Rationale:
SYNGAP1 is a heterogeneous genetic disorder associated with intellectual disability and infantile-onset seizures. Other common features include behavioral disturbances, autism, delayed or absent language, impaired motor skills, gastrointestinal issues, and sleeping difficulties. There is no disease-modifying treatment. This study aims to create a “disease concept model” to enumerate and rank the symptoms of SYNGAP1 that have the largest impact on the lives of patients and their caregivers. Disease concept models are foundational to identify meaningful clinical outcomes for use in future clinical trials.
Methods:
We developed a disease concept model via five exercises: a scoping review of SYNGAP1 clinical features, semi-structured interviews with caregivers, a survey of caregivers, a survey of clinical experts, and review of charts of children with SYNGAP1 at one center (Weill Cornell Medicine). We provide a narrative summary of the key findings.
Results:
We reviewed 19 articles, conducted 16 interviews of caregivers, received responses from 90 caregivers and 15 clinical experts on the survey, and reviewed seven charts.
Integrating findings from these exercises indicates that caregivers and providers both consider seizures/epilepsy, intellectual disability, and emotional regulation to be the most important therapeutic targets. Caregivers differ from providers in that they also ranked communication a high priority (Figure 1). Chart review revealed that many symptoms discussed in the caregiver interviews (i.e., lack of danger awareness, heat/cold intolerance, lack of satiety) are not found in clinicians’ notes (Figure 2). Conclusions:
Seizures, intellectual disability, communication, and emotional regulation are the four most meaningful clinical outcomes to target for investigating clinical interventions for SYNGAP1, according to caregivers. Instruments to measure these outcomes might include EEG and/or seizure diaries, Bayley Scales of Infant and Toddler Development and/or Vineland Adaptive Behavior Scales, Observer-Reported Communication Ability (ORCA) Measure, and Clinical Evaluation of Emotional Regulation (CEER).
Funding: 2023 Syngap Research Foundation Medical Student Award