The skeletal muscle channelopathies are caused by mutations in key voltage-gated ion channels that determine muscle fibre membrane excitability at rest and during activity. Patients present with isolated or combined clinical phenotypes which can include; periodic paralysis (PP), mild or severe myotonia, cardiac arrhythmias or progressive disabling myopathy. Advances in our understanding of genetics and molecular pathophysiology are paving the way for translation into new clinical trials.

Over the past 12 years, as part of our nationally funded UK muscle channel service (rare neuromuscular disease consortium), our group has identified a large number of new mutations allowing correlations between genotype and clinical/electrophysiological phenotype. It is now clear that "gain of function" point mutations in the voltage gated sodium channel (SCN4A) result in delayed/altered channel inactivation and associate with a range of phenotypes including hyperkalaemic periodic paralysis, paramyotonia congenita and pure sodium channel myotonia. In addition, we have recently defined transient neonatal hypotonia and neonatal stridor as probable sodium channelopathies. In contrast, the molecular pathophysiology of the commonest form of periodic paralysis, hypokalaemic periodic periodic paralysis-HypoPP, is not yet fully determined. Although mutations in the voltage gated calcium channel CACNA1S frequently cause HypoPP, mutant channel expression studies have shown only subtle channel functional defects not sufficient to account for the sustained membrane depolarisation typical of HypoPP attacks. We have recently shown that "loss of positive charge" point mutations in the S4 regions of both CACNA1S and SCN4A cause HypoPP in 74/83 (90%) of UK families. This finding supports the hypothesis that HypoPP may be caused by a non-alpha pore, S4 gating pore leak. The pore leak hypothesis raises interesting new questions about the molecular pathogenesis of HypoPP as a well as potential new targets for therapy. Some patients with periodic paralysis have Andersen's syndrome characterised by PP, cardiac arrhythmias and specific craniofacial features. Most UK Andersen's families studied have point mutations in the voltage independent potassium channel gene KCNJ2. All KCNJ2 mutations we have expressed induce a dominant negative effect on the tetrameric potassium channel predicting impaired membrane repolarisation.

Myotonia congenita is the commonest inherited myotonia and associates with over 100 different recessive or dominant mutations in the dimeric voltage gated muscle chloride channel which determines the resting membrane potential. One unresolved question in MC is the significant proportion of affected individuals that appear to have recessive MC but only harbour a single recessive mutation despite analysis of all CLCN-1 exons and splice-donor site regions. We have recently shown that some cases are accounted for by large scale deletions on the other allele and we are investing additional potential mechanisms.

Despite major advances in genetics, molecular pathophysiology and new electrodiagnostics there are no established treatments that have been rigorously proven to prevent attacks, reduce myopathy and improve quality of life in patients with muscle channelopathies. Recent MRC Neuromuscular Centre Cochrane reviews concluded that there is insufficient evidence to recommend any treatment as the standard. Even though certain medications such as acetazolamide and mexiletine are widely prescribed they are not licensed for these indications. Randomised control trial evidence is required to establish standard treatments for patients with muscle channelopathies. I will discuss our current MRC Centre NIH funded natural history studies and clinical treatment trials in non-dystrophic myotonias and periodic paralysis and highlight the exciting challenges of developing new treatments in rare diseases.