title: Focal seizures with affective symptoms are a major feature of PCDH19 gene-related epilepsy.
abstract: OBJECTIVE
  Mutations of the protocadherin19 gene (PCDH19) cause a female-related epilepsy of variable severity, with or without mental retardation and autistic features. Despite the increasing number of patients and mutations reported, the epilepsy phenotype associated with PCDH19 mutations is still unclear. We analyzed seizure semiology through ictal video-electroencephalography (EEG) recordings in a large series of patients.
  
  
  METHODS
  We studied 35 patients with PCDH19 gene-related epilepsy and analyzed clinical history and ictal video-EEG recordings obtained in 34 of them.
  
  
  RESULTS
  Clusters of focal febrile and afebrile seizures had occurred in 34 patients, at a mean age of 10 months. The predominant and more consistent ictal sign was fearful screaming, occurring in 24 patients (70.5%); it was present since epilepsy onset in 12 and appeared later on, during the course in the remaining 12 patients. In infancy, fearful screaming mainly appeared within the context of seizures with prominent hypomotor semiology, whereas during follow-up it was associated with prominent early motor manifestations. In 16 patients, seizures were video-EEG recorded both at onset and during follow-up: in five patients (31%) seizure semiology remained identical, in 7 (44%) semiology varied and in four patients it was unclear whether ictal semiology changed with age. Three patients (9%) had both focal and generalized seizures, the latter consisting of absences and myoclonus. Ictal EEG during focal seizures showed a prominent involvement of the frontotemporal regions (22 patients). About 45% of patients had an alternating EEG pattern, with the ictal discharge migrating from one hemisphere to the contralateral during the same ictal event. Status epilepticus occurred in 30% of patients. Cognitive impairment occurred in 70%, ranging from mild (42%) to moderate (54%) and severe (4%); autistic features occurred in 28.5%. Direct sequencing detected 33 different heterozygous candidate mutations, 8 of which were novel. Mutations were missense substitutions (48.5%), premature termination (10 frameshift, 4 nonsense, and 2 splice-site mutations; 48.5%), and one in-frame deletion. Thirty candidate mutations (91%) were de novo. No specific genotype-phenotype correlation could be established, as missense and truncating mutations were associated with phenotypes of comparable severity.
  
  
  CONCLUSIONS
  Most patients with PCDH19 mutations exhibit a distinctive electroclinical pattern of focal seizures with affective symptoms, suggesting an epileptogenic dysfunction involving the frontotemporal limbic system. Awareness of this distinctive phenotype will likely enhance recognition of this disorder.
authors.affiliation: Pediatric Neurology Unit, A. Meyer Children's Hospital-University of Florence, Florence, Italy.
authors.forename: Carla
authors.initials: C
authors.lastname: Marini
authors.forename: Francesca
authors.initials: F
authors.lastname: Darra
authors.forename: Nicola
authors.initials: N
authors.lastname: Specchio
authors.forename: Davide
authors.initials: D
authors.lastname: Mei
authors.forename: Alessandra
authors.initials: A
authors.lastname: Terracciano
authors.forename: Lucio
authors.initials: L
authors.lastname: Parmeggiani
authors.forename: Annarita
authors.initials: A
authors.lastname: Ferrari
authors.forename: Federico
authors.initials: F
authors.lastname: Sicca
authors.forename: Massimo
authors.initials: M
authors.lastname: Mastrangelo
authors.forename: Luigina
authors.initials: L
authors.lastname: Spaccini
authors.forename: Maria Lucia
authors.initials: ML
authors.lastname: Canopoli
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Cesaroni
authors.forename: Nelia
authors.initials: N
authors.lastname: Zamponi
authors.forename: Lorella
authors.initials: L
authors.lastname: Caffi
authors.forename: Paolo
authors.initials: P
authors.lastname: Ricciardelli
authors.forename: Salvatore
authors.initials: S
authors.lastname: Grosso
authors.forename: Tiziana
authors.initials: T
authors.lastname: Pisano
authors.forename: Maria Paola
authors.initials: MP
authors.lastname: Canevini
authors.forename: Tiziana
authors.initials: T
authors.lastname: Granata
authors.forename: Patrizia
authors.initials: P
authors.lastname: Accorsi
authors.forename: Domenica
authors.initials: D
authors.lastname: Battaglia
authors.forename: Raffaella
authors.initials: R
authors.lastname: Cusmai
authors.forename: Federico
authors.initials: F
authors.lastname: Vigevano
authors.forename: Bernardo
authors.initials: B
authors.lastname: Dalla Bernardina
authors.forename: Renzo
authors.initials: R
authors.lastname: Guerrini
mesh_terms: D000293:Adolescent; D000328:Adult; D000342:Affective Symptoms / Q000150:complications / Q000235:genetics*; D015820:Cadherins / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D003072:Cognition Disorders / Q000209:etiology / Q000235:genetics; D019295:Computational Biology; D004252:DNA Mutational Analysis; D004569:Electroencephalography; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D009154:Mutation / Q000235:genetics*; D009483:Neuropsychological Tests; D000091363:Protocadherins; D012640:Seizures / Q000150:complications / Q000235:genetics*; D014741:Video Recording; D055815:Young Adult
chemical_list: D015820:Cadherins; C438605:PCDH19 protein, human; D000091363:Protocadherins