Epilepsy and BRAF mutations: Phenotypes, natural history and genotype-phenotype correlations

Domenica Immacolata Battaglia, Maria Luigia Gambardella, Stefania Veltri, Ilaria Contaldo, Giovanni Chillemi, Chiara Veredice, Michela Quintiliani, Chiara Leoni, Roberta Onesimo, Tommaso Verdolotti, Francesca Clementina Radio, Diego Martinelli, Daniela Martinelli, Marina Trivisano, Nicola Specchio, Charlotte Dravet, Marco Tartaglia, Giuseppe Zampino

Risultato della ricerca: Contributo in rivistaArticolo in rivistapeer review


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–phenotype 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–phenotype 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.
Lingua originaleEnglish
pagine (da-a)1-15
Numero di pagine15
Stato di pubblicazionePubblicato - 2021


  • BRAF
  • Cardiofaciocutaneous syndrome
  • Epilepsy
  • Genotype–phenotype correlations
  • Hyperekplexia
  • Phenotype
  • Status epilepticus


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