The epilepsy–autism phenotype associated with developmental and epileptic encephalopathies: New mechanism‐based therapeutic options

作者：N. Specchio, Valentina Di Micco, E. Aronica, S. Auvin, S. Balestrini, A. Brunklaus, E. Gardella, Mirte Scheper, Maurizio Taglialatela, M. Trivisano, P. Curatolo · 发表于：Epilepsia · 年份：2025 · DOI：10.1111/epi.18209 · 被引用次数：27 · 研究领域：Medicine

Epilepsy and autism often co‐occur in genetic developmental and epileptic encephalopathies (DEEs), but their underlying neurobiological processes remain poorly understood, complicating treatment. Advances in molecular genetics and understanding the neurodevelopmental pathogenesis of the epilepsy–autism phenotype may lead to mechanism‐based treatments for children with DEEs and autism. Several genes, including the newly reported PPFIA3, MYCBP2, DHX9, TMEM63B, and RELN, are linked to various neurodevelopmental and epileptic disorders, intellectual disabilities, and autistic features. These findings underscore the clinical heterogeneity of genetic DEEs and suggest diverse neurobiological mechanisms influenced by genetic, epigenetic, and environmental factors. Mechanisms linking epilepsy and autism include γ‐aminobutyric acidergic (GABAergic) signaling dysregulation, synaptic plasticity, disrupted functional connectivity, and neuroinflammatory responses. GABA system abnormalities, critical for inhibitory neurotransmission, contribute to both conditions. Dysregulation of the mechanistic target of rapamycin (mTOR) pathway and neuroinflammation are also pivotal, affecting seizure generation, drug resistance, and neuropsychiatric comorbidities. Abnormal synaptic function and connectivity further underscore the epilepsy–autism phenotype. New treatment options targeting specific mechanisms linked to the epilepsy–autism phenotype are emerging. Genetic variants in potassium channel genes...