SYNGAP1 encephalopathy: A distinctive generalized developmental and epileptic encephalopathy

Danique R. M. Vlaskamp, Benjamin J. Shaw, Rosemary Burgess, Davide Mei, Martino Montomoli, Han Xie, Candace T. Myers, Mark F. Bennett, Wenshu Xiangwei, Danielle Williams, Saskia M. Maas, Alice S. Brooks, Grazia M. S. Mancini, Ingrid M. B. H. van de Laar, Johanna M. van Hagen, Tyson L. Ware, Richard I. Webster, Stephen Malone, Samuel F. Berkovic, Renate M. KalninsFederico Sicca, G. Christoph Korenke, Conny M. A. van Ravenswaaij-Arts, Michael S. Hildebrand, Heather C. Mefford, Yuwu Jiang, Renzo Guerrini, Ingrid E. Scheffer

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

To delineate the epileptology, a key part of the SYNGAP1 phenotypic spectrum, in a large patient cohort.MethodsPatients were recruited via investigators' practices or social media. We included patients with (likely) pathogenic SYNGAP1 variants or chromosome 6p21.32 microdeletions incorporating SYNGAP1. We analyzed patients' phenotypes using a standardized epilepsy questionnaire, medical records, EEG, MRI, and seizure videos.ResultsWe included 57 patients (53% male, median age 8 years) with SYNGAP1 mutations (n = 53) or microdeletions (n = 4). Of the 57 patients, 56 had epilepsy: generalized in 55, with focal seizures in 7 and infantile spasms in 1. 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 of 56 (96%) patients for whom early developmental history was available. Developmental plateauing or regression occurred with seizures in 56 in the context of a developmental and epileptic encephalopathy (DEE). Fifty-five of 57 patients had intellectual disability, which was moderate to severe in 50. Other common features included behavioral 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%).ConclusionsSYNGAP1 mutations cause a generalized DEE with a distinctive syndrome combining epilepsy with eyelid myoclonia with absences and myoclonic-atonic seizures, as well as a predilection to seizures triggered by eating.
Original languageEnglish
Pages (from-to)E96-E107
JournalNeurology
Volume92
Issue number2
DOIs
Publication statusPublished - 8 Jan 2019
Externally publishedYes

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