Understanding focal cortical dysplasia: A path to novel treatments

Background

Focal cortical dysplasia (FCD) is a malformation of brain development, the most common cause of drug-resistant epilepsy and often caused by mutations in mammalian target of rapamycin (mTOR) pathway genes. Patients with FCD develop drug-resistant seizures.

Summary

Our study will look at FCD tissue removed during epilepsy surgery and aims to detect mutations in mTOR pathway genes in brain cells. Secondly, we will establish if evidence of mutations found in brain cells can also be detected as circulating free DNA (cfDNA) in blood. By looking at which genes are made into proteins in individual cells found in epilepsy surgical tissue (single cell expression profiling), we will attempt to identify new genetic targets in FCD. In a pilot trial we will assess if refractory patients with FCD experience a reduction in seizure frequency when treated with a novel mTOR inhibitor drug.

Patient representatives will be invited to form an advisory panel and be involved in the design of the pilot trial, research governance and peer recruitment.

Significance:

The main outcome will be finding new causes of epilepsy with FCD and the development of new diagnostic and screening tools.

Secondly, this study may identify a potentially new and causal treatment for people with FCD due to mTOR pathway mutations.

Results from this study will allow us to set up a multi-centre trial to confirm our findings and may become applicable to refractory focal epilepsy patients in the medium term.

This research will identify novel mutations/pathways leading to FCD, novel methods to test for mTOR mutations and develop new screening tools by performing a simple blood test or nasal swab.It will quickly answer if mTOR inhibitor treatment results in a useful seizure frequency reduction in drug-resistant patients.