Tuberous sclerosis complex

Tuberous sclerosis complex (TSC) is a rare genetic disease caused by heterozygous loss-of-function variants in TSC1 or TSC2. Patients present with benign tumours known as hamartomas in the brain, eyes, lungs, kidneys, heart and skin. Many hamartomas contain mosaic second hit variants in TSC1 or TSC2. The most disabling features of TSC include epilepsy and TSC-associated neuropsychiatric disorders (TAND) such as intellectual disability and autism spectrum disorder. Remarkable progress has been made both in understanding the pathogenesis of TSC and in its clinical management, largely due to the discovery of the link between TSC1 and TSC2 and the mechanistic target of rapamycin (mTOR) signalling pathway. TSC1 and TSC2 form a protein complex that inhibits mTOR. Naturally occurring inhibitors of mTOR (rapamycin) and its analogues, collectively known as rapalogues, have been used to test various hypotheses in preclinical models and are approved for the treatment of several manifestations of TSC. Approved drug treatments (rapalogues) exist for subependymal giant cell astrocytomas, renal angiomyolipomas, pulmonary lymphangioleiomyomatosis, facial angiofibromas and refractory seizures. However, there is still an unmet need for effective treatment of TAND and refractory epilepsy, despite the available medical and surgical options.