Abstracts

Rationale: SCN8A-related developmental and epileptic encephalopathy (DEE) is a rare disease associated with pathogenic variants in the SCN8A gene encoding the voltage-gated sodium channel alpha subunit Nav1.6. Due to significant phenotypic heterogeneity, including seizures, movement disorders, and intellectual disability, comprehensive understanding of disease impact and progression is limited. In this study, clinical data generated using Invitae’s Ciitizen patient-consented, real-world data platform were used to explore disease burden in SCN8A-DEE. 

Methods: Real-world clinical data were extracted from patients with an SCN8A variant using the Ciitizen platform (www.ciitizen.com), which employs a proprietary approach combining machine learning and expert human review to streamline generation of research-grade data from unstructured health records spanning ~10 years. Extracted data included seizure history, comorbidities, and therapeutic interventions. Data were analyzed according to age at seizure onset and seizure type at initial presentation, as informed by parallel work in SCN2A-DEE. 

Results: A total of 79 patients were enrolled and contributed data for analyses. Mean patient age was 8.2 years (range, 1-23), with similar percentages of males and females. Patients were categorized based on age at seizure onset; ≤3 months (38%) or >3 months (57%). A further group included patients with autism or intellectual disability without seizures (5%). Patients with seizure onset at >3 months included two sub-groups characterized by the presence (9%) or absence (48%) of infantile spasms at initial presentation. _x000D_ _x000D_ Mean age at seizure onset was 33.4 (1-85) days for patients with early (≤3 months) seizures, 202 (100-288) days for those with later (>3 months) seizures characterized by infantile spasms at initial presentation, and 557 (93-4409) days for those with later seizures without infantile spasms. While seizure frequency was variable, most patients continued to experience seizures over time. Procedural interventions and hospitalizations were high across the lifespan; nearly a third occurring in the first year of life. The mean number of medications prescribed over a patient’s lifetime was 18 (3-44). Patients experienced multiple comorbidities; global developmental delay was the most common (81%), while sleep disorders, hypotonia, feeding difficulties and GERD were reported in >50% of patients. _x000D_
Conclusions: This work represents a new generation of natural history study providing the most robust real-world dataset to date on disease burden and progression in SCN8A-DEE. Knowledge derived from this study is anticipated to accelerate drug development efforts by providing new insights into the broad, longitudinal impact of disease, therefore informing trial endpoints beyond seizure symptomatology. Together with ongoing efforts to better understand underlying genotype-phenotype relationships, our findings will guide development of targeted, innovative therapies that can benefit patients and their caregivers.

Funding: Praxis Precision Medicines