Developmental epileptic encephalopathy in DLG4‐related synaptopathy
Authors: Kassabian Benedetta , Levy Amanda M. , Gardella Elena , Aledo‐Serrano Angel , Ananth Amitha L. , Brea‐Fernández Alejandro J. , Caumes Roseline , Chatron Nicolas , Dainelli Alice , De Wachter Matthias , Denommé‐Pichon Anne‐Sophie , Dye Thomas J. , Fazzi Elisa , Felt Roxanne , Fernández‐Jaén Alberto , Fernández‐Prieto Montse , Gantz Emily , Gasperowicz Piotr , Gil‐Nagel Antonio , Gómez‐Andrés David , Greiner Hansel M. , Guerrini Renzo , Haanpää Maria K. , Helin Minttu , Hoyer Juliane , Hurst Anna C. E. , Kallish Staci , Karkare Shefali N. , Khan Amjad , Kleinendorst Lotte , Koch Johannes , Kothare Sanjeev V. , Koudijs Suzanna M. , Lagae Lieven , Lakeman Phillis , Leppig Kathleen A. , Lesca Gaetan , Lopergolo Diego , Lusk Laina , Mackenzie Alex , Mei Davide , Møller Rikke S. , Pereira Elaine M. , Platzer Konrad , Quelin Chloe , Revah‐Politi Anya , Rheims Sylvain , Rodríguez‐Palmero Agustí , Rossi Andrea , Santorelli Filippo , Seinfeld Syndi , Sell Erick , Stephenson Donna , Szczaluba Krzysztof , Trinka Eugen , Umair Muhammad , Van Esch Hilde , van Haelst Mieke M. , Veenma Danielle C. M. , Weber Sacha , Weckhuysen Sarah , Zacher Pia , Tümer Zeynep , Rubboli Guido 
Published: December 2023

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.