Abstract
Tuberous sclerosis complex (TSC) is a genetic multisystem disorder characterized by the development of hamartomas in several organs. Mutations in the TSC1 and TSC2 tumor suppressor genes determin overactivation of the mammalian target of rapamycin (mTOR) signaling pathway and subsequent abnormalities in numerous cell processes. As a result, mTOR inhibitors such as sirolimus and everolimus have the potential to provide targeted therapy for TSC patients. Everolimus has been recently approved as a pharmacotherapy option for TSC patients with subependymal giant-cell astrocytomas (SEGAs) or renal angiomyolipomas (AMLs). However, clinical evidence suggests that this treatment can benefit other TSC-associated disease manifestations, such as skin manifestations, pulmonary lymphangioleiomyomatosis, cardiac rhabdomyomas, and epilepsy. Therefore, the positive effects that mTOR inhibition have on a wide variety of TSC disease manifestations make this a potential systemic treatment option for this genetic multifaceted disorder.
Highlights
Tuberous sclerosis complex (TSC) is a variably expressed autosomal dominant genetic disorder characterized by the presence of benign, non-invasive, tumor-like lesions in the brain, heart, skin, kidney, lung, and liver [1]
Central Nervous System is almost invariably affected in TSC (85–90% of children and adolescents), causing disabling neurological manifestations, including epilepsy, subependymal nodules (SENs; 90–100%), subependymal giant cell astrocytomas (SEGAs; 5–20%), and mental delay (44–64%) [1]
Positive data regarding mammalian target of rapamycin (mTOR) inhibitors efficacy in pulmonary LAM come both from case series and from specific randomized trials, even if these were not initially designed for TSC patients [35,36,37]
Summary
Tuberous sclerosis complex (TSC) is a variably expressed autosomal dominant genetic disorder characterized by the presence of benign, non-invasive, tumor-like lesions (hamartomas) in the brain, heart, skin, kidney, lung, and liver [1]. MTOR inhibitors’ efficacy in determining a reduction of SEGA volume is well established, so that Everolimus has been the first drug licensed in the USA and Europe for the treatment of TSC patients aged ≥3 years with TSC-related SEGA who require therapeutic intervention, but are not candidates for curative surgical resection. Clinical studies of rapamycin in human epilepsy are limited, but suggest that mTOR inhibitors at least have antiseizure effects in tuberous sclerosis patients.
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