Report

Teaser, summary, work performed and final results

Periodic Reporting for period 2 - EPITOR (NEUROBIOLOGY OF EPILEPSY GENES)

Teaser

Focal Cortical Dysplasia (FCDs) are rare genetic malformations of the brain cortical development which manifests with childhood-onset epilepsy, and developmental delay. FCDs are characterized by abnormal brain-MRI and characteristic neuropathologic hallmarks. FCDs are...

Summary

Focal Cortical Dysplasia (FCDs) are rare genetic malformations of the brain cortical development which manifests with childhood-onset epilepsy, and developmental delay. FCDs are characterized by abnormal brain-MRI and characteristic neuropathologic hallmarks. FCDs are drug-resistant to antiepileptics, and treatment often requires epilepsy surgery to control seizures. Nowadays, in the evolving landscape of epilepsy surgery population, FCDs represent a growing proportion and thus bring crucial challenges for patient care and treatment. Pathologically-relevant brain tissue obtained from epilepsy surgery offers unique opportunities for research purposes. Thanks to a tight collaboration with a pediatric neurosurgery department in Paris (Fondation Rothschild), our team has collected and biobanked frozen resected brain tissues and blood samples from a unique cohort of 150 children who underwent epilepsy surgery. Excitingly, we and others have recently shown that FCDs are caused by somatic mutations occurring during brain development, in genes belonging to the mTOR pathway, a signaling cascade regulating cell growth, proliferation, and senescence.

The overall objective of the proposal is to better understand how a genetic defect in the mTOR pathway causes epileptogenic malformations of cortical development based on the understanding of the underlying cellular pathogenic mechanisms.

Work performed

The research project encompasses the investigation of the genetic etiology of focal epilepsies, in particular those associated with Focal Cortical Dysplasia (FCD) and the establishment of Depdc5 knockout mouse models for focal epilepsies. DEPDC5, a repressor of mTOR signaling pathway, is recognized as the most frequently mutated gene in familial focal epilepsies.
We have generated two mice models of Depdc5-deficiency that successfully both recapitulate aspects of the diseases, in particular spontaneous seizures. We were able to elucidate the genetic etiology of 29% of FCD1 patients and 63% of FCD2 patients by panel sequencing.

Final results

By the end of the project, we expect to better understand the underlying pathogenic mechanisms and thus bridge the gap between a hyperactivation of the mTOR pathway and neuronal excitability that sustain epileptic seizures. Identification of brain partners of Depdc5 will help point out pathways.
We also aim to identify novel genes for focal epilepsies with focal cortical dysplasia and there fore elucidate the genetic cause in most patients.