Developmental epileptic encephalopathy in DLG4-related synaptopathy

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

doi:https://doi.org/10.1111/epi.17876

Developmental epileptic encephalopathy in DLG4-related synaptopathy

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

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

OBJECTIVE: The postsynaptic density protein of excitatory neurons PSD-95 is encoded by 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 EEG and/or video-polygraphy and brain MRI were collected. Anti-seizure medication response was retrospectively assessed by the referring clinician.

RESULTS: A large variety of seizure types was reported, though focal seizures were the most common. Encephalopathy related to status epilepticus during slow sleep (ESES)/developmental epileptic encephalopathy with spike-wave activation during sleep (DEE-SWAS) was diagnosed in more than 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 has DEE, and around 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 to be properly investigated with sleep EEG.

Original language	English
Journal	Epilepsia
DOIs	https://doi.org/10.1111/epi.17876
Publication status	E-pub ahead of print - 22 Dec 2023

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https://doi.org/10.1111/epi.17876

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Kassabian, B., Levy, A. M., Gardella, E., Aledo-Serrano, A., Ananth, A. L., Brea-Fernández, A. J., Caumes, R., Chatron, N., Dainelli, A., De Wachter, M., Denommé-Pichon, A.-S., Dye, T. J., Fazzi, E., Felt, R., Fernández-Jaén, A., Fernández-Prieto, M., Gantz, E., Gasperowicz, P., Gil-Nagel, A., ... Rubboli, G. (2023). Developmental epileptic encephalopathy in DLG4-related synaptopathy. Epilepsia. Advance online publication. https://doi.org/10.1111/epi.17876

@article{3d9c45c1b18946c8a843d8ef51d2b03d,

title = "Developmental epileptic encephalopathy in DLG4-related synaptopathy",

abstract = "OBJECTIVE: The postsynaptic density protein of excitatory neurons PSD-95 is encoded by 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 EEG and/or video-polygraphy and brain MRI were collected. Anti-seizure medication response was retrospectively assessed by the referring clinician.RESULTS: A large variety of seizure types was reported, though focal seizures were the most common. Encephalopathy related to status epilepticus during slow sleep (ESES)/developmental epileptic encephalopathy with spike-wave activation during sleep (DEE-SWAS) was diagnosed in more than 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 has DEE, and around 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 to be properly investigated with sleep EEG.",

author = "Benedetta Kassabian and Levy, {Amanda M} and Elena Gardella and Angel Aledo-Serrano and Ananth, {Amitha L} and Brea-Fern{\'a}ndez, {Alejandro J} and Roseline Caumes and Nicolas Chatron and Alice Dainelli and {De Wachter}, Matthias and Anne-Sophie Denomm{\'e}-Pichon and Dye, {Thomas J} and Elisa Fazzi and Roxanne Felt and Alberto Fern{\'a}ndez-Ja{\'e}n and Montserrat Fern{\'a}ndez-Prieto and Emily Gantz and Piotr Gasperowicz and Antonio Gil-Nagel and David G{\'o}mez-Andr{\'e}s and Greiner, {Hansel M} and Renzo Guerrini and Haanp{\"a}{\"a}, {Maria K} and Minttu Helin and Juliane Hoyer and Hurst, {Anna C E} and Staci Kallish and Karkare, {Shefali N} and Amjad Khan and Lotte Kleinendorst and Johannes Koch and Kothare, {Sanjeev V} and Koudijs, {Suzanna V} and Lieven Lagae and Phillis Lakeman and Leppig, {Kathleen A} and Gaetan Lesca and Diego Lopergolo and Laina Lusk and Alex Mackenzie and Davide Mei and M{\o}ller, {Rikke S} and Pereira, {Elaine M} and Konrad Platzer and Chloe Quelin and Anya Revah-Politi and Sylvain Rheims and Agust{\'i} Rodr{\'i}guez-Palmero and Andrea Rossi and Filippo Santorelli and Syndi Seinfeld and Erick Sell and Donna Stephenson and Krzysztof Szczaluba and Eugen Trinka and Muhammad Umair and {Van Esch}, Hilde and {van Haelst}, {Mieke M} and Veenma, {Danielle C M} and Sacha Weber and Sarah Weckhuysen and Pia Zacher and Zeynep T{\"u}mer and Guido Rubboli",

year = "2023",

month = dec,

day = "22",

doi = "https://doi.org/10.1111/epi.17876",

language = "English",

journal = "Epilepsia",

issn = "0013-9580",

publisher = "Wiley-Blackwell",

}

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, A-S, 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, ACE, Kallish, S, Karkare, SN, Khan, A, Kleinendorst, L, Koch, J, Kothare, SV, Koudijs, SV, 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, DCM, Weber, S, Weckhuysen, S, Zacher, P, Tümer, Z & Rubboli, G 2023, 'Developmental epileptic encephalopathy in DLG4-related synaptopathy', Epilepsia. https://doi.org/10.1111/epi.17876

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, Montserrat

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 V

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

PY - 2023/12/22

Y1 - 2023/12/22

N2 - OBJECTIVE: The postsynaptic density protein of excitatory neurons PSD-95 is encoded by 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 EEG and/or video-polygraphy and brain MRI were collected. Anti-seizure medication response was retrospectively assessed by the referring clinician.RESULTS: A large variety of seizure types was reported, though focal seizures were the most common. Encephalopathy related to status epilepticus during slow sleep (ESES)/developmental epileptic encephalopathy with spike-wave activation during sleep (DEE-SWAS) was diagnosed in more than 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 has DEE, and around 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 to be properly investigated with sleep EEG.

AB - OBJECTIVE: The postsynaptic density protein of excitatory neurons PSD-95 is encoded by 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 EEG and/or video-polygraphy and brain MRI were collected. Anti-seizure medication response was retrospectively assessed by the referring clinician.RESULTS: A large variety of seizure types was reported, though focal seizures were the most common. Encephalopathy related to status epilepticus during slow sleep (ESES)/developmental epileptic encephalopathy with spike-wave activation during sleep (DEE-SWAS) was diagnosed in more than 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 has DEE, and around 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 to be properly investigated with sleep EEG.

U2 - https://doi.org/10.1111/epi.17876

DO - https://doi.org/10.1111/epi.17876

M3 - Article

C2 - 38135915

SN - 0013-9580

JO - Epilepsia

JF - Epilepsia

ER -