Abstract:
Congenital myasthenic syndromes (CMS) are clinically and genetically heterogeneous diseases caused by mutations affecting neuromuscular transmission. Even if the first symptoms mainly occur during childhood, adult neurologists must confront this challenging diagnosis and manage these patients throughout their adulthood. However, long-term follow-up data from large cohorts of CMS patients are lacking and the long-term prognosis of these patients is largely unknown. We report the clinical features, diagnostic difficulties, and long-term prognosis of a French nationwide cohort of 235 adult patients with genetically confirmed CMS followed in 23 specialized neuromuscular centres. Data were retrospectively analysed. Of the 235 patients, 123 were female (52.3%). The diagnosis was made in adulthood in 139 patients, 110 of whom presented their first symptoms before the age of 18. Mean follow-up time between first symptoms and last visit was 34 years (SD = 15.1). Pathogenic variants were found in 19 disease-related genes. CHRNE-low expressor variants were the most common (23.8%), followed by variants in DOK7 (18.7%) and RAPSN (14%). Genotypes were clustered into four groups according to the initial presentation: ocular group (CHRNE-LE, CHRND, FCCMS), distal group (SCCMS), limb-girdle group (RAPSN, COLQ, DOK7, GMPPB, GFPT1), and a variable-phenotype group (MUSK, AGRN). The phenotypical features of CMS did not change throughout life. Only four genotypes had a proportion of patients requiring intensive care unit (ICU) admission that exceeded 20%: RAPSN (54.8%), MUSK (50%), DOK7 (38.6%) and AGRN (25.0%). In RAPSN and MUSK patients most ICU admissions occurred before age 18 years and in DOK7 and AGRN patients at or after 18 years of age. Different patterns of disease course (stability, improvement and progressive worsening) may succeed one another in the same patient throughout life, particularly in AGRN, DOK7 and COLQ. At the last visit, 55% of SCCMS and 36.3% of DOK7 patients required ventilation; 36.3% of DOK7 patients, 25% of GMPPB patients and 20% of GFPT1 patients were wheelchair-bound; most of the patients who were both wheelchair-bound and ventilated were DOK7 patients. Six patients died in this cohort. The positive impact of therapy was striking, even in severely affected patients. In conclusion, even if motor and/or respiratory deterioration could occur in patients with initially moderate disease, particularly in DOK7, SCCMS and GFPT1 patients, the long-term prognosis for most CMS patients was favourable, with neither ventilation nor wheelchair needed at last visit. CHRNE patients did not worsen during adulthood and RAPSN patients, often severely affected in early childhood, subsequently improved.
摘要:
先天性肌无力综合征(CMS)是由影响神经肌肉传递的突变引起的临床和遗传异质性疾病。即使最初的症状主要发生在儿童时期,成人神经科医师必须面对这一具有挑战性的诊断,并在这些患者的整个成年期间对其进行管理.然而,缺乏来自大型CMS患者队列的长期随访数据,这些患者的长期预后在很大程度上未知.我们报告了临床特征,诊断困难,在23个专门的神经肌肉中心,对法国全国235例遗传证实的CMS成年患者进行了长期预后研究。对数据进行回顾性分析。在235名患者中,123人是女性(52.3%)。该诊断是在139名患者的成年期做出的,其中110人在18岁之前出现了最初的症状。首次出现症状和最后一次就诊之间的平均随访时间为34年(SD=15.1)。在19个疾病相关基因中发现了致病变异。CHRNE低表达变异是最常见的(23.8%),其次是DOK7(18.7%)和RAPSN(14%)。根据最初的表现,基因型分为四组:眼部组(CHRNE-LE,CHRND,FCCMS),远端组(SCCMS),肢体束带组(RAPSN,COLQ,DOK7,GMPPB,GFPT1),和一个可变表型组(MUSK,AGRN)。CMS的表型特征在整个生命周期中都没有变化。只有四种基因型的患者需要重症监护病房(ICU)入院的比例超过20%:RAPSN(54.8%),MUSK(50%),DOK7(38.6%)和AGRN(25.0%)。在RAPSN和MUSK患者中,大多数ICU入院发生在18岁之前,DOK7和AGRN患者发生在18岁或之后。不同的病程模式(稳定性,改善和进行性恶化)可能会在同一患者的一生中相互成功,特别是在AGRN中,DOK7和COLQ在最后一次访问中,55%的SCCMS和36.3%的DOK7患者需要通气;36.3%的DOK7患者,25%的GMPPB患者和20%的GFPT1患者使用轮椅;大多数同时使用轮椅和通风的患者是DOK7患者。该队列中有6名患者死亡。治疗的积极影响是惊人的,即使是受影响严重的患者。总之,即使最初患有中度疾病的患者可能发生运动和/或呼吸恶化,特别是在DOK7,SCCMS和GFPT1患者中,大多数CMS患者的长期预后良好,上次访问时既不需要通风也不需要轮椅。CHRNE患者在成年期和RAPSN患者中没有恶化,通常在儿童早期受到严重影响,随后有所改善。