Clinical Research Network for Episodic Ataxia: The Episodic Ataxia Registry

By Joanna C. Jen, MD, PhD, Robert W. Baloh, MD & Robert C. Griggs, MD
on behalf of the investigators of the Consortium for Clinical Investigations of Neurological Channelopathies (CINCH)

Special to The Movement Disorder Society

April/May 2010

Neurologic channelopathies are caused by genetic mutations that affect the function of ion channels in cell membranes that can lead to episodes of incoordination, muscle weakness, and stiffness. Andersen-Tawil syndrome, the non-dystrophic myotonias, and the episodic ataxias are all rare forms of neurologic channelopathies. The underlying causes of these conditions are only partially understood, and there are no established treatments. CINCH is a collaborative organization of doctors, patient advocacy groups, and federal health agencies that want to learn more about these diseases so that ultimately they can offer better treatments to patients. Designated the episodic ataxia centers for the Rare Diseases Clinical Research Network sponsored by the National Institutes of Health, we are referred patients with EA from across the country and have a patient registry for EA subjects with natural history data maintained at the Data Management and Coordinating Center (DMCC) of the University of Florida.

The episodic ataxias are characterized by dramatic and repeated attacks of clumsiness and imbalance commonly triggered by emotional stress, physical exertion, or fatigue. There are at least seven designated subtypes of heritable episodic ataxia (EA1-EA7) classified on the basis of distinctive clinical and genetic features. EA1 is caused by mutations in a neuronal voltage-gated potassium channel Kv1.1 and presents with episodic ataxia lasting seconds and interictal myokymia variably associated with epilepsy. EA2, the most common and best characterized EA subtype, is caused by mutations in a neuronal calcium channel Cav2.1. EA2 is clinically characterized by ataxia episodes lasting hours, with interictal nystagmus and variably associated with progressive ataxia, migraine, epilepsy, dystonia, and myasthenia. The other EA subtypes are defined by unique families. Of note, EA5 is caused by a mutation in an accessory beta subunit of Cav2.1, and EA6 is defined by mutations in a glial glutamate transporter EAAT1. We have not been able to identify mutations in the four known EA genes in about half of the index patients with episodic ataxia, suggesting genetic heterogeneity for EA.

Every patient and physician can play an important part in helping to find out more about EA and related channelopathies: their causes, triggers, natural history, and potential treatments. If your patient has symptoms of EA, one very important way you can help is to inform your patient of the EA Patient Contact Registry to consider taking part in clinical research. We are actively recruiting interested individuals who are affected by episodic ataxia to visit us at one of the participating centers for interview, neurological examination, blood draw (for genetic analysis), and follow up by phone using an interactive voice response system to maintain a log of the ataxia attacks. Those who cannot travel to one of the study centers are still encouraged to contact us to arrange for alternative means to participate in research. The ongoing natural history study coupled with the genetic analysis has enabled us and will continue to help us refine the clinical spectrum of each EA subtype, correlate the clinical manifestations with the genetic defects, identify new EA phenotypes/genotypes, and explore the use of existing measures for health-related quality of life in EA2. Our long term goal is to improve the recognition, diagnosis, and treatment of EA.

Genetic definition provides a molecular basis for patient stratification for clinical trials. 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. We are actively planning a double-blind, placebo-controlled crossover trial for 4-aminopyridine (4AP) in patients with genetically confirmed EA2. Our main goal in the randomized trial for 4AP is to investigate whether extended release 4AP, 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 alternative treatment. We would also like to analyze the impact of 4AP on treatment satisfaction and health-related quality of life in EA2.

We will update the public through our website on the status of the ongoing CINCH natural history study and active as well as pending clinical trials. We appreciate physician referrals and patient participation.

For more information, please visit us at: Consortium for Clinical Investigations of Neurological Channelopathies (CINCH)

About Robert W. Baloh, MD

Robert W. Baloh, MDRobert W. Baloh, MD, is Professor of Neurology and Surgery/Otolaryngology at UCLA School of Medicine. He obtained his medical degree from the University of Pittsburgh and after an internship and medical residency at the University of Pittsburgh he moved to Los Angeles where he completed a Neurology residency. Dr. Baloh has been on the faculty at UCLA since the early 1970's where he has specialized in the study of dizziness and balance disorders. He has written more than 300 articles in peer reviewed journals and has authored several books on this topic. He is the principle investigator of the episodic ataxia section in the multi-center Consortium for Clinical Investigations of Neurological Channelopathies (CINCH) headed by Dr. Robert Griggs at the University of Rochester.

About Robert C. Griggs

Robert C. Griggs, MDRobert C. Griggs, MD, is Professor of Neurology, Medicine, Pathology and Laboratory Medicine and Pediatrics at the University of Rochester School of Medicine and Dentistry. He is currently President (2009-2011) of the American Academy of Neurology. He was Chair of the Department of Neurology and Neurologist-in-Chief at Strong Memorial Hospital 1986-2008. He stepped down in July 2008 to be able to devote more time to the NIH-funded Clinical Investigation of Neurologic Channelopathies (CINCH) and his other research. Dr. Griggs is an internist/neurologist specializing in neuromuscular diseases with a focus on experimental therapeutics. Dr. Griggs has over 30 years experience in clinical research on neuromuscular ion channelopathies with over 100 peer-reviewed publications pertaining to channelopathy research and developing new treatment for these disorders. Dr. Griggs has directed the NIH-funded training program "The Experimental Therapeutics of Neurological Disease" since 1989. This program has trained over 50 clinical neuroscientists, >90% of whom remain in academic careers.

About Joanna C. Jen

Joanna C. Jen, MD, PhDJoanna C. Jen, MD, PhD, is Professor of Neurology at UCLA School of Medicine. She obtained her medical and graduate degrees from Yale University, completed neurology residency at UCLA, and pursued fellowship training in neurotology, physiology, and human genetics, also at UCLA. Her clinical interest in neurotology is complemented by research performed in her laboratory, which focuses on the genetic and physiological bases of rare disorders affecting balance and eye movement control in neurodevelopment and neurodegeneration. She has conducted ongoing clinical and basic scientific studies on episodic ataxia for the past decade and is the principal investigator of an NIH-funded project on the genetics of familial episodic ataxia. She is an investigator in a multi-center Consortium for Clinical Investigations of Neurological Channelopathies (CINCH) headed by Dr. Robert Griggs at the University of Rochester.


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