Epilepsy Course and Developmental Trajectories in <i>STXBP1</i> -DEE

Abstract

<h3>Background and Objectives</h3> Clinical manifestations in <i>STXBP1</i> developmental and epileptic encephalopathy (DEE) vary in severity and outcome, and the genotypic spectrum is diverse. We aim to trace the neurodevelopmental trajectories in individuals with <i>STXBP1</i>-DEE and dissect the relationship between neurodevelopment and epilepsy. <h3>Methods</h3> Retrospective standardized clinical data were collected through international collaboration. A composite neurodevelopmental score system compared the developmental trajectories in <i>STXBP1</i>-DEE. <h3>Results</h3> Forty-eight patients with de novo <i>STXBP1</i> variants and a history of epilepsy were included (age range at the time of the study: 10 months to 35 years, mean 8.5 years). At the time of inclusion, 65% of individuals (31/48) had active epilepsy, whereas 35% (17/48) were seizure free, and 76% of those (13/17) achieved remission within the first year of life. Twenty-two individuals (46%) showed signs of developmental impairment and/or neurologic abnormalities before epilepsy onset. Age at seizure onset correlated with severity of developmental outcome and the developmental milestones achieved, with a later seizure onset associated with better developmental outcome. In contrast, age at seizure remission and epilepsy duration did not affect neurodevelopmental outcomes. Overall, we did not observe a clear genotype-phenotype correlation, but monozygotic twins with de novo <i>STXBP1</i> variant showed similar phenotype and parallel disease course. <h3>Discussion</h3> The disease course in <i>STXBP1</i>-DEE presents with 2 main trajectories, with either early seizure remission or drug-resistant epilepsy, and a range of neurodevelopmental outcomes from mild to profound intellectual disability. Age at seizure onset is the only epilepsy-related feature associated with neurodevelopment outcome. These findings can inform future dedicated natural history studies and trial design.