Applying the Lessons of Tuberous Sclerosis: The 2015 Hower Award Lecture

Abstract Tuberous sclerosis complex is a dominantly inherited disorder that variably affects the brain, skin, kidneys, heart, and other organs. Its neurological manifestations include epilepsy, autism, cognitive and behavioral dysfunction, and giant cell tumors. A mutation of either TSC1 or TSC2 can cause tuberous sclerosis complex. Their two gene products, hamartin and tuberin, form a physical complex which normally inhibits protein synthesis mediated through the mechanistic target of rapamycin, so a TSC1 or TSC2 mutation results in overactivation of the mechanistic target of rapamycin cascade. In addition to their tumor suppressor roles, TSC1 and TSC2 help to regulate cell size, neuronal migration, axon formation, and synaptic plasticity. Clinical trials of two different the mechanistic target of rapamycin inhibitors have demonstrated substantial improvement of tuberous sclerosis complex–related tumors, and a recent trial also showed a benefit from the mechanistic target of rapamycin inhibitor everolimus in the treatment of refractory epilepsy due to tuberous sclerosis complex. Effective mechanism-based therapy is now available for some manifestations of tuberous sclerosis complex.