PCDH19-Related Epilepsies

Protocadherin-19 (PCDH19) is considered one of the most relevant genes related to epilepsy. To date, more than 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. More recently, mosaic-males (i.e., exhibiting the variants in less than 25% of their cells) have been described as affected by infant-onset epilepsy associated with intellectual disability, as well as compulsive or aggressive behavior and autistic features. Although little is known about the physiological role of PCDH19 protein and the pathogenic mechanisms that lead to EIEE9, many reports and clinical observation seem to suggest a relevant role of this protein in the development of cellular hyperexcitability. However, a genotype-phenotype correlation is difficult to establish. The main feature of EIEE9 consists in early onset of seizures, which generally occur in clusters lasting 1 to 5 minutes and repeating up to 10 times a day for several days. Seizures tend to present during febrile episodes, similarly to the first phases of Dravet syndrome and PCDH19 variants have been found in similar to 25% of females who present with features of Dravet syndrome and testing negative for SCN1A variants. There is no "standardized" treatment for PCDH19-related epilepsy and most of the patients receiving a combination of several drugs. In this review, we focus on the latest researches on these aspects, with regard to protein expression, its known functions, and the mechanisms by which the protein acts. The clinical phenotypes related to PCDH19 mutations are also discussed.