[en] OBJECTIVES: Epilepsy with Eyelid Myoclonia (EEM) spectrum, is a generalized form of epilepsy characterized by eyelid myoclonia with or without absences, eye closure-induced seizures with EEG paroxysms, and photosensitivity. Based on the specific clinical features, age of onset and familial occurrence, a genetic cause has been postulated. Pathogenic variants in CHD2, SYNGAP1, NEXMIF and RORB and GABRA1 have been reported in individuals with photosensitivity and eyelid myoclonia, but whether other genes are also involved, or a single gene is uniquely linked with EEM, or its subtypes, is not yet known. We aimed to dissect the genetic aetiology of EEM.
METHODS: we studied a cohort of 105 individuals by using whole-exome sequencing. Individuals were divided into two groups: EEM- (isolated EEM) and EEM+ (EEM accompanied by intellectual disability, ID, or any other neurodevelopmental/psychiatric disorder) RESULTS: We identified nine variants classified as pathogenic/likely pathogenic in the entire cohort (8.57%); among these eight (five in CHD2, one in NEXMIF, one in SYNGAP1 and one in TRIM8) were found in the EEM+ sub-cohort (28.57%). Only one variant (IFIH1) was found in the EEM- sub-cohort (1.29%); however, since the phenotype of the proband did not fit with published data, additional evidence is needed before considering IFIH1 variants and EEM- an established association. Burden analysis did not identify any single burdened gene or gene set.
SIGNIFICANCE: Our results suggest that for EEM, as for many other epilepsies, the identification of a genetic cause is more likely with co-morbid ID and/or other neurodevelopmental disorders. Pathogenic variants were mostly found in CHD2 and the association of CHD2-EEM+ can now be considered a reasonable gene-disease association. We provide further evidence to strengthen the association of EEM+ with NEXMIF and SYNGAP1. Possible new associations between EEM+ and TRIM8, and EEM- and IFIH1, are also reported. While we provided robust evidence for gene variants associated with EEM+, the core genetic aetiology of EEM- remains to be elucidated.
Centre de recherche :
Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) ULHPC - University of Luxembourg: High Performance Computing
Disciplines :
Génétique & processus génétiques Neurologie
Auteur, co-auteur :
Coppola, Antonietta ; Department of Neuroscience, Reproductive and Odontostomatological Sciences, Federico II University, Naples, Italy
Krithika, S; Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, WC1N 3BG, London, UK ; The Chalfont Centre for Epilepsy, Chalfont-St-Peter, Bucks, UK ; School of Life Sciences, Anglia Ruskin University, Cambridge, UK
Iacomino, Michele; Unit of Medical Genetics, IRCCS IRCCS Istituto Giannina Gaslini, Genova, Italy
BOBBILI, Dheeraj Reddy ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Bioinformatics Core ; Bioinformatics Core, Luxembourg Centre for Systems Biomedicine (LCSB), Belvaux, Luxembourg
Balestrini, Simona ; Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, WC1N 3BG, London, UK ; The Chalfont Centre for Epilepsy, Chalfont-St-Peter, Bucks, UK ; Meyer Children Hospital, Neuroscience Department, Meyer Children's Hospital IRCSS- University of Florence, Italy
Bagnasco, Irene; Division of Child Neuropsychiatry, Martini Hospital, Torino, Italy
Bilo, Leonilda; Department of Neuroscience, Reproductive and Odontostomatological Sciences, Federico II University, Naples, Italy
Buti, Daniela; Pediatric Neurology Unit and Laboratories, Children's Hospital A. Meyer-University of Florence, Florence, Italy
Casellato, Susanna; Unit of Child Neuropsychiatry, University Hospital of Sassari, Sassari, Italy
Cuccurullo, Claudia ; Department of Neuroscience, Reproductive and Odontostomatological Sciences, Federico II University, Naples, Italy
Ferlazzo, Edoardo; Department of Medical and Surgical Sciences, Magna Graecia University of Catanzaro, Italy, Regional Epilepsy Centre, Great Metropolitan Hospital, Bianchi-Melacrino Morelli, Reggio Calabria, Italy
Leu, Costin; Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, WC1N 3BG, London, UK ; Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH ; Stanley Center of Psychiatric Research, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA
Giordano, Lucio; Unit of Child Neurology and Psychiatry, ASST Spedali Civili di Brescia, Italy
Gobbi, Giuseppe; Child Neurology Unit, IRCCS Istituto delle Scienze Neurologiche, Bologna, Italy
Hernandez-Hernandez, Laura; Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, WC1N 3BG, London, UK ; The Chalfont Centre for Epilepsy, Chalfont-St-Peter, Bucks, UK
Lench, Nick; MRC Nucleic Acid Therapy Accelerator, Research Complex at Harwell, Rutherford Appleton Laboratory,Harwell, OX11 0FA, UK
Martins, Helena; Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, WC1N 3BG, London, UK ; The Chalfont Centre for Epilepsy, Chalfont-St-Peter, Bucks, UK
Meletti, Stefano ; Department of Biomedical, Metabolic, and Neural Science, University of Modena and Reggio Emilia, Modena, Italy ; Neurology Unit, OCB Hospital, Azienda Ospedaliera Universitaria di Modena, Italy
Messana, Tullio; IRCCS Istituto delle Scienze Neurologiche di Bologna, UOC Neuropsichiatria Infantile, Bologna, Italy
Nigro, Vincenzo; Telethon Institute of Genetics and Medicine, Naples, Italy
Pinelli, Michele ; Telethon Institute of Genetics and Medicine, Naples, Italy
Pippucci, Tommaso; Computational Genomics Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Italy
Bellampalli, Ravishankara; Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, WC1N 3BG, London, UK ; The Chalfont Centre for Epilepsy, Chalfont-St-Peter, Bucks, UK
Salis, Barbara; Unit of Child Neuropsychiatry, ASST Fatebenefratelli Sacco -, Milano
Sofia, Vito; Department of Medical and Surgical Sciences and Advanced Technologies "G.F. Ingrassia", Section of Neurosciences, University of Catania, via Santa Sofia 78, Catania, Italy
Striano, Pasquale ; Pediatric Neurology and Muscular Diseases Unit, IRCCS Istituto Giannina Gaslini, member of ERN-Epicare, Genova, Italy ; Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), University of Genoa, Genoa, Italy
Striano, Salvatore; Department of Neuroscience, Reproductive and Odontostomatological Sciences, Federico II University, Naples, Italy
Tassi, Laura; "Claudio Munari" Epilepsy Surgery Center, Niguarda Hospital, Milan, Italy
Vignoli, Aglaia; Department of Health Sciences, Università degli Studi di Milano, Milan, Italy
Vaudano, Anna Elisabetta ; Department of Biomedical, Metabolic, and Neural Science, University of Modena and Reggio Emilia, Modena, Italy ; Neurology Unit, OCB Hospital, Azienda Ospedaliera Universitaria di Modena, Italy
Viri, Maurizio; Department of Child Neurology and Psychiatry, AOU Maggiore della Carità Novara, Novara, Italy
Scheffer, Ingrid E ; Department of Medicine, Austin Health, Epilepsy Research Centre, University of Melbourne, Heidelberg, Vic, Australia ; Florey Institute of Neuroscience and Mental Health, Heidelberg, Vic, Australia ; Murdoch Children's Research Institute and Department of Paediatrics, Royal Children's Hospital, University of Melbourne, Parkville, Vic, Australia
MAY, Patrick ; University of Luxembourg ; Bioinformatics Core, Luxembourg Centre for Systems Biomedicine (LCSB), Belvaux, Luxembourg
Zara, Federico; Unit of Medical Genetics, IRCCS IRCCS Istituto Giannina Gaslini, Genova, Italy ; Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), University of Genoa, Genoa, Italy
Sisodiya, Sanjay M ; Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, WC1N 3BG, London, UK ; The Chalfont Centre for Epilepsy, Chalfont-St-Peter, Bucks, UK
U-AGR-7124 - INTER/DFG/21/16394868/MechEPI2 (01/01/2022 - 31/12/2024) - MAY Patrick
Organisme subsidiant :
BMBF - Bundesministerium für Bildung und Forschung
N° du Fonds :
01GM2210B,; 01GM1907D
Subventionnement (détails) :
DRB and PM were supported by the the Fonds National de la Recherche Luxembourg (FNR) (Research Unit FOR-2715, FNR grant INTER/DFG/21/16394868 MechEPI2) and PM by the German Federal Ministry for Education and Research (Treat-ION, BMBF 01GM1907D, Treat-Ion2, 01GM2210B).
Jeavons PM. Nosological problems of myoclonic epilepsies in childhood and adolescents. Dev Med Child Neurol. 1977;19:3–8.
Specchio N, Wirrell EC, Scheffer IE, Nabbout R, Riney K, Samia P, et al. International league against epilepsy classification and definition of epilepsy syndromes with onset in childhood: position paper by the ILAE task force on nosology and definitions. Epilepsia. 2022;63:1398–1442.
Appleton RE, Panayiotopoulos CP, Acomb BA, Beirne M. Eyelid myoclonia with typical absences: an epilepsy syndrome. J Neurol Neurosurg Psychiatry. 1993;56:1312–1316.
Cerulli Irelli E, Cocchi E, Ramantani G, Caraballo RH, Giuliano L, Yilmaz T, et al. Electroclinical features and long-term seizure outcome in patients with eyelid Myoclonia with absences. Neurology. 2022;98:e1865–e1876.
Giuliano L, Fatuzzo D, Mainieri G, Maira G, Elia M, Ferlazzo E, et al. Eyelid myoclonia with absences: electroclinical features and prognostic factors. Epilepsia. 2019;60:1104–1113.
Smith KM, Wirrell EC, Andrade DM, Choi H, Trenité DKN, Jones H, et al. Clinical presentation and evaluation of epilepsy with eyelid myoclonia: results of an international expert consensus panel. Epilepsia. 2023;64:2330–2341.
Adachi M, Inoue T, Tsuneishi S, Takada S, Nakamura H. Eyelid myoclonia with absences in monozygotic twins. Pediatr Int. 2005;47:343–347.
Capovilla G, Striano P, Gambardella A, Beccaria F, Hirsch E, Casellato S, et al. Eyelid fluttering, typical EEG pattern, and impaired intellectual function: a homogeneous epileptic condition among the patients presenting with eyelid myoclonia. Epilepsia. 2009;50:1536–1541.
Sadleir LG, Vears D, Regan B, Redshaw N, Bleasel A, Scheffer IE. Family studies of individuals with eyelid myoclonia with absences. Epilepsia. 2012;53:2141–2148.
Kasteleijn-Nolst Trenite DG. Photosensitivity in epilepsy. Electrophysiological and clinical correlates. Acta Neurol Scand Suppl. 1989;125:3–149.
Tauer U, Lorenz S, Lenzen KP, Heils A, Muhle H, Gresch M, et al. Genetic dissection of photosensitivity and its relation to idiopathic generalized epilepsy. Ann Neurol. 2005;57:866–873.
pi4K Consortium, Epilepsy Phenome/Genome Project, Allen AS, Berkovic SF, Cossette P, Delanty N, et al. De novo mutations in epileptic encephalopathies. Nature. 2013;501:217–221.
Suls A, Jaehn JA, Kecskes A, Weber Y, Weckhuysen S, Craiu DC, et al. De novo loss-of-function mutations in CHD2 cause a fever-sensitive myoclonic epileptic encephalopathy sharing features with Dravet syndrome. Am J Hum Genet. 2013;93:967–975.
Thomas RH, Zhang LM, Carvill GL, Archer JS, Heavin SB, Mandelstam SA, et al. CHD2 myoclonic encephalopathy is frequently associated with self-induced seizures. Neurology. 2015;84:951–958.
Courage C, Houge G, Gallati S, Schjelderup J, Rieubland C. 15q26.1 microdeletion encompassing only CHD2 and RGMA in two adults with moderate intellectual disability, epilepsy and truncal obesity. Eur J Med Genet. 2014;57:520–523.
Galizia EC, Myers CT, Leu C, de Kovel CGF, Afrikanova T, Cordero-Maldonado ML, et al. CHD2 variants are a risk factor for photosensitivity in epilepsy. Brain. 2015;138:1198–1207.
Mignot C, von Stulpnagel C, Nava C, Ville D, Sanlaville D, Lesca G, et al. Genetic and neurodevelopmental spectrum of SYNGAP1-associated intellectual disability and epilepsy. J Med Genet. 2016;53:511–522.
Vlaskamp DRM, Shaw BJ, Burgess R, Mei D, Montomoli M, Xie H, et al. SYNGAP1 encephalopathy: a distinctive generalized developmental and epileptic encephalopathy. Neurology. 2019;92:e96–e107.
Stamberger H, Hammer TB, Gardella E, Vlaskamp DRM, Bertelsen B, Mandelstam S, et al. NEXMIF encephalopathy: an X-linked disorder with male and female phenotypic patterns. Genet Med. 2021;23:363–373.
Rudolf G, Lesca G, Mehrjouy MM, Labalme A, Salmi M, Bache I, et al. Loss of function of the retinoid-related nuclear receptor (RORB) gene and epilepsy. Eur J Hum Genet. 2016;24:1761–1770.
Johannesen K, Marini C, Pfeffer S, Møller RS, Dorn T, Niturad CE, et al. Phenotypic spectrum of GABRA1: from generalized epilepsies to severe epileptic encephalopathies. Neurology. 2016;87:1140–1151.
Ramu A, Noordam MJ, Schwartz RS, Wuster A, Hurles ME, Cartwright RA, et al. DeNovoGear: de novo indel and point mutation discovery and phasing. Nat Methods. 2013;10:985–987.
Wang K, Li M, Hakonarson H. ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res. 2010;38:e164.
Investigators GPP, Smedley D, Smith KR, et al. 100,000 genomes pilot on rare-disease diagnosis in health care—preliminary report. N Engl J Med. 2021;385:1868–1880.
Martin AR, Williams E, Foulger RE, Leigh S, Daugherty LC, Niblock O, et al. PanelApp crowdsources expert knowledge to establish consensus diagnostic gene panels. Nat Genet. 2019;51:1560–1565.
Robinson JT, Thorvaldsdottir H, Wenger AM, Zehir A, Mesirov JP. Variant review with the integrative genomics viewer. Cancer Res. 2017;77:e31–e34.
Richards S, Aziz N, Bale S, Bick D, das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–424.
Samanta D, Willis E. KIAA2022-related disorders can cause Jeavons (eyelid myoclonia with absence) syndrome. Acta Neurol Belg. 2020;120:205–207.
Kircher M, Witten DM, Jain P, O'Roak BJ, Cooper GM, Shendure J. A general framework for estimating the relative pathogenicity of human genetic variants. Nat Genet. 2014;46:310–315.
McKenna A, Hanna M, Banks E, Sivachenko A, Cibulskis K, Kernytsky A, et al. The Genome analysis toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res. 2010;20:1297–1303.
Koko M, Motelow JE, Stanley KE, Bobbili DR, Dhindsa RS, May P, et al. Association of ultra-rare coding variants with genetic generalized epilepsy: a case-control whole exome sequencing study. Epilepsia. 2022;63:723–735.
Cioclu MC, Coppola A, Tondelli M, Vaudano AE, Giovannini G, Krithika S, et al. Cortical and subcortical network dysfunction in a female patient with NEXMIF encephalopathy. Front Neurol. 2021;12:722664.
Assoum M, Lines MA, Elpeleg O, Darmency V, Whiting S, Edvardson S, et al. Further delineation of the clinical spectrum of de novo TRIM8 truncating mutations. Am J Med Genet A. 2018;176:2470–2478.
Tian Z, Tang J, Liao X, et al. TRIM8 inhibits breast cancer proliferation by regulating estrogen signaling. Am J Cancer Res. 2020;10:3440–3457.
Lund C, Brodtkorb E, Oye AM, Rosby O, Selmer KK. CHD2 mutations in Lennox-Gastaut syndrome. Epilepsy Behav. 2014;33:18–21.
Benson KA, White M, Allen NM, Byrne S, Carton R, Comerford E, et al. A comparison of genomic diagnostics in adults and children with epilepsy and comorbid intellectual disability. Eur J Hum Genet. 2020;28:1066–1077.
Scala M, Bianchi A, Bisulli F, Coppola A, Elia M, Trivisano M, et al. Advances in genetic testing and optimization of clinical management in children and adults with epilepsy. Expert Rev Neurother. 2020;20:251–269.
Chen WL, Mefford HC. Diagnostic considerations in the epilepsies-testing strategies, test type advantages, and limitations. Neurotherapeutics. 2021;18:1468–1477.
Bernardo P, Galletta D, Iasevoli F, D'Ambrosio L, Troisi S, Gennaro E, et al. CHD2 mutations: only epilepsy? Description of cognitive and behavioral profile in a case with a new mutation. Seizure. 2017;51:186–189.
Weng PL, Majmundar AJ, Khan K, Lim TY, Shril S, Jin G, et al. De novo TRIM8 variants impair its protein localization to nuclear bodies and cause developmental delay, epilepsy, and focal segmental glomerulosclerosis. Am J Hum Genet. 2021;108:357–367.
Sakai Y, Fukai R, Matsushita Y, Miyake N, Saitsu H, Akamine S, et al. De novo truncating mutation of TRIM8 causes early-onset epileptic encephalopathy. Ann Hum Genet. 2016;80:235–240.
Al Mutairi F, Alfadhel M, Nashabat M, et al. Phenotypic and molecular Spectrum of Aicardi-Goutieres syndrome: a study of 24 patients. Pediatr Neurol. 2018;78:35–40.
