Developmental epileptic encephalopathy in DLG4-related synaptopathy
Por:
Kassabian, B, Levy, AM, Gardella, E, Aledo-Serrano, A, Ananth, AL, Brea-Fernandez, AJ, Caumes, R, Chatron, N, Dainelli, A, De Wachter, M, Denomme-Pichon, AS, Dye, TJ, Fazzi, E, Felt, R, Fernandez-Jaen, A, Fernandez-Prieto, M, Gantz, E, Gasperowicz, P, Gil-Nagel, A, Gómez-Andrés, D, Greiner, HM, Guerrini, R, Haanpaeae, MK, Helin, M, Hoyer, J, Hurst, ACE, 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, DVD, Moller, RS, Pereira, EM, Platzer, K, Quelin, C, Revah-Politi, A, Rheims, S, Rodriguez-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, DCM, Weber, S, Weckhuysen, S, Zacher, P, Tümer, Z and Rubboli, G
Publicada:
1 abr 2024
Ahead of Print:
1 feb 2024
Resumen:
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.
Filiaciones:
Kassabian, B:
European Reference Network EpiCARE, Danish Epilepsy Ctr Filadelfia, Dept Epilepsy Genet & Precis Med, Dianalund, Denmark
Univ Padua, Dept Neurosci, Neurol Unit, Padua, Italy
Levy, AM:
Copenhagen Univ Hosp, Kennedy Ctr, Dept Clin Genet, Rigshosp, Copenhagen, Denmark
Gardella, E:
European Reference Network EpiCARE, Danish Epilepsy Ctr Filadelfia, Dept Epilepsy Genet & Precis Med, Dianalund, Denmark
Univ Southern Denmark, Dept Reg Hlth Res, Odense, Denmark
Aledo-Serrano, A:
Vithas La Milagrosa Univ Hosp, Vithas Hosp Grp, Epilepsy & Neurogenet Unit, Madrid, Spain
Ananth, AL:
Univ Alabama Birmingham, Div Pediat Neurol, Birmingham, AL USA
Brea-Fernandez, AJ:
Univ Santiago de Compostela, Ctr Singular Invest Med Mol & Enfermedades Cron C, Ctr Invest Biomed Red Enfermedades Raras Inst Sal, Grp Genom & Bioinformat, Santiago De Compostela, Spain
Fdn Publ Galega Med Xen, Inst Invest Sanitaria IDIS, Santiago De Compostela, Spain
Caumes, R:
CHU Lille, Clin Genet, Lille, France
Chatron, N:
Hosp Civils Lyon, Serv Genet, Bron, France
Univ Lyon, Univ Claude Bernard Lyon 1, Inst NeuroMyoGene, INSERM U1315, Lyon, France
Dainelli, A:
Meyer Childrens Hosp IRCCS, Ist Ricovero & Cura Carattere Sci, Neurosci Dept, European Reference Network EpiCARE, Florence, Italy
De Wachter, M:
Univ Antwerp, Antwerp Univ Hosp, Dept Pediat Neurol, Edegem, Belgium
Denomme-Pichon, AS:
Dijon Bourgogne Univ Hosp, Funct Unit Diagnost Innovat Rare Dis, Federat Hosp Univ Medecine TRANSLat & Anomalies D, Dijon, France
Univ Burgundy, INSERM, UMR 1231, Genet Anomalies Dev GAD, Dijon, France
Dye, TJ:
Cincinnati Childrens Hosp Med Ctr, Div Neurol, Cincinnati, OH USA
Univ Cincinnati, Coll Med, Dept Pediat, Cincinnati, OH USA
Fazzi, E:
Univ Brescia, Dept Clin & Expt Sci, Brescia, Italy
Unit Child Neurol & Psychiat, Azienda Socio Sanit Terr ASST Spedali Civili Bres, Brescia, Italy
Felt, R:
Kaiser Permanente Bellevue Med Ctr, Dept Neurol, Bellevue, WA USA
Fernandez-Jaen, A:
Hosp Univ Quironsalud, Dept Pediat Neurol, Neurogenet Sect, Madrid, Spain
Univ Europea, Fac Med, Madrid, Spain
Fernandez-Prieto, M:
Univ Santiago de Compostela, Ctr Singular Invest Med Mol & Enfermedades Cron C, Ctr Invest Biomed Red Enfermedades Raras Inst Sal, Grp Genom & Bioinformat, Santiago De Compostela, Spain
Fdn Publ Galega Med Xen, Inst Invest Sanitaria IDIS, Santiago De Compostela, Spain
Gantz, E:
Univ Alabama Birmingham, Div Pediat Neurol, Birmingham, AL USA
Gasperowicz, P:
Med Univ Warsaw, Dept Med Genet, Warsaw, Poland
Gil-Nagel, A:
Ruber Int Hosp, Neurol Dept, Epilepsy Program, Madrid, Spain
Gómez-Andrés, D:
Hosp Universitari Vall dHebron, Vall dHebron Res Inst, Child Neurol Unit, Barcelona, Spain
Greiner, HM:
Cincinnati Childrens Hosp Med Ctr, Div Neurol, Cincinnati, OH USA
Univ Cincinnati, Coll Med, Dept Pediat, Cincinnati, OH USA
Guerrini, R:
Meyer Childrens Hosp IRCCS, Ist Ricovero & Cura Carattere Sci, Neurosci Dept, European Reference Network EpiCARE, Florence, Italy
Haanpaeae, MK:
Turku Univ Hosp, Dept Genom, Turku, Finland
Helin, M:
Turku Univ Hosp, Dept Pediat Neurol, Turku, Finland
Hoyer, J:
Friedrich Alexander Univ Erlangen Nurnberg, Inst Human Genet, Erlangen, Germany
Hurst, ACE:
Univ Alabama Birmingham, Dept Genet, Birmingham, AL USA
Kallish, S:
Univ Penn, Dept Med, Div Translat Med & Human Genet, Philadelphia, PA USA
Karkare, SN:
Cohen Childrens Med Ctr, Dept Pediat, Div Pediat Neurol, New Hyde Pk, NY USA
Khan, A:
Univ Lakki Marwat, Fac Biol Sci, Dept Zool, Lakki Marwat, Pakistan
Univ Tubingen, Inst Med Genet & Appl Genom, Tubingen, Germany
Kleinendorst, L:
Amsterdam Univ Med Ctr UMC, Univ Amsterdam, Dept Human Genet, Amsterdam, Netherlands
Univ Amsterdam, Amsterdam Univ Med Ctr UMC, Emma Ctr Personalized Med, Amsterdam, Netherlands
Koch, J:
Paracelsus Med Univ, Univ Childrens Hosp, Salzburg, Austria
Kothare, SV:
Cohen Childrens Med Ctr, Dept Pediat, Div Pediat Neurol, New Hyde Pk, NY USA
Koudijs, SM:
Erasmus MC Sophia Childrens Hosp, Univ Med Ctr Rotterdam, Dept Neurol, Rotterdam, Netherlands
Erasmus Med Ctr ENCORE, GRIN Expertise Ctr, Erfelijke Neurocognitieve Ontwikkelingsstoornisse, Rotterdam, Netherlands
Lagae, L:
Univ Hosp Leuven, Dept Dev & Regenerat, Sect Paediat Neurol, European Reference Network EpiCARE, Leuven, Belgium
Lakeman, P:
Amsterdam Univ Med Ctr UMC, Univ Amsterdam, Dept Human Genet, Amsterdam, Netherlands
Leppig, KA:
Kaiser Permanente Washington, Genet Serv, Seattle, WA USA
Lesca, G:
Hosp Civils Lyon, Serv Genet, Bron, France
Univ Lyon, Univ Claude Bernard Lyon 1, Inst NeuroMyoGene, INSERM U1315, Lyon, France
Lopergolo, D:
Univ Siena, Dept Med Surg & Neurosci, Siena, Italy
IRCCS Stella Maris Fdn, Mol Med Neurodegenerat & Neuromuscular Dis Unit, Pisa, Italy
Lusk, L:
Childrens Hosp Philadelphia, Div Neurol, Epilepsy Neurogenet Initiat, Philadelphia, PA USA
Mackenzie, A:
Childrens Hosp Eastern Ontario, Res Inst, Ottawa, ON, Canada
Univ Ottawa, Fac Med, Ottawa, ON, Canada
Mei, DVD:
Meyer Childrens Hosp IRCCS, Ist Ricovero & Cura Carattere Sci, Neurosci Dept, European Reference Network EpiCARE, Florence, Italy
Moller, RS:
European Reference Network EpiCARE, Danish Epilepsy Ctr Filadelfia, Dept Epilepsy Genet & Precis Med, Dianalund, Denmark
Univ Southern Denmark, Dept Reg Hlth Res, Odense, Denmark
Pereira, EM:
Columbia Univ, Vagelos Coll Phys & Surg, New York Presbyterian Morgan Stanley Childrens Ho, Div Clin Genet,Dept Pediat, New York, NY USA
Platzer, K:
Univ Leipzig, Med Ctr, Inst Human Genet, Leipzig, Germany
Quelin, C:
CHU Rennes, Dept Med Genet, Rennes, France
Revah-Politi, A:
Columbia Univ, Irving Med Ctr, Inst Genom Med, New York, NY USA
Rheims, S:
Hosp Civils Lyon & Lyon 1 Univ, Dept Funct Neurol & Epileptol, European Reference Network EpiCARE, Lyon, France
:
Univ Autonoma Barcelona, Hosp Univ Germans Trias & Pujol, Dept Pediat, Paediat Neurol Unit, Barcelona, Spain
Inst Salud Carlos III, Grp Invest Biomed Red Enfermedades Raras, Madrid, Spain
Rossi, A:
Unit Child Neurol & Psychiat, Azienda Socio Sanit Terr ASST Spedali Civili Bres, Brescia, Italy
Santorelli, F:
IRCCS Stella Maris Fdn, Mol Med Neurodegenerat & Neuromuscular Dis Unit, Pisa, Italy
Seinfeld, S:
Joe DiMaggio Childrens Hosp, Neurosci Ctr, Dept Pediat Neurol, Hollywood, FL USA
Sell, E:
Childrens Hosp Eastern Ontario, Div Neurol, Ottawa, ON, Canada
Stephenson, D:
Childrens Hosp Philadelphia, Div Neurol, Philadelphia, PA USA
Szczaluba, K:
Med Univ Warsaw, Dept Med Genet, Warsaw, Poland
Med Univ Warsaw, Ctr Excellence Rare & Undiagnosed Dis, Warsaw, Poland
Trinka, E:
Paracelsus Med Univ, Ctr Cognit Neurosci, Salzburg, Austria
Umair, M:
King Saud Bin Abdulaziz Univ Hlth Sci, King Abdullah Int Med Res Ctr, Med Genom Res Dept, Minist Natl Guard Hlth Affairs, Riyadh, Saudi Arabia
Univ Management & Technol, Sch Sci, Dept Life Sci, Lahore, Pakistan
Van Esch, H:
Univ Hosp Leuven, Ctr Human Genet, Leuven, Belgium
van Haelst, MM:
Amsterdam Univ Med Ctr UMC, Univ Amsterdam, Dept Human Genet, Amsterdam, Netherlands
Univ Amsterdam, Amsterdam Univ Med Ctr UMC, Emma Ctr Personalized Med, Amsterdam, Netherlands
Veenma, DCM:
Erasmus Med Ctr ENCORE, GRIN Expertise Ctr, Erfelijke Neurocognitieve Ontwikkelingsstoornisse, Rotterdam, Netherlands
Sophia Hosp, Erasmus Med Ctr MC, Dept Pediat, Rotterdam, Netherlands
Weber, S:
Ctr Hosp Univ Caen Normandie, Dept Neurol, Caen, France
Ctr Hospitalier Univ Caen Normandie, Dept Neurol, Caen, France
Weckhuysen, S:
VIB Ctr Mol Neurol, Vlaams Inst Biotechnol, Appl & Translat Neurogen Grp, Antwerp, Belgium
Antwerp Univ Hosp, Dept Neurol, Antwerp, Belgium
Zacher, P:
Epilepsy Ctr Kleinwachau, Radeberg, Germany
Tümer, Z:
Copenhagen Univ Hosp, Kennedy Ctr, Dept Clin Genet, Rigshosp, Copenhagen, Denmark
Univ Copenhagen, Fac Hlth & Med Sci, Dept Clin Med, Copenhagen, Denmark
Rubboli, G:
European Reference Network EpiCARE, Danish Epilepsy Ctr Filadelfia, Dept Epilepsy Genet & Precis Med, Dianalund, Denmark
Univ Copenhagen, Fac Hlth & Med Sci, Dept Clin Med, Copenhagen, Denmark
Green Published
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