{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T15:28:04Z","timestamp":1791646084365,"version":"4.3.4"},"reference-count":35,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2021,8,26]],"date-time":"2021-08-26T00:00:00Z","timestamp":1629936000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Italian Ministry of Health,","award":["Ricerca Corrente 2019, 2020 to M.T."],"award-info":[{"award-number":["Ricerca Corrente 2019, 2020 to M.T."]}]},{"DOI":"10.13039\/501100005010","name":"AIRC","doi-asserted-by":"publisher","award":["IG 21614 to M.T."],"award-info":[{"award-number":["IG 21614 to M.T."]}],"id":[{"id":"10.13039\/501100005010","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Objective: Cardiofaciocutaneous syndrome (CFCS) is a rare developmental disorder caused by upregulated signaling through the RAS-mitogen-activated protein kinase (MAPK) pathway, mostly resulting from de novo activating BRAF mutations. Children with CFCS are prone to epilepsy, which is a major life-threatening complication. The aim of our study was to define the natural history of epilepsy in this syndrome and exploring genotype\u2013phenotype correlations. Methods: We performed an observational study, including 34 patients with molecularly confirmed diagnosis (11 males, mean age: 15.8 years). The mean follow-up period was 9.2 years. For all patients, we performed neurological examination, cognitive assessment when possible, neuroimaging, electrophysiological assessment and systematic assessment of epilepsy features. Correlation analyses were performed, taking into account gender, age of seizure onset, EEG features, degree of cognitive deficits, type of mutation, presence of non-epileptic paroxysmal events and neuroimaging features. Results: Epilepsy was documented in 64% of cases, a higher prevalence compared to previous reports. Patients were classified into three groups based on their electroclinical features, long-term outcome and response to therapy. A genotype\u2013phenotype correlation linking the presence\/severity of epilepsy to the nature of the structural\/functional consequences of mutations was observed, providing a stratification based on genotype to improve the clinical management of these patients.<\/jats:p>","DOI":"10.3390\/genes12091316","type":"journal-article","created":{"date-parts":[[2021,8,26]],"date-time":"2021-08-26T09:27:57Z","timestamp":1629970077000},"page":"1316","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Epilepsy and BRAF Mutations: Phenotypes, Natural History and Genotype-Phenotype Correlations"],"prefix":"10.3390","volume":"12","author":[{"given":"Domenica I.","family":"Battaglia","sequence":"first","affiliation":[{"name":"Child Neurology and Psychiatry Unit, Fondazione Policlinico Universitario Agostino Gemelli, IRCCS, 00168 Rome, Italy"},{"name":"Dipartimento Scienze della Vita, Universit\u00e0 Cattolica del Sacro Cuore, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Luigia","family":"Gambardella","sequence":"additional","affiliation":[{"name":"Child Neurology and Psychiatry Unit, Fondazione Policlinico Universitario Agostino Gemelli, IRCCS, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefania","family":"Veltri","sequence":"additional","affiliation":[{"name":"Child Neurology and Psychiatry Unit, Fondazione Policlinico Universitario Agostino Gemelli, IRCCS, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilaria","family":"Contaldo","sequence":"additional","affiliation":[{"name":"Child Neurology and Psychiatry Unit, Fondazione Policlinico Universitario Agostino Gemelli, IRCCS, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3901-6926","authenticated-orcid":false,"given":"Giovanni","family":"Chillemi","sequence":"additional","affiliation":[{"name":"Department for Innovation in Biological Agro-Food and Forest Systems (DIBAF), University of Tuscia, 01100 Viterbo, Italy"},{"name":"Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies, Centro Nazionale delle Ricerche, 70126 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Veredice","sequence":"additional","affiliation":[{"name":"Child Neurology and Psychiatry Unit, Fondazione Policlinico Universitario Agostino Gemelli, IRCCS, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michela","family":"Quintiliani","sequence":"additional","affiliation":[{"name":"Dipartimento Scienze della Vita, Universit\u00e0 Cattolica del Sacro Cuore, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Leoni","sequence":"additional","affiliation":[{"name":"Center for Rare Disease and Congenital Defects, Fondazione Policlinico Universitario Agostino Gemelli, IRCCS, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3128-6657","authenticated-orcid":false,"given":"Roberta","family":"Onesimo","sequence":"additional","affiliation":[{"name":"Center for Rare Disease and Congenital Defects, Fondazione Policlinico Universitario Agostino Gemelli, IRCCS, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8094-2847","authenticated-orcid":false,"given":"Tommaso","family":"Verdolotti","sequence":"additional","affiliation":[{"name":"Department of Radiology Fondazione Policlinico Universitario Agostino Gemelli, IRCCS, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1993-8018","authenticated-orcid":false,"given":"Francesca Clementina","family":"Radio","sequence":"additional","affiliation":[{"name":"Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Ges\u00f9, IRCCS, 00146 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diego","family":"Martinelli","sequence":"additional","affiliation":[{"name":"Division of Metabolism, Ospedale Pediatrico Bambino Ges\u00f9, IRCCS, 00165 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina","family":"Trivisano","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Ospedale Pediatrico Bambino Ges\u00f9, IRCCS, 00165 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8120-0287","authenticated-orcid":false,"given":"Nicola","family":"Specchio","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Ospedale Pediatrico Bambino Ges\u00f9, IRCCS, 00165 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charlotte","family":"Dravet","sequence":"additional","affiliation":[{"name":"Child Neurology and Psychiatry Unit, Fondazione Policlinico Universitario Agostino Gemelli, IRCCS, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7736-9672","authenticated-orcid":false,"given":"Marco","family":"Tartaglia","sequence":"additional","affiliation":[{"name":"Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Ges\u00f9, IRCCS, 00146 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Zampino","sequence":"additional","affiliation":[{"name":"Dipartimento Scienze della Vita, Universit\u00e0 Cattolica del Sacro Cuore, 00168 Rome, Italy"},{"name":"Center for Rare Disease and Congenital Defects, Fondazione Policlinico Universitario Agostino Gemelli, IRCCS, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,8,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"4984","DOI":"10.1016\/j.febslet.2006.08.025","article-title":"Functions of the MAPK family in vertebrate-development","volume":"580","author":"Krens","year":"2006","journal-title":"FEBS Lett."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1038\/nrn1346","article-title":"MAPK cascade signalling and synaptic plasticity","volume":"5","author":"Thomas","year":"2004","journal-title":"Nat. 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A"}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/12\/9\/1316\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:52:30Z","timestamp":1760165550000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/12\/9\/1316"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8,26]]},"references-count":35,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2021,9]]}},"alternative-id":["genes12091316"],"URL":"https:\/\/doi.org\/10.3390\/genes12091316","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,8,26]]}}}