Abstracts

Rationale: The phenotypic landscape of STXBP1­-related disorders is characterized by epilepsy in 90% and neurodevelopmental delay in 95% of individuals. However, the range of outcomes is wide, and little is known about the complex interplay between seizures and developmental trajectories.

Methods: We harmonized longitudinal clinical data across 124 individuals with STXBP1-related disorders, analyzing 165,005 phenotypic annotations across 1,098 patient-years. Leveraging time-stamped data provided through the Ciitizen platform and within our local cohort, we reconstructed the epilepsy histories of 92 individuals with STXBP1-related disorders, capturing > 25 seizure types and categorical seizure severities in one-month time increments using the Pediatric Epilepsy Learning Health System (PELHS)-championed framework. We mapped the longitudinal phenotypic landscape of STXBP1-related disorders, including developmental trajectories stratified by clinical and variant subgroups.

Results: Epilepsy histories were assessed across 92 individuals with seizures, with a median onset of 2 months (IQR 1 month–9 months). Seizures were most prominent in the first year of life with 59/90 (66%) individuals having multiple seizures per day; the most common seizure types during this time were focal-onset seizures (n=44) and infantile spasms (n=27). Thirty-six individuals had neonatal seizures, with 25/36 (70%) later developing focal-onset seizures and 15 (42%) developing into infantile spasms. Individuals with protein-truncating variants and deletions in STXBP1 (n=75) were 2-fold more likely to have infantile spasms between 3 and 12 months, while individuals with missense variants (n=56) had an over 3-fold increased risk for spasticity. Longitudinal phenotypic reconstruction highlighted age-related clinical features, including a higher frequency of ataxia and tremor after 5 years of age. Individuals with no history of seizures (n=32) were more likely to achieve developmental milestones than individuals with seizures, however, of individuals who achieved milestones, there was no significant difference in the age at which milestones were achieved. Of individuals with STXBP1-related disorders who were able to achieve specific milestones, 90% were able to roll over by 18 months and sit by 2 years. Of those who were able to walk, 90% reached the milestone by the age of 5 years. In individuals older than 15 months old in which language ability was assessed, 51/55 (93%) individuals were non-verbal.

Conclusions: We delineated the longitudinal disease history of STXBP1­-related disorders, highlighting subgroups defined by epilepsy outcomes and developmental trajectories. Understanding the seizure and developmental landscape of STXBP1­-related disorders will be critical for counseling families, developing outcome measures, and informing future trial design.

Funding: The Hartwell Foundation, National Institute of Neurological Disorders and Stroke, Children’s Hospital of Philadelphia