The Contribution of Rapamycin-Insensitive Processes to Neurological Symptoms in TSC

Tuberous sclerosis complex (TSC) is a neurocutaneous syndrome that is characterized by benign tumors in multiple organs and associated with neurological symptoms such as epilepsy, autism spectrum disorder (ASD), intellectual disability, and other neuropsychiatric disorders. Together, these neurological disorders have been termed TSC-associated neuropsychiatric disorders (TAND),and there is growing recognition of the impact of these symptoms on the lives of patients with TSC. TSC is caused by mutations in eitherTSC1 or TSC2, and these proteins form a complex (TSC1/2) that functions as a critical inhibitor of the kinase, mammalian target of rapamycin (mTOR). mTOR is important signaling hub that regulates cell growth and proliferation, and it becomes inappropriately active in TSC, leading to many of the symptoms. The mTOR inhibitors rapamycin and everolimus (termed rapalogs) have revolutionized the treatment of many manifestations of TSC, but the neurological symptoms have been more recalcitrant. Everolimus was shown to be effective as an adjunct for refractory epilepsy in TSC, but there was an average 50 percent reduction in seizure frequency with most patients continuing to have several seizures per day. In addition, two trials of everolimus for behavioral and neuropsychiatric disorders associated with TSC have shown no effect. Therefore, we hypothesize that rapalog-insensitive effects contribute to the development and expression of the neurological symptoms associated with TSC.