The NDM are a heterogeneous group of neuromuscular disorders caused by mutations in skeletal muscle ion channels. People with NDM experience impaired muscle relaxation following contraction associated with stiffness, incoordination, and pain. The symptoms are not life-threatening but do cause lifetime morbidity and a decrease in patients'functional status. Most cases of NDM are related to mutations in voltage-dependent sodium or chloride channels. Mexiletine is a class 1B antiarrhythmic medication that has high affinity for muscle sodium channels. In vitro data indicates that mexiletine corrects delayed inactivation of sodium channels in common NDM sodium channel mutations expressed in cell culture. Mexiletine also improves functional behavior in a mouse model of severe recessive myotonia congenita. In humans, mexiletine has been shown to be beneficial in reducing symptoms of myotonia in patients with NDM, both in case reports and single-blind clinical trials. However;there are currently no FDA approved therapies for NDM, and the optimal treatment for different subtypes of NDM is unknown. The goal of this study is to determine if mexiletine is an effective treatment in NDM. Because of the rarity of NDM, randomized double-blind placebo controlled clinical trials were not feasible in the past. Utilizing the infrastructure established by Clinical Investigation of Neurologic Channelopathies (CINCH) NDM longitudinal natural history study, the investigators have the unique opportunity to perform a randomized, double- blind, placebo controlled, cross-over trial of mexiletine in NDM. The cross-over design permits each participant to serve as his/her own control and allows the investigators to study individual differences in the response of patients to the same dose of mexiletine, and determine if response correlated with different subtypes of NDM. The primary outcome measure for this study is a decrease in patient-assessed prominent clinical symptom: stiffness. This will be quantitated by an Interactive Voice Response System (IVR) in which the patient will rate their stiffness. The secondary measures include patient assessed changes in pain, weakness, fatigue, improvement in quality of life, and quantitative measures of myotonia. These secondary measures will be quantified by lndividual Neuromuscular Quality of Life (INQOL), SF-36 (adults), SF-10 (children), grip myotonia, physical exam, and electrophysiological testing, respectively.

National Institute of Health (NIH)
Food and Drug Administration (FDA)
Research Project (R01)
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Special Emphasis Panel (ZFD1-OPD-L (01))
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Needleman, Katherine
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University of Kansas
Schools of Medicine
Kansas City
United States
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Statland, Jeffrey M; Bundy, Brian N; Wang, Yunxia et al. (2012) Mexiletine for symptoms and signs of myotonia in nondystrophic myotonia: a randomized controlled trial. JAMA 308:1357-65
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