Protocadherin 19 Clustering Epilepsy and Neurosteroids: Opportunities for Intervention

Steroids yield great influence on neurological development through nuclear hormone receptor (NHR)-mediated gene regulation. We recently reported that cell adhesion molecule protocadherin 19 (encoded by the PCDH19 gene) is involved in the coregulation of steroid receptor activity on gene expression. PCDH19 variants cause early-onset developmental epileptic encephalopathy clustering epilepsy (CE), with altered steroidogenesis and NHR-related gene expression being identified in these individuals. The implication of hormonal pathways in CE pathogenesis has led to the investigation of various steroid-based antiepileptic drugs in the treatment of this disorder, with mixed results so far. Therefore, there are many unmet challenges in assessing the antiseizure targets and efficiency of steroid-based therapeutics for CE. We review and assess the evidence for and against the implication of neurosteroids in the pathogenesis of CE and in view of their possible clinical benefit.