Electroclinical features of MEF2C haploinsufficiency-related epilepsy: A multicenter European study

Federico Raviglione; Sofia Douzgou; Marcello Scala; Alessia Mingarelli; Stefano D'Arrigo; Elena Freri; Francesca Darra; Sabrina Giglio; Maria C Bonaglia; Chiara Pantaleoni; Massimo Mastrangelo; Roberta Epifanio; Maurizio Elia; Veronica Saletti; Silvia Morlino; Maria Stella Vari; Paola De Liso; Julija Pavaine; Luigina Spaccini; Elisa Cattaneo; Elena Gardella; Rikke S Møller; Francesca Marchese; Clara Colonna; Claudia Gandioli; Giuseppe Gobbi; Dipak Ram; Orazio Palumbo; Massimo Carella; Michele Germano; Davide Tonduti; Diego De Angelis; Davide Caputo; Patrizia Bergonzini; Francesca Novara; Orsetta Zuffardi; Alberto Verrotti; Alessandro Orsini; Alice Bonuccelli; Maria Carmela De Muto; Marina Trivisano; Federico Vigevano; Tiziana Granata; Bernardo Dalla Bernardina; Antonia Tranchina; Pasquale Striano

doi:10.1016/j.seizure.2021.03.025

Electroclinical features of MEF2C haploinsufficiency-related epilepsy: A multicenter European study

Federico Raviglione^*, Sofia Douzgou, Marcello Scala, Alessia Mingarelli, Stefano D'Arrigo, Elena Freri, Francesca Darra, Sabrina Giglio, Maria C Bonaglia, Chiara Pantaleoni, Massimo Mastrangelo, Roberta Epifanio, Maurizio Elia, Veronica Saletti, Silvia Morlino, Maria Stella Vari, Paola De Liso, Julija Pavaine, Luigina Spaccini, Elisa CattaneoElena Gardella, Rikke S Møller, Francesca Marchese, Clara Colonna, Claudia Gandioli, Giuseppe Gobbi, Dipak Ram, Orazio Palumbo, Massimo Carella, Michele Germano, Davide Tonduti, Diego De Angelis, Davide Caputo, Patrizia Bergonzini, Francesca Novara, Orsetta Zuffardi, Alberto Verrotti, Alessandro Orsini, Alice Bonuccelli, Maria Carmela De Muto, Marina Trivisano, Federico Vigevano, Tiziana Granata, Bernardo Dalla Bernardina, Antonia Tranchina, Pasquale Striano

^*Corresponding author af dette arbejde

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Publikation: Bidrag til tidsskrift › Artikel › Forskning › peer review

Abstract

PURPOSE: Epilepsy is a main manifestation in the autosomal dominant mental retardation syndrome caused by heterozygous variants in MEF2C. We aimed to delineate the electro-clinical features and refine the genotype-phenotype correlations in patients with MEF2C haploinsufficiency.

METHODS: We thoroughly investigated 25 patients with genetically confirmed MEF2C-syndrome across 12 different European Genetics and Epilepsy Centers, focusing on the epileptic phenotype. Clinical features (seizure types, onset, evolution, and response to therapy), EEG recordings during waking/sleep, and neuroimaging findings were analyzed. We also performed a detailed literature review using the terms "MEF2C", "seizures", and "epilepsy".

RESULTS: Epilepsy was diagnosed in 19 out of 25 (~80%) subjects, with age at onset <30 months. Ten individuals (40%) presented with febrile seizures and myoclonic seizures occurred in ~50% of patients. Epileptiform abnormalities were observed in 20/25 patients (80%) and hypoplasia/partial agenesis of the corpus callosum was detected in 12/25 patients (~50%). Nine patients harbored a 5q14.3 deletion encompassing MEF2C and at least one other gene. In 7 out of 10 patients with myoclonic seizures, MIR9-2 and LINC00461 were also deleted, whereas ADGRV1 was involved in 3/4 patients with spasms.

CONCLUSION: The epileptic phenotype of MEF2C-syndrome is variable. Febrile and myoclonic seizures are the most frequent, usually associated with a slowing of the background activity and irregular diffuse discharges of frontally dominant, symmetric or asymmetric, slow theta waves with interposed spike-and-waves complexes. The haploinsufficiency of ADGRV1, MIR9-2, and LINC00461 likely contributes to myoclonic seizures and spasms in patients with MEF2C syndrome.

Originalsprog	Engelsk
Sider (fra-til)	60-72
Antal sider	13
Tidsskrift	Seizure
Vol/bind	88
Tidlig onlinedato	30 mar. 2021
DOI	https://doi.org/10.1016/j.seizure.2021.03.025
Status	Udgivet - maj 2021

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Adgang til dokumentet

10.1016/j.seizure.2021.03.025

Citationsformater

Raviglione, F., Douzgou, S., Scala, M., Mingarelli, A., D'Arrigo, S., Freri, E., Darra, F., Giglio, S., Bonaglia, M. C., Pantaleoni, C., Mastrangelo, M., Epifanio, R., Elia, M., Saletti, V., Morlino, S., Vari, M. S., De Liso, P., Pavaine, J., Spaccini, L., ... Striano, P. (2021). Electroclinical features of MEF2C haploinsufficiency-related epilepsy: A multicenter European study. Seizure, 88, 60-72. https://doi.org/10.1016/j.seizure.2021.03.025

@article{0e91be58102d41d4aadfaaa3e93af99e,

title = "Electroclinical features of MEF2C haploinsufficiency-related epilepsy: A multicenter European study",

abstract = "PURPOSE: Epilepsy is a main manifestation in the autosomal dominant mental retardation syndrome caused by heterozygous variants in MEF2C. We aimed to delineate the electro-clinical features and refine the genotype-phenotype correlations in patients with MEF2C haploinsufficiency.METHODS: We thoroughly investigated 25 patients with genetically confirmed MEF2C-syndrome across 12 different European Genetics and Epilepsy Centers, focusing on the epileptic phenotype. Clinical features (seizure types, onset, evolution, and response to therapy), EEG recordings during waking/sleep, and neuroimaging findings were analyzed. We also performed a detailed literature review using the terms {"}MEF2C{"}, {"}seizures{"}, and {"}epilepsy{"}.RESULTS: Epilepsy was diagnosed in 19 out of 25 (~80%) subjects, with age at onset <30 months. Ten individuals (40%) presented with febrile seizures and myoclonic seizures occurred in ~50% of patients. Epileptiform abnormalities were observed in 20/25 patients (80%) and hypoplasia/partial agenesis of the corpus callosum was detected in 12/25 patients (~50%). Nine patients harbored a 5q14.3 deletion encompassing MEF2C and at least one other gene. In 7 out of 10 patients with myoclonic seizures, MIR9-2 and LINC00461 were also deleted, whereas ADGRV1 was involved in 3/4 patients with spasms.CONCLUSION: The epileptic phenotype of MEF2C-syndrome is variable. Febrile and myoclonic seizures are the most frequent, usually associated with a slowing of the background activity and irregular diffuse discharges of frontally dominant, symmetric or asymmetric, slow theta waves with interposed spike-and-waves complexes. The haploinsufficiency of ADGRV1, MIR9-2, and LINC00461 likely contributes to myoclonic seizures and spasms in patients with MEF2C syndrome.",

author = "Federico Raviglione and Sofia Douzgou and Marcello Scala and Alessia Mingarelli and Stefano D'Arrigo and Elena Freri and Francesca Darra and Sabrina Giglio and Bonaglia, {Maria C} and Chiara Pantaleoni and Massimo Mastrangelo and Roberta Epifanio and Maurizio Elia and Veronica Saletti and Silvia Morlino and Vari, {Maria Stella} and {De Liso}, Paola and Julija Pavaine and Luigina Spaccini and Elisa Cattaneo and Elena Gardella and M{\o}ller, {Rikke S} and Francesca Marchese and Clara Colonna and Claudia Gandioli and Giuseppe Gobbi and Dipak Ram and Orazio Palumbo and Massimo Carella and Michele Germano and Davide Tonduti and {De Angelis}, Diego and Davide Caputo and Patrizia Bergonzini and Francesca Novara and Orsetta Zuffardi and Alberto Verrotti and Alessandro Orsini and Alice Bonuccelli and {De Muto}, {Maria Carmela} and Marina Trivisano and Federico Vigevano and Tiziana Granata and Bernardina, {Bernardo Dalla} and Antonia Tranchina and Pasquale Striano",

note = "Copyright {\textcopyright} 2021. Published by Elsevier Ltd.",

year = "2021",

month = may,

doi = "10.1016/j.seizure.2021.03.025",

language = "English",

volume = "88",

pages = "60--72",

journal = "Seizure",

issn = "1059-1311",

publisher = "W.B. Saunders Ltd",

}

Raviglione, F, Douzgou, S, Scala, M, Mingarelli, A, D'Arrigo, S, Freri, E, Darra, F, Giglio, S, Bonaglia, MC, Pantaleoni, C, Mastrangelo, M, Epifanio, R, Elia, M, Saletti, V, Morlino, S, Vari, MS, De Liso, P, Pavaine, J, Spaccini, L, Cattaneo, E, Gardella, E , Møller, RS, Marchese, F, Colonna, C, Gandioli, C, Gobbi, G, Ram, D, Palumbo, O, Carella, M, Germano, M, Tonduti, D, De Angelis, D, Caputo, D, Bergonzini, P, Novara, F, Zuffardi, O, Verrotti, A, Orsini, A, Bonuccelli, A, De Muto, MC, Trivisano, M, Vigevano, F, Granata, T, Bernardina, BD, Tranchina, A & Striano, P 2021, 'Electroclinical features of MEF2C haploinsufficiency-related epilepsy: A multicenter European study', Seizure, bind 88, s. 60-72. https://doi.org/10.1016/j.seizure.2021.03.025

TY - JOUR

T1 - Electroclinical features of MEF2C haploinsufficiency-related epilepsy

T2 - A multicenter European study

AU - Raviglione, Federico

AU - Douzgou, Sofia

AU - Scala, Marcello

AU - Mingarelli, Alessia

AU - D'Arrigo, Stefano

AU - Freri, Elena

AU - Darra, Francesca

AU - Giglio, Sabrina

AU - Bonaglia, Maria C

AU - Pantaleoni, Chiara

AU - Mastrangelo, Massimo

AU - Epifanio, Roberta

AU - Elia, Maurizio

AU - Saletti, Veronica

AU - Morlino, Silvia

AU - Vari, Maria Stella

AU - De Liso, Paola

AU - Pavaine, Julija

AU - Spaccini, Luigina

AU - Cattaneo, Elisa

AU - Gardella, Elena

AU - Møller, Rikke S

AU - Marchese, Francesca

AU - Colonna, Clara

AU - Gandioli, Claudia

AU - Gobbi, Giuseppe

AU - Ram, Dipak

AU - Palumbo, Orazio

AU - Carella, Massimo

AU - Germano, Michele

AU - Tonduti, Davide

AU - De Angelis, Diego

AU - Caputo, Davide

AU - Bergonzini, Patrizia

AU - Novara, Francesca

AU - Zuffardi, Orsetta

AU - Verrotti, Alberto

AU - Orsini, Alessandro

AU - Bonuccelli, Alice

AU - De Muto, Maria Carmela

AU - Trivisano, Marina

AU - Vigevano, Federico

AU - Granata, Tiziana

AU - Bernardina, Bernardo Dalla

AU - Tranchina, Antonia

AU - Striano, Pasquale

PY - 2021/5

Y1 - 2021/5

N2 - PURPOSE: Epilepsy is a main manifestation in the autosomal dominant mental retardation syndrome caused by heterozygous variants in MEF2C. We aimed to delineate the electro-clinical features and refine the genotype-phenotype correlations in patients with MEF2C haploinsufficiency.METHODS: We thoroughly investigated 25 patients with genetically confirmed MEF2C-syndrome across 12 different European Genetics and Epilepsy Centers, focusing on the epileptic phenotype. Clinical features (seizure types, onset, evolution, and response to therapy), EEG recordings during waking/sleep, and neuroimaging findings were analyzed. We also performed a detailed literature review using the terms "MEF2C", "seizures", and "epilepsy".RESULTS: Epilepsy was diagnosed in 19 out of 25 (~80%) subjects, with age at onset <30 months. Ten individuals (40%) presented with febrile seizures and myoclonic seizures occurred in ~50% of patients. Epileptiform abnormalities were observed in 20/25 patients (80%) and hypoplasia/partial agenesis of the corpus callosum was detected in 12/25 patients (~50%). Nine patients harbored a 5q14.3 deletion encompassing MEF2C and at least one other gene. In 7 out of 10 patients with myoclonic seizures, MIR9-2 and LINC00461 were also deleted, whereas ADGRV1 was involved in 3/4 patients with spasms.CONCLUSION: The epileptic phenotype of MEF2C-syndrome is variable. Febrile and myoclonic seizures are the most frequent, usually associated with a slowing of the background activity and irregular diffuse discharges of frontally dominant, symmetric or asymmetric, slow theta waves with interposed spike-and-waves complexes. The haploinsufficiency of ADGRV1, MIR9-2, and LINC00461 likely contributes to myoclonic seizures and spasms in patients with MEF2C syndrome.

AB - PURPOSE: Epilepsy is a main manifestation in the autosomal dominant mental retardation syndrome caused by heterozygous variants in MEF2C. We aimed to delineate the electro-clinical features and refine the genotype-phenotype correlations in patients with MEF2C haploinsufficiency.METHODS: We thoroughly investigated 25 patients with genetically confirmed MEF2C-syndrome across 12 different European Genetics and Epilepsy Centers, focusing on the epileptic phenotype. Clinical features (seizure types, onset, evolution, and response to therapy), EEG recordings during waking/sleep, and neuroimaging findings were analyzed. We also performed a detailed literature review using the terms "MEF2C", "seizures", and "epilepsy".RESULTS: Epilepsy was diagnosed in 19 out of 25 (~80%) subjects, with age at onset <30 months. Ten individuals (40%) presented with febrile seizures and myoclonic seizures occurred in ~50% of patients. Epileptiform abnormalities were observed in 20/25 patients (80%) and hypoplasia/partial agenesis of the corpus callosum was detected in 12/25 patients (~50%). Nine patients harbored a 5q14.3 deletion encompassing MEF2C and at least one other gene. In 7 out of 10 patients with myoclonic seizures, MIR9-2 and LINC00461 were also deleted, whereas ADGRV1 was involved in 3/4 patients with spasms.CONCLUSION: The epileptic phenotype of MEF2C-syndrome is variable. Febrile and myoclonic seizures are the most frequent, usually associated with a slowing of the background activity and irregular diffuse discharges of frontally dominant, symmetric or asymmetric, slow theta waves with interposed spike-and-waves complexes. The haploinsufficiency of ADGRV1, MIR9-2, and LINC00461 likely contributes to myoclonic seizures and spasms in patients with MEF2C syndrome.

U2 - 10.1016/j.seizure.2021.03.025

DO - 10.1016/j.seizure.2021.03.025

M3 - Article

C2 - 33831796

SN - 1059-1311

VL - 88

SP - 60

EP - 72

JO - Seizure

JF - Seizure

ER -

Electroclinical features of MEF2C haploinsufficiency-related epilepsy: A multicenter European study

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