TY  - INPR
ID  - discovery10206658
KW  - Autism spectrum disorder; developmental and epileptic encephalopathies; epilepsy; newly reported DEE-associated genes; personalized treatment
A1  - Specchio, Nicola
A1  - Di Micco, Valentina
A1  - Aronica, Eleonora
A1  - Auvin, Stéphane
A1  - Balestrini, Simona
A1  - Brunklaus, Andreas
A1  - Gardella, Elena
A1  - Scheper, Mirte
A1  - Taglialatela, Maurizio
A1  - Trivisano, Marina
A1  - Curatolo, Paolo
UR  - https://doi.org/10.1111/epi.18209
AV  - restricted
JF  - Epilepsia
N2  - 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 ?-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 like KCNQ2 and KCNT1 are frequent causes of early onset DEEs. Personalized treatments like retigabine and quinidine have been explored with heterogeneous responses. Efforts are ongoing to develop more effective KCNQ activators and KCNT1 blockers. SCN1A genetic variants, particularly in Dravet syndrome, show potential for treatment of autistic symptoms with low-dose clonazepam, fenfluramine, and cannabidiol, although human trials have yet to consistently replicate animal model successes. Early intervention before the age of 3?years, particularly in SCN1A- and tuberous sclerosis complex-related DEEs, is crucial. Additionally, targeting the mTOR pathway shows promise for seizure control and managing epilepsy-associated comorbidities. Understanding the distinct autism spectrum disorder phenotype in DEEs and implementing early behavioral interventions are essential for improving outcomes. Despite genetic advances, significant challenges persist in diagnosing and treating DEE-associated epilepsy?autism phenotypes. Future clinical trials should adopt precision health approaches to improve neurodevelopmental outcomes.
EP  - 18
TI  - The epilepsy?autism phenotype associated with developmental and epileptic encephalopathies: New mechanism-based therapeutic options
Y1  - 2025/02/22/
SN  - 0013-9580
N1  - This version is the author accepted manuscript. For information on re-use, please refer to the publisher?s terms and conditions.
PB  - Wiley
ER  -