The congenital myasthenic syndromes: expanding genetic and phenotypic spectrums and refining treatment strategies

Abstract

Purpose of reviewCongenital myasthenic syndromes (CMS) are a group of heterogeneous inherited disorders caused by mutations in genes encoding proteins whose function is essential for the integrity of neuromuscular transmission. This review updates the reader on the expanding phenotypic spectrum and suggested improved treatment strategies.Recent findingsAs next-generation sequencing is taken into the clinic, its use is both continuing to unearth new causative genes in which mutations underlie CMS and also broadening the phenotypic spectrum for known CMS genes. The number of genes in which mutations may cause neuromuscular transmission defects has now passed 30. The defective transmission may be part of an overall more complex phenotype in which there may be muscle, central nervous system or other involvement. Notably, mutations in series of genes encoding proteins located in the presynatic motor bouton have been identified. Rare cases of mutations in basal laminar proteins of the synaptic cleft are coming to light and additional mutations/phenotypic features have been located in some of the larger neuromuscular junction proteins such as AGRN and MUSK, where previously mutation screening by sanger sequencing was time consuming and costly. Finally, there are more reports of the beneficial effects of treatment with β2-adrenergic receptor agonists in patients, and the study of their action in disease models.SummaryRecent studies of the CMS illustrate the increasing complexity of the genetics and pathophysiological mechanisms involved. With therapy tailored for the underlying disease mechanism treatment, although incomplete, is usually life-transforming. However, treatment for newly identified conditions in which myasthenia is only one component within complex multisystem disorder will prove challenging.

Myasthenia Gravis: From the Viewpoint of Pathogenicity Focusing on Acetylcholine Receptor Clustering, Trans-Synaptic Homeostasis and Synaptic Stability

“…Besides the biological signal (compensatory presynaptic Ca 2+ homeostasis) triggered by G protein-coupled receptor, it is worthy to note that BDNF in the synapse is activated by β 2 -adrenoceptor agonists and thereby contributes to the maintenance of the structural and functional integrity of motor end-plate; this signaling pathway may include the cyclic adenosine monophosphate (cAMP)/protein kinase A/cAMPresponsive element-binding protein; Bartus et al, 2015). The therapeutic pre-and post-synaptic benefits of β 2 -adrenoceptor agonists (salbutamol and ephedrine) have been reported in MuSK MG animal model (Ghazanfari et al, 2014), autoimmune MG patients (Rodríquez Cruz et al, 2015b;Lipka et al, 2017; and various types of congenital myasthenic syndromes (Engel et al, 2015;Beeson, 2016) including the patients with mutations in MuSK (Gallenmller et al, 2014;Rodríquez Cruz et al, 2020;Vanhaesebrouck and Beeson, 2019), Lrp4 (Selcen et al, 2015;Beeson, 2016), Dok7 (Lashley et al, 2010;Liewluck et al, 2011;Burke et al, 2013;Lorenzoni et al, 2013), agrin (Nicole et al, 2014;Beeson, 2016;Beeson, 2019), collagen Q (McMacken et al, 2019) and collagen XIII (Beeson, 2016;Rodríguez Cruz et al, 2018Dusl et al, 2019). In pharmacotherapeutic options, the β 2 -agonist stimulation could be chosen as a novel therapeutic strategy in autoimmune and genetic myasthenias.…”

New Therapeutics Options for Pediatric Neuromuscular Disorders

“…Application of next generation sequencing techniques has resulted not only in identification of new genes and proteins, but also in a better understanding of the pathophysiology of the neuromuscular junction. This has enabled a more tailored therapeutic approach (44). While drugs like pyridostigmine, an acetylcholine (ACh) esterase inhibitor, often used in tandem with 3,4-diaminonpyridine, a potassium channel blocker increasing ACh release, are more or less effective in some of these conditions, they may worsen symptoms in slowchannel forms, in which prolonged ACh receptor-gated channel opening causes deleterious entry of Ca2+ into the postsynaptic region and consecutive degeneration of post-synaptic structures (43,44).…”

Pathomechanisms and Clinical Implications of Myasthenic Syndromes Exacerbated and Induced by Medical Treatments

“…Other conditions affecting neuromuscular transmission include Lambert-Eaton myasthenic syndrome (LEMS) (Titulaer et al, 2011), a range of congenital myasthenic syndromes (CMS) due to variants in > 30 different genes (e.g., CHRNE, RAPSN, DOK7, etc.) (Vanhaesebrouck and Beeson, 2019) and botulism (Guidon, 2019), all of which may be caused by various presynaptic, postsynaptic or combined mechanisms at the NMJ. In addition, drugs or medical treatments may also compromise neuromuscular transmission, the physiology of which will be introduced before outlining the mechanisms underlying the exacerbation of myasthenic syndromes by medical treatments.…”