ABSTRACT
PCDH19 syndrome is a monogenic epilepsy related to the protein protocadherin-19 (PCDH19) gene, which encodes for a protein important for brain development. The protein also seems to regulate gamma-aminobutyric acid type A receptors (GABA(A)(R)). The disease presents with refractory epilepsy that is characterized by seizures occurring in clusters. Till now, the pathophysiology of the disease is mainly unknown, so we conducted a literature review to elucidate the pathophysiology of PCDH19-related epilepsy. We used two databases to investigate this literature review (Google Scholar and PubMed). We selected full-text papers that are published in the English language and published after the year 2000. We selected initially 64 papers and ended up with 29 to conduct this literature review. We found four main theories for the pathophysiology of PCDH19-related epilepsy: GABA(A)(R) dysregulation, blood-brain barrier (BBB) dysfunction, cellular interference, and the AKR1C1-3 gene product deficiency. GABA(A)(R) dysfunction and expression cause decreased effective inhibitory currents predisposing patients to epilepsy. BBB dysfunction allows the passage of methyl-D-aspartate (NMDA)-type glutamate receptor antibodies (abs-NR) through the BBB susceptible membrane. The cellular interference hypothesis establishes that the mutant and non-mutant cells interfere with each other's communication within the same tissue. Women are more susceptible to being affected by this hypothesis as men only have one copy of the x gene and interference is mediated by this gene, meaning that it cannot occur in them. Finally, downregulation and deficiency of the AKR1C3/AKR1C2 products lead to decreasing levels of allopregnanolone, which diminish the regulation of GABA(A)(R).
