Epilepsy in the RASopathies

Clinical manifestations of epilepsy in the RASopathies, a constellation of syndromes characterized by defects in the RAS/Mitogen-activated protein kinase (MAPK) pathway, display remarkable heterogeneity. This chapter explores the underlying molecular mechanisms in the RAS/MAPK pathway contributing to epileptogenesis, including the roles of BRAF, Extracellular signal-regulated kinases (ERKs), mitogen-activated protein kinase kinase (MEKs), RAS-GRF1, HRAS, and SYNGAP. Aberrations in the function of these components have been found to disrupt synaptic plasticity and exacerbate neuronal hyperexcitability, culminating in epileptogenesis. In addition, we review therapeutic and diagnostic considerations for the diverse epilepsy phenotypes across RASopathies, including Neurofibromatosis type 1, Noonan syndrome, Cardio-facio-cutaneous syndrome, Costello syndrome, Noonan syndrome with multiple lentigines, and SYNGAP1 syndrome. The chapter concludes by highlighting recent advances and future directions in therapeutics, including the repurposing of certain oncologic therapies, such as selumetinib, to tackle intractable seizures in these syndromes.