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

F Raviglione, S Douzgou, M Scala, A Mingarelli, S D'Arrigo, E Freri, F Darra, S Giglio, MC Bonaglia, C Pantaleoni, M Mastrangelo, R Epifanio, M Elia, V Saletti, S Morlino, MS Vari, P De Liso, J Pavaine, L Spaccini, E CattaneoE Gardella, RS Moller, F Marchese, C Colonna, C Gandioli, G Gobbi, D Ram, O Palumbo, M Carella, M Germano, D Tonduti, D De Angelis, D Caputo, P Bergonzini, F Novara, O Zuffardi, A Verrotti, A Orsini, A Bonuccelli, MC De Muto, M Trivisano, F Vigevano, T Granata, B Dalla Bernardina, A Tranchina, P Striano

Research output: Contribution to journalArticlepeer-review


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.

Original languageItalian
Pages (from-to)60-72
Number of pages13
Publication statusPublished - 2021

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