Our understanding of the molecular pathogenesis of the neuromuscular ion
channelopathies has increased rapidly over the past two decades due to the identification of many of the genes whose mutation causes these diseases. These molecular discoveries have facilitated identification and classification of the hereditary periodic
paralyses and the
myotonias, and are likely to shed light on acquired ion
channelopathies as well. Despite our better understanding of the pathogenesis of these disorders, current treatments are largely empirical and the evidence in favor of specific
therapy largely anecdotal. For periodic
paralysis,
dichlorphenamide--a
carbonic anhydrase inhibitor--has been shown in a controlled trial to prevent attacks for many patients with both hypokalemic and
hypokalemic periodic paralysis. A second trial, comparing
dichlorphenamide with
acetazolamide versus placebo, is currently in progress. For
myotonia, there is only anecdotal evidence for treatment, but a controlled trial of
mexiletine versus placebo is currently being funded by a Food and Drug Administration-orphan products grant and is scheduled to begin in late 2008. In the future, mechanism-based approaches are likely to be developed. For example, exciting advances have already been made in one
disorder, myotonic dystrophy-1 (DM-1). In a mouse model of DM-1, a
morpholino antisense oligonucleuotide targeting the
3' splice site of CLCN1 exon 7a repaired the RNA splicing defect by promoting the production of full-length
chloride channel transcripts. Abnormal
chloride conductance was restored, and
myotonia was abolished. Similar strategies hold potential for DM-2. The era of molecularly-based treatments is about to begin.