Neurodevelopment and PCDH19-related developmental and epileptic encephalopathy (PCDH19-DDE)

Abstract Infantile epileptic encephalopathy-9 (EIEE9) is a developmental and epileptic encephalopathy (DEE) with infantile onset of clusters of focal seizures triggered by febrile illness and subsequent intellectual disability, autism spectrum disorder, and psychiatric comorbidity in most patients. This pathology is due to de novo or inherited mutations in the X-chromosome gene PCDH19 (Xq22.1), and its inheritance mode is peculiar since healthy carrier fathers transmit the mutations to their affected daughters. Therefore a “cell-interference model” has been hypothesized, according to which PCDH19-related DDE (PCDH19-DDE) symptoms would arise from the coexistence of PCDH19-positive and PCDH19-negative cells, as a consequence of the random X-chromosome inactivation in females. PCDH19 is emerging as a cell-adhesion molecule broadly involved in several core stages of neurodevelopment, from neurulation to neuronal network wiring passing through cell migration and proliferation. Despite PCDH19-DDE treatments still representing an open battle, the ongoing research on PCDH19 biological function is expected to provide important therapeutic hints.