Seizure Type and Antiepileptic Drug Use Drive Neurobehavioral Severity in Genetically Defined Autism: Evidence from Fragile X and Rett Syndromes

Background: Autism spectrum disorder (ASD) and genetically defined conditions such as Fragile X syndrome (FXS) and Rett syndrome (RTT) are characterized by substantial neurobehavioral heterogeneity. Although sensory and executive dysfunction are well established, the relative contribution of epilepsy burden and pharmacological treatment to autism severity remains unclear. Methods: This study included 263 children with ASD (n = 96), FXS (n = 84), and RTT (n = 83). Sensory reactivity, executive functioning, and autism severity were assessed using standardized caregiver-reported scales. Group comparisons, correlation analyses, and multiple regression models were conducted to examine multidomain relationships. Results: A consistent gradient of impairment was observed across groups (ASD < FXS < RTT). While sensory and executive domains were significantly associated with autism severity, epilepsy-related variables emerged as the strongest predictors, particularly in RTT. Seizure type and antiepileptic drug use showed the largest effects, with regression analyses indicating that these factors accounted for a substantial proportion of variance in autism severity. In contrast, environmental and intervention-related factors had stronger effects in ASD and FXS, suggesting greater neurodevelopmental plasticity. Correlation analyses further revealed distinct network patterns, with ASD showing a flexible multidomain structure and RTT a more biologically constrained profile. Conclusions: These findings support an epilepsy-driven model of neurobehavioral severity in genetically defined autism and highlight the differential balance between biological constraint and environmental modulation across diagnostic groups. Integrating seizure phenotype and treatment burden into clinical assessment may improve individualized intervention strategies and advance precision medicine approaches in neurodevelopmental disorders.