Somatic variants activating the RAS-MAPK pathway confer susceptibility to hippocampal sclerosis in drug-resistant epilepsy

Abstract Hippocampal sclerosis is a frequent finding in pediatric epilepsy surgery and has traditionally been regarded as an acquired lesion. It commonly co-occurs with focal cortical dysplasia (FCD IIIa), yet whether hippocampal injury is secondary to seizures or reflects a shared underlying etiology remains unresolved. Here we identified somatic variants activating the RAS–MAPK pathway in 40% of patients with hippocampal sclerosis, but in none with non-sclerotic hippocampus. Gain-of-function variants in PTPN11 were the most common finding, with mutations present in both cortex and hippocampus and enriched in hippocampal neurons, consistent with a shared developmental origin. In mice, Ptpn11D61Y mutants developed profound hippocampal degeneration and gliosis following subthreshold kainic acid exposure, whereas wild-type controls were unaffected. p38-dependent stress pathways were upregulated in patients and mice, suggesting a mechanism through which ERK-p38 crosstalk lowers the threshold for seizure-induced injury. These results provide a genetic explanation for FCD IIIa, elucidate the role of somatic mutations within the RAS-MAPK pathway in driving hippocampal sclerosis, and provide a target for pathway-specific interventions for intractable seizures. Competing Interest Statement The authors have declared no competing interest. Footnotes The journal that was listed for submission was deleted at the top of page 1.