This application responds to RFA RR-03-008, Rare Diseases Clinical Research Network and proposes the investigation of 3 rare neurological channelopathies: periodic paralysis, non-dystrophic myotonic disorders and episodic ataxia. The research plan will exploit the strengths of 7 collaborating centers to link molecular scientists studying these disorders with clinical investigators with established expertise in the development of new treatments for neurological disease. It will extend a prototype NIH training program in experimental therapeutics to train a cadre of patient-oriented-researchers committed to rare disorders. Study investigators have strong links with the patient advocacy organizations focused on these rare disorders: the Periodic Paralysis Association, the National Ataxia Foundation and the Muscular Dystrophy Association. A particular strength of the collaborating institutions is an established nationwide infrastructure, including GCRCs and a biostatistician, for the implementation of multicenter clinical trials that will facilitate investigation of the efficacy of putative new treatments for rare diseases. Currently-supported studies of the pathophysiology of the 3 specific target diseases will provide resources for molecular characterization of subjects and make it possible to: (1) begin the characterization of the phenotype/natural history of each; (2) devise outcome measures for treatment trials; (3) assess quality of life -- all in preparation for pilot clinical trials of novel treatments. The focus of investigation is on: (1) Andersen's syndrome, a periodic paralysis with associated life-threatening cardiac arrhythmias for which no treatment has been identified; (2) the nondystrophic myotonias caused by sodium and chloride channel mutations for which there is no established treatment and there have been no well-designed clinical trials; (3) the episodic ataxias EA1 and EA2 for which treatment is not yet defined. Both cellular model systems and animal models, funded separately, are (or soon will be) available for each of these disorders and can provide pre- clinical data necessary for proposed phase 1 and 2 trials of novel treatments. These 3 disorders are prototypes for the development of treatment strategies for over 50 other rare neurological channelopathies. They may also offer a window for understanding common disorders likely to be caused by CNS channel mutations/dysfunction such as migraine and epilepsy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
3U54NS059065-05S2
Application #
7688212
Study Section
Special Emphasis Panel (ZRG1-EDC-1 (50))
Program Officer
Stewart, Randall R
Project Start
2003-09-30
Project End
2011-07-31
Budget Start
2007-08-01
Budget End
2011-07-31
Support Year
5
Fiscal Year
2008
Total Cost
$1,115,907
Indirect Cost
Name
University of Rochester
Department
Neurology
Type
Schools of Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
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Tomlinson, Susan E; Tan, S Veronica; Burke, David et al. (2016) In vivo impact of presynaptic calcium channel dysfunction on motor axons in episodic ataxia type 2. Brain 139:380-91
Tan, S Veronica; Z'graggen, Werner J; Boërio, Delphine et al. (2016) In vivo assessment of muscle membrane properties in myotonic dystrophy. Muscle Nerve 54:249-57
Ke, Qing; He, Fangping; Lu, Lingping et al. (2015) The R900S mutation in CACNA1S associated with hypokalemic periodic paralysis. Neuromuscul Disord 25:955-8
Ke, Qing; Qi, Ming; Wu, Weiping et al. (2014) Rare disease centers for periodic paralysis: China versus the United States and United Kingdom. Muscle Nerve 49:171-4
Graves, Tracey D; Cha, Yoon-Hee; Hahn, Angelika F et al. (2014) Episodic ataxia type 1: clinical characterization, quality of life and genotype-phenotype correlation. Brain 137:1009-18
Tan, S Veronica; Z'Graggen, Werner J; Boërio, Delphine et al. (2014) Chloride channels in myotonia congenita assessed by velocity recovery cycles. Muscle Nerve 49:845-57
Trivedi, Jaya R; Bundy, Brian; Statland, Jeffrey et al. (2013) Non-dystrophic myotonia: prospective study of objective and patient reported outcomes. Brain 136:2189-200
Ke, Qing; Luo, Benyan; Qi, Ming et al. (2013) Gender differences in penetrance and phenotype in hypokalemic periodic paralysis. Muscle Nerve 47:41-5
Platt, Daniel; Griggs, Robert C (2012) Use of acetazolamide in sulfonamide-allergic patients with neurologic channelopathies. Arch Neurol 69:527-9

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