Global Overview of SYNGAP1 Natural History Studies - Support the SYNGAP1 #ProMMiS – #S10e175

July 16, 2025. Week 29.

1. What is a natural history study (NHS)? And why do we care?

We care because we haven’t done this before, heal those born with disease.

Natural history studies, which examine the progression of a disease over time, can be either retrospective or prospective. Retrospective studies analyze existing data, like medical records, while prospective studies collect new data over time. Both types are valuable for understanding a disease's course and informing research and treatment strategies.

⁠NHS are critical for clinical trial design. Size and Quality matter. Validated scales are better than PROs regardless of what the current rhetoric is.

1. What’s going on now?

USA - https://curesyngap1.org/resources/studies/syngap1-ProMMiS/ - 135+ over three sites, some with FOUR visits, and counting - Adding GCP - Collaborating with world class institutions and excellent clinicians at Stanford, Children’s Colorado and, of course, CHOP.

USA - https://Citizen.Health/partners/srf has almost 300 patients! Retrospective Health Data.

USA - https://rare-x.org/syngap1/ is where we collect PROs.

Australia - Dr. Sheffer is running a study, talk to her or Dani.

Latin America - SYNGAP1 Argentina with others joining.

Europe - https://www.patre.info/syngap1/ 

1. Key takeaways for Industry

SYNGAP1 is well positioned to work with… Vlasskamp and Wiltrout are published, Citizen Health is growing & ProMMiS is truly exceptional – and growing, and Rare-X is collecting eight key PROs. Additionally, there are significant international efforts in Australia, Latin America & Europe. Census: https://curesyngap1.org/blog/syngap1-census-2025-update-55-in-q2-2025-total-1636/ 

If you are in industry and thinking about starting another NHS for your asset, please don't. Please instead partner with existing PAGs and NHS studies in your key geographies to move faster, have bigger N and not waste precious patients time, we need to accelerate drug development not slow it down by diluting patients and clinicians between too many studies.

Baseline papers on SYNGAP1:

1998 - Huganir - SynGAP: a synaptic RasGAP that associates with the PSD-95/SAP90 protein family - https://pubmed.ncbi.nlm.nih.gov/9581761/

2009 - Michaud - Mutations in SYNGAP1 in autosomal nonsyndromic mental retardation - https://pubmed.ncbi.nlm.nih.gov/19196676/

2013 - Carvill - Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1 - https://pubmed.ncbi.nlm.nih.gov/23708187/

2019 - Vlasskamp - SYNGAP1 encephalopathy: A distinctive generalized developmental and epileptic encephalopathy - https://pubmed.ncbi.nlm.nih.gov/30541864/

2023 - Rong - Adult Phenotype of SYNGAP1-DEE - https://pubmed.ncbi.nlm.nih.gov/38045990/

2024 - Wiltrout - Comprehensive phenotypes of patients with SYNGAP1-related disorder reveals high rates of epilepsy and autism - https://pubmed.ncbi.nlm.nih.gov/38470175/

Pubmed is at 28 (so less than one a week…) https://pubmed.ncbi.nlm.nih.gov/?term=syngap1&filter=years.2025-2025&timeline=ex