Abstracts

Rationale: Epilepsy and mental retardation limited to females (EFMR) is a disorder seen in both familial and sporadic cases. Mutations in the protocadherin 19 gene (PCDH19) cause EFMR. We sought to determine the frequency of PCDH19 mutations in girls presenting with seizures before 3 years of age who also had developmental delay and/or intellectual disability. Methods: We studied 121 unrelated female patients. We analysed the patients for PCDH19 gene variation by high resolution melt curve analysis and variants were confirmed by sequencing. Where available, we analysed the inheritance of the mutation in parents and other family members. Results: We identified PCDH19 mutations in 2/121 unrelated females. The missense mutation L25P was found in Australian sisters. Patient 1 is an almost 15 year old adolescent whose seizures began at 8 months with clusters of ~18 convulsive seizures over a few days. They were triggered by fever every 6-8 weeks but eventually afebrile tonic and tonic-clonic seizures occurred. Status epilepticus occurred once at 4 years. Seizures were refractory but responded to clonazepam with her last seizure at 13 years. Early development was normal with regression at seizure onset. She has moderate intellectual disability, autism spectrum disorder and major behavioural problems. Her older sister has severe intellectual disability with disabling aggression and also carries the PCDH19 mutation. Both parents are unaffected and negative for the mutation, indicating parental mosaicism. Their sister with a history of febrile seizures does not have the PCDH19 mutation. Patient 2 has a German father and Thai mother and presented with a tonic-clonic seizure at 17 months with her second seizure a year later. She had relatively infrequent clusters of convulsions with fever. At 14 years, she has mild to moderate intellectual disability. Patient 2 has a frameshift mutation I208A fsX222 and family members are currently being tested for the mutation. Conclusions: We found that approximately 1.5% of females who experience seizures in infancy with a history of intellectual disability have a mutation in the PCDH19 gene. This is the first report of parental mosaicism in EFMR, a finding that carries significant genetic counselling implications for families.