Linkage Evidence for a Two-Locus Inheritance of LQT-Associated Seizures in a Multigenerational LQT Family With a Novel KCNQ1 Loss-of-Function Mutation.

Mutations in several genes encoding ion channels can cause the long-QT (LQT) syndrome with cardiac arrhythmias, syncope and sudden death. Recently, mutations in some of these genes were also identified to cause epileptic seizures in these patients, and the sudden unexplained death in epilepsy (SUDEP) was considered to be the pathologic overlap between the two clinical conditions. For LQT-associated KCNQ1 mutations, only few investigations reported the coincidence of cardiac dysfunction and epileptic seizures. Clinical, electrophysiological and genetic characterization of a large pedigree (n = 241 family members) with LQT syndrome caused by a 12-base-pair duplication in exon 8 of the KCNQ1 gene duplicating four amino acids in the carboxyterminal KCNQ1 domain (KCNQ1dup12; p.R360_Q361dupQKQR, NM_000218.2, hg19). Electrophysiological recordings revealed no substantial KCNQ1-like currents. The mutation did not exhibit a dominant negative effect on wild-type KCNQ1 channel function. Most likely, the mutant protein was not functionally expressed and thus not incorporated into a heteromeric channel tetramer. Many LQT family members suffered from syncopes or developed sudden death, often after physical activity. Of 26 family members with LQT, seizures were present in 14 (LQTplus seizure trait). Molecular genetic analyses confirmed a causative role of the novel KCNQ1dup12 mutation for the LQT trait and revealed a strong link also with the LQTplus seizure trait. Genome-wide parametric multipoint linkage analyses identified a second strong genetic modifier locus for the LQTplus seizure trait in the chromosomal region 10p14. The linkage results suggest a two-locus inheritance model for the LQTplus seizure trait in which both the KCNQ1dup12 mutation and the 10p14 risk haplotype are necessary for the occurrence of LQT-associated seizures. The data strongly support emerging concepts that KCNQ1 mutations may increase the risk of epilepsy, but additional genetic modifiers are necessary for the clinical manifestation of epileptic seizures.

Dissociative and associated psychopathological symptoms in patients with epilepsy, pseudoseizures, and both seizure forms.

PURPOSE: A controversy currently exists regarding the significance of dissociation and conversion in the pathogenesis of pseudoepileptic seizures. After the abolition of the term "hysterical neurosis" from the current diagnostic systems, these seizures were diagnosed as either Dissociative Disorders (ICD-10) or in the DSM IV as Somatoform disorder, most often of conversion type. Recent studies of patients with Dissociative Disorders found that most patients also had conversion symptoms. METHODS: In the present study, 60 patients of an outpatient clinic for epilepsy were assessed for the presence of dissociative symptoms and general psychopathologic symptoms by using the German version of the Dissociative Experience Scale (DES) and the Symptom Check List (SCL-90-R). RESULTS: The patients with pseudoepileptic seizures showed a significantly higher incidence of dissociation (p < 0.0098) and general psychopathologic symptoms (p < 0.0083). Depression, anxiety, and obsession were dominating psychopathologic symptoms in all patients. CONCLUSIONS: The significantly higher incidence of dissociation in the patients with pseudoepileptic seizures suggests dissociation in the pathogenesis of these seizures.