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

Warren, L. M.; Holub, A.; Sran, S.; Ramadesikan, S.; Suh, K.; Thompson, A.; Anderson, J. J.; Rivaldi, A.; Zavarella, A.; Chandler, M.; Allison, D.; Strawser, C.; Garfinkle, E.; Pindrik, J.; Shaikhouni, A.; Leonard, J.; Boue, D.; Thomas, D.; Pierson, C.; Mardis, E.; Miller, K.; Ostendorf, A.; Koboldt, D.; Bedrosian, T.

doi:10.64898/2026.04.06.716727

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bioRxiv · 10.64898/2026.04.06.716727

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

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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.

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Warren, L. M., Holub, A., Sran, S., Ramadesikan, S., Suh, K., Thompson, A., Anderson, J. J., Rivaldi, A., Zavarella, A., Chandler, M., Allison, D., Strawser, C., Garfinkle, E., Pindrik, J., Shaikhouni, A., Leonard, J., Boue, D., Thomas, D., Pierson, C., Mardis, E., Miller, K., Ostendorf, A., Koboldt, D., Bedrosian, T.. 2026-04-08. Somatic variants activating the RAS-MAPK pathway confer susceptibility to hippocampal sclerosis in drug-resistant epilepsy. https://doi.org/10.64898/2026.04.06.716727

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