Leukocytes Transcriptome Analysis of Genes Associated with Epilepsy Duration and Age of Onset

Epilepsy is increasingly understood not as a fixed condition, but a dynamic and potentially progressive disorder. Beyond its primary impact on the brain, growing evidence indicates that epilepsy also exerts widespread systemic effects, influencing multiple physiological systems. Two temporal factors-the age at seizure onset and duration of epilepsy-could help understand if time with epilepsy shapes systemic molecular changes and in turn provide new insights into disease progression and therapeutic resistance. To identify systemic signatures associated with age of onset and epilepsy duration, we investigated the molecular correlates of them using leukocyte transcriptome. Differential expression analyses of short (≤ 20 years) vs. long (> 20 years) disease duration and childhood (≤ 12 years) vs. adolescent (> 12 years) onset-age revealed distinct leukocyte transcriptomics signatures. Gene expression changes related to disease duration were enriched for pathways involved in oxidative stress and disruptions in RNA/DNA regulatory processes. Epilepsy onset was linked to enrichment of protein demannosylation, deglycosylation and immune-related pathways, particularly those involving the MHC protein complex and antigen presentation. Spearman's correlation analyses uncovered genes whose expression correlated with age of onset and duration. Additionally, we found many differentially expressed genes located within the EJM1 locus on chromosome 6p21, the known major susceptibility locus for juvenile myoclonic epilepsy (JME). This finding suggests that co-regulated gene networks within this locus may act synergistically to influence neuroimmune interactions relevant to both the development and progression of epilepsy. The study suggests dynamic immune-related transcriptomic changes in epilepsy, which may warrant further investigation as potential biomarkers of disease onset and progression.