KCNH2 Gene Mutation: A Potential Link Between Epilepsy and Long QT-2 Syndrome

Abstract

Long QT syndrome (LQTS) is closely associated with syncope, seizure, and sudden death but LQTS is frequently misdiagnosed as epilepsy. LQTS and epilepsy both belong to the group of ion channelopathies that manifest in the heart and brain. Therefore, genetic analysis of genes associated with potassium and sodium homeostasis and electrical disorders may reveal a link between epilepsy and lethal cardiac arrhythmia. Here, the authors report a young woman who suffered recurrent seizure episodes and syncopes that occurred while walking and also during rest. She showed electroencephalogram abnormalities and a pathological prolonged QTc interval in electrocardiogram. The patient and the patient's asymptomatic family members underwent genetic screening of the three genes most frequently associated with LQTS: KCNQ1, KCNH2, and SCN5A. The patient and the family members did not show DNA alterations in the genes KCNQ1 and SCN5A associated with LQT-1 and LQT-3, respectively. However, the patient showed a de novo mutation 2587T→C in exon 10 of KCNH2 gene associated with LQT-2. The mutation caused a stop codon substitution (R863X) in the HERG channel, leading to a 296-amino acid deletion. The patient's asymptomatic relatives did not show the KCNH2 gene mutation. R863X alteration in HERG channel may be involved in both prolonged QTc interval and epilepsy. This fact raises the possibility that R863X alteration in KCNH2-encoded potassium channel may confer susceptibility for epilepsy and cardiac LQT-2 arrhythmia.

Epilepsy Misdiagnosed as Long QT Syndrome: It Can Go Both Ways

“…4 In this era of increased awareness of LQTS, a real risk of overdiagnosis of generalized seizure-like spells as cardiogenic syncope is emerging, which may subsequently lead to lifestyle alterations, unnecessary medications, and ultimately invasive procedures with implantation of unnecessary devices. This overdiagnosis of LQTS seems ever present, as recently, we demonstrated that 40% of the patients that came to Mayo Clinic with the diagnosis of LQTS left our institution without that diagnosis.…”

A woman in her thirties with seizure relapse after a previous diagnosis of epilepsy

“…The proteins that are coded in the KCNH2 gene are also found in ion channels in the astrocyte membrane of the hippocampus. This association is postulated as a possible explanation for the link between long QT syndrome and epilepsy (14)(15)(16)(17). Further, it is shown that patients with long QT syndrome type 2 more often have a history that includes epileptic seizures and are more often treated with antiepileptic drugs than patients with long QT syndrome types 1 and 3 (17).…”

“…The clinical background for the assumption of a common pathophysiological substrate between epilepsy and long QT syndrome has mainly been limited to case reports (13)(14)(15)(16). The proteins that are coded in the KCNH2 gene are also found in ion channels in the astrocyte membrane of the hippocampus.…”

The Human Ether-A-Go-Go–Related Gene Activator NS1643 Enhances Epilepsy-Associated KCNQ Channels

“…Many patients with recurrent convulsions who were treated for epilepsy for years were finally diagnosed with LQT (Gatto et al, 1993;Scheepers et al, 1998;Medina-Villanueva et al, 2002;Hunt and Tang, 2005;Johnson et al, 2009;MacCormick et al, 2009;Jorge et al, 2011). Although the responsible genes of the two channelopathies are different, besides misdiagnosis, increasing evidence argues for a close pathogenic relationship between LQT2 and epilepsy (Johnson et al, 2009;Keller et al, 2009;MacCormick et al, 2009;Omichi et al, 2010;Zamorano-Leon et al, 2012). For example, in a chart review study (Johnson et al, 2009), a seizure phenotype was observed in 98 patients among 343 LQT patients (98/343, 29%).…”

“…In fact, there is a common misdiagnosis of LQT2 versus epilepsy (Johnson et al, 2009;MacCormick et al, 2009). In some cases, seizures of LQT2 are likely due to cardiac syncope (Keller et al, 2009;Jorge et al, 2011;Zamorano-Leon et al, 2012). In addition, increasing evidences suggest LQT2 and epilepsy coexist (Johnson et al, 2009;MacCormick et al, 2009;Jorge et al, 2011).…”