title: Genetics of tuberous sclerosis complex: implications for clinical practice.
abstract: Tuberous sclerosis complex (TSC) is a multisystem disorder that results from heterozygous mutations in eitherTSC1orTSC2. 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 forTSC1andTSC2, 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.
authors.affiliation: Department of Neurology; Shriners Hospitals Pediatric Research Center, Temple University School of Medicine.
authors.forename: Carolina
authors.initials: C
authors.lastname: Caban
authors.affiliation: Department of Neurology; Shriners Hospitals Pediatric Research Center, Temple University School of Medicine.
authors.forename: Nubaira
authors.initials: N
authors.lastname: Khan
authors.affiliation: Department of Neurology, St. Christopher's Hospital for Children, Drexel University College of Medicine, Philadelphia, PA, USA.
authors.forename: Daphne M
authors.initials: DM
authors.lastname: Hasbani
authors.affiliation: Department of Neurology; Shriners Hospitals Pediatric Research Center, Temple University School of Medicine.
authors.forename: Peter B
authors.initials: PB
authors.lastname: Crino
keywords: TSC; epilepsy; genetics; mTOR; rapamycin