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.

Keywords: Fatigue; Genes; Hereditary; Mutation; Myasthenia; Myasthenic syndrome; Repetitive nerve stimulation; Weakness.

Fig. 1

Scheme of the main pathophysiological mechanisms involved in CMS: (1) acetylcholine biosynthesis defects and vesicular transport and fusion defects; (2) AchE deficiency; (3) AchR defects; (4) agrin deficiency; (5) disorders of glycosylation; (6) channelopathies; (7) myopathies with secondary neuromuscular transmission defects; and (8) mitochondrial dysfunction; ChAT: choline acetyltransferase; ErbBR: epidermal growth factor receptor; MASC: muscle-associated specificity component; Lrp4: low-density lipoprotein receptor-related protein 4 [reproduced from Sousa et al. Arq Neuropsquiatr 2016;74:750 [24, 143] [permission applied]