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This Article Figures Only Full Text Full Text (PDF) CME: Take the course for this article: Volume 72, Number 3, January 20, 2009 Japanese Translation All Versions of this Article: 01.wnl.0000335760.02995.cav1 72/3/224    most recent Correspondence: Submit a response Alert me when this article is cited Alert me when Correspondence are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Johnson, J. N. Articles by Ackerman, M. J. Search for Related Content PubMed PubMed Citation Articles by Johnson, J. N. Articles by Ackerman, M. J. Related Collections All Pediatric Cardiac; see Cerebrovascular Disease/Cardiac Syncope All Epilepsy/Seizures Ion channel gene defects Related Article

Identification of a possible pathogenic link between congenital long QT syndrome and epilepsy

From the Department of Pediatrics/Division of Pediatric Cardiology (J.N.J., C.M.H., M.J.A.), Department of Molecular Pharmacology and Experimental Therapeutics (C.M.H., M.J.A.), Department of Neurology/Division of Epilepsy (G.D.C.), and Department of Medicine/Division of Cardiovascular Diseases (M.J.A.), Mayo Clinic, Rochester, MN; and Departments of Clinical Genetics (N.H.) and Cardiology (A.A.M.W.), Academic Medical Center, Amsterdam, The Netherlands.

Address correspondence and reprint requests to Dr. Michael J. Ackerman, Director, Long QT Syndrome Clinic and the Mayo Clinic Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Guggenheim 501, 200 First Street SW, Rochester, MN 55905 ackerman.michael{at}mayo.edu.

Background: Long QT syndrome (LQTS) typically presents with syncope, seizures, or sudden death. Patients with LQTS have been misdiagnosed with a seizure disorder or epilepsy and treated with antiepileptic drug (AED) medication. The gene, KCNH2, responsible for type 2 LQTS (LQT2), was cloned originally from the hippocampus and encodes a potassium channel active in hippocampal astrocytes. We sought to test the hypothesis that a "seizure phenotype" was ascribed more commonly to patients with LQT2.

Methods: Charts were reviewed for 343 consecutive, unrelated patients (232 females, average age at diagnosis 27 ± 18 years, QTc 471 ± 57 msec) clinically evaluated and genetically tested for LQTS from 1998 to 2006 at two large LQTS referral centers. A positive seizure phenotype was defined as the presence of either a personal or family history of seizures or history of AED therapy.

Results: A seizure phenotype was recorded in 98/343 (29%) probands. A seizure phenotype was more common in LQT2 (36/77, 47%) than LQT1 (16/72, 22%, p < 0.002) and LQT3 (7/28, 25%, p < 0.05, NS). LQT1 and LQT3 combined cohorts did not differ significantly from expected, background rates of a seizure phenotype. A personal history of seizures was more common in LQT2 (30/77, 39%) than all other subtypes of LQTS (11/106, 10%, p < 0.001).

Conclusions: A diagnostic consideration of epilepsy and treatment with antiepileptic drug medications was more common in patients with LQT2. Like noncardiac organ phenotypes observed in other LQTS-susceptibility genes such as KCNQ1/deafness and SCN5A/gastrointestinal symptoms, this novel LQT2-epilepsy association raises the possibility that LQT2-causing perturbations in the KCNH2-encoded potassium channel may confer susceptibility for recurrent seizure activity.

Abbreviations: AED = antiepileptic drug; LQT1 = type 1 LQTS; LQT2 = type 2 LQTS; LQTS = long QT syndrome; TdP = torsades de pointes.

Editorial, page 208

e-Pub ahead of print on November 26, 2008, at www.neurology.org.

*These two authors contributed equally to the research and writing of this article.

Dr. Michael Ackerman's research program was supported by the Mayo Clinic Windland Smith Rice Comprehensive Sudden Cardiac Death Program. M.J.A. is also an Established Investigator of the AHA and is supported by the NIH (HD42569). Dr. Arthur Wilde's research program was supported by the Netherlands Heart Foundation (NHS 2000.059) and the Foundation Leducq (Grant 05 CVD, Alliance against Sudden Cardiac Death).

Disclosure: Dr. Ackerman is a consultant for PGxHealth, Medtronic, and Pfizer.

Received January 7, 2008. Accepted in final form July 16, 2008.

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Seizures and arrhythmias: Differing phenotypes of a common channelopathy?

Jill V. Hunter and Arthur J. Moss
Neurology 2009 72: 208-209. [Full Text] [PDF]

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				A. M. Goldman, E. Glasscock, J. Yoo, T. T. Chen, T. L. Klassen, and J. L. Noebels Arrhythmia in Heart and Brain: KCNQ1 Mutations Link Epilepsy and Sudden Unexplained Death Science Translational Medicine, October 14, 2009; 1(2): 2ra6 - 2ra6. [Abstract] [Full Text] [PDF]

				J. V. Hunter and A. J. Moss Seizures and arrhythmias: Differing phenotypes of a common channelopathy? Neurology, January 20, 2009; 72(3): 208 - 209. [Full Text] [PDF]