Authors :
Presenting Author: Sam Pierce, PT, PhD – Children’s Hospital of Philadelphia
Kristin Cunningham, OT – Children’s Hospital of Philadelphia
JoeyLynn Coyne, RT – Children's Hospital of Philadelphia
Danielle Decampo, MD, PhD – Children's Hospital of Philadelphia
Scott Demarest, MD – Children's Hospital Colorado
Mike Graglia, MBA, MA – SynGAP Research Fund
James Goss, PhD – STXBP1 Foundation
Alicia Harrison, GC – Children's Hospital of Philadelphia
Kathryn Helde, PhD – SynGAP Research Fund
Jillian McKee, MD, PhD – Children's Hospital of Philadelphia
Charlene Son Rigby, BA, MBA – STXBP1 Foundation
Katie Sullivan, GC – Children’s Hospital of Philadelphia
Sarah Tefft, MSN, RN, CRNP – Children's Hospital of Philadelphia
Hsiao-Tuan Chao, MD, PhD – Baylor College of Medicine
Zachary Grinspan, MD, MS – Weill Cornell Medicine
Andrea Miele, PhD – Children’s Hospital Colorado
Michael Boland, PhD – University of Pennsylvania
Sarah Ruggerio, GC – Children’s Hospital of Philadelphia
Ingo Helbig, MD – Children's Hospital of Philadelphia
Rationale:
STXBP1-Related Disorders (
STXBP1-RD) and
SYNGAP1-Related Disorders (
SYNGAP1-RD) are two genetic conditions characterized by developmental delay, intellectual disability, and seizures
. These disorders are targets for drug and gene therapy, however, there is limited information describing their natural history which impedes the development of possible therapeutics. Here, we describe developmental outcome measures from a prospective natural history study of individuals with
STXBP1-RD and
SYNGAP1-RD.
Methods: This investigation is a multi-center, prospective study, conducted under local IRB approval. An initial list of developmental outcome measures was selected from previously developed disease concept models to comprehensively assess key domains. A series of meetings with the STXBP1 Foundation and SynGAP Research Fund reviewed the selected outcome measures, and a battery of standardized assessments was selected to account for a wide range of clinical phenotypes and ages. See Table 1 for a description of outcome measures.
Results: A total of 56 individuals with
STXBP1-RD (mean age = 8.7 years, range from 1.0 to 42.2 years) and 62 individuals with
SYNGAP1-RD (mean age = 9.9 years, range from 1.6 to 67.5 years) participated. No subject from either cohort scored a minimum or maximum total score on any measure except one infant with
SYNGAP1-RD had a maximum score in the Alberta Infant Motor Scale. One subject with
STXBP1-RD scored at the minimum age equivalent score with 4 subtests of the Bayley-IV. Finally, one child with
SYNGAP1-RD met the maximum age equivalent score for 4 subtests of the Bayley-IV, while an additional child met the maximum score for one subtest. See Table 2 for a summary of outcome measures.
Only one individual with
STXBP1-RD and one with
SYNGAP1-RD were unable to complete the GMFM-66 while all subjects completed the Alberta Infant Motor Scales. For individuals with
STXBP1-RD, 84% were able to be complete the Bayley 4 and Peabody 3 while 60% and 79% of the cohort with
SYNGAP1-RD were able to be complete the Bayley 4 and Peabody 3 respectively. Subjects who were unable to complete testing were limited by fatigue and behavior.
Conclusions: Our study provides strong evidence that a comprehensive and meaningful battery of assessments is feasible in
STXBP1-RD and
SYNGAP1-RD, while avoiding floor and ceiling effects, allowing for the full range of developmental outcomes to be captured across a wide chronological age range. Understanding the natural history of
STXBP1-RD and
SYNGAP1-RD is critical for future clinical trials, which will include developmental measures as clinical endpoints. The use of these tools will allow us to comprehensively assess developmental outcomes which will improve clinical trial readiness so that future treatments can be assessed expeditiously in individuals with
STXBP1-RD and
SYNGAP1-RD.
Funding: This work was supported by the Center for Epilepsy and Neurodevelopmental Disorders at Children’s Hospital of Philadelphia, the University of Pennsylvania Perelman School, STXBP1 Foundation, American Epilepsy Society, Pediatric Epilepsy Research Foundations & SynGAP Research Fund through a Research Training Fellowship for Clinicians.