De novo and inherited mutations of X-chromosome cell adhesion molecule protocadherin 19 (PCDH19) cause frequent, highly variable epilepsy, autism, cognitive decline and behavioural problems syndrome.
We evaluated whether psychosis and serious behavioral problems had occurred in 60 females (age 2-75 years) with PCDH19 pathogenic variants belonging to 35 families.
To date about 150 mutations have been identified as causative for PCDH19-female epilepsy (also known as early infantile epileptic encephalopathy-9, EIEE9), which is characterized by early onset epilepsy, intellectual disabilities, and behavioral disturbances.
Our findings emphasize that de novo PCDH19 mutations are associated with infantile or early childhood onset of febrile or afebrile seizures often occurring in clusters.
To extend the mutational and clinical spectra associated with PCDH19, we screened 150 unrelated patients (113 females) with febrile and afebrile seizures for mutations or rearrangements in the gene.
Patients with PCDH19 and SCN1A mutations had very similar clinical features including the association of early febrile and afebrile seizures, seizures occurring in clusters, developmental and language delays, behavioural disturbances, and cognitive regression.
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.
For example, CDH15 and PCDH19 are associated with cognitive impairment; CDH5, CDH8, CDH9, CDH10, CDH13, CDH15, PCDH10, PCDH19 and PCDHb4 with autism; CDH7, CDH12, CDH18, PCDH12 and FAT with bipolar disease and schizophrenia; and CDH11, CDH12 and CDH13 with methamphetamine and alcohol dependency.
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.
No mutations were identified in the Rett syndrome and autism spectrum disorders cohorts suggesting that despite sharing similar clinical characteristics with EFMR, PCDH19 mutations are not generally associated with these disorders.
For example, CDH15 and PCDH19 are associated with cognitive impairment; CDH5, CDH8, CDH9, CDH10, CDH13, CDH15, PCDH10, PCDH19 and PCDHb4 with autism; CDH7, CDH12, CDH18, PCDH12 and FAT with bipolar disease and schizophrenia; and CDH11, CDH12 and CDH13 with methamphetamine and alcohol dependency.
Protocadherin 19 (PCDH19) female limited epilepsy (PCDH19-FE; also known as epilepsy and mental retardation limited to females, EFMR; MIM300088) is an infantile onset epilepsy syndrome with or without intellectual disability (ID) and autism.