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

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.

Figure Prevalence of “seizure phenotype” in long QT syndrome subtypes Percentage of patients from the combined cohort for each genotypic classification having a positive seizure phenotype (black bar), personal history of seizures (diagonal line), or history of treatment for seizures with antiepileptic drugs (AEDs, white bar). Not shown are patients with LQT5, LQT6, and LQT7 (n = 6), none of whom had a positive seizure phenotype. *Significance value of combined cohort of LQT2 patients compared to other long QT genotypes. **Significance value of combined cohort of LQT2 patients compared to the other LQTS genotypes (i.e. LQT1 and LQT3) and the genotype negative background rates. When compared to LQT3, LQT2 is more common (47% vs 25%) but did not achieve significance (p = 0.07).