{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T00:45:40Z","timestamp":1789865140631,"version":"4.0.1"},"reference-count":49,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2025,12,30]],"date-time":"2025-12-30T00:00:00Z","timestamp":1767052800000},"content-version":"vor","delay-in-days":1,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003196","name":"Italian Ministry of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100021856","name":"Ministry of University and Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100021856","id-type":"DOI","asserted-by":"publisher"}]},{"name":"National Recovery and Resilience Plan"},{"name":"Investment 1.5 Ecosystems of Innovation, Project Tuscany Health Ecosystem"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,1,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Epilepsy with myoclonic-atonic seizures, formerly myoclonic-astatic epilepsy or Doose syndrome, accounts for 1\u20132.2% of childhood-onset epilepsies. We investigated genetic determinants, long-term clinical outcomes and prognostic indicators in a large cohort using homogeneous inclusion criteria. We studied 60 patients (26.7% female), mean age 14.5 years (\u00b19.1, range 3.2\u201341), followed between 1986 and 2024 at two paediatric neurology centres. Average follow-up was 11.7 years. Inclusion criteria were seizure onset between 6 months and 8 years, generalized 2\u20136\u2005Hz spike-wave discharges and video-EEG documented myoclonic-atonic, myoclonic seizures or both. We analysed clinical, EEG, neuroimaging, neuropsychological and genetic data obtained with next-generation sequencing. We used \u03c7\u00b2 test, t-test, Log-rank test, Cox regression, population-averaged logistic models and Benjamini\u2013Yekutieli procedure to identify predictors of seizure outcome, intellectual disability and other neurodevelopmental comorbidities. We observed myoclonic-atonic seizures in 55\/60 (91.7%), tonic-vibratory seizures in 44\/60 (73.4%), absence seizures in 30\/60 (50%), myoclonic seizures without post-myoclonic atonia in 25\/60 (42%) and non-convulsive status epilepticus in 13\/60 (21.7%). A \u2018stormy\u2019 onset occurred in 26\/60 patients (43.3%). The most effective drugs were valproate, ethosuximide, benzodiazepines and phenobarbital, used in different combinations, whereas the newer drugs offered no benefit. Long-term outcomes were variable. Thirty-seven patients (61.7%) achieved seizure freedom after 5.1 years on average. We observed drug resistance in 23\/60 patients (38.3%) and intellectual disability in 35\/60 (58.3%). One adult patient died (mortality rate 1.80\/1000-person-years). Attention deficit hyperactivity disorder was the most common comorbidity (24\/60, 40%). \u2018Stormy\u2019 onset did not predict a worse prognosis. Global developmental delay at epilepsy onset was associated with drug resistance (P = 0.004, Q = 0.064) and with intellectual disability (P = 0.003, Q = 0.048). We found pathogenic variants in 15\/39 (38.5%) patients undergoing next-generation sequencing, including four genes novel for this syndrome (KMT2E; POGZ; SHANK3; YWHAG), with exome sequencing yielding higher diagnostic rates than gene panels. Epilepsy with myoclonic-atonic seizures is a complex syndrome with diverse genetic causes and variable seizure severity and outcomes. Our findings expand its genetic landscape and highlight the prognostic value of prompt overall neurodevelopmental assessment at clinical onset. Whole exome sequencing should be prioritized for early diagnosis and counselling.<\/jats:p>","DOI":"10.1093\/braincomms\/fcaf507","type":"journal-article","created":{"date-parts":[[2025,12,25]],"date-time":"2025-12-25T12:52:28Z","timestamp":1766667148000},"source":"Crossref","is-referenced-by-count":1,"title":["Epilepsy with myoclonic-atonic seizures: genetic aetiologies, outcomes and prognostic indicators"],"prefix":"10.1093","volume":"8","author":[{"given":"Simona","family":"Pellacani","sequence":"first","affiliation":[{"name":"Neuroscience and Human Genetics Department, Meyer Children's Hospital IRCCS , Florence 50139 ,","place":["Italy"]},{"name":"Neuroscience, Pharmacology and Child Health Department, University of Florence , Florence 50139 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5639-1969","authenticated-orcid":false,"given":"Simona","family":"Balestrini","sequence":"additional","affiliation":[{"name":"Neuroscience and Human Genetics Department, Meyer Children's Hospital IRCCS , Florence 50139 ,","place":["Italy"]},{"name":"Neuroscience, Pharmacology and Child Health Department, University of Florence , Florence 50139 ,","place":["Italy"]},{"name":"Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology , WC1N 3BG London ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edoardo","family":"Fino","sequence":"additional","affiliation":[{"name":"Neuroscience and Human Genetics Department, Meyer Children's Hospital IRCCS , Florence 50139 ,","place":["Italy"]},{"name":"Neuroscience, Pharmacology and Child Health Department, University of Florence , Florence 50139 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5445-5842","authenticated-orcid":false,"given":"Carmen","family":"Barba","sequence":"additional","affiliation":[{"name":"Neuroscience and Human Genetics Department, Meyer Children's Hospital IRCCS , Florence 50139 ,","place":["Italy"]},{"name":"Neuroscience, Pharmacology and Child Health Department, University of Florence , Florence 50139 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mara","family":"Cavallin","sequence":"additional","affiliation":[{"name":"Neuroscience and Human Genetics Department, Meyer Children's Hospital IRCCS , Florence 50139 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiziana","family":"Pisano","sequence":"additional","affiliation":[{"name":"Neuroscience and Human Genetics Department, Meyer Children's Hospital IRCCS , Florence 50139 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Parrini","sequence":"additional","affiliation":[{"name":"Neuroscience and Human Genetics Department, Meyer Children's Hospital IRCCS , Florence 50139 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna Rita","family":"Ferrari","sequence":"additional","affiliation":[{"name":"Department of Developmental Neuroscience, IRCCS Stella Maris Foundation , Pisa 56128 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Marzi","sequence":"additional","affiliation":[{"name":"Department of Statistics, Computer Science, Applications, University of Florence , Florence 50139 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Grisotto","sequence":"additional","affiliation":[{"name":"Department of Environmental and Prevention Sciences, University of Ferrara , Ferrara 44122 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7272-7079","authenticated-orcid":false,"given":"Renzo","family":"Guerrini","sequence":"additional","affiliation":[{"name":"Neuroscience and Human Genetics Department, Meyer Children's Hospital IRCCS , Florence 50139 ,","place":["Italy"]},{"name":"Neuroscience, Pharmacology and Child Health Department, University of Florence , Florence 50139 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,12,29]]},"reference":[{"issue":"suppl.1","key":"2026011205562016200_fcaf507-B1","first-page":"S163","article-title":"Myoclonic-astatic epilepsy","volume":"6","author":"Doose","year":"1992","journal-title":"Epilepsy Res"},{"issue":"1","key":"2026011205562016200_fcaf507-B2","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1111\/epi.16752","article-title":"Epilepsy with myoclonic-atonic seizures (Doose syndrome): Clarification of diagnosis and treatment options through a large retrospective multicenter cohort","volume":"62","author":"Nickels","year":"2021","journal-title":"Epilepsia"},{"key":"2026011205562016200_fcaf507-B3","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1055\/s-0028-1091841","article-title":"Centrencephalic myoclonic-astatic petit ma. Clinical and genetic investigation","volume":"2","author":"Doose","year":"1970","journal-title":"Neuropadiatrie"},{"key":"2026011205562016200_fcaf507-B4","first-page":"173","volume-title":"Epileptic syndromes of infancy, childhood and adolescence","author":"Guerrini","year":"2019","edition":"6th ed"},{"issue":"4","key":"2026011205562016200_fcaf507-B5","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1111\/j.1528-1167.2010.02522.x","article-title":"Revised terminology and concepts for organization of seizures and epilepsies: Report of the ILAE Commission on Classification and Terminology, 2005\u20132009","volume":"51","author":"Berg","year":"2010","journal-title":"Epilepsia"},{"issue":"5","key":"2026011205562016200_fcaf507-B6","doi-asserted-by":"crossref","first-page":"995","DOI":"10.1111\/epi.16508","article-title":"Phenotypic and genetic spectrum of epilepsy with myoclonic atonic seizures","volume":"61","author":"Tang","year":"2020","journal-title":"Epilepsia"},{"issue":"6","key":"2026011205562016200_fcaf507-B7","doi-asserted-by":"crossref","first-page":"1398","DOI":"10.1111\/epi.17241","article-title":"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","volume":"63","author":"Specchio","year":"2022","journal-title":"Epilepsia"},{"issue":"1","key":"2026011205562016200_fcaf507-B8","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/S0920-1211(99)00021-2","article-title":"Delineation of cryptogenic Lennox-Gastaut syndrome and myoclonic astatic epilepsy using multiple correspondence analysis","volume":"36","author":"Kaminska","year":"1999","journal-title":"Epilepsy Res"},{"key":"2026011205562016200_fcaf507-B9","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.ejpn.2021.11.009","article-title":"Epilepsy with myoclonic-atonic seizures, also known as Doose syndrome: Modification of the diagnostic criteria","volume":"36","author":"Oguni","year":"2022","journal-title":"Eur J Paediatr Neurol"},{"key":"2026011205562016200_fcaf507-B10","doi-asserted-by":"crossref","first-page":"106482","DOI":"10.1016\/j.yebeh.2019.106482","article-title":"Usefulness of preschool and school versions of the Behavioral Rating Inventory of Executive Functions in the evaluation of the daily life executive function in myoclonic-atonic epilepsy","volume":"99","author":"Breuillard","year":"2019","journal-title":"Epilepsy Behav"},{"issue":"4","key":"2026011205562016200_fcaf507-B11","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1016\/S1474-4422(25)00032-8","article-title":"Epilepsy with myoclonic-atonic seizures: An update on genetic causes, nosological limits, and treatment strategies","volume":"24","author":"Guerrini","year":"2025","journal-title":"Lancet Neurol"},{"issue":"6","key":"2026011205562016200_fcaf507-B12","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1046\/j.1528-1157.2002.30301.x","article-title":"Different neurophysiologic patterns of myoclonus characterize Lennox-Gastaut syndrome and myoclonic astatic epilepsy","volume":"43","author":"Bonanni","year":"2002","journal-title":"Epilepsia"},{"issue":"1","key":"2026011205562016200_fcaf507-B13","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/S1388-2457(03)00327-4","article-title":"Electrophysiological characterization of spontaneous and carbamazepine-induced epileptic negative myoclonus in benign childhood epilepsy with centro-temporal spikes","volume":"115","author":"Parmeggiani","year":"2004","journal-title":"Clin Neurophysiol"},{"key":"2026011205562016200_fcaf507-B14","first-page":"23","article-title":"Pathophysiology of myoclonic epilepsies","volume":"95","author":"Guerrini","year":"2005","journal-title":"Adv Neurol"},{"key":"2026011205562016200_fcaf507-B15","volume-title":"Motor assessment of the developing infant","author":"Piper","year":"1994"},{"key":"2026011205562016200_fcaf507-B16","volume-title":"Macarthur communicative development inventories: User's guide and technical manual","author":"Fenson","year":"2002"},{"issue":"6","key":"2026011205562016200_fcaf507-B17","doi-asserted-by":"crossref","first-page":"1069","DOI":"10.1111\/j.1528-1167.2009.02397.x","article-title":"Definition of drug resistant epilepsy: Consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies","volume":"51","author":"Kwan","year":"2010","journal-title":"Epilepsia"},{"issue":"2","key":"2026011205562016200_fcaf507-B18","doi-asserted-by":"crossref","first-page":"379","DOI":"10.2307\/1126464","article-title":"Comparisons of mental and motor test scores for ages 1\u201315 months by sex, birth order, race, geographical location, and education of parents","volume":"36","author":"Bayley","year":"1965","journal-title":"Child Dev"},{"key":"2026011205562016200_fcaf507-B19","volume-title":"Bayley scales of infant development","author":"Bayley","year":"1993","edition":"2nd ed."},{"key":"2026011205562016200_fcaf507-B20","volume-title":"Bayley scales of infant and toddler development","author":"Bayley","year":"2006","edition":"3rd ed"},{"key":"2026011205562016200_fcaf507-B21","volume-title":"Columbia mental maturity scale","author":"Burgemeister","year":"1971"},{"key":"2026011205562016200_fcaf507-B22","volume-title":"Developmental profile 3","author":"Alpern","year":"2009","edition":"3rd ed."},{"key":"2026011205562016200_fcaf507-B23","volume-title":"The abilities of young children","author":"Griffiths","year":"1970"},{"key":"2026011205562016200_fcaf507-B24","volume-title":"Leiter international performance scale","author":"Leiter","year":"1940"},{"key":"2026011205562016200_fcaf507-B25","volume-title":"Leiter international performance scale-revised (Leiter-R)","author":"Roid","year":"1997"},{"key":"2026011205562016200_fcaf507-B26","volume-title":"Leiter international performance scale","author":"Roid","year":"2013","edition":"3rd ed"},{"key":"2026011205562016200_fcaf507-B27","volume-title":"Assessment in infancy: Ordinal scales of psychological development","author":"Uzgiris","year":"1975"},{"key":"2026011205562016200_fcaf507-B28","volume-title":"Vineland adaptive behavior scales","author":"Sparrow","year":"1984"},{"key":"2026011205562016200_fcaf507-B29","volume-title":"Vineland adaptive behavior scales","author":"Sparrow","year":"2005","edition":"2nd ed"},{"key":"2026011205562016200_fcaf507-B30","volume-title":"Vineland adaptive behavior scales","author":"Sparrow","year":"2016","edition":"3rd ed"},{"key":"2026011205562016200_fcaf507-B31","volume-title":"Wechsler intelligence scale for children-revised","author":"Wechsler","year":"1974"},{"key":"2026011205562016200_fcaf507-B32","volume-title":"The Wechsler intelligence scale for children","author":"Wechsler","year":"1991","edition":"3rd ed"},{"key":"2026011205562016200_fcaf507-B33","volume-title":"The Wechsler intelligence scale for children","author":"Wechsler","year":"2003","edition":"4th ed"},{"key":"2026011205562016200_fcaf507-B34","volume-title":"Wechsler intelligence scale for children","author":"Wechsler","year":"2014","edition":"5th ed"},{"issue":"2","key":"2026011205562016200_fcaf507-B35","first-page":"258","article-title":"A rationale for degrees of retardation","volume":"60","author":"Sloan","year":"1955","journal-title":"Am J Ment Defic"},{"key":"2026011205562016200_fcaf507-B36","volume-title":"Manual for the ASEBA preschool forms and profiles","author":"Achenbach","year":"2000"},{"key":"2026011205562016200_fcaf507-B37","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.seizure.2020.11.017","article-title":"Results of an international Delphi consensus in epilepsy with myoclonic atonic seizures\/Doose syndrome","volume":"85","author":"Joshi","year":"2021","journal-title":"Seizure"},{"issue":"9","key":"2026011205562016200_fcaf507-B38","doi-asserted-by":"crossref","first-page":"1152","DOI":"10.1001\/archneurol.2011.102","article-title":"Glucose transporter 1 deficiency as a treatable cause of myoclonic astatic epilepsy","volume":"68","author":"Mullen","year":"2011","journal-title":"Arch Neurol"},{"issue":"1","key":"2026011205562016200_fcaf507-B39","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1016\/j.ajhg.2020.12.002","article-title":"De novo variants in POLR3B cause ataxia, spasticity, and demyelinating neuropathy","volume":"108","author":"Djordjevic","year":"2021","journal-title":"Am J Hum Genet"},{"issue":"11","key":"2026011205562016200_fcaf507-B40","doi-asserted-by":"crossref","first-page":"3303","DOI":"10.1111\/epi.18115","article-title":"POLR3B is associated with a developmental and epileptic encephalopathy with myoclonic-atonic seizures and ataxia","volume":"65","author":"Symonds","year":"2024","journal-title":"Epilepsia"},{"issue":"6","key":"2026011205562016200_fcaf507-B41","doi-asserted-by":"crossref","first-page":"104746","DOI":"10.1016\/j.ejmg.2023.104746","article-title":"Consensus recommendations on Epilepsy in Phelan-McDermid syndrome","volume":"66","author":"De Coo","year":"2023","journal-title":"Eur J Med Genet"},{"key":"2026011205562016200_fcaf507-B42","volume-title":"GeneReviews\u00ae","author":"Assia Batzir","year":"2021"},{"issue":"5","key":"2026011205562016200_fcaf507-B43","doi-asserted-by":"crossref","first-page":"1439","DOI":"10.1111\/epi.17939","article-title":"Clinical and molecular characterization of patients with YWHAG-related epilepsy","volume":"65","author":"Cetica","year":"2024","journal-title":"Epilepsia"},{"key":"2026011205562016200_fcaf507-B44","volume-title":"Gene Reviews\u00ae","author":"Pais","year":"2024"},{"issue":"2","key":"2026011205562016200_fcaf507-B45","doi-asserted-by":"crossref","first-page":"fcaa170","DOI":"10.1093\/braincomms\/fcaa170","article-title":"Current knowledge of SLC6A1-related neurodevelopmental disorders","volume":"2","author":"Goodspeed","year":"2020","journal-title":"Brain Commun"},{"key":"2026011205562016200_fcaf507-B46","doi-asserted-by":"crossref","first-page":"107514","DOI":"10.1016\/j.eplepsyres.2025.107514","article-title":"4-Phenylbutyrate restored GABA uptake, mitigated seizures in SLC6A1 and SLC6A11 microdeletions\/3p- syndrome: From cellular models to human patients","volume":"210","author":"DeLeeuw","year":"2025","journal-title":"Epilepsy Res"},{"issue":"5","key":"2026011205562016200_fcaf507-B47","doi-asserted-by":"crossref","first-page":"1972","DOI":"10.1002\/epi4.13034","article-title":"Effectiveness of add-on acetazolamide in children with drug-resistant CHD2-related epilepsy and in a zebrafish CHD2 model","volume":"9","author":"Melikishvili","year":"2024","journal-title":"Epilepsia Open"},{"issue":"1","key":"2026011205562016200_fcaf507-B48","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1038\/s41572-024-00546-6","article-title":"Developmental and epileptic encephalopathies","volume":"10","author":"Scheffer","year":"2024","journal-title":"Nat Rev Dis Primers"},{"key":"2026011205562016200_fcaf507-B49","first-page":"139","volume-title":"Epileptic syndromes of infancy, childhood and adolescence","author":"Dravet","year":"2019","edition":"6th ed"}],"container-title":["Brain Communications"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/braincomms\/advance-article-pdf\/doi\/10.1093\/braincomms\/fcaf507\/66149962\/fcaf507.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/braincomms\/article-pdf\/8\/1\/fcaf507\/66149962\/fcaf507.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/braincomms\/article-pdf\/8\/1\/fcaf507\/66149962\/fcaf507.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,12]],"date-time":"2026-01-12T10:56:38Z","timestamp":1768215398000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/braincomms\/article\/doi\/10.1093\/braincomms\/fcaf507\/8407101"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,29]]},"references-count":49,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2026,1,2]]}},"URL":"https:\/\/doi.org\/10.1093\/braincomms\/fcaf507","relation":{},"ISSN":["2632-1297"],"issn-type":[{"value":"2632-1297","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2026]]},"published":{"date-parts":[[2025,12,29]]},"article-number":"fcaf507"}}