aminopyridine treatment may extend to patients with pathogenic variants in VAMP2 and other genes influencing presynaptic function or GABAergic tone, and tested in vitro before treatment.

中文翻译：

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用 4-氨基吡啶治疗克服 VAMP2 突变的突触前效应。

5 名具有突触小泡相关膜蛋白 2 (VAMP2)从头致病性变异的无关患者的临床和遗传特征揭示了整体发育迟缓、自闭症倾向、行为障碍和更高的癫痫发作倾向的共同特征。对于一名患者，一名认知受损的青少年患有新的停止增益VAMP2突变，我们测试了一种潜在的治疗策略，通过在体外和体内使用氨基吡啶家族钾通道阻滞剂 4-氨基吡啶和 3,4-二氨基吡啶延长动作电位来增强神经传递。通过活细胞成像和电生理学分析了表达三种 VAMP2 变体的神经元中的突触小泡再循环和神经传递。在细胞模型中，与野生型相比，两种变体降低了胞吐速率和从回收池中释放的突触小泡数量。氨基吡啶治疗增加了胞吐作用和总突触电荷转移的速率和程度，并使 GABA 释放不同步。患者对 2 年标签外氨基吡啶治疗的临床反应包括父母报告改善的情绪和行为调节，标准化认知测量的客观改善。氨基吡啶治疗可能扩展到具有 VAMP2 致病变异和其他影响突触前功能或 GABA 能调的基因的患者，并在治疗前进行体外测试。