Therapeutics for Tuberous Sclerosis

Tuberous Sclerosis Complex (TSC) is a disease characterized by abnormal hamartomas and benign neoplasms in multiple organs. The diagnosis is made by the presence of 2 major features, or 1 major feature accompanied by 2 minor features. These features include various growths in different parts of the body, such as facial angiofibromas, cardiac rhabdomyomas, or renal angiomyolipomas to name a few. TSC is typically managed by controlling symptoms that arise from the various growths (i.e. surgical excision of disfiguring tumors or antiepileptic medication for seizures related to brain tumors). The disease is caused by mutations to the genes that encode for tuberin and/or hamartin. Tuberin and hamartin form a complex that leads to downstream inactivation of mTOR Complex 1 (mTORC1), a protein complex that promotes cell growth and inhibits cell death. With the loss of tuberin and/or hamartin via gene mutations, mTORC1 becomes disinhibited, resulting in neoplasia. Sirolimus and Everolimus are mTOR inhibitors that have been shown to be effective in treating some patients with TSC. These drugs bind FKBP12, and this complex then binds and inhibits the overactive mTORC1. Patients with lymphangiomyomatosis from TSC may also respond to oophorectomy, medroxyprogesterone, and tamoxifen therapy as these cells express estrogen and progesterone receptors. Lastly, patients with TSC who have seizures that are refractory to antiepileptic therapy may benefit from the addition of cannabidiols to their treatment regimen.[1] Brakemeier S, Bachmann F, Budde K. Treatment of renal angiomyolipoma in tuberous sclerosis complex (TSC) patients. Pediatr Nephrol. Jul 2017;32(7):1137-1144. doi:10.1007/s00467-016-3474-6; [2] D'Antona L, Amato R, Brescia C, et al. Kinase Inhibitors in Genetic Diseases. Int J Mol Sci. Mar 9 2023;24(6)doi:10.3390/ijms24065276; [3] Feliciano DM. The Neurodevelopmental Pathogenesis of Tuberous Sclerosis Complex (TSC). 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