Abstracts

Rationale: The STXBP1 gene codes for Syntaxin-Binding Protein 1 play an important role in synaptic vesicle binding and release of neurotransmitters. Mutations in the gene result in an early-onset, monogenic developmental and epileptic encephalopathy with a broad phenotype are studied cross-sectionally in large cohorts. There remains a need to understand how these individuals change across their lifespans and to establish disorder-specific neurodevelopmental norms to support clinical care and therapeutic trials.

The objective of this study is to prospectively characterize the neurodevelopmental natural history of individuals with STXBP1 encephalopathy.

Methods: We enrolled any-age participants with STXBP1 mutations from neurology and genetics clinics across Canada and through the STXBP1.ca website. Participants (parents/primary caregivers) complete REDCap-based surveys, medical records are reviewed, and a battery of standardized neurodevelopmental questionnaires (DBC-2, Vineland-3, SRS-2, SDIS) are completed and repeated annually, along with clinical updates and interviews.

Results: Since January 2020, twenty three participants (14 females) from across Canada have been enrolled, with median age of nine years (2 - 43 years). Longitudinal data was collected in the form of yearly clinical updates from 19/23 participants, as well as through completed questionnaires in 16/23 patients. Clinically, seizure onset was usually in the neonatal period or in first year of life (14/23) with improvement in seizure control with age and more than half are seizure-free at most recent update. Participants achieved seizure freedom on a variety of medications including levetiracetam, oxcarbazepine and ketogenic diet. Four participants never experienced seizures. There were no deaths and no emergent systemic co-morbidities. Developmentally, a majority (14/23) are non-verbal, (6/23) diagnosed with autism, and (13/23) were not ambulating by four years of age. Most had a movement disorder (17/23), most commonly tremor. Longitudinal questionnaire data is summarized in Figure 1. Overall, parent ratings of adaptive function using the Vineland 3 scale show that comparisons between and within participants based on age indicate progressive decline in adaptive functioning over time. Furthermore, challenges with behavior, anxiety, and sleep are also prominent and stable in this population.

Conclusions: This ongoing study provides early longitudinal STXBP1-specific neurodevelopmental norms. Generally, participants remained healthy with well-managed early-onset epilepsy, significant but stable gross motor delay, tremor, behavioural challenges, non-verbal and some with autism. The longitudinal data suggests a concerning decline in adaptive functioning over time; this is a potentially important target for further clinical and investigational understanding and intervention.

Funding: Rare Diseases Foundation