Developmental epileptic encephalopathy in DLG4-related synaptopathy
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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.
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | Epilepsia |
| Vol/bind | 65 |
| Udgave nummer | 4 |
| Sider (fra-til) | 1029-1045 |
| Antal sider | 17 |
| ISSN | 0013-9580 |
| DOI | |
| Status | Udgivet - 2024 |
Bibliografisk note
Funding Information:
E.T. has received consultancy fees from Arvelle Therapeutics, Argenx, Clexio, Celegene, UCB Pharma, Eisai, Epilog, Bial, Medtronic, Everpharma, Biogen, Takeda, LivaNova, Newbridge, Sunovion, GW Pharmaceuticals, and Marinus; speaker fees from Arvelle Therapeutics, Bial, Biogen, Böhringer Ingelheim, Eisai, Everpharma, GSK, GW Pharmaceuticals, Hikma, LivaNova, Newbridge, Novartis, Sanofi, Sandoz, and UCB Pharma; and research funding (directly or to his institution) from GSK, Biogen, Eisai, Novartis, Red Bull, Bayer, and UCB Pharma outside the submitted work. E.T. receives grants from the Austrian Science Fund, Österreichische Nationalbank, and the European Union. E.T. is the CEO of Neuroconsult. None is related to the present study. P.Z. has received speaking fees from Jazz Pharmaceuticals and Angelini Pharma. S.Wec. has received consultancy fees from UCB, Xenon Pharmaceuticals, Lundbeck, Knopp Biosciences, Encoded Therapeutics, Angelini Pharma, and Roche. G.R. has received speaker honoraria from UCB, Eisai, Angelini Pharma, and UNEEG. The remaining authors have no conflicts of interest. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.
Funding Information:
We are thankful to SHINE syndrome foundation ( www.shinesyndrome.org ) and all the families who have contributed to this study. Several of the authors of this publication are members of the European Reference Network on Rare Congenital Malformations and Rare Intellectual Disability ERN‐ITHACA (EU Framework Partnership Agreement ID: 3HP‐HP‐FPA ERN‐01‐2016/739516) and/or ERN‐EpiCARE. Ángel Carracedo and Jesus Eiris have assisted in the clinical description of individual #13. We thank Ingrid van Ingelghem for her contributions. This work was supported by Jascha Fonden (grant 2022‐0011; A.M.L.); Fundacion INCE (A.G.‐N.); Regione Toscana under the Call for Health 2018 (grant DECODE‐EE) and the Human Brain Optical Mapping Project by Fondazione Cassa di Risparmio di Firenze (R.G.); National Center for Advancing Translational Sciences, National Institutes of Health (NIH; grant UL1TR001873; A.R.Po.; the content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH); Ricerca Corrente 5X1000 (F.S.); KAIMRC (grant RC23R/177/02; M.U.); and FWO (grant 1861419N; S.Wec.).
Publisher Copyright:
© 2023 International League Against Epilepsy.
ID: 385685938