Developmental epileptic encephalopathy in DLG4-related synaptopathy.

Kassabian B, Levy AM, Gardella E, Aledo-Serrano A, Ananth AL, Brea-Fernández AJ, Caumes R, Chatron N, Dainelli A, De Wachter M, Denommé-Pichon AS, Dye TJ, Fazzi E, Felt R, Fernández-Jaén A, Fernández-Prieto M, Gantz E, Gasperowicz P, Gil-Nagel A, Gómez-Andrés D, Greiner HM, Guerrini R, Haanpää MK, Helin M, Hoyer J, Hurst AC, Kallish S, Karkare SN, Khan A, Kleinendorst L, Koch J, Kothare SV, Koudijs SM, Lagae L, Lakeman P, Leppig KA, Lesca G, Lopergolo D, Lusk L, Mackenzie A, Mei D, Møller RS, Pereira EM, Platzer K, Quelin C, Revah-Politi A, Rheims S, Rodríguez-Palmero A, Rossi A, Santorelli F, Seinfeld S, Sell E, Stephenson D, Szczaluba K, Trinka E, Umair M, Van Esch H, van Haelst MM, Veenma DC, Weber S, Weckhuysen S, Zacher P, Tümer Z, Rubboli G (2024)

Publication Language: English

Publication Type: Journal article

Publication year: 2024

Journal

Book Volume: 65

Pages Range: 1029-1045

Journal Issue: 4

DOI: 10.1111/epi.17876

Abstract

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.

Authors with CRIS profile

Involved external institutions

Filadelfia Denmark (DK) Rigshospitalet Denmark (DK) Vithas Madrid La Milagrosa Hospital Spain (ES) University of Alabama at Birmingham (UAB) United States (USA) (US) University of Santiago de Compostela / Universidad de Santiago de Compostela (USC) Spain (ES) Centre Hospitalier Régional Universitaire de Lille (CHRU de Lille) France (FR) Hospices Civils de Lyon (CHU) France (FR) Azienda Ospedaliera Universitaria Meyer Italy (IT) Hospital Network Antwerp / Ziekenhuis Netwerk Antwerpen (ZNA) Belgium (BE) Centre hospitalier universitaire (CHU) de Dijon Bourgogne France (FR) Wrocław Medical University / Uniwersytet Medyczny we Wrocławiu Poland (PL) Ruber International Hospital Spain (ES) Vall d'Hebron University Hospital / Hospital Universitari Vall d'Hebron Spain (ES) Cincinnati Children's Hospital Medical Center United States (USA) (US) Turku University Hospital / Turun yliopistollinen keskussairaala (TYKS) Finland (FI) Cardiology PC United Kingdom (GB) Penn Medicine United States (USA) (US) Cohen Children's Medical Center United States (USA) (US) University of Lakki Marwat Pakistan (PK) Amsterdam University Medical Centers (Amsterdam UMC) / Amsterdam Universitair Medische Centra Netherlands (NL) Universitätskliniken Salzburg Austria (AT) Erasmus MC - Sophia Children’s Hospital Netherlands (NL) University Hospital Leuven (UZ) / Universitaire ziekenhuizen Leuven Belgium (BE) Kaiser Permanente United States (USA) (US) Università degli Studi di Siena (UNISI) / University of Siena Italy (IT) Children's Hospital of Philadelphia United States (USA) (US) Children's Hospital of Eastern Ontario (CHEO) / Centre hospitalier pour enfants de l'est de l'Ontario Canada (CA) Columbia University Irving Medical Center (CUIMC) United States (USA) (US) Universität Leipzig Germany (DE) Centre hospitalier universitaire de Rennes / CHU Rennes France (FR) Health Sciences Research Institute of the “Germans Trias i Pujol” Foundation (IGTP) Spain (ES) Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia Italy (IT) National Institute of Gastroenterology "Servio de Bellis" Research Hospital / Ente Ospedaliero Specializzato in Gastroenterologia “Saverio de Bellis” Italy (IT) Joe DiMaggio Children's Hospital United States (USA) (US) Christian Doppler Klinik Austria (AT) National Guard Health Affairs Saudi Arabia (SA) Erasmus University Medical Center (MC) Netherlands (NL) CHU de Caen Normandie France (FR) Flanders Institute for Biotechnology / Vlaams Instituut voor Biotechnologie (VIB) Belgium (BE) Kleinwachau - Sächsisches Epilepsiezentrum Radeberg gGmbH Germany (DE) Università degli Studi di Brescia Italy (IT) Hospital Universitario Quirónsalud Madrid Spain (ES)

How to cite

APA:

Kassabian, B., Levy, A.M., Gardella, E., Aledo-Serrano, A., Ananth, A.L., Brea-Fernández, A.J.,... Rubboli, G. (2024). Developmental epileptic encephalopathy in DLG4-related synaptopathy. Epilepsia, 65(4), 1029-1045. https://doi.org/10.1111/epi.17876

MLA:

Kassabian, Benedetta, et al. "Developmental epileptic encephalopathy in DLG4-related synaptopathy." Epilepsia 65.4 (2024): 1029-1045.

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