Developmental outcome of electroencephalographic findings in SYNGAP1 encephalopathy
Authors: Ribeiro-Constante Juliana , Tristán-Noguero Alba , Martínez Calvo Fernando Francisco , Ibañez-Mico Salvador , Peña Segura José Luis , Ramos-Fernández José Miguel , Moyano Chicano María del Carmen , Camino León Rafael , Soto Insuga Víctor , González Alguacil Elena , Valera Dávila Carlos , Fernández-Jaén Alberto , Plans Laura , Camacho Ana , Visa-Reñé Nuria , Martin-Tamayo Blázquez María del Pilar , Paredes-Carmona Fernando , Marti-Carrera Itxaso , Hernández-Fabián Aránzazu , Tomas Davi Meritxell , Sanchez Merce Casadesus , Herraiz Laura Cuesta , Pita Patricia Fuentes , Gonzalez Teresa Bermejo , O'Callaghan Mar , Iglesias Santa Polonia Federico Felipe , Cazorla María Rosario , Ferrando Lucas María Teresa , González-Meneses Antonio , Sala-Coromina Júlia , Macaya Alfons , Lasa-Aranzasti Amaia , Cueto-González Anna Ma , Valera Párraga Francisca , Campistol Plana Jaume , Serrano Mercedes , Alonso Xenia , Del Castillo-Berges Diego , Schwartz-Palleja Marc , Illescas Sofía , Ramírez Camacho Alia , Sans Capdevila Oscar , García-Cazorla Angeles , Bayés Àlex , Alonso-Colmenero Itziar 
Published: March 2024

SYNGAP1 haploinsufficiency results in a developmental and epileptic encephalopathy (DEE) causing generalized epilepsies accompanied by a spectrum of neurodevelopmental symptoms. Concerning interictal epileptiform discharges (IEDs) in electroencephalograms (EEG), potential biomarkers have been postulated, including changes in background activity, fixation-off sensitivity (FOS) or eye closure sensitivity (ECS). In this study we clinically evaluate a new cohort of 36 SYNGAP1-DEE individuals. Standardized questionnaires were employed to collect clinical, electroencephalographic and genetic data. We investigated electroencephalographic findings, focusing on the cortical distribution of interictal abnormalities and their changes with age. Among the 36 SYNGAP1-DEE cases 18 presented variants in the SYNGAP1 gene that had never been previously reported. The mean age of diagnosis was 8 years and 8 months, ranging from 2 to 17 years, with 55.9% being male. All subjects had global neurodevelopmental/language delay and behavioral abnormalities; 83.3% had moderate to profound intellectual disability (ID), 91.7% displayed autistic traits, 73% experienced sleep disorders and 86.1% suffered from epileptic seizures, mainly eyelid myoclonia with absences (55.3%). A total of 63 VEEGs were revised, observing a worsening of certain EEG findings with increasing age. A disorganized background was observed in all age ranges, yet this was more common among older cases. The main IEDs were bilateral synchronous and asynchronous posterior discharges, accounting for ≥50% in all age ranges. Generalized alterations with maximum amplitude in the anterior region showed as the second most frequent IED (≥15% in all age ranges) and were also more common with increasing age. Finally, diffuse fast activity was much more prevalent in cases with 6 years or older. To the best of our knowledge, this is the first study to analyze EEG features across different age groups, revealing an increase in interictal abnormalities over infancy and adolescence. Our findings suggest that SYNGAP1 haploinsufficiency has complex effects in human brain development, some of which might unravel at different developmental stages. Furthermore, they highlight the potential of baseline EEG to identify candidate biomarkers and the importance of natural history studies to develop specialized therapies and clinical trials.