A familial epilepsy with behavioural features associated with a PCDH19 mutation

Aims: Delineation of the genetic cause of a familial epilepsy. Description of the phenotype of a previously unreported heterozygous missense mutation of the PCDH19 gene.

Methods: Retrospective analysis of clinical features in 4 affected females in 3 generations: the 18-year-old proposita, her mother (36yrs.), maternal aunt (29yrs.) and maternal grandmother (58yrs.). Mutational analysis of a candidate gene.

Results: The proposita had absence-like seizures with onset at age 8 months and suffered from GTCS later on, mostly associated with fever, often during sleep. Seizures ceased at age 15 years, with antiepileptic treatment including VPA and LEV. EEGs were largely normal, with occasional focal epileptic discharges. MRI of the brain was normal. Behavioural peculiarities started at kindergarten with difficulties in approaching other children and gaining and continuing friendships. Psychological investigations at age 14 and 16 years revealed normal verbal cognitive abilities, but a heterogeneous performance profile and diagnostic criteria of Asperger autism, based on evaluation using ADOS. The patient attends grammar school with average performance.

Her mother, maternal aunt and maternal grandmother had absence-like seizures and GTCS during childhood with cessation at ages 10 to 14 years. Seizures occurred mostly during sleep and were largely associated with fever. EEGs were normal or showed multifocal epileptic discharges. Behavioural manifestation is apparent in these females as well.

Mutational analysis of the PCDH19 gene revealed a previously unreported heterozygous missense mutation c.1914T>G, p.Y638X in exon 1. Genetic and psychological investigations in the other affected patients are in progress.

Conclusion: This PCDH19 mutation is associated with mostly febrile seizures during childhood and early youth in the proposita and her maternal grandmother, as well as Asperger autism in the proposita.