Epilepsy and autism commonly co-occur in genetic developmental and epileptic encephalopathies (DEEs), yet their shared neurobiological mechanisms remain poorly understood. Recent genetic discoveries—including variants in PPFIA3, MYCBP2, DHX9, TMEM63B, and RELN—highlight the clinical and genetic heterogeneity of DEEs, shaped by genetic, epigenetic, and environmental factors. Dysregulation of GABAergic signaling, synaptic plasticity, functional connectivity, and neuroinflammation are central to both epilepsy and autism. Notably, abnormalities in the GABA system and mTOR pathway are linked to seizure generation, drug resistance, and neuropsychiatric symptoms, reinforcing the need for mechanism-based interventions.
Targeted therapies for DEE-associated epilepsy–autism phenotypes are emerging, with early results from treatments like retigabine, quinidine, cannabidiol, and fenfluramine showing mixed success. Genetic variants in KCNQ2, KCNT1, and SCN1A remain key therapeutic targets. Early intervention, especially before age three in SCN1A- and tuberous sclerosis complex-related DEEs, is critical for improving outcomes. mTOR inhibitors also show promise in managing seizures and comorbidities. Recognizing the specific autism phenotype in DEEs and implementing early behavioral therapy are essential. Future trials should adopt precision medicine approaches to better tailor treatments and improve neurodevelopmental outcomes.
Reference: Specchio N, Di Micco V, Aronica E, et al. The epilepsy-autism phenotype associated with developmental and epileptic encephalopathies: New mechanism-based therapeutic options. Epilepsia. 2025 Apr;66(4):970-987. doi: 10.1111/epi.18209. Epub 2025 Feb 22. PMID: 39985505.
