Genetics of tuberous sclerosis complex: implications for clinical practice

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.

Figure 1

A schematic diagram depicting the TSC-mTOR signaling pathway. Notes: mTOR is modulated by the TSC1–TSC2–TBC1D7 complex, integrating inputs from growth factors via PI3K, amino acids via the GATOR1 complex, and cellular energy levels (ATP) via AMPK. Enhanced mTOR signaling in response to these cues or as a consequence of TSC1 or TSC2 mutations leads to increased protein synthesis and cell growth. Abbreviations: TSC, tuberous sclerosis complex; mTOR, mechanistic target of rapamycin; PI3K, PI3 kinase; p70S6K, p70 S6 kinase.