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

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.

BibTeX: Download