Epilepsy Course and Developmental Trajectories in STXBP1-DEE

Abstract

Background and objectives: Clinical manifestations in STXBP1 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 STXBP1-DEE and dissect the relationship between neurodevelopment and epilepsy.

Methods: Retrospective standardized clinical data were collected through international collaboration. A composite neurodevelopmental score system compared the developmental trajectories in STXBP1-DEE.

Results: Forty-eight patients with de novo STXBP1 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 STXBP1 variant showed similar phenotype and parallel disease course.

Discussion: The disease course in STXBP1-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.

Figure 1. STXBP1 Variants Over Exons and Linear Protein Structure

Novel variants are highlighted in red.

Figure 2. Neurodevelopmental Features in Individuals With STXBP1-DEE Stratified per Age Range at Seizure Onset

(A) Cumulative incidence of neurodevelopmental impairment from birth to early childhood in the overall cohort (n = 48) and per age at seizure onset (<1 month n = 23, 1–12 months n = 20, >1 year n = 5). *p = 0.033, one-way ANOVA. (B) Developmental milestones achieved at last assessment in n = 36 individuals with STXBP1-DEE ≥3 years old (median age 8.35 years, range 3–35 years). (C.a) Development before epilepsy based on age range at seizure onset: neurologic abnormalities before epilepsy onset were evident in 7/23 individuals (30%) with seizure onset <1 month; signs of developmental impairment before epilepsy onset were evident in 12/20 (60%) of patients with seizure onset between 1 and 12 months and in 3/5 (60%) of patients with seizure onset >1 year. (C.b) Development after epilepsy onset based on age range at seizure onset: only 2/48 individuals (4%) did not present with impaired development after epilepsy onset at the last examination (at 10 and 13 months).

Figure 3. Impact of Epilepsy on Development in Individuals With STXBP1-DEE

(A). STXBP1_DevScore distribution in n = 36 individuals with STXBP1-DEE ≥3 years old (median age 8.35 years, range 3–35 years) based on age at seizure onset (log₁₀ scale). Seizure onset <1 month (n = 15) 1–12 months (n = 16), >12 months (n = 5). (Pearson correlation coefficient). (B) Developmental milestones subscores (mean) stratified per age range at seizure onset. **p = 0.0049, one-way ANOVA. (C) STXBP1_DevScore distribution based on age at seizure offset or age at last examination in the case of active epilepsy (log₁₀ scale). Active epilepsy (n = 23), seizure free (n = 13) (Pearson correlation coefficient). (D) Developmental milestones subscores (means) stratified per epilepsy outcomes. Active epilepsy (n = 23), seizure free (n = 13). *p = 0.0348. (E) STXBP1_DevScore domain correlations with seizure onset, offset, and epilepsy duration. Violin plots show only significant correlations (Wilcoxon rank-sum test).