SYNGAP1 encephalopathy: a distinctive generalized developmental and epileptic encephalopathy

Objective. To delineate the epileptology, a key part of the SYNGAP1 phenotypic spectrum, in a large patient cohort.
Methods. Patients were recruited via investigators’ practices or social media. We included patients with (likely) pathogenic SYNGAP1 variants or chromosome 6p21.32 microdeletions incorporating SYNGAP1. We analysed patients’ phenotypes using a standardized epilepsy questionnaire, medical records, EEG, MRI and seizure videos.
Results. We included 57 patients (53% male, median age 8 years) with SYNGAP1 mutations (n=53) or microdeletions (n=4). 56/57 patients had epilepsy: generalized in 55, with focal seizures in seven and infantile spasms in one. Median seizure onset age was 2 years. A novel type of drop attack was identified comprising eyelid myoclonia evolving to a myoclonic-atonic (n=5) or atonic (n=8) seizure. Seizure types included eyelid myoclonia with absences (65%), myoclonic seizures (34%), atypical (20%) and typical (18%) absences and atonic seizures (14%), triggered by eating in 25%. Developmental delay preceded seizure onset in 54/56 (96%) patients of whom early developmental history was available. Developmental plateauing or regression occurred with seizures in 56 in the context of developmental and epileptic encephalopathies (DEEs). 55/57 patients had intellectual disability, which was moderate to severe in 50. Other common features included behavioural problems (73%), high pain threshold (72%), eating problems including oral aversion (68%), hypotonia (67%), sleeping problems (62%), autism spectrum disorder (54%) and ataxia or gait abnormalities (51%).
Conclusions. SYNGAP1 mutations cause a generalized DEE with a distinctive syndrome combining epilepsy with eyelid myoclonia and myoclonic-atonic seizures, and predilection to seizures triggered by eating.