TY - JOUR

T1 - Developmental epileptic encephalopathy in DLG4-related synaptopathy

AU - Kassabian, Benedetta

AU - Levy, Amanda M.

AU - Gardella, Elena

AU - Aledo-Serrano, Angel

AU - Ananth, Amitha L.

AU - Brea-Fernández, Alejandro J.

AU - Caumes, Roseline

AU - Chatron, Nicolas

AU - Dainelli, Alice

AU - De Wachter, Matthias

AU - Denommé-Pichon, Anne-Sophie

AU - Dye, Thomas J.

AU - Fazzi, Elisa

AU - Felt, Roxanne

AU - Fernández-Jaén, Alberto

AU - Fernández-Prieto, Montse

AU - Gantz, Emily

AU - Gasperowicz, Piotr

AU - Gil-Nagel, Antonio

AU - Gómez-Andrés, David

AU - Greiner, Hansel M.

AU - Guerrini, Renzo

AU - Haanpää, Maria K.

AU - Helin, Minttu

AU - Hoyer, Juliane

AU - Hurst, Anna C. E.

AU - Kallish, Staci

AU - Karkare, Shefali N.

AU - Khan, Amjad

AU - Kleinendorst, Lotte

AU - Koch, Johannes

AU - Kothare, Sanjeev V.

AU - Koudijs, Suzanna M.

AU - Lagae, Lieven

AU - Lakeman, Phillis

AU - Leppig, Kathleen A.

AU - Lesca, Gaetan

AU - Lopergolo, Diego

AU - Lusk, Laina

AU - Mackenzie, Alex

AU - Mei, Davide

AU - Møller, Rikke S.

AU - Pereira, Elaine M.

AU - Platzer, Konrad

AU - Quelin, Chloe

AU - Revah-Politi, Anya

AU - Rheims, Sylvain

AU - Rodríguez-Palmero, Agustí

AU - Rossi, Andrea

AU - Santorelli, Filippo

AU - Seinfeld, Syndi

AU - Sell, Erick

AU - Stephenson, Donna

AU - Szczaluba, Krzysztof

AU - Trinka, Eugen

AU - Umair, Muhammad

AU - Van Esch, Hilde

AU - van Haelst, Mieke M.

AU - Veenma, Danielle C. M.

AU - Weber, Sacha

AU - Weckhuysen, Sarah

AU - Zacher, Pia

AU - Tümer, Zeynep

AU - Rubboli, Guido

N1 - Publisher Copyright: © 2023 International League Against Epilepsy.

PY - 2024

Y1 - 2024

N2 - 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.

AB - 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.

KW - DEE-SWAS

KW - epilepsy

KW - ESES

KW - PSD-95

KW - SHINE syndrome

U2 - 10.1111/epi.17876

DO - 10.1111/epi.17876

M3 - Journal article

C2 - 38135915

AN - SCOPUS:85185516622

VL - 65

SP - 1029

EP - 1045

JO - Epilepsia

JF - Epilepsia

SN - 0013-9580

IS - 4

ER -