title: 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.
authors.affiliation: 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, USA.
authors.forename: J N
authors.initials: JN
authors.lastname: Johnson
authors.forename: N
authors.initials: N
authors.lastname: Hofman
authors.forename: C M
authors.initials: CM
authors.lastname: Haglund
authors.forename: G D
authors.initials: GD
authors.lastname: Cascino
authors.forename: A A M
authors.initials: AA
authors.lastname: Wilde
authors.forename: M J
authors.initials: MJ
authors.lastname: Ackerman
mesh_terms: D000293:Adolescent; D000328:Adult; D000927:Anticonvulsants / Q000627:therapeutic use; D053447:Channelopathies / Q000235:genetics*; D015331:Cohort Studies; D004827:Epilepsy / Q000188:drug therapy / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D051657:KCNQ1 Potassium Channel / Q000235:genetics*; D008133:Long QT Syndrome / Q000145:classification / Q000151:congenital* / Q000235:genetics*; D008297:Male; D008499:Medical Records; D008875:Middle Aged; D010641:Phenotype; D055815:Young Adult
chemical_list: D000927:Anticonvulsants; D051657:KCNQ1 Potassium Channel