@article{ca59119a18a64e58b7b86c2ea996ff51,
title = "The non-dystrophic myotonias: Molecular pathogenesis, diagnosis and treatment",
abstract = "The non-dystrophic myotonias are an important group of skeletal muscle channelopathies electrophysiologically characterized by altered membrane excitability. Many distinct clinical phenotypes are now recognized and range in severity from severe neonatal myotonia with respiratory compromise through to milder late-onset myotonic muscle stiffness. Specific genetic mutations in the major skeletal muscle voltage gated chloride channel gene and in the voltage gated sodium channel gene are causative in most patients. Recent work has allowed more precise correlations between the genotype and the electrophysiological and clinical phenotype. The majority of patients with myotonia have either a primary or secondary loss of membrane chloride conductance predicted to result in reduction of the resting membrane potential. Causative mutations in the sodium channel gene result in an abnormal gain of sodium channel function that may show marked temperature dependence. Despite significant advances in the clinical, genetic and molecular pathophysiological understanding of these disorders, which we review here, there are important unresolved issues we address: (i) recent work suggests that specialized clinical neurophysiology can identify channel specific patterns and aid genetic diagnosis in many cases however, it is not yet clear if such techniques can be refined to predict the causative gene in all cases or even predict the precise genotype; (ii) although clinical experience indicates these patients can have significant progressive morbidity, the detailed natural history and determinants of morbidity have not been specifically studied in a prospective fashion; (iii) some patients develop myopathy, but its frequency, severity and possible response to treatment remains undetermined, furthermore, the pathophysiogical link between ion channel dysfunction and muscle degeneration is unknown; (iv) there is currently insufficient clinical trial evidence to recommend a standard treatment. Limited data suggest that sodium channel blocking agents have some efficacy. However, establishing the effectiveness of a therapy requires completion of multi-centre randomized controlled trials employing accurate outcome measures including reliable quantitation of myotonia. More specific pharmacological approaches are required and could include those which might preferentially reduce persistent muscle sodium currents or enhance the conductance of mutant chloride channels. Alternative strategies may be directed at preventing premature mutant channel degradation or correcting the mis-targeting of the mutant channels.",
keywords = "EMG, Genetics, Ion channels, Neuromuscular",
author = "E. Matthews and D. Fialho and Tan, {S. V.} and Venance, {S. L.} and Cannon, {S. C.} and D. Sternberg and B. Fontaine and Amato, {A. A.} and Barohn, {R. J.} and Griggs, {R. C.} and Hanna, {M. G.}",
note = "Funding Information: The authors are members of The Consortium for Clinical Investigation of Neurologic Channelopathies (CINCH) funded by the National Institutes of Health, [5 U54 NS059 065-05S2 (NINDS/ORD) and R13 NS057 995]. In UK, this work was supported by the Brain Research Trust, a Medical Research Council Centre grant [G0601 943] and by the National Center for Research Resources [5U54 RR019 498-05]. Part of this work was undertaken at University College London Hospitals/University College London, which received a proportion of funding from the Department of Health{\textquoteright}s National Institute for Health Research Biomedical Research Centres funding scheme. In the United States, the work was supported by GCRC/CTSA grants [No.1 M01 RR023 940 (Kansas), No. UL1 RR 024 160 (Rochester) and No. UL1 RR024 982 (Texas)]. In France, the work of B.F. is supported by a grant from Agence Nationale pour la Recherche-maladies rares (Resocanaux) and Association Franc¸aise contre les Myopathies. Funding Information: This report summarizes the findings presented at the International Conference on Non-Dystrophic Myotonias (Kansas, June 2007). The conference was generously supported by a National Institutes of Health conference grant [R13 NS057 995]. Participants of the meeting listed alphabetically: Anthony Amato (Brigham and Women{\textquoteright}s Hospital), Marianne Arzel-Hezode (Pitie-Salpetriere, France), Tetsuo Ashizawa (University of Texas), Richard Barohn (University of Kansas), Brian Bundy (DTCC, Florida), Steve Cannon (University of Texas Southwestern), Yoon-Hee Cha (UCLA), James Cleland (University of Rochester), John Day (University of Minnesota), Robert Dirksen (University of Rochester), Christoph Fahlke (Institute of Neurophysiology, Hannover, Germany), Doreen Fialho (Institute of Neurology, UK), Bertrand Fontaine (Pitie-Salpetriere, France), Alfred L. George (Vanderbilt University, Nashville), Tracey Graves (Institute of Neurology, UK), Robert Griggs (University of Rochester), Angelika Hahn (London Health Science Centre, Canada), Michael G. Hanna (Institute of Neurology, UK), Laura Herbelin (University of Kansas), Barbara Herr (University of Rochester), Jeffrey Krischer (DTCC, Florida), Robert Layzer (University of California), Emma Matthews (Institute of Neurology, UK), Giovanni Meola (University of Milan, Italy), Richard T. Moxley III(University of Rochester), Shree Pandya (University of Rochester), Ming Qi (University of Rochester), Sanjeev Rajakulendran (Institute of Neurology, UK), Jeffrey Ralph (University of California), Mohammed Salajegheh (Brigham and Women{\textquoteright}s Hospital), David Saperstein (University of Kansas), Patty Smith (University of Rochester), Damien Sternberg (Pitie-Salpetriere, France), Rabi Tawil (University of Rochester), Charles Thornton (University of Rochester), Susie Tomlinson (Institute of Neurology, UK), Jaya Trivedi (University of Texas Southwestern), Paul Twydell (University of Rochester), Shannon Venance (London Health Science Centre, Canada), Julio Vergara (University of California), Savine Vicart(Pitie-Salpetriere, France), Ronan Walsh (Brigham and Women{\textquoteright}s Hospital), Yunxia Wang (University of Kansas), Thurman Wheeler (University of Rochester).",
year = "2010",
month = jan,
doi = "10.1093/brain/awp294",
language = "English (US)",
volume = "133",
pages = "9--22",
journal = "Brain",
issn = "0006-8950",
publisher = "Oxford University Press",
number = "1",
}