Congenital myasthenic syndrome: Correlation between clinical features and molecular diagnosis

Abstract

Objectives To present phenotype features of a large cohort of congenital myasthenic syndromes (CMS) and correlate them with their molecular diagnosis. Methods Suspected 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. Results Seventy‐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. Conclusions Stricter clinical criteria increase the chance of confirming a CMS diagnosis, but may lose sensitivity, especially for some specific genes.

Two patients with congenital myasthenic syndrome caused by COLQ gene mutations and the consequent ColQ protein defect

“…The diagnosis of CMS was confirmed by two compound heterozygous mutations at c.173delC and c.C706T in the COLQ gene. Our patients conform typical COLQ gene related CMS summarized by the literatures [ 15 , 16 ].…”

“…Classical phenotype of COLQ gene mutation including neonatal manifestations, hypotonia, ptosis, opthalmoparesis, poor crying and suckling, or respiratory insufficiency. AChE inhibitors will aggravate muscle weakness in COLQ gene related CMS, whereas treatment with Salbutamol and Ephedrine are effective [ 1 , 6 , 15 ]. The diagnosis of CMSs from COLQ gene mutations is based on the myasthenic symptoms since birth, exertion-induced weakness on examination, negative AChR and MuSK antibodies, and a decremental CMAP response at low-frequency on RNS test [ 2 ].…”

A <i>Dpagt1</i> Missense Variant Causes Early Degenerative Retinopathy without Myasthenic Syndrome in Mice

“…Additional examination at an advanced age would be desirable to assess potential long-term effects of the Dpagt1 tvrm76 mutation on muscle function. It should be noted that a large number of patients harboring DPAGT1 variants were subject to underdiagnosis in clinics as well [36,[43][44][45]. Nevertheless, our results demonstrate that Dpagt1 mutations exist that primarily present with an eye phenotype with minimal muscle involvement.…”

A Dpagt1 Missense Variant Causes Degenerative Retinopathy without Myasthenic Syndrome in Mice

“…Additional examination at an advanced age would be desirable to assess potential long-term effects of the Dpagt1 tvrm76 mutation on muscle function. It should be noted that a large number of patients harboring DPAGT1 variants were subject to underdiagnosis in clinics as well [ 45 , 52 , 53 , 54 ]. Nevertheless, our results demonstrate that Dpagt1 mutations exist which primarily present with an eye phenotype with minimal muscle involvement.…”