Abstracts

This is a Late Breaking abstract

Rationale: Pathogenic variants on the SCN2A gene alter sodium ion flow in the brain causing a developmental and epileptic encephalopathy (DEE). Epilepsy is difficult to manage in most children with SCN2A-DEE and all have additional comorbidities and severe neurodevelopmental impairments. Because of its specific molecular pathways, SCN2A-DEE is being targeted for precision medicine and gene therapy trials. However, there are few outcome measures with validation data and no available data on minimal clinically important differences (MCID). This study explored how parents describe minimally important changes in functional ability domains.

Methods: As part of The Inchstone Project, a pilot was conducted at a SCN2A family conference in July 2022 to better understand how current tools need to be adapted to capture change in the most severely affected populations. Within this project, a qualitative descriptive study was conducted to explore parent estimates of individual within-patient change that would constitute an important difference in four functional domains: gross motor, fine motor, communication, and activities of daily living. Eight interviews were conducted with eight mothers and three fathers with a child with SCN2A-DEE. This was a “concept elicitation” approach where parents were asked what changes in their child’s function would be just enough for them to enter a small molecule trial and what difference would be just enough for them to enter a gene therapy trial, for each domain. Expressed important differences for each domain were tabulated using Excel.

Results: The children’s ages ranged from 4 to 21 years and seven were male. Five children were considered to have severe impairments and could walk independently, had some hand function but were nonverbal or minimally verbal. Three children were more profoundly impaired and could not walk independently, had minimal to no hand use and were non-verbal. For small molecule trials, parents of children with severe impairments described improvements in more complex skills (e.g., more walking endurance, able to use a pincer grasp, able to use simple sentences, practical involvement in toileting), whereas parents of children with more profound impairments described improvements in basic skills (e.g., able to sit, open the hand, make choices consistently, co-operate with toileting). Parents described larger important differences for gene therapy trials than for small molecule trials (Table).

Conclusions: This pilot provided an opportunity for evaluation of standardized outcome measures for non-seizure outcomes and understand how they need to be adapted to meet the needs of those more severely impacted by DEEs. A critical component of outcome measure validation is establishing meaningful change thresholds for score interpretation. This study was a preliminary qualitative approach that will inform future studies to determine quantitative MCID values for specific clinical outcome assessments in individuals with SCN2A-DEE.

Funding: The Inchstone Project, a project of Wishes for Elliott and FamilieSCN2A Foundation