Tuberous sclerosis complex (
TSC) is an autosomal dominant disorder that affects multiple organ systems and is caused by loss-of-function mutations in one of two genes: TSC1 or TSC2. The disorder can affect both adults and children. First described in depth by Bourneville in 1880, it is now estimated that nearly 2 million people are affected by the disease worldwide. The clinical features of
TSC are distinctive and can vary widely between individuals, even within one family. Major features of the disease include tumours of the brain, skin, heart, lungs and kidneys,
seizures and
TSC-associated neuropsychiatric disorders, which can include
autism spectrum disorder and cognitive disability. TSC1 (also known as
hamartin) and TSC2 (also known as
tuberin) form the
TSC protein complex that acts as an inhibitor of the mechanistic target of
rapamycin (mTOR) signalling pathway, which in turn plays a pivotal part in regulating cell growth, proliferation, autophagy and
protein and
lipid synthesis. Remarkable progress in basic and translational research, in addition to several randomized controlled trials worldwide, has led to regulatory approval of the use of
mTOR inhibitors for the treatment of renal
angiomyolipomas, brain subependymal giant cell
astrocytomas and pulmonary
lymphangioleiomyomatosis, but further research is needed to establish full indications of therapeutic treatment. In this Primer, we review the state-of-the-art knowledge in the
TSC field, including the molecular and cellular basis of the disease, medical management, major knowledge gaps and ongoing research towards a cure.