Abstracts

Rationale: SYNGAP1-related disorder is a common monogenic cause of generalized epilepsy, autism, and intellectual disability. While retrospective analyses have characterized the predominant clinical features, detailed prospective studies including standardized clinical outcome assessments are lacking. Determining key outcome measures and disease trajectories is critical for clinical trial readiness. Here, we present data from the first prospective natural history study of SYNGAP1-related disorders.


Methods: This was an IRB-approved, single-site natural history study. Inclusion criteria included a molecular diagnosis of SYNGAP1-related disorder. Individuals were excluded if they had an additional genetic or neurologic diagnosis contributing to their clinical presentation. Monthly seizure histories, including seizure types and frequencies, were reconstructed from medical records and caregiver interviews for a subset of individuals. Study visits occurred every 6 months and included standardized clinical histories, neurological examinations, caregiver-reported outcomes, clinical scales, and standardized assessments, as appropriate given the age and developmental level of the participant.


Results: 69 individuals with SYNGAP1 have been evaluated within the natural history study to date. The ages at initial assessment ranged from 1.6 to 67.5 years (median 6.8 years). Consistent with the previously described genetic landscape, most individuals had protein-truncating variants (PTVs, 85%), while a minority had missense variants (15%). Of the 20 individuals who had seizures reconstructed longitudinally, 67% (n=14/21) experienced seizures of any type, all of which were generalized by semiology. Atonic seizures were the most common (64%, n=9/14), followed by eyelid myoclonia (50%, n=7/14), absence (36%, n=5/14) and myoclonic seizures (29%, n=4/14). Median seizure onset was at age 2 years (range 1.3-5.3 years) and the highest seizure burden was seen between ages 2-4 years, when 75% of the cohort with epilepsy had seizures. Standardized classification scales demonstrated more significant deficits in communication compared to gross motor function (p=3.27x10^-7). Autism was very prevalent, with 96% meeting criteria for mild/moderate (55%) or severe (41%) symptoms.


Conclusions: SYNGAP1-related disorder is a highly variable neurodevelopmental condition with dynamic seizure trajectories and a wide range of developmental outcomes. Given the current development of precision medicine therapies, it is critical to thoroughly characterize the natural history of the disorder and identify outcome measures for clinical trial readiness. Here, we demonstrate the initial landscape of epilepsy and developmental trajectories in SYNGAP1.


Funding:
The Center for Epilepsy and Neurodevelopmental Disorders (ENDD), NINDS (R01 NS127830-01A1, R01 NS131512-01 and K02 NS112600 to IH), the American Epilepsy Society (AES), Pediatric Epilepsy Research Foundations (PERF) & SynGAP Research Fund (SRF) through a Research Training Fellowship for Clinicians (JM), and the American Academy of Neurology (AAN), AES, Epilepsy Foundation, & the American Brain Foundation (ABF) through the Susan Spencer Award (JM).