Novel de novo PCDH19 mutations in three unrelated females with epilepsy female restricted mental retardation syndrome

Abstract

Epilepsy and Mental Retardation Limited to Females (EFMR) [OMIM 300088] was first described in 1971 [Juberg and Hellman, 1971] in 15 related females with early onset grand mal seizures and mental retardation. Although EFMR demonstrates X-linked inheritance, it follows an unusual pattern by sparing transmitting males and affecting only heterozygous females. In 2008, mutations within the protocadherin 19 (PCDH19) gene were implicated as causative of EFMR [Dibbens et al. (2008); Nat Genet 40:776-781]. The EFMR phenotype is typically characterized by seizure onset in infancy and mild to severe intellectual impairment. Several individuals with EFMR have also been described as having autistic features. We describe three unrelated female individuals, ranging in age from 3 to 19 years, with de novo novel PCDH19 mutations. All three individuals have seizure onset in infancy and require the use of multiple antiepileptic drugs. They also have varying degrees of intellectual impairment along with the presence of autistic features. Although most individuals with EFMR described to date demonstrate this unusual familial X-linked inheritance, our three unrelated females with de novo mutations highlight the importance of testing PCDH19 in females with early onset epilepsy, intellectual impairment, and autistic features, regardless of family history.

Epilepsy genetics—past, present, and future

“…PCDH19 mutations have been identified by multiple groups in sporadic cases of epilepsy in females with intellectual disability as well as infantile onset epilepsy, even that resembling the severe myoclonic epilepsy of infancy phenotype of Dravet syndrome [54-57]. …”

Etiologies for Seizures Around the Time of Vaccination

“…15,[30][31][32] Although fever is a known seizure precipitant in children with a PCDH19 mutation, a 1q-terminal deletion, and SCN1A-related GEFS+ syndrome, [33][34][35][36] our study is the first to acknowledge vaccination-related onset in the latter 3 syndromes. A chance association is unlikely because vaccinationrelated seizures recurred after a second vaccination in both the GEFS+ and 1qter case, occurred in an additional case of SCN1A-related GEFS+ syndrome with only febrile seizures (Table 1), and have previously been reported in another girl with a PCDH19 mutation 19 and 2 GEFS+ cases. 37 The majority of children with vaccinationrelated onset of epilepsy in our study were reported to have fever-sensitive epilepsy at follow-up.…”

“…Only a few case reports have shown that occasionally other genetic causes of epilepsy also present with seizures after vaccination. 19,20 To assess underlying causes in children with any epilepsy syndrome with onset after vaccination, we studied a nationwide 10-year cohort of children reporting possible epileptic seizures after vaccination.…”

PCDH19 mutations in female patients from Southern Italy

“…In the literature, indeed, four distinct mutations in the exon 4 (framshift, nonsense, and splicing site mutation) were already reported. [7][8][9] The exon 4 encodes to the intracellular cadherin domains of the PCDH19 protein. It interacts with cytoskeleton and with signal transmission pathway.…”