Developmental epileptic encephalopathy in DLG4-related synaptopathy

Benedetta Kassabian, Amanda M. Levy, Elena Gardella, Angel Aledo-Serrano, Amitha L. Ananth, Alejandro J. Brea-Fernández, Roseline Caumes, Nicolas Chatron, Alice Dainelli, Matthias De Wachter, Anne Sophie Denommé-Pichon, Thomas J. Dye, Elisa Fazzi, Roxanne Felt, Alberto Fernández-Jaén, Montse Fernández-Prieto, Emily Gantz, Piotr Gasperowicz, Antonio Gil-Nagel, David Gómez-AndrésHansel M. Greiner, Renzo Guerrini, Maria K. Haanpää, Minttu Helin, Juliane Hoyer, Anna C.E. Hurst, Staci Kallish, Shefali N. Karkare, Amjad Khan, Lotte Kleinendorst, Johannes Koch, Sanjeev V. Kothare, Suzanna M. Koudijs, Lieven Lagae, Phillis Lakeman, Kathleen A. Leppig, Gaetan Lesca, Diego Lopergolo, Laina Lusk, Alex Mackenzie, Davide Mei, Rikke S. Møller, Elaine M. Pereira, Konrad Platzer, Chloe Quelin, Anya Revah-Politi, Sylvain Rheims, Agustí Rodríguez-Palmero, Andrea Rossi, Filippo Santorelli, Syndi Seinfeld, Erick Sell, Donna Stephenson, Krzysztof Szczaluba, Eugen Trinka, Muhammad Umair, Hilde Van Esch, Mieke M. van Haelst, Danielle C.M. Veenma, Sacha Weber, Sarah Weckhuysen, Pia Zacher, Zeynep Tümer*, Guido Rubboli*


Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review


Objective: The postsynaptic density protein of excitatory neurons PSD-95 is encoded by discs large MAGUK scaffold protein 4 (DLG4), de novo pathogenic variants of which lead to DLG4-related synaptopathy. The major clinical features are developmental delay, intellectual disability (ID), hypotonia, sleep disturbances, movement disorders, and epilepsy. Even though epilepsy is present in 50% of the individuals, it has not been investigated in detail. We describe here the phenotypic spectrum of epilepsy and associated comorbidities in patients with DLG4-related synaptopathy. Methods: We included 35 individuals with a DLG4 variant and epilepsy as part of a multicenter study. The DLG4 variants were detected by the referring laboratories. The degree of ID, hypotonia, developmental delay, and motor disturbances were evaluated by the referring clinician. Data on awake and sleep electroencephalography (EEG) and/or video-polygraphy and brain magnetic resonance imaging were collected. Antiseizure medication response was retrospectively assessed by the referring clinician. Results: A large variety of seizure types was reported, although focal seizures were the most common. Encephalopathy related to status epilepticus during slow-wave sleep (ESES)/developmental epileptic encephalopathy with spike–wave activation during sleep (DEE-SWAS) was diagnosed in >25% of the individuals. All but one individual presented with neurodevelopmental delay. Regression in verbal and/or motor domains was observed in all individuals who suffered from ESES/DEE-SWAS, as well as some who did not. We could not identify a clear genotype–phenotype relationship even between individuals with the same DLG4 variants. Significance: Our study shows that a subgroup of individuals with DLG4-related synaptopathy have DEE, and approximately one fourth of them have ESES/DEE-SWAS. Our study confirms DEE as part of the DLG4-related phenotypic spectrum. Occurrence of ESES/DEE-SWAS in DLG4-related synaptopathy requires proper investigation with sleep EEG.

Udgave nummer4
Sider (fra-til)1029-1045
StatusUdgivet - apr. 2024

Bibliografisk note

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© 2023 International League Against Epilepsy.


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