Liu Yue, Li Zhiguang, Shi Yan, Xu Yongpei, Wang Zhiqiang, Wang Ning, Yang Kang
Department of Neurology and Institute of Neurology of First Affiliated Hospital, Institute of Neuroscience, and Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, China.
Department of Neurology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China.
FASEB J. 2025 Jul 31;39(14):e70865. doi: 10.1096/fj.202501466R.
Congenital myasthenic syndromes (CMS) represent a heterogeneous group of inherited disorders resulting from mutations in genes that encode proteins essential for neuromuscular transmission. Among these, mutations in the collagen-like tail subunit of asymmetric acetylcholinesterase (COLQ) define a distinct subtype of CMS, necessitating specialized diagnostic and therapeutic strategies to improve patient outcomes. Herein, we analyzed five COLQ-CMS patients, focusing on their clinical features, electrophysiologic findings, genetic characteristics, and therapeutic responses. All five patients exhibited limb-girdle weakness, and two experienced acute respiratory insufficiency. The age of symptom onset ranged from 2 to 33 years, with an average diagnostic delay of 14 years. All patients exhibited a decremental response to repetitive nerve stimulation and myopathic features on electromyography. Using whole exome sequencing (WES), complemented by PCR-based screening and reverse transcription-PCR (RT-PCR) to clarify deletion and splicing mutations, five variants of the COLQ gene were identified. These included two novel splicing mutations, c.393 + 3A>G and c.814_814 + 2dup, which caused aberrant splicing and premature truncation. Additionally, we found the deletion of exon 14-15 of the COLQ gene in three patients. All patients received salbutamol, leading to significant alleviation of primary symptoms during treatment. In conclusion, our findings offer critical insights into the clinical diagnosis and management of COLQ-CMS and highlight the importance of recognizing clinical heterogeneity, diagnostic delays, and early genetic diagnosis, which may ultimately assist clinicians in accurately identifying and effectively treating such conditions.
先天性肌无力综合征（CMS）是一组由编码神经肌肉传递必需蛋白质的基因突变引起的遗传性疾病，具有异质性。其中，不对称乙酰胆碱酯酶（COLQ）的胶原样尾部亚基突变定义了CMS的一种独特亚型，需要专门的诊断和治疗策略来改善患者预后。在此，我们分析了5例COLQ - CMS患者，重点关注他们的临床特征、电生理检查结果、遗传特征和治疗反应。所有5例患者均表现为肢带肌无力，2例出现急性呼吸功能不全。症状出现的年龄范围为2至33岁，平均诊断延迟14年。所有患者对重复神经刺激均表现出递减反应，肌电图显示有肌病特征。通过全外显子组测序（WES），辅以基于PCR的筛查和逆转录PCR（RT - PCR）以明确缺失和剪接突变，共鉴定出COLQ基因的5种变异。其中包括2种新的剪接突变，即c.393 + 3A>G和c.814_814 + 2dup，它们导致异常剪接和过早截断。此外，我们在3例患者中发现了COLQ基因外显子14 - 15的缺失。所有患者均接受了沙丁胺醇治疗，治疗期间主要症状得到显著缓解。总之，我们的研究结果为COLQ - CMS的临床诊断和管理提供了重要见解，并强调了认识临床异质性、诊断延迟和早期基因诊断的重要性，这最终可能有助于临床医生准确识别和有效治疗此类疾病。
