Therapeutic strategies for congenital myasthenic syndromes

Abstract

To date, more than 25 genes have been implicated in the etiology of the congenital myasthenic syndromes (CMS), and an ever-growing phenotypic landscape is now encountered in the CMS clinic. Unlike the autoimmune form of myasthenia, there is no role for immunomodulatory agents in the treatment of CMS. The present-day drug repertoire comprises acetylcholinesterase inhibitors (mainly pyridostigmine), 3,4-diaminopyridine (3,4-DAP), ephedrine, salbutamol/albuterol, open-channel blockers (fluoxetine, quinidine), or a combination of these. These are prescribed by the specialist in an off-label manner, as there is no drug currently licensed for the treatment of these rare diseases. The effective pharmacological agent varies according to the genetic form of CMS, and it is important to realize that an agent that provides benefit in one CMS subtype can be harmful in another. In addition, the time to treatment response is variable and tends to be commensurate with the drug used. Here, we summarize for the clinician the therapeutic strategies employed in this ever-evolving disease spectrum. We also address the barriers to treatment and discuss the treatment of CMS in pregnancy.

Collagen XIII and Other ECM Components in the Assembly and Disease of the Neuromuscular Junction

“…Typically, decrementing of responses in electromyography studies demonstrates the patient's NMJ dysfunction. To date, mutations in more than 25 separate genes have been linked to CMSs, of various types (Hantai et al, ; Rodriguez Cruz et al, ; Rodriguez Cruz et al, ; Engel et al, ; Souza et al, ; Lee et al, ). Although all CMSs are rare and the diseases' diversity, clinical variability, and diagnostic challenges render prevalence rates difficult to determine with accuracy, the number of confirmed cases among children under 18 years of age in the UK is found approaching 10:1,000,000 (Parr et al, ).…”

“…On top of information gleaned from human patients, research on mouse models, both spontaneous and purposefully created, has considerably increased our knowledge of the NMJ and advanced the understanding of many human NMJ diseases (Vainzof et al, ; Webster, ). Owing to the varied etiologies, CMS patients respond differently to a given medication; therefore, all available information helps clinicians to design therapeutic strategies (Lee et al, ).…”

“…AChE inhibitors such as pyridostigmine extend cholinergic transmission by inhibiting hydrolysis of ACh by AChE. This enhances neurotransmission in the synaptic cleft but may also have systemic side effects (Sieb, ; Lee et al, ). It is noteworthy that, in addition to having medical use, inhibition of AChE is the mechanism of action of a large group of organophosphate compounds that are commonly utilized as pesticides but have also been developed into extremely potent chemical weapons, such as nerve agents sarin and XV (Bailey et al, ).…”

Pregnancy‐associated respiratory failure in muscle specific kinase congenital myasthenic syndrome

“…Other similarities between the 2 are a predominant limb‐girdle pattern and poor response to pyridostigmine. Both are responsive to β adrenergic drugs (salbutamol, ephedrine); 3,4‐diaminopyridine must be used with caution . The intracellular activation of MuSK by DOK7 is imperative for the reorganization of the actin cytoskeleton and AChR clustering.…”

“…Both are responsive to β adrenergic drugs (salbutamol, ephedrine); 3,4-diaminopyridine must be used with caution. 13,14 The intracellular activation of MuSK by DOK7 is imperative for the reorganization of the actin cytoskeleton and AChR clustering. Mutations in either gene can impair this interaction, leading to CMS with similar clinical features.…”