Ribeiro-Constante J, Tristán-Noguero A, Martínez Calvo FF, Ibañez-Mico S, Peña Segura JL, Ramos-Fernández JM, Moyano Chicano MDC, Camino León R, Soto Insuga V, González Alguacil E, Valera Dávila C, Fernández-Jaén A, Plans L, Camacho A, Visa-Reñé N, Martin-Tamayo Blázquez MDP, Paredes-Carmona F, Marti-Carrera I, Hernández-Fabián A, Tomas Davi M, Sanchez MC, Herraiz LC, Pita PF, Gonzalez TB, O'Callaghan M, Iglesias Santa Polonia FF, Cazorla MR, Ferrando Lucas MT, González-Meneses A, Sala-Coromina J, Macaya A, Lasa-Aranzasti A, Cueto-González AM, Valera Párraga F, Campistol Plana J, Serrano M, Alonso X, Del Castillo-Berges D, Schwartz-Palleja M, Illescas S, Ramírez Camacho A, Sans Capdevila O, García-Cazorla A, Bayés À, and Alonso-Colmenero I
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., Competing Interests: AG-C has received honoraria for research support and lectures from PTC Therapeutics, she has received honoraria for lectures from Biomarin, Immedica and Recordati Rare Diseases Foundation, and is a co-founder of the Hospital Sant Joan de Déu start-up “Neuroprotect Life Sciences”. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Ribeiro-Constante, Tristán-Noguero, Martínez Calvo, Ibañez-Mico, Peña Segura, Ramos-Fernández, Moyano Chicano, Camino León, Soto Insuga, González Alguacil, Valera Dávila, Fernández-Jaén, Plans, Camacho, Visa-Reñé, Martin-Tamayo Blázquez, Paredes-Carmona, Marti-Carrera, Hernández-Fabián, Tomas Davi, Sanchez, Herraiz, Pita, Gonzalez, O'Callaghan, Iglesias Santa Polonia, Cazorla, Ferrando Lucas, González-Meneses, Sala-Coromina, Macaya, Lasa-Aranzasti, Cueto-González, Valera Párraga, Campistol Plana, Serrano, Alonso, Del Castillo-Berges, Schwartz-Palleja, Illescas, Ramírez Camacho, Sans Capdevila, García-Cazorla, Bayés and Alonso-Colmenero.)