title: Clinical and genetic aspects of PCDH19-related epilepsy syndromes and the possible role of PCDH19 mutations in males with autism spectrum disorders.
abstract: Epilepsy and mental retardation limited to females (EFMR), caused by PCDH19 mutations, has a variable clinical expression that needs further exploration. Onset of epilepsy may be provoked by fever and can resemble Dravet syndrome. Furthermore, transmitting males have no seizures, but are reported to have rigid personalities suggesting possible autism spectrum disorders (ASD). Therefore, this study aimed to determine the phenotypic spectrum associated with PCDH19 mutations in Dravet-like and EFMR female patients and in males with ASD. We screened 120 females suffering from Dravet-like epilepsy, 136 females with EFMR features and 20 males with ASD. Phenotypes and genotypes of the PCDH19 mutation carriers were compared with those of 125 females with EFMR reported in the literature. We report 15 additional patients with a PCDH19 mutation. Review of clinical data of all reported patients showed that the clinical picture of EFMR is heterogeneous, but epilepsy onset in infancy, fever sensitivity and occurrence of seizures in clusters are key features. Seizures remit in the majority of patients during teenage years. Intellectual disability and behavioural disturbances are common. Fifty percent of all mutations are missense mutations, located in the extracellular domains only. Truncating mutations have been identified in all protein domains. One ASD proband carried one missense mutation predicted to have a deleterious effect, suggesting that ASD in males can be associated with PCDH19 mutations.
authors: Department of Medical Genetics, University Medical Center Utrecht, P.O. Box 85090, 3508 AB Utrecht, The Netherlands.
authors: J J T
authors: JJ
authors: van Harssel
authors: S
authors: S
authors: Weckhuysen
authors: M J A
authors: MJ
authors: van Kempen
authors: K
authors: K
authors: Hardies
authors: N E
authors: NE
authors: Verbeek
authors: C G F
authors: CG
authors: de Kovel
authors: W B
authors: WB
authors: Gunning
authors: E
authors: E
authors: van Daalen
authors: M V
authors: MV
authors: de Jonge
authors: A C
authors: AC
authors: Jansen
authors: R J
authors: RJ
authors: Vermeulen
authors: W F M
authors: WF
authors: Arts
authors: H
authors: H
authors: Verhelst
authors: A
authors: A
authors: Fogarasi
authors: J F
authors: JF
authors: de Rijk-van Andel
authors: A
authors: A
authors: Kelemen
authors: D
authors: D
authors: Lindhout
authors: P
authors: P
authors: De Jonghe
authors: B P C
authors: BP
authors: Koeleman
authors: A
authors: A
authors: Suls
authors: E H
authors: EH
authors: Brilstra
mesh_terms: D000293:Adolescent; D015820:Cadherins / Q000235:genetics* / Q000502:physiology; D002648:Child; D002659:Child Development Disorders, Pervasive / Q000150:complications / Q000453:epidemiology* / Q000235:genetics*; D002675:Child, Preschool; D015331:Cohort Studies; D004831:Epilepsies, Myoclonic / Q000453:epidemiology / Q000235:genetics; D004827:Epilepsy / Q000150:complications / Q000453:epidemiology* / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D008607:Intellectual Disability / Q000150:complications / Q000453:epidemiology / Q000235:genetics; D008297:Male; D009154:Mutation / Q000502:physiology*; D019683:Penetrance; D000091363:Protocadherins; D012727:Sex Characteristics; D013577:Syndrome
chemical_list: D015820:Cadherins; C438605:PCDH19 protein, human; D000091363:Protocadherins