目的:神经肌肉接头(NMJ)的遗传性缺陷包括越来越多的疾病。最近发现的几个基因突出了周围神经病变和先天性肌无力综合征(CMS)之间的重叠。β-2肾上腺素能受体激动剂沙丁胺醇已被证明在CMS中提供症状益处,同时改善NMJ的结构缺陷。基于这些发现,我们确定了伴有NMJ功能障碍的运动神经病变病例,并评估了沙丁胺醇对运动功能的影响.
方法:运动神经病伴显著NMJ功能障碍的病例,使用重复神经刺激和单纤维肌电图进行鉴定。口服沙丁胺醇12个月。在基线时进行重复的神经生理学和临床评估,6个月和12个月。
结果:在15名具有一系列遗传缺陷的患者中发现了明显的神经肌肉传递缺陷,包括GARS1、DNM2、SYT2和DYNC1H的突变。口服沙丁胺醇12个月后,对运动功能没有明显的益处;然而,患者报告的疲劳有显著改善.此外,在接受沙丁胺醇治疗的患者中,对神经生理参数没有明显影响。在患者队列中,由于脱靶β-肾上腺素能作用引起的副作用是显着的。
结论:这些结果强调了NMJ参与了几种运动神经病的亚型,包括线粒体融合分裂缺陷引起的神经病变亚型,突触小泡运输,钙通道和tRNA合成酶。尚不清楚NMJ功能障碍是否仅仅是由于肌肉神经支配或与神经支配无关的病理。NMJ的参与可能代表了这些病症中的新治疗靶标。然而,对于原发性遗传性神经肌肉传递缺陷的患者,治疗方案需要更有针对性.
OBJECTIVE: Inherited defects of the neuromuscular junction (NMJ) comprise an increasingly diverse range of diseases. Several recently identified genes highlight the overlap between peripheral neuropathies and congenital myasthenic syndromes (CMS). The beta-2 adrenergic receptor agonist salbutamol has been shown to provide symptomatic benefit in CMS, while improving structural defects at the NMJ. Based on these findings, we identified cases of motor neuropathy with NMJ dysfunction and assessed the effect of salbutamol on motor function.
METHODS: Cases of motor neuropathy with significant NMJ dysfunction, were identified using repetitive nerve stimulation and single fibre electromyography. Oral salbutamol was administered for 12 months. Repeat neurophysiological and clinical assessments were undertaken at baseline, 6 months and 12 months.
RESULTS: Significant defects of neuromuscular transmission were identified in 15 patients harbouring a range of genetic defects, including mutations in GARS1, DNM2, SYT2 and DYNC1H. No clear benefit on motor function was seen following the administration of 12 months of oral salbutamol; however, there was a significant improvement in patient reported fatigue. In addition, no clear effect on neurophysiological parameters was seen in patients treated with salbutamol. Side-effects due to off-target beta-adrenergic effects were significant in the patient cohort.
CONCLUSIONS: These results highlight the involvement of the NMJ in several subtypes of motor neuropathies, including subtypes of neuropathy due to deficits in mitochondrial fusion-fission, synaptic vesicle transport, calcium channels and tRNA synthetases. Whether the NMJ dysfunction is simply due to muscle reinnervation or a pathology unrelated to denervation is unknown. The involvement of the NMJ may represent a novel therapeutic target in these conditions. However, treatment regimens will need to be more targeted for patients with primary inherited defects of neuromuscular transmission.