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Genetics of tuberous sclerosis complex: implications for clinical practice

Authors Caban C, Khan N, Hasbani DM, Crino PB

Received 27 February 2016

Accepted for publication 22 April 2016

Published 21 December 2016 Volume 2017:10 Pages 1—8

DOI https://doi.org/10.2147/TACG.S90262

Checked for plagiarism Yes

Review by Single-blind

Peer reviewer comments 4

Editor who approved publication: Prof. Dr. Martin H. Maurer


Carolina Caban,1,2 Nubaira Khan,1,2 Daphne M Hasbani,3 Peter B Crino1,2

1Department of Neurology, 2Shriners Hospitals Pediatric Research Center, Temple University School of Medicine, 3Department of Neurology, St. Christopher’s Hospital for Children, Drexel University College of Medicine, Philadelphia, PA, USA

Abstract: Tuberous sclerosis complex (TSC) is a multisystem disorder that results from heterozygous mutations in either TSC1 or TSC2. The primary organ systems that are affected include the brain, skin, lung, kidney, and heart, all with variable frequency, penetrance, and severity. Neurological features include epilepsy, autism, and intellectual disability. There are more than 1,500 known pathogenic variants for TSC1 and TSC2, including deletion, nonsense, and missense mutations, and all pathogenic mutations are inactivating, leading to loss of function effects on the encoded proteins TSC1 and TSC2. These proteins form a complex to constitutively inhibit mechanistic target of rapamycin (mTOR) signaling cascade, and as a consequence, mTOR signaling is constitutively active within all TSC-associated lesions. The mTOR inhibitors rapamycin (sirolimus) and everolimus have been shown to reduce the size of renal and brain lesions and improve pulmonary function in TSC, and these compounds may also decrease seizure frequency. The clinical application of mTOR inhibitors in TSC has provided one of the first examples of precision medicine in a neurodevelopmental disorder.

Keywords: TSC, epilepsy, genetics, mTOR, rapamycin

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