PCDH19-Related Epilepsy
PCDH19-related epilepsy is an X-linked genetic condition quite literally marked by early-onset clustered seizures, intellectual disability, and behavioral abnormalities. To solve the challenges associated with PCDH19-related epilepsy, Protheragen is dedicating its resources to advanced technologies and specialists focused on developing effective therapies. The integrated support services that we offer will accelerate your journey from drug candidate development to commercialization.
Overview of PCDH19-Related Epilepsy
PCDH19-related epilepsy falls within the category of rare X-linked dominant disorders which arises from a mutation within PCDH19 gene. This disorder manifests as a combination of clustered focal seizures, intellectual disability, and various forms of behavioral abnormalities. It is a disorder with an incidence rate of approximately 1 in 10,000 to 30,000 live births, mainly occurring in females. This is due to X-chromosome inactivation mosaicism. Males are only very rarely affected due to hemizygous lethality.
Fig.1 Schematic drawing depicting the available tools for understanding the pathophysiology of PCDH19-CE. (Borghi, Rossella, et al., 2022)
Pathogenesis of PCDH19-Related Epilepsy
The pathogenesis of PCDH19-related epilepsy primarily stems from loss-of-function mutations in the PCDH19 gene, which disrupt neuronal cell adhesion and GABAergic synapse formation through a unique "cellular interference" mechanism where mosaic expression of mutant PCDH19 (due to X-inactivation in females) causes non-cell-autonomous dysfunction in mixed neuronal populations, leading to network hyperexcitability, seizure clusters, and neurodevelopmental impairments characteristic of the disorder.
Fig.2 Schematic presentation of the cellular interference mechanism with PCDH19 mutation and in normal individuals. (Szalai, Renata, et al., 2024)
Therapeutic Development for PCDH19-Related Epilepsy
| Drug Names | Mechanism of Action | Targets | Research Phase |
| Clobazam | Positive allosteric modulator of GABAA receptors; enhances inhibitory Cl- influx | GABAA receptors | Approved |
| Bromide | Non-specific GABAA potentiation; voltage-gated chloride channel modulation | GABAA receptors, CLC channels | Approved |
Disclaimer: Protheragen focuses on providing preclinical research services. This table is for information exchange purposes only. This table is not a treatment plan recommendation. For guidance on treatment options, please visit a regular hospital.
Our Services
Understanding the challenge of accurately diagnosing and treating PCDH19-related epilepsy, Protheragen is focused on assembling the needed specialists to develop innovative PCDH19 diagnostics and therapeutics. Our focus is on providing comprehensive service options to address each client's specific and diverse research needs pertaining to therapy development. We are also leaders in the generation of accurate disease models that are microscopically engineered to replicate the distinctive aspects of PCDH19-related epilepsy.
Therapeutic Development Services
By Mechanism of Action
Disease Model Development Services
In Vitro Model Development
- PCDH1919 Knockout Mice: Genetically engineered with complete PCDH19 gene deletion to study seizure susceptibility and neuronal migration defects.
- PCDH19 Knockdown Rats: Partially PCDH19 expression reduces to simulate mosaic dysfunction.
Protheragen is pleased to provide a complete preclinical research service for PCDH19-related epilepsy using modern disease models. These services cover all components of drug research such as pharmacodynamics (PD), pharmacokinetics (PK), and safety assessments, thus providing a balanced and integrated strategy to address this condition. If you would like to know more about our services, kindly reach out to us for further details and pricing documents of related services.
References
- Borghi, Rossella, et al. "Modeling PCDH19-CE: From 2D Stem Cell Model to 3D Brain Organoids." International Journal of Molecular Sciences 23.7 (2022): 3506.
- Szalai, Renata, et al. "NGS-Based Identification of Two Novel PCDH19 Mutations in Female Patients with Early-Onset Epilepsy." International Journal of Molecular Sciences 25.11 (2024): 5732.