Tuberous Sclerosis Complex (TSC) is a rare genetic disorder that results from a mutation in the TSC1 or TSC2 genes leading to constitutive activation of the mechanistic target of rapamycin complex 1 (mTORC1). TSC is associated with autism, intellectual disability and severe epilepsy. Cortical tubers are believed to represent the neuropathological substrates of these disabling manifestations in TSC. The expansion of neurosurgical epilepsy programs has offered the possibility of disposing clinically well-characterized human tissue, so that molecular mechanisms underlying the structural and functional reorganization within the epileptic focus can be investigated on a large scale. In our project a large cohort of TSC cases with representative cortical tubers and perituberal cortex has been collected and selected cases were used to generate a lesion classification system based on semi‑automated histological quantification. Moreover, we used high-throughput RNA sequencing in combination with systems/computational analytic approaches to investigate the complexity of the TSC molecular network.. Through the analysis of the neuropathological and molecular and functional features specific of TSC brain lesions, a more defined picture of the relationship between the neuropathology and epileptogenesis can be achieved. Recent evidence support the hypothesis of developmental immaturity in TSC brain as unifying mechanism to explain the complex neurological and neuropsychiatric phenotypes and treatment challenges in TSC patients. Moreover, neuron‑glia interactions involving inflammatory molecules may also play a critical role in the generation of seizures and cognitive dysfunction. Both neuropathological and molecular features of TSC brain lesions will be discussed, highlighting the involvement of different, but often converging epileptogenic mechanisms. FINANCIAL SUPPORT: European Union’s Seventh Framework Programme (FP7/2007–2013) under the grant agreement no. 602391 (project acronym EPISTOP.
Department of Neuropathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
Stichting Epilepsie Instellingen Nederland (SEIN), The Netherlands