Abstracts

Rationale: STXBP1-related disorder (STXBP1-RD) is a complex neurodevelopmental disorder, characterized by severe early-onset epilepsy and developmental delays, the range of which is incompletely understood. Though STXBP1-RD has been defined through large comprehensive retrospective analyses, a prospective natural history study consisting of standardized clinical outcome assessments is needed to identify disease-specific and age-appropriate outcome measures and endpoints. Here, we present initial data of the first prospective natural history study for STXBP1-RD.

Methods: Individuals with disease-causing variants in STXBP1 were prospectively evaluated at an IRB-approved, multi-site natural history study. Seizures for a subset of individuals were reconstructed from medical records and clinical seizure histories, including information on seizure type and month-by-month evaluations of frequency. Study visits included standardized clinical histories, neurological examinations, and structured assessments including GMFCS, MACS, CFCS, AIMS, GMFM-66, Peabody-3, Bayley-4, and CARS-2, which were ascertained depending upon the chronological and developmental age of the child.

Results: Fifty-seven individuals (age 1 to 42, 42% female) with STXBP1-RD were evaluated, of which 40 had longitudinal seizure histories reconstructed. Individuals demonstrated both protein-truncating (PTVs, n=31) and missense variants (n=26). Of the 40 individuals for whom seizures were reconstructed, 77.5% experienced seizures of any type. The most common seizure type was focal-onset seizures, most often with motor manifestations (71%), followed by generalized-onset seizures (29%). Epileptic spasms were present in 35.5% of individuals (n=14). The highest seizure burden was seen in the first year of life, when 45% of the cohort had seizures. Following the first year of life, no more than 25% of the cohort experienced seizures during any time increment. For the entire cohort of 57 individuals, standardized outcome measures demonstrated a wide range of developmental capabilities, with some notable differences between subgroups. Significant differences were observed between individuals with PTVs and missense variants; individuals with PTVs were more likely to demonstrate a higher raw score on the Expressive Communication domain of the Bayley-4 (p=0.018). In addition, individuals with recurrent missense variants at p.R292 scored significantly lower when assessed with the GMFM (p=0.039).

Conclusions: STXBP1-RD is a complex neurodevelopmental disorder that is the target for current and future precision medicine strategies. Given the dynamic nature of seizures and the variable developmental outcomes in this condition, careful and thorough natural history characterization is essential to achieve clinical trial readiness. We report the initial landscape of development in STXBP1-RD, and that factors such as genetic variant type and seizure frequency may influence developmental outcomes.

Funding: This study was funded by the Center for Epilepsy and Neurodevelopmental Disorders (ENDD), the STXBP1 Foundation STARR Study, and the National Institute for Neurological Disorders and Stroke (R01 NS127830-01A1, R01 NS131512-01 and K02 NS112600).