Objective Spinal muscular atrophy (SMA) is a motor neuron disease caused by low levels of survival motor neuron (SMN) protein. Prior work in models and patients has demonstrated electrophysiological and morphological defects at the neuromuscular junction (NMJ). Therapeutic development has resulted in clinically available therapies to increase SMN protein levels in patients and improve muscle function. Here we aimed to investigate the effect of SMN restoration (via nusinersen) on NMJ transmission in adults with SMA. Methods Participants undergoing nusinersen treatment underwent 3 Hz repetitive nerve stimulation (RNS) of the spinal accessory nerve to assess compound muscle action potential amplitude decrement. Maximum voluntary isometric contraction (MVICT), Revised Upper Limb Module (RULM), and 6 min walk test (6MWT) were assessed for correlations with decrement. Results Data from 13 ambulatory (7 men/6 women, mean age 40±11 years) and 11 non-ambulatory (3 men/8 women, mean age 38±12 years) participants were analysed. Cross-sectional analyses of RNS decrement were similar at 14 months of nusinersen (−14.2%±11.5%, n=17) vs baseline (−11.9%±8.3%, n=15) (unpaired t-test, p=0.5202). Longitudinal comparison of decrement in eight participants showed no change at 14 months (−13.9%±6.7%) vs baseline (−16.9%±13.4%) (paired t-test, p=0.5863). Decrement showed strong correlations with measures of MVICT, RULM and 6MWT but not age or disease duration. Conclusion Adults with SMA had significant NMJ transmission defects that were not corrected with 14 months of nusinersen treatment. NMJ defects were negatively associated with physical function, and thus may represent a promising target for additive or combinatorial treatments. We will make all data available to qualified investigators upon reasonable request.

中文翻译：

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nusinersen 治疗成人脊髓性肌萎缩症的持续性神经肌肉接头传递缺陷

目的脊髓性肌萎缩症（SMA）是一种运动神经元疾病，由运动神经元存活（SMN）蛋白水平低引起。先前在模型和患者中的工作已经证明了神经肌肉接头 (NMJ) 的电生理学和形态学缺陷。治疗发展已经导致临床上可用的治疗方法来增加患者的 SMN 蛋白水平并改善肌肉功能。在这里，我们旨在研究 SMN 恢复（通过 nusinersen）对 SMA 成人 NMJ 传播的影响。方法 接受 nusinersen 治疗的参与者对脊髓副神经进行 3 Hz 重复神经刺激 (RNS)，以评估复合肌肉动作电位幅度衰减。最大自主等长收缩（MVICT），修订上肢模块（RULM），和 6 分钟步行测试 (6MWT) 评估与递减的相关性。结果 分析了 13 名非卧床（7 名男性/6 名女性，平均年龄 40±11 岁）和 11 名非卧床（3 名男性/8 名女性，平均年龄 38±12 岁）参与者的数据。在 nusinersen (-14.2%±11.5%, n=17) 与基线 (-11.9%±8.3%, n=15) 的 14 个月时，RNS 减少的横断面分析相似（未配对 t 检验，p=0.5202） . 8 名参与者的减量纵向比较显示，14 个月时（-13.9%±6.7%）与基线（-16.9%±13.4%）相比没有变化（配对 t 检验，p=0.5863）。减量与 MVICT、RULM 和 6MWT 的测量值显示出强相关性，但与年龄或疾病持续时间无关。结论 SMA 成人有显着的 NMJ 传输缺陷，在 14 个月的 nusinersen 治疗中未得到纠正。NMJ 缺陷与身体功能呈负相关，因此，它可能代表了一个有希望的添加或组合治疗的目标。我们将根据合理要求向合格的调查人员提供所有数据。