A disease concept model for STXBP1-related disorders

Abstract

Objective: STXBP1-related disorders are common genetic epilepsies and neurodevelopmental disorders, but the impact of symptoms across clinical domains is poorly understood. Disease concept models are formal frameworks to assess the lived experience of individuals and their families and provide a basis for generating outcome measures. Methods: We conducted semi-structured, qualitative interviews with 19 caregivers of 16 individuals with STXBP1-related disorders and 7 healthcare professionals. We systematically coded themes using NVivo software and grouped concepts into the domains of symptoms, symptom impact and caregiver impact. We quantified the frequency of concepts throughout the life span and across clinical subgroups stratified by seizure history and developmental trajectories. Results: Over 25 hours of interviews, we coded a total of 3626 references to 38 distinct concepts. In addition to well recognized clinical features such as developmental delay (n=240 references), behavior (n=201), and seizures (n=147), we identified previously underrepresented symptoms including gastrointestinal (n=68) and respiratory symptoms (n=24) and pain (n=30). The most frequently referenced symptom impacts were autonomy (n=96), socialization (n=64), and schooling (n=61). Emotional impact (n=354), support (n=200), and daily life & activities (n=108) were highly cited caregiver impacts. We found that seizures (OR=8.84, 95% CI 5.97-13.1) were more commonly referenced in infancy than in other age groups, while behavior (OR=2.15, 95% CI 1.56-2.95), and socialization (OR=2.26, 95% CI 1.28-3.96) were more likely to be referred in childhood. We found that caregivers of individuals with ongoing seizures were less likely to reference developmental delay (OR=0.59, 95% CI 0.42-0.82), possibly due to the relatively high impact of seizures (OR=8.84, 95% CI 5.97-13.1). Significance: STXBP1-related disorders are complex conditions affecting a wide range of clinical and social domains. We comprehensively mapped symptoms and their impact on families to generate a comprehensive disease model as a foundation for clinical endpoints in future trials.

A draft conceptual model of SLC6A1 neurodevelopmental disorder

“…The draft conceptual model of SLC6A1-NDD will likely be very similar to that of many other neurodevelopmental disorders, such as Angelman syndrome ( Willgoss et al, 2020 ) and STXBP1-Related Disorder ( Sullivan et al, 2022 ), with only a few distinguishing domains, such as the presence of cognitive regression, and the idiosyncratic hand use described by KOLs as the first noticeable symptom of the disorder. Neither of these domains has been well-studied or reported in the published literature to date.…”

“…It is a crucial time point to develop a conceptual model of disease for SLC6A1-NDD. A conceptual model, or disease concept map, is a comprehensive description of the lived experience of people with a disorder derived from comprehensive open-ended qualitative interviews of patients, caregivers and health care providers ( Grieco et al, 2019 ; Willgoss et al, 2020 ; Staunton et al, 2022 ; Sullivan et al, 2022 ). A disease concept map can serve as the basis for standards of clinical care, natural history study design, and endpoints for clinical trials ( Gonzalez-McQuire et al, 2019 ).…”

Responding to the Need of the Hour: Natural History Studies

“…Disease concept models, as discussed in a recent preprint by the group of Helbig in Philadelphia, are one way to help identify outcomes of importance before designing a clinical trial. 6 Natural history studies (NHS) are another means to make a disease as known and predictable as possible. In a highly informative publication about the importance of NHS, authors Palmer et al 7 point out that either retrospective cross-sectional or prospective longitudinal NHS are urgently needed for rare DEE.…”