Delineating clinical and developmental outcomes in STXBP1-related disorders

Abstract

STXBP1-related disorders are among the most common genetic epilepsies and neurodevelopmental disorders. However, the longitudinal epilepsy course and developmental endpoints have not yet been described in detail, which is a critical prerequisite for clinical trial readiness. Here, we assessed 1,281 cumulative patient-years of seizure and developmental histories in 162 individuals with STXBP1-related disorders and established a natural history framework. STXBP1-related disorders are characterized by a dynamic pattern of seizures in the first year of life and high variability in neurodevelopmental trajectories in early childhood. Epilepsy onset differed across seizure types, with 90% cumulative onset for infantile spasms by 6 months and focal-onset seizures by 27 months of life. Epilepsy histories diverged between variant subgroups in the first 2 years of life, when individuals with protein-truncating variants and deletions in STXBP1 (n=39) were more likely to have infantile spasms between 5 and 6 months followed by seizure remission, while individuals with missense variants (n=30) had an increased risk for focal seizures and ongoing seizures after the first year. Developmental outcomes were mapped using milestone acquisition data in addition to standardized assessments including the Gross Motor Function Measure-66 Item Set and the Grasping and Visual-Motor Integration subsets of the Peabody Developmental Motor Scales. Quantification of endpoints revealed high variability during the first five years of life, with emerging stratification between clinical subgroups, most prominently between individuals with and without infantile spasms. We found that individuals with neonatal seizures or early infantile seizures followed by seizure offset by 12 months of life had more predictable seizure trajectories in early to late childhood than compared to individuals with more severe seizure presentations, including individuals with refractory epilepsy throughout the first year. Characterization of anti-seizure medication response revealed age-dependent response over time, with phenobarbital, levetiracetam, topiramate, and adrenocorticotropic hormone effective in reducing seizures in the first year of life, while clobazam and the ketogenic diet were effective in long-term seizure management. Virtual clinical trials using seizure frequency as the primary outcome resulted in wide range of trial success probabilities across the age span, with the highest probability in early childhood between 1 year and 3.5 years. In summary, we delineated epilepsy and developmental trajectories in STXBP1-related disorders using standardized measures, providing a foundation to interpret future therapeutic strategies and inform rational trial design.

Keywords: STXBP1; developmental and epileptic encephalopathy; genetics; natural history study; outcome measures.

Figure 1. Overall landscape of seizures in STXBP1-related disorders.

(A) Longitudinal distribution of seizure types across the age span. The heterogeneous pattern of epilepsy progression in the first year of life (inset), showing the proportion of individuals with seizures at a certain frequency during each respective month. (B) Cumulative onset of seizures in individuals with epilepsy. (C) Seizure remission indicated by risk of having refractory seizures over time, defined by not achieving 12 consecutive months of seizure freedom. (D) Stratification by seizure types in STXBP1 demonstrate a dynamic pattern of risk across the first 10 years of life with infantile spasms most prominent in the first 6 months of life and other seizure types including focal-onset seizures and tonic seizures more broadly distributed.

Figure 2. Difference in seizure histories between individuals with protein-truncating variants (PTV) and deletions versus missense variants in STXBP1.

(A) Progression of epilepsy on a monthly basis in a subgroup of individuals with seizures at any point in the first 3 years of life (n=30 missense, n=39 PTV). (B) Longitudinal significance of the difference in the distribution of overall seizure frequencies in each respective month across the two subgroups (above). (C) Distribution of common seizure types across individuals with PTV/deletions, contrasted with (D) the distribution of seizure types across individuals with missense variants in STXBP1 in the first 10 years of life.

Figure 3. Developmental outcomes and endpoints in STXBP1-related disorders.

(A) Cumulative milestone acquisition by age in 158 individuals with STXBP1. Dashed lines indicate the age at when 75% of typically developing children achieve each respective milestone as reported by the Center for Disease Control and Prevention (CDC). The distribution of gross motor, fine motor, and language development is primarily in the first 5 years of life (inset, showing age achieved indicated by each respective color versus age at which individuals were last assessed in grey). (B) Proportion of milestones achieved in the overall cohort, showing a wide range of percentages with verbal communication and language at the lower end. (C) Distribution of 57 GMFM-66-IS scores over time across 45 individuals. (D) Distribution of PDMS-2 raw scores for grasping and visual motor integration over time across 21 individuals.

Figure 4. Longitudinal modeling of seizure histories in the first year of life in STXBP1 revealed two subgroups with unpredictable and predictable epilepsy trajectories later in life.

(A) Observed and predicted monthly seizure trajectory for one individual. The seizure history during the first 12 months were used to define a reference cohort of most phenotypically similar individuals. Seizure frequencies in the reference subgroup were then used to predict the individual’s trajectory. The difference in observed and predicted seizure frequencies across months was used to characterize the variability. (B) Variability was assessed across the cohort (n=78), with two subgroups: high-fidelity subgroup defined by predictable trajectories versus low-fidelity subgroup defined by unpredictable trajectories, showing seizure frequencies in the first year of life that resulted in high or low-fidelity predictions of longitudinal epilepsy trajectories later in life. (C) Seizure types leading to risk of having unpredictable seizures later in life. (D) Single decision tree, showing the branching of subgroups based on epilepsy characteristics or predictors for unpredictable seizure trajectories.

Figure 5. Characterization of treatment strategies and medication response in STXBP1-related disorders.

(A) Anti-seizure medication landscape across 61 individuals with STXBP1, showing the relative density of ASMs used in at least 10 individuals across the age span. (B) Characterization of medication response over time following treatment initiation, showing the reduction in seizure frequencies on a monthly basis for seizure more broadly (top) and spasms (bottom). (C) Relative effectiveness of ASM for seizures vary across short-term and long-term treatment response, with phenobarbital as a superior ASM in reducing seizure frequency while clobazam and the ketogenic diet were effective in maintaining seizure freedom. Only medications used in at least 10 individuals are shown.

Figure 6. Virtual clinical trial framework for STXBP1-related disorders.

(A) Virtual clinical trial using seizure frequency as the primary outcome, highlighting optimal age windows in green. The observed frequency of trial success (OFTS) is defined as the proportion of trials out of 1,000 virtual trials in which a significant effect can be detected if the trial were to be started at the respective month. A trial duration of 6-month versus 12-month period and the targeted seizure reduction ranging from 10% to 50% was selected based on the widest distribution of OFTS across the age span. (B) Virtual trials for targeting infantile spasms demonstrate an early window for optimal intervention starting at 3 months, and a second window is observed after 7 months for individuals with intractable spasms. (C) Virtual trials for targeting focal-onset seizures show an optimal window of 6 to 18 months and 2 to 3.5 years, although the OFTS was more variable. (D) Virtual trials for targeting tonic seizure, showing broad windows between 8 months to just prior to 2 years and 2 to 3.5 years.