Navigating STXBP1-related disorders: Unraveling clinical and developmental outcomes

By Dr. Sushama R. Chaphalkar, PhD.Reviewed by Benedette Cuffari, M.Sc.Dec 4 2023

In a recent study published in Brain, researchers examined the combined patient-years of seizure and developmental histories in individuals with disorders related to the syntaxin-binding protein 1 (STXBP1) gene.

Study: Delineating clinical and developmental outcomes in STXBP1-related disorders. Image Credit: Madrigal8 / Shutterstock.com

Background

One in 30,000 individuals throughout the world are affected by STXBP1-related disorders, with 80% and 95% of cases manifesting as genetic epilepsies and neurodevelopmental disorders, respectively. However, the significant heterogeneity in neurodevelopmental features of these conditions limits subgroup identification, genotype-phenotype mapping, and treatment response comprehension, which has limited our understanding of development and clinical outcomes in STXBP1-related disorders.

STXBP1 encodes a molecule that plays a key role in synaptic vesicle fusion, thus serving as a prime target for gene therapy and clinical trials. While phenotypic signatures of STXBP1 variants have been identified, researchers continue to investigate the genomic architecture to understand the clinical heterogeneity.

Understanding the long-term clinical progression in STXBP1-related disorders is challenging. Interpretation of results from previous cross-sectional studies was limited by varied cohorts and study design differences, whereas larger cohort studies lacked detailed longitudinal trajectories.

Additionally, diverse outcome measures and seizure patterns complicate clinical trial readiness. Thus, there remains an urgent need for systematic evaluation of longitudinal clinical data and validation of disease- and subgroup-specific measures.

About the study

The present study included 162 patients with STXBP1-related disorders. Pathogenic, likely pathogenic, or de novo variants were selected. An epilepsy history of 765 patient-years was retrospectively reconstructed using medical records.

Based on the Pediatric Epilepsy Learning Health System (PELHS), over 20 seizure types were identified. Seizure frequencies (SF) were categorized as: multiple daily seizures (SF = 5), several daily seizures (SF = 4), daily seizures (SF = 3), weekly seizures (SF = 2), monthly seizures (SF = 1), and no seizures (SF = 0).

Development was assessed by analyzing milestone acquisition using records as well as clinical care outcomes. Language abilities, gross motor function, and fine motor function were evaluated and classified based on specific criteria and systems respectively.

The study aimed to categorize subgroups in STXBP1-related epilepsy based on seizure variability across ages. Using a forecasting model, the researchers compared predicted and actual seizure trajectories, identifying subgroups with unpredictable seizures and analyzing features in the first year of life associated with unpredictability.

Using medical records, seizure endpoints were studied and treatments for various seizure types were compared in terms of efficacy and effectiveness. Virtual trials were conducted and the observed frequency of trial success (OFTS) was determined as a novel measure to identify optimal time windows in which real-world treatment response may be observed.

The statistical analysis involved the use of the Kaplan-Meier estimate, log-rank sum test, Wilcoxon rank sum test, Pearson correlation coefficient, Spearman correlation coefficient, and Fisher’s exact test.

Study findings

About 71.3% of the patients with STXBP1-related disorders had a history of seizures and 98% showed intellectual disability or a developmental delay. Focal-onset seizures and infantile spasms were the most common types of seizures observed in the cohort.

Seizure onset was prominent in the first year of life, which could be neonatal or beyond the first month. Individuals with neonatal or early infantile seizures followed by seizure offset within 12 months had more predictable seizure trajectories in early-to-late childhood as compared to those with more severe presentations throughout the first year.

The pattern of epilepsy over time was dynamic across seizure types. While infantile spasms peaked between two and six months, focal and tonic seizures primarily occurred in the first three years, and bilateral tonic-clonic seizures manifested later.  About 57% of patients had more than one seizure type.

Seizure remission occurred in 38 individuals, independent of seizure type, with variable median offset times. Seizures reoccurred in 20 individuals; however, given the primarily pediatric cohort, robust conclusions could not be made on childhood-to-adulthood patterns.

Genetic analysis showed a spectrum of missense, frameshift, splice site, gene deletion, and in-frame insertion/deletion mutations. Individuals with missense variants exhibited higher seizure frequencies than those with protein-truncating variants/deletions during specific age intervals.

The use of anti-seizure medications in isolation or combination reduced treatment burden by 50% within five months of initiation. Treatment effects varied over time, aligning with current guidelines.

OFTS measures determined clinical trial success to be the highest between eight months and 3.5 years of life. Optimal treatment windows determined in virtual trials varied based on age and seizure-type.

Conclusions

The present study establishes a baseline for understanding disease trajectory in STXBP1-related disorders and an assessment framework that is crucial for informing therapeutic strategies, trial design, and tailored care.