Leukocyte Gene Expression Involved in Apoptosis is Prognostic for High vs Low Frequency Temporal Lobe Epilepsy

Introduction: Temporal lobe epilepsy (TLE) is the most prevalent form of focal epilepsy in adults and the most likely to be medically refractory. Differentially expressed genes (DEGs) in leukocytes have been proposed to be an effective biomarker for the severity of epilepsy, categorized as high seizure frequency and low seizure frequency TLE. The hypothesis tested was that leukocyte gene expression related to cellular apoptosis was predictive of high vs low seizure frequency.

Methods: Sixteen patients were diagnosed with medically intractable TLE and placed into high seizure frequency group (>2 seizures/month) or low seizure frequency group ( < 2 seizures/month). Whole blood samples were obtained and analyzed using RNA sequencing techniques to identify a list of DEGs based on a threshold of 3.5-fold change, p< 0.01, FDR < 0.05, and the involvement in at least one biological pathway in Reactome. Several of the gene mechanisms and pathway involvement were researched using online gene and literature databases.

Results: There were five patients in the high frequency cohort and eleven patients in the low frequency cohort. 10 differentially expressed genes were identified: RPPH1, RMRP, TXK, LTF, LCN2, PAWR, HTRA1, HCAR3, ADM, and FZD1, 6 which were overexpressed and 4 which were under expressed in the high compared to the low seizure frequency groups. These 10 genes were found to be involved in specific pathways implicated in cellular apoptosis. Furthermore, 5 of these genes were found to be associated with epileptogenicity or other neurodegenerative diseases, including RMRP, TXK, LCN2, PAWR, and FZD1.

Conclusion : This study demonstrates two distinguishable disease entities, high and low seizure frequency TLE, predicted by the dysregulation of specific leukocyte genes involved in apoptotic pathways. These genes hold predictive value for the diagnosis of TLE, its severity and response to therapy. Further research is necessary to determine the causative factors at play between apoptosis and epilepsy.