Regional Somatic Mosaicism in Pediatric Drug-resistant Epilepsy
Abstract number :
1.484
Submission category :
1. Basic Mechanisms / 1B. Epileptogenesis of genetic epilepsies
Year :
2024
Submission ID :
1655
Source :
www.aesnet.org
Presentation date :
12/7/2024 12:00:00 AM
Published date :
Authors :
Presenting Author: Danielle Sanchez, BS Candidate – Stanford University
Nishanth Narayan, BS – Stanford University
Bunmi Fariyike, MD Candidate – Stanford University
H. Westley Phillips, MD – Stanford University School of Medicine
Rationale: Epilepsy is the most common neurological disorder in children, characterized by unprovoked chronic seizures. While anti-seizure medications (ASM) are the first line of treatment, about 1/3 of patients develop drug-resistant epilepsy (DRE) after failing 2 or more ASMs. For these patients, surgical interventions may be indicated in select patients. Genetic analyses of resected brain tissue have linked brain-limited pathogenic mutations to epilepsy pathogenesis. However, logistical hurdles in tissue collection and processing often fail to include the anatomic orientation of specimens received for sequencing. Recent studies suggest a relationship between epileptic regions and associated pathogenic variants due to somatic mosaicism. These regional gradients propose a dose-dependent function of mutation burden and epileptogensis. This study investigates the genetic profiles of multiple brain regions obtained from the same patient following a stereo-EEG (sEEG)-guided open surgical resection for DRE to explore the relationship between the electrophysiologic and genetic signatures of epilepsy.
Methods: We identified pediatric patients who underwent sEEG and subsequent surgical resection for DRE at our epilepsy center from January to July 2024. Resections were based on sEEG-presumed seizure onset zones (SOZ) and decided at a multidisciplinary conference. Bulk brain biopsies from various regions throughout a planned resection were correlated to the location of previously implanted sEEG electrodes. Peripheral blood samples were also collected. Genomic DNA extracted from bulk brain tissue and blood samples underwent targeted gene panel sequencing to identify pathogenic variants. Candidate variants were then validated by amplicon sequencing. Variant allele fractions (VAFs) were compared and mapped according to sEEG-derived epileptogenic regions. Clinical data, including post-operative seizure frequency, were collected via retrospective chart review.
Results: We identified 7 patients who underwent sEEG for SOZ localization and subsequent resection surgery. Samples were collected from patients with varying etiologies, primarily malformations of cortical development (86%). The cohort was 71% male, with an average age of 7.14 years (range 2-16). Using a targeted gene panel of 283 known epilepsy and cancer-related genes, we performed next-generation sequencing achieving 1000x coverage. We hypothesize that pathogenic mutations will be enriched in epileptic tissues compared to non-epileptic regions. At last follow-up, all patients displayed reduced seizure frequency, with 71.4% achieving seizure freedom.
Conclusions: Pediatric DRE is prevalent and debilitating. sEEG-informed resection can reduce or cure seizures in select patients. Brain-limited somatic mutations are linked to DRE and establishing the impact of somatic mosaicism across an epileptic network is paramount to further our understanding of the molecular mechanisms of epilepsy.
Funding: N/A
Basic Mechanisms