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. 2017 Mar 14;12(1):51.
doi: 10.1186/s13023-017-0596-2.

mTOR Inhibitors in the Pharmacologic Management of Tuberous Sclerosis Complex and Their Potential Role in Other Rare Neurodevelopmental Disorders

Free PMC article

mTOR Inhibitors in the Pharmacologic Management of Tuberous Sclerosis Complex and Their Potential Role in Other Rare Neurodevelopmental Disorders

David N Franz et al. Orphanet J Rare Dis. .
Free PMC article


Tuberous sclerosis complex (TSC) is a rare autosomal dominant genetic disorder that affects multiple organ systems throughout the body. Dysregulation of the mammalian target of rapamycin (mTOR) pathway is implicated in the disease pathology, and evidence exists to support the use of mTOR inhibitors in treatment. The mTOR pathway has also been investigated as a potential treatment target for several other rare diseases. TSC research has highlighted the value of pursuing targeted therapies based on underlying molecular pathophysiology. One goal of current research is to identify the role of mTOR inhibition in neurologic and developmental disorders apart from TSC. There is also particular interest in the potential role of mTOR inhibitors in preventing seizures, neurodevelopmental disabilities, renal tumors, cutaneous tumors, and other manifestations typically seen in TSC. It is foreseeable that use of mTOR inhibition to prevent long-term morbidity in TSC will become mainstream therapeutic practice. This review will provide an overview of the relationship between the mTOR pathway and TSC disease pathology, summarize the clinical evidence supporting the use of mTOR inhibitors for treatment of the various manifestations of TSC, and discuss the potential therapeutic role of mTOR inhibitors in several rare diseases.

Keywords: Hamartomas; Mammalian target of rapamycin inhibitors; Morbidity; Neurologic manifestations; Tuberous sclerosis complex.


Fig. 1
Fig. 1
The mammalian target of rapamycin (mTOR) signaling pathway and possible involvement of rare diseases in the pathway. Stimulants such as insulin-like growth factor bind to tyrosine kinase receptors, which leads to the phosphorylation of phosphatidylinositol 3-kinase (PI3K) [23]. A cascade of subsequent phosphorylation events results in the activation of protein kinase B (AKT), which in turn phosphorylates and inhibits the TSC1/TSC2 complex, a negative regulator of mTOR that is directed against the positive regulator Ras homolog enriched in brain (Rheb). As a result, inhibition of the TSC1/TSC2 complex results in the activation of mTOR [–25]. NF1-encoded neurofibromin and NF2-encoded Merlin proteins also act as negative regulators of the mTOR pathway. Neurofibromin functions as a Ras-GTPase activating protein that inhibits the actions of Ras on PI3K [26], while Merlin acts directly on mTOR complex 1 (mTORC1) [27]. Sirolimus and everolimus both bind to and form complexes with FK506-binding protein-12 (FKBP12), resulting in the inhibition of mTORC1 activity [24]. While mechanisms are complex and not fully clear in Leigh and Down syndrome, evidence has shown a relationship between mTOR activity and ATP (Leigh syndrome), and decreased autophagy with increased protein production and oxidation with mTOR hyperactivation (Down syndrome) [62, 65, 66]

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