Congenital myasthenic syndromes

Abstract

Objectives Congenital myasthenic syndromes (CMSs) are a genotypically and phenotypically heterogeneous group of neuromuscular disorders, which have in common an impaired neuromuscular transmission. Since the field of CMSs is steadily expanding, the present review aimed at summarizing and discussing current knowledge and recent advances concerning the etiology, clinical presentation, diagnosis, and treatment of CMSs. Methods Systematic literature review. Results Currently, mutations in 32 genes are made responsible for autosomal dominant or autosomal recessive CMSs. These mutations concern 8 presynaptic, 4 synaptic, 15 post-synaptic, and 5 glycosilation proteins. These proteins function as ion-channels, enzymes, or structural, signalling, sensor, or transporter proteins. The most common causative genes are CHAT, COLQ, RAPSN, CHRNE, DOK7, and GFPT1. Phenotypically, these mutations manifest as abnormal fatigability or permanent or fluctuating weakness of extra-ocular, facial, bulbar, axial, respiratory, or limb muscles, hypotonia, or developmental delay. Cognitive disability, dysmorphism, neuropathy, or epilepsy are rare. Low- or high-frequency repetitive nerve stimulation may show an abnormal increment or decrement, and SF-EMG an increased jitter or blockings. Most CMSs respond favourably to acetylcholine-esterase inhibitors, 3,4-diamino-pyridine, salbutamol, albuterol, ephedrine, fluoxetine, or atracurium. Conclusions CMSs are an increasingly recognised group of genetically transmitted defects, which usually respond favorably to drugs enhancing the neuromuscular transmission. CMSs need to be differentiated from neuromuscular disorders due to muscle or nerve dysfunction.

AGRN Gene Mutation Leads to Congenital Myasthenia Syndromes: A Pediatric Case Report and Literature Review

“…The late-onset type is characterized by ptosis, bulbar paralysis, and mild facial and bulbar weakness. 1 The dropped head phenotype was reported in one case. 12 Five patients had positive repetitive nerve stimulation, and most patients had a fluctuating course of disease that was aggravated at night, in hot weather, or during excessive activity.…”

“…For the treatment of AGRN-related CMS, as reported in the literature and presented in our patient, cholinesterase inhibitors are generally ineffective and may even exacerbate muscle weakness over time. 1 Adrenoceptor agonists are effective, 7 patients received ephedrine and 2 patients received ephedrine with significant improvement in symptoms and 70% efficacy. The switch to salbutamol also improved the quality of life among patients in a family reported in 2017 when ephedrine was not available.…”

“…The congenital myasthenic syndromes (CMS [MIM 608931]) are a group of genetic disorders due to mutations in genes encoding proteins involved in the neuromuscular junction (NMJ) structure and function. 1,2 To date, 32 genes have been reported to be related to CMS, most of which are autosomal recessive, 1 while, some of the slow-channel syndrome genes are transmitted in an autosomal dominant fashion. 3 The AGRN/LRP4/MuSK/Dok-7/Rapsyn pathway is involved in end plate development and maintenance of the NMJ.…”

“…6 The main treatment for early-onset CMS is an adrenal receptor agonist, such as albuterol and ephedrine. 1,7,8 We report herein a new patient with CMS and retrospectively summarize the 12 previously reported patients.…”

Congenital myasthenic syndrome in Golden Retrievers is associated with a novelCOLQmutation

“…Congenital myasthenic syndrome (CMS) refers to a heterogenous group of inherited disorders of neuromuscular transmission that may be presynaptic, synaptic or post‐synaptic . To date, 32 CMSs have been described in people with autosomal recessive and autosomal dominant modes of inheritance . Clinical signs of CMS in dogs usually begin at weaning with progressive muscle weakness that is exacerbated by exercise.…”