Ras-MAPK somatic variants in mesial temporal lobe epilepsy

Mesial temporal lobe epilepsy is the most common focal epilepsy in adults and has historically been attributed to acquired hippocampal injury caused by precipitating insults such as prolonged febrile seizures and head trauma. However, recent studies have identified somatic variants activating Ras-MAPK signaling in more than 40% of surgically resected mesial temporal lobe epilepsy (MTLE) hippocampi. These variants, which are enriched in cases with hippocampal sclerosis (MTLE-HS), exhibit evidence of positive clonal selection and are localized to neuroglial lineages arising from hippocampal progenitors. Here, we review emerging evidence supporting a role for somatic Ras-mitogen-activated protein kinase (MAPK) mosaicism in MTLE pathogenesis and propose a two-hit model in which acquired insults promote clonal expansion of Ras-MAPK-mutant progenitors, resulting in aberrant neurogenesis, hippocampal remodeling, and epileptogenesis. These findings suggest new opportunities for disease prevention and precision therapeutics targeting Ras-MAPK signaling.