Focal cortical dysplasia (FCD) are malformations of cortical development (MCD) associated to severe pediatric refractory epilepsies subjected to neurosurgery. My talk will provide a comprehensive view of the occurrence of germline and brain somatic variants in a large cohort of patients with FCD. We used ultra-deep sequencing in paired brain/blood patient samples, as well as in pools of microdissected dysmorphic neurons and balloon cells to elucidate the etiology of these neurodevelopmental disorders. Our study revealed frequent mutations in mTOR-pathway genes, and highlighted a strong link between genetics findings and neuropathology. Our data also emphasize that a single hit in activators of the mTOR pathway or in MTOR itself is sufficient to cause the MCD, while two-hit mutations are necessary in repressors of the pathway (i.e. DEPDC5). We established a preclinical mouse model of brain somatic mutations which faithfully reproduced clinical and neuropathological phenotypes of focal epilepsy linked to FCD linked to mTOR hyperactivity.
G.M. van Woerden