CORDIS - Forschungsergebnisse der EU

Exploring new genetic causes and pathological mechanisms of epileptic focal cortical dysplasia


Wie kortikale Dysplasie mit Epilepsie verknüpft ist

Die fokale kortikale Dysplasie ist eine seltene genetische Fehlbildung der Großhirnrinde, die mit fokaler Epilepsie einhergehen kann. Auch wenn die abnormen Zellen, die in den der fokalen kortikalen Dysplasie entsprechenden Läsionen zu finden sind, die Quelle der für Epilepsie typischen Aktivität sein könnten, ist der Ursprung dieser Zellen unklar. Das EU-finanzierte Projekt CODICES hat die molekulare und genetische Charakterisierung dieser abnormen Zellen zum Ziel, die eine Hyperaktivierung des mTOR-Signalwegs aufweisen. Die Forschenden werden Humanorganoide verwenden, um die für die Entstehung von Epilepsie entscheidenden Entwicklungsmechanismen zu enträtseln. Langfristig wird CODICES den Weg zu wirkungsvolleren und weniger invasiven Behandlungen der fokalen Epilepsie weisen.


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.


€ 196 707,84
75013 Paris

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Ile-de-France Ile-de-France Paris
Research Organisations
€ 196 707,84