Abstracts

Rationale: Genetic generalized epilepsies (GGE) are characterized by specific clinical and EEG features and are presumed to have a genetic basis. Most GGEs present in early childhood and are often outgrown by adulthood. However, a subset of GGEs persists into adulthood, may appear as new onset, and can sometimes progress to intractability. We hypothesize that patients with intractable GGE possess distinct genetic variants in genes, which influence gene expression in the brain. This study aims to identify a pattern of genes associated with intractable GGE in adults.

Methods: After obtaining IRB approval, adult patients >18 years at Henry Ford Epilepsy clinics, with clinico-electrographic features of intractable GGE were selected to participate in the study. After obtaining informed consent, a single blood draw was conducted and DNA was extracted. Whole-genome sequencing (WGS) was then performed on the DNA samples. Variant calling was conducted using GATK HaplotypeCaller. Identified variants were annotated using SnpEff to assess their impact on gene function.

Results: A total of 10 patients with GGE (age 20-52 years, mean 37.2 years; 7 females; 4 white, 3 black, 1 hispanic, 2 others) were included with mean age at epilepsy onset of 13.7 years (range 4-32 years). Data analysis revealed high-impact variants, which were compared to the LabCorp Comprehensive Epilepsy gene panel of 804 genes. We identified three genes with high-impact variants present in all 10 patient samples and 17 genes with such variants in at least 50 percent of the patients. Additionally, 121 genes with high-impact variants were found in all 10 patients, and 466 genes had high-impact variants in at least half of the patients. Metascape analysis of genes with high-impact variants in all 10 patients revealed enriched terms, including 'Defective GALNT3 causes HFTC,' 'Drug metabolism - cytochrome P450,' 'PI Metabolism,' and 'Adaptive immune response.'

Conclusions: This pilot study is the first to analyze and identify genetic markers in adults with intractable GGE. The study reveals high-impact genetic variants in key pathways, including cytochrome P450 drug metabolism, PI metabolism, and the adaptive immune response. These variants may affect antiseizure drug processing, neuronal function, and neuroinflammation, contributing to drug resistance and seizure persistence in intractable epilepsy. These findings highlight the need for personalized treatment approaches and will guide future studies in determining early intervention options with suitable anti-seizure drugs to improve seizure control and prevent drug resistance.


Funding: This study was funded by Henry Ford Internal Funding Grant.