Congenital myasthenic syndrome: Correlation between clinical features and molecular diagnosis

• DOI: 10.1111/ene.15173
• Publication Date: 2021-11-08T17:39:58Z
• Authors: Eduardo P. Estephan; Antonio A. Zambon; Rachel Thompson; Kiran Polavarapu; Danny Jomaa; Ana Töpf; Paulo V. P. Helito; Carlos O. Heise; Cristiane A. M. M...; André M. S. Silva; Joao A. Kouyoumdjian; Maria da Penha Mo...; Umbertina C. Reed; Hanns Lochmüller; Edmar Zanoteli
• Keywords: Cohort Studies; Myasthenic Syndromes, Congenital; 0301 basic medicine; 03 medical and health sciences; Phenotype; Biopsy; Mutation; 610; Humans; NAV1.4 Voltage-Gated Sodium Channel; Muscle, Skeletal; 3. Good health

AbstractObjectivesTo present phenotype features of a large cohort of congenital myasthenic syndromes (CMS) and correlate them with their molecular diagnosis.MethodsSuspected CMS patients were divided into three groups: group A (limb, bulbar or axial weakness, with or without ocular impairment, and all the following: clinical fatigability, electrophysiology compatible with neuromuscular junction involvement and anticholinesterase agents response), group B (limb, bulbar or axial weakness, with or without ocular impairment, and at least one of additional characteristics noted in group A) and group C (pure ocular syndrome). Individual clinical findings and the clinical groups were compared between the group with a confirmed molecular diagnosis of CMS and the group without molecular diagnosis or with a non‐CMS molecular diagnosis.ResultsSeventy‐nine patients (68 families) were included in the cohort: 48 in group A, 23 in group B and 8 in group C. Fifty‐one were considered confirmed CMS (30 CHRNE, 5 RAPSN, 4 COL13A1, 3 DOK7, 3 COLQ, 2 GFPT1, 1 CHAT, 1 SCN4A, 1 GMPPB, 1 CHRNA1), 7 probable CMS, 5 non‐CMS and 16 unsolved. The chance of a confirmed molecular diagnosis of CMS was significantly higher for group A and lower for group C. Some individual clinical features, alterations on biopsy and electrophysiology enhanced specificity for CMS. Muscle imaging showed at least mild alterations in the majority of confirmed cases, with preferential involvement of soleus, especially in CHRNE CMS.ConclusionsStricter clinical criteria increase the chance of confirming a CMS diagnosis, but may lose sensitivity, especially for some specific genes.