Familial episodic ataxia (EA) syndromes are rare and heterogeneous monogenic disorders characterized by dramatic episodes of imbalance and uncoordination. Episodic ataxia type 2 (EA2) is the most common and the best characterized of all the EA syndromes. EA2 caused by mutations in CACNA1A (a neuronal calcium channel gene) typically presents with early onset debilitating ataxia episodes variably associated with nystagmus, headaches, and fluctuating weakness. Since the discovery of dramatic response of EA2 to acetazolamide, acetazolamide has been the first-line treatment for EA2. Yet, some patients are not responsive to acetazolamide, cannot tolerate the side effects, or are allergic to acetazolamide. For these patients (roughly a third of individuals who are currently participating in an ongoing UCLA Episodic Ataxia study as well a collaborative study with the University of Rochester), there are no alternative treatments. 4-Aminopyridine (4AP) was found in Europe to be effective in a few patients with EA2, and an extended release formulation of 4AP by Acorda Therapeutics has just been approved by the FDA in January 2010 for use in patients with multiple sclerosis. With assurance from Acorda to supply 4AP and placebo, a randomized trial is proposed to test the efficacy of 4AP in reducing ataxia episode frequency and secondarily to evaluate its tolerability and its impact on treatment satisfaction and health-related quality of life in patients with EA2. Recruitment of 20 subjects for this 3-year, double-blind, two-crossover, randomized trial of 4AP is proposed.

Public Health Relevance

TO PUBLIC HEALTH Designated the episodic ataxia centers for the Rare Diseases Clinical Research Network sponsored by the National Institutes of Health;we are referred patients with episodic ataxia from across the country. We have recruited a large number of patients with episodic ataxia and diagnosed many with episodic ataxia type 2. Although the majority of EA2 patients respond well to acetazolamide, about a third of the patients cannot tolerate acetazolamide or continue to have frequent debilitating ataxia attacks despite treatment. Our main goal in the proposed randomized trial for 4AP is to investigate whether extended release 4-aminopyridine, newly approved by the FDA in January 2010 for use in patients with multiple sclerosis, can decrease ataxia attack frequency in EA2 patients who have no other alternative treatment. We hope to improve the treatment of EA2.

National Institute of Health (NIH)
Food and Drug Administration (FDA)
Research Project (R01)
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Special Emphasis Panel (ZFD1-OPD-N (S1))
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Needleman, Katherine
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University of California Los Angeles
Schools of Medicine
Los Angeles
United States
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