title: Spectrum of phenotypes in female patients with epilepsy due to protocadherin 19 mutations.
abstract: OBJECTIVE
  To describe clinical and neuropsychological features of six consecutive sporadic girls with protocadherin 19 (PCDH19) mutations.
  
  
  METHODS
  Following recent descriptions of PCDH19 mutation in girls with epilepsy, we sequenced this gene in patients with infantile or early childhood seizures onset, either focal or generalized, without an obvious etiology.
  
  
  RESULTS
  Mean age at the time of the study was 13.5 ± 11 years. Mean age at seizure onset was 15.5 ± 11 months (range 9-38). All patients experienced clusters of either focal or generalized seizures, precipitated during febrile illness in five patients. Attacks were very frequent at onset, but they became less numerous during follow-up. Ictal electroencephalography (EEG) showed temporal lobe involvement in five patients. Periictal EEG showed focal or multifocal epileptiform and slow abnormalities. Cognitive impairment became obvious after seizure onset in three patients and was associated with autistic features in two. Genetic analysis revealed five new and one known de novo PCDH19 mutation that were missense in four and frameshift in two. Variants are clustered in the large exon 1, corresponding to the extracellular domain of the PCDH19 protein.
  
  
  CONCLUSIONS
  Our findings emphasize that de novo PCDH19 mutations are associated with infantile or early childhood onset of febrile or afebrile seizures often occurring in clusters. Cognitive impairment is not constantly present and autistic features are observed in some patients. Most patients have a "stormy" seizure onset, often related to fever; however, seizure severity does not clearly correlate with the degree of cognitive deficit. PCDH19 is likely a major epilepsy gene; phenotypes associated with mutations of this gene range from epileptic encephalopathies to mild epilepsy, yet large series of patients will be necessary to fully delineate phenotypic spectrum.
authors.affiliation: Neurology Unit, Department of Neuroscience, Bambino Gesu' Children's Hospital-IRCCS, Piazza S. Onofrio 4, Rome, Italy. nicola.specchio@opbg.net
authors.forename: Nicola
authors.initials: N
authors.lastname: Specchio
authors.forename: Carla
authors.initials: C
authors.lastname: Marini
authors.forename: Alessandra
authors.initials: A
authors.lastname: Terracciano
authors.forename: Davide
authors.initials: D
authors.lastname: Mei
authors.forename: Marina
authors.initials: M
authors.lastname: Trivisano
authors.forename: Federico
authors.initials: F
authors.lastname: Sicca
authors.forename: Lucia
authors.initials: L
authors.lastname: Fusco
authors.forename: Raffaella
authors.initials: R
authors.lastname: Cusmai
authors.forename: Francesca
authors.initials: F
authors.lastname: Darra
authors.forename: Bernardo Dalla
authors.initials: BD
authors.lastname: Bernardina
authors.forename: Enrico
authors.initials: E
authors.lastname: Bertini
authors.forename: Renzo
authors.initials: R
authors.lastname: Guerrini
authors.forename: Federico
authors.initials: F
authors.lastname: Vigevano
mesh_terms: D017668:Age of Onset; D001921:Brain / Q000503:physiopathology; D015820:Cadherins / Q000235:genetics*; D002675:Child, Preschool; D004569:Electroencephalography; D004827:Epilepsy / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D016368:Frameshift Mutation / Q000235:genetics; D006801:Humans; D007223:Infant; D020125:Mutation, Missense / Q000235:genetics; D010641:Phenotype; D000091363:Protocadherins; D012640:Seizures / Q000235:genetics
chemical_list: D015820:Cadherins; C438605:PCDH19 protein, human; D000091363:Protocadherins