Exploring new genetic causes and pathological mechanisms of epileptic focal cortical dysplasia
Focal cortical dysplasia (FCD) is a rare, genetic, non-syndromic developmental malformation of the cerebral cortex that accounts for 5-10% of patients with focal epilepsy. FCD represents the main cause of pharmacologically intractable epilepsy, the only treatment available consisting of invasive surgical resection of the epileptogenic zone, which results effective in only 62% of patients. Thus, a better understanding of this disorder is necessary to develop more effective and less invasive treatments. FCD type 2 (FCD2) is an mTORopathy caused by genetic mutations that cause hyperactivation of the mTOR pathway, leading to abnormal cell size (cytomegalic dysmorphic neurons and balloon cells) and disruption of the structure of the cortex. Recently, the supervisor S. Baulac and others have partially explained the focal nature of the disorder by identifying post-zygotic somatic (mosaic) mutations in a percentage of cells that correlates with the size of the lesion. Despite this, the underling genetics remains unknown for ~40% of FCD2 patients. My first objective is to perform deep whole-exome sequencing of a cohort of 60 unsolved FCD2 cases to explore alternative pathways and find possibly pathogenic variants, focusing on those with an established link with mTOR pathway and/or neurodevelopment. Abnormal cells found in FCD2 lesions have been hypothesized as the source of the epileptogenic activity. However, the developmental origins of these cells are still unclear, and there is a need to find clear biomarkers that can clarify the link between mTOR hyperactivation and neuronal hyperexcitability. This project aims to clarify these aspects by applying my expertise in single cell genomics and S. Baulac’s expertise in functional studies and disease modelling in human brain organoids. The MSCA IF will allow me to reintegrate in Europe after a 4-years+ postdoc in the US and complete my training with the objective of applying to set up my own lab at the end of the two years.