Spectrum of Phenotypic, Genetic, and Functional Characteristics in Patients With Epilepsy With KCNC2 Pathogenic Variants

Background and ObjectivesKCNC2 encodes Kv3.2, a member of the Shaw-related (Kv3) voltage-gated potassium channel subfamily, which is important for sustained high-frequency firing and optimized energy efficiency of action potentials in the brain. The objective of this study was to analyze the clinical phenotype, genetic background, and biophysical function of disease-associated Kv3.2 variants.MethodsIndividuals with KCNC2 variants detected by exome sequencing were selected for clinical, further genetic, and functional analysis. Cases were referred through clinical and research collaborations. Selected de novo variants were examined electrophysiologically in Xenopus laevis oocytes.ResultsWe identified novel KCNC2 variants in 18 patients with various forms of epilepsy, including genetic generalized epilepsy (GGE), developmental and epileptic encephalopathy (DEE) including early-onset absence epilepsy, focal epilepsy, and myoclonic-atonic epilepsy. Of the 18 variants, 10 were de novo and 8 were classified as modifying variants. Eight drug-responsive patients became seizure-free using valproic acid as monotherapy or in combination, including severe DEE cases. Functional analysis of 4 variants demonstrated gain of function in 3 severely affected DEE cases and loss of function in 1 case with a milder phenotype (GGE) as the underlying pathomechanisms.DiscussionThese findings implicate KCNC2 as a novel causative gene for epilepsy and emphasize the critical role of KV3.2 in the regulation of brain excitability

GWAS meta-analysis of over 29,000 people with epilepsy identifies 26 risk loci and subtype-specific genetic architecture

Epilepsy is a highly heritable disorder affecting over 50 million people worldwide, of which about one-third are resistant to current treatments. Here we report a multi-ancestry genome-wide association study including 29,944 cases, stratified into three broad categories and seven subtypes of epilepsy, and 52,538 controls. We identify 26 genome-wide significant loci, 19 of which are specific to genetic generalized epilepsy (GGE). We implicate 29 likely causal genes underlying these 26 loci. SNP-based heritability analyses show that common variants explain between 39.6% and 90% of genetic risk for GGE and its subtypes. Subtype analysis revealed markedly different genetic architectures between focal and generalized epilepsies. Gene-set analyses of GGE signals implicate synaptic processes in both excitatory and inhibitory neurons in the brain. Prioritized candidate genes overlap with monogenic epilepsy genes and with targets of current antiseizure medications. Finally, we leverage our results to identify alternate drugs with predicted efficacy if repurposed for epilepsy treatment

The phenotypic and genotypic spectrum of epilepsy and intellectual disability in adults: Implications for genetic testing

OBJECTIVE: The phenotypic and genotypic spectrum of adult patients with epilepsy and intellectual disability (ID) is less clear than in children. We investigated an adult patient cohort to further elucidate this and inform the genetic testing approach. METHODS: Fifty-two adult patients (30 male, 22 female) with epilepsy, at least mild ID and no known genetic or acquired cause were included and phenotyped. Variants identified through exome sequencing were evaluated using ACMG criteria. Identified variants were compared with commercially available gene panels. Cluster analysis of two features, age at seizure onset and age at ascertainment of cognitive deficits, was performed. RESULTS: Median age was 27 years (range 20-57 years) with median seizure onset at 3 years and median ascertainment of cognitive deficits at 1 year. Likely pathogenic/pathogenic variants were identified in 16/52 patients (31%) including 14 (27%) single nucleotide variants and 2 (4%) copy number variants. Simulated yield of commercial gene panels varied between 13% in small (≤144 genes) and 27% in large panels (≥1478 genes). Cluster analysis (optimal number 3 clusters) identified a cluster with early seizure onset and early developmental delay (developmental and epileptic encephalopathy, n=26), a cluster with early developmental delay but late seizure onset (ID with epilepsy, n=16) and a third cluster with late ascertainment of cognitive deficits and variable seizure onset (n=7). The smaller gene panels particularly missed the genes identified in the cluster with early ascertainment of cognitive deficits and later onset of epilepsy (0/4) as opposed to the cluster with developmental and epileptic encephalopathy (7/10). SIGNIFICANCE: Our data indicates that adult patients with epilepsy and ID represent a heterogeneous cohort that includes grown-up patients with DEE but also patients with primary ID and later onset of epilepsy. To maximize diagnostic yield in this cohort either large gene panels or exome sequencing should be used

Treatment of Otosclerosis with a Superelastic Nitinol Piston: First Results

Stapedotomy with implantation of an alloplastic prosthesis is a well-established therapy for the treatment of otosclerosis. Since the middle of 2008, a new Nitinol prosthesis with memory function and superelastic properties has been available which is expected to make fixation on the long process of the incus much easier. The advantage of this prosthesis is that heat-induced wire crimping is no longer necessary and damage to the incus caused by heat is avoided. Since May 2008, laser-assisted stapedotomy with implantation of a Nitinol prosthesis was performed in 21 patients suffering from otosclerosis. The prostheses used for all patients had a size of 4.5 mm × 0.4 mm. The patient collective consisted of 14 women and 7 men with a mean age of 53.4 years. Pre- and postoperatively, an ENT examination was carried out followed by an audiological evaluation of the hearing result. In addition, the properties of the prosthesis (“proper fitt”, “handling”, and “overall rating”) were evaluated intraoperatively by means of a test protocol. The Nitinol prosthesis was implanted successfully in all 21 patients. The mean air-bone gap for the frequencies from 0.5 to 4 kHz was 9.83 dB postoperatively. Intraoperatively, the fit of the prosthesis was rated as “good to very good”, the handling as “good” and the overall rating of the system was “good to very good”. Our patient collective showed good postoperative hearing results. Due to simple intraoperative handling, especially placing the Nitinol prosthesis in position, the critical work step of crimping is no longer necessary