About this Research Topic
Skeletal muscle channelopathies (SMCs) represent a large heterogeneous group of rare genetic diseases resulting in long−term disabilities, posing a significant burden to the patients, their families and National Health Care Services. SMCs are caused by mutations in genes encoding skeletal muscle ion channels that control muscle excitability, such as CLCN1, SCN4A, CACNA1S, and KCNJ2. Based on the predominant clinical feature, SMCs are typically classified as nondystrophic myotonias (NDMs) or periodic paralyses (PPs). NDMs include myotonia congenita, paramyotonia congenita and sodium channel myotonia. PPs comprise hypo- and hyperkaliemic PP and Andersen-Tawil syndrome (ATS). However, considerable clinical overlap has been reported in SMCs, making challenging genotype-phenotype correlations. Diagnosis of SMCs requires a high clinical suspicion, being mainly based on detailed clinical history and neurological examination.
To date, only symptomatic treatments to reduce myotonia or frequency of paralytic attacks are available. Disease rarity can make recruitment for randomised controlled trials challenging and data on their efficacy in SMCs consists mostly of case series, open-label and single-blind, controlled trials, although a few randomized controlled trials have recently been performed. Mexiletine is considered the gold-standard treatment for myotonia, as confirmed by a phase 2 international randomized, placebo-controlled, crossover clinical trial and by a series of N-of-1 trials of mexiletine vs placebo. Mexiletine however, has reported side effects, mainly gastrointestinal, in a significant proportion of patients. Additionally, 10-30% of patients had suboptimal or no response. Acetazolamide has traditionally been used as the treatment of choice for PP. Although acetazolamide is mainly effective in hypokalaemic PP due to mutations in CACNA1S, it has also been used to treat myotonia. A recent study confirmed the efficacy of dichlorphenamide in hypokalaemic PP. Diuretics, either potassium sparing or wasting depending on the subtype of periodic paralysis, are also a mainstay of treatment. Treatment options are expanding however, and newer drugs have been recently reported as effective in SMC treatment, including flecainide, lamotrigine and ranolazine. The cardiac presentations of ATS can pose a therapeutic challenge with some requiring an implantable cardioverter defibrillator insertion.
Recently, many achievements have increased complexity in the SMCs field, including new phenotypes caused by mutations in SCN4A and CACNA1S genes, such as severe neonatal episodic laryngospasms, severe foetal hypokinesia, congenital myopathy, rhabdomyolysis, myalgia and exercise intolerance, congenital myasthenic syndrome and sudden infant death syndrome. Conversely, new genes associated with PP (often with additional clinical features) have been reported, e.g. ATP1A2, KCNJ5, RYR1, mATP6 and mATP8.
This Research Topic aims to provide a deep insight in SMCs through an interdisciplinary approach, combining clinical and basic research data. We welcome internationally recognized experts in the field to contribute with papers including original data on emerging topics, such as new disease mechanisms, for example those related to channel regulatory partners, phenotypes, treatments and biomarkers, novel clinical trial design, and review manuscripts focused on more recent achievements in SMCs.
Jean-François Desaphy is a co-inventor, with no personal financial interest, of a European patent assigned to a pharmaceutical company regarding the use of a company drug in myotonic syndromes.
Keywords: Myotonia, Periodic Paralyses, Channelopathies, Neuromuscular Diseases
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