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

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Johnson JN, Hofman N, Haglund CM, Cascino GD, Wilde AAM, and Ackerman MJ (2009) Identification of a possible pathogenic link between congenital long QT syndrome and epilepsy. Neurology 72:3 224–31.

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Abstract: 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.



  • Retrospective study of 343 patients evaluated for LQTS over 8 year period to determine whether type 2 LQTS, which is due to mutation in KCNH2, a potassium channel active in hippocampal astrocytes, was more likely to present with a “seizure phenoptype” than were other types of LQTS. The phenotype was considered present with personal or family history of seizure or history of AED treatment. Significantly higher proportions of LQT2 patients had positive seizure phenotype, history of seizures, and history of treatment with AED than did patients with any other type of LQTS. This suggests Type 1 LQTS patients may be predisposed to seizures, possibly due to abnormalities in glial potassium signaling in the brain. This represents an example of potential mechanistic links between cardiac dysfunction and epilepsy.


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