Grant: Project Grant

Focal cortical dysplasia (FCD) is a developmental malformation of the cerebral cortex, composed of disorganized and abnormal neurons and glia. FCDs are the most common cause of drug-resistant epilepsy in children and adults. Antiseizure medications are usually ineffective, and only a subset of patients is amenable to surgical resection. The pathophysiological mechanisms underlying FCDs are poorly understood. Recent studies have revealed that somatic mutations (ie those present only in a subset of cells) in genes of the mTOR pathway underlie many FCDs. The mutations all cause the hyperactivation of the pathway and are surprisingly present in only a small proportion of cells within the FCD, usually as low as 1 to 5%. It is unknown which cell types harbour the mutations, and how such as small proportion of mutated cells can result in such devastating epilepsy. We propose to determine which cell types within the FCD carry mutations and study the impact of the mutations on the mutant cells as well as adjacent non-mutant cells. We hypothesize that mutations are primarily found in neurons, and that the mutant neurons cause dysfunction of the surrounding non-mutant cells within the FCD tissue. We will perform single nucleus sequencing in FCD samples that we have genetically characterized, in order to: Aim 1: Determine which cell types within the FCD contain mutations, and the impact of the mutations on mutant cells Aim 2: Compare the expression of non-mutant cells that are within the FCD lesion, with those outside the FCD lesion. Understanding the genetic mechanisms and pathophysiology underlying FCDs is crucial for the development of novel targeted and specific treatments for patients with FCD. Moreover, the mechanisms we will discover have the potential to be applied to other epilepsies and genetic disorders caused by mTOR dysfunction.