PCDH19 clustering epilepsy (PCDH19-CE) is an X-linked epilepsy disorder associated with intellectual disability (ID) and behavioral disturbances, which is caused by PCDH19 gene variants. PCDH19 pathogenic variant leads to epilepsy in heterozygous females, not in hemizygous males and the inheritance pattern is unusual. The hypothesis of cellular interference was described as a key pathogenic mechanism. According to that, males do not develop the disease because of the uniform expression of PCDH19 (variant or wild type) unless they have a somatic variation. We conducted a literature review on PCDH19-CE pathophysiology and concluded that other significant mechanisms could contribute to pathogenesis including: asymmetric cell division and heterochrony, female-related allopregnanolone deficiency, altered steroid gene expression, decreased Gamma-aminobutyric acid receptor A (GABAA) function, and blood-brain barrier (BBB) dysfunction. Being aware of these mechanisms helps us when we should decide which therapeutic option is more suitable for which patient.
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| http://dx.doi.org/10.1016/j.yebeh.2024.109730 | DOI Listing |
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Triplication of the Gene as a Novel Disease Mechanism Leading to Epileptic Encephalopathy Resembling Loss-of-Function Pathogenic Variants.
Genes (Basel)
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Translational Research Group in Genetics, La Fe Health Research Institute, 46026 Valencia, Spain.
Background/objectives: Developmental and epileptic encephalopathy 9 (DEE9) (MIM #300088) affects heterozygous females and males with somatic pathogenic variants, while male carriers with hemizygous pathogenic variants are clinically unaffected. There are hundreds of pathogenic single nucleotide variants in the gene reported in the literature, which lead to the loss of function of the PCDH19 protein. To date, no phenotypes associated with overexpression or copy number gains have been described in this gene.
View Article and Find Full Text PDFAbnormal cell sorting and altered early neurogenesis in a human cortical organoid model of Protocadherin-19 clustering epilepsy.
Front Cell Neurosci
April 2024
Department of Neurology, University of Michigan, Ann Arbor, MI, United States.
Article Synopsis
- Protocadherin-19 (PCDH19) -Clustering Epilepsy (PCE) is a genetic disorder mainly affecting females due to mutations in the PCDH19 gene on the X-chromosome, which disrupts cell interactions in the brain.
- Researchers created a new model using isogenic human embryonic stem cells to simulate the mosaic expression of mutant and normal cells, which is key for studying PCE.
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Mapping combinatorial expression of non-clustered protocadherins in the developing brain identifies novel PCDH19-mediated cell adhesion properties.
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School of Biomedicine and Robinson Research Institute, University of Adelaide, Adelaide, South Australia 5005, Australia.
Non-clustered protocadherins (ncPcdhs) are adhesive molecules with spatio-temporally regulated overlapping expression in the developing nervous system. Although their unique role in neurogenesis has been widely studied, their combinatorial role in brain physiology and pathology is poorly understood. Using probabilistic cell typing by sequencing, we demonstrate combinatorial inter- and intra-familial expression of ncPcdhs in the developing mouse cortex and hippocampus, at single-cell resolution.
View Article and Find Full Text PDFPCDH19-clustering epilepsy, pathophysiology and clinical significance.
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Child Neurology Division and Children's Epilepsy Monitoring Unit, Children's Medical Centre, Tehran University of Medical Sciences, Tehran, Iran.
PCDH19 clustering epilepsy (PCDH19-CE) is an X-linked epilepsy disorder associated with intellectual disability (ID) and behavioral disturbances, which is caused by PCDH19 gene variants. PCDH19 pathogenic variant leads to epilepsy in heterozygous females, not in hemizygous males and the inheritance pattern is unusual. The hypothesis of cellular interference was described as a key pathogenic mechanism.
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