Abstract
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.
Highlights
Protocadherin 19 (PCDH19) clustering epilepsy (CE, previously known as girls clustering epilepsy, GCE; female-limited epilepsy, FE; or epilepsy and mental retardation limited to females, EFMR: OMIM #300088) is an X-linked encephalopathy with an incidence rate of 1 per 20,600 liveborn females and is characterized by seizures with an average onset of 11.9 months [1,2,3,4,5].These seizures occur in clusters and generally reduce in frequency by adolescence [1].CE individuals are often affected by psychiatric comorbidities such as autism spectrum disorder (ASD), hyperactive and/or attention-deficit disorder (ADHD), and behavioural disturbances [1,2]
Recent research into the role of steroids in CE pathogenesis has resulted in the identification of CE gene dysregulation, altered steroidogenesis, and the implication of PCDH19 in NHRmediated gene regulation
Many aspects relating to the mechanism of CE pathogenesis, that can directly or indirectly facilitate development of treatments, remain unexplored
Summary
PCDH19 clustering epilepsy (CE, previously known as girls clustering epilepsy, GCE; female-limited epilepsy, FE; or epilepsy and mental retardation limited to females, EFMR: OMIM #300088) is an X-linked encephalopathy with an incidence rate of 1 per 20,600 liveborn females and is characterized by seizures with an average onset of 11.9 months [1,2,3,4,5]. These seizures occur in clusters and generally reduce in frequency by adolescence [1]. This area of research is the focus of this critical review
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