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.
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The work of S.J. in this study has been partially supported by the 7th Framework Programme of European Commission within the large-scale integrating project EPISTOP (Proposal No. 602391–2). The work of E.P.H. was partially supported by the Lucy J. Engles Program in TSC/LAM Research. E.A.T. acknowledges the Carol and James Herscot Center for Children and Adults with TSC at Massachusetts General Hospital. The authors are grateful to J. Nijmeh for assistance with preparation of the manuscript.
S.J. has been a consultant for UCB Pharma and Eisai, has received speakers honoraria from Novartis and is a site principal investigator for Novartis clinical trials. J.R.S. has received grant funding and honoraria from Novartis. J.C.K. has received honoraria for lectures and consultancy from Novartis. E.A.T. is a consultant for GW Pharmaceuticals and Zogenix, has received grants from GW Pharmaceuticals, Lundbeck and Cyberonics, is a site principal investigator for GW Pharmaceuticals and Zogenix clinical trials and has been a site principal investigator for Novartis clinical trials. E.P.H. has been a consultant to LAM Therapeutics and was an investigator on a Novartis-sponsored trial of everolimus in lymphangioleiomyomatosis, for which no compensation or salary support was provided.
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Henske, E., Jóźwiak, S., Kingswood, J. et al. Tuberous sclerosis complex. Nat Rev Dis Primers 2, 16035 (2016). https://doi.org/10.1038/nrdp.2016.35
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