Beyond Seizure Burden: Seizure Semiology, but not Frequency, Is Associated With Caregiver-Reported Autistic Behaviors in SYNGAP1-DEE

1.PurposeSYNGAP1-related developmental and epileptic encephalopathy (SYNGAP1-DEE) is characterized by high rates of both epilepsy and autism spectrum disorder (ASD). While the clinical spectrum is well-documented, the link between specific seizure semiologies and caregiver-reported autistic behaviors is not well understood. This study analyzed the correlation between ten distinct seizure types, their frequencies, and a caregiver-reported autistic behavior score. MethodClinical data were extracted from the PATRE (PATient-based phenotyping and evaluation of therapy for Rare Epilepsies) Registry for SYNGAP1, in the framework of the EURAS project (Grant No. 101080580, Horizon Europe). This study employed a retrospective cross-sectional analysis of caregiver-reported registry data. Analysis was restricted to an analytic cohort of N=337 participants with complete data for both the epilepsy questionnaire (including epilepsy status, seizure semiology, and peak seizure frequency items) and the behavior questionnaire (from a total N=522 registry participants). Caregiver-reported autistic behaviors were quantified using a standardized caregiver-reported scale (Likert 1-5). Statistical associations were evaluated using the Wilcoxon rank-sum test to compare caregiver-reported autistic behavior scores across different seizure semiologies and Spearmans rank correlation to assess the impact of seizure frequency (9-point scale). ResultsWithin the analytic cohort (N=337), epilepsy was reported in 259 patients. Eyelid myoclonia was the most prevalent semiology, affecting 64.9% (n=168) of the epilepsy-positive group. Atypical absences (n=77) demonstrated the most profound and statistically robust association with higher caregiver-reported autistic behavior scores (FDR-adjusted p = 0.001). Significant associations were also observed for typical absences (n=70, FDR-adjusted p = 0.018), eyelid myoclonia (FDR-adjusted p = 0.018), myoclonic-atonic seizures (n=40, FDR-adjusted p = 0.019), and atonic seizures (n=72, FDR-adjusted p = 0.025). Focal and tonic-clonic seizures showed weaker associations (FDR-adjusted p = 0.026 and p = 0.047, respectively). Crucially, quantitative analysis revealed no significant correlation between ordinal caregiver-reported peak seizure frequency ratings and caregiver-reported autistic behavior scores across all semiologies (e.g., Eyelid Myoclonia: p=0.096; Atypical Absences: p=0.744), indicating no detectable association between peak-frequency ratings and caregiver-reported autistic behavior scores. ConclusionHigher caregiver-reported autistic behavior scores in SYNGAP1-DEE were most strongly associated with the presence of atypical absences, representing a generalized, thalamocortical seizure network dysfunction. In contrast, no detectable association was observed between caregiver-reported autistic behavior scores and the ordinal caregiver-reported peak seizure frequency metric. Atypical absences and related semiologies may serve as clinical "red flags" for increased neurodevelopmental comorbidity severity, regardless of reported peak seizure frequency. Abstract SummaryThis study investigates the relationship between ten seizure semiologies, seizure frequency, and severity of caregiver-reported autistic behaviors in a large-scale international cohort of N=337 patients with SYNGAP1-DEE. We identify a robust association between elevated caregiverreported autistic behavior scores and specific thalamocortical seizure patterns, most prominently atypical absences. Notably, our analysis reveals that this association is independent of seizure frequency, demonstrating no detectable association between this ordinal, caregiver-reported seizure frequency metric and caregiver-reported autistic behaviors.