Mammalian Target of Rapamycin Inhibitors and Life-Threatening Conditions in Tuberous Sclerosis Complex☆
Introduction
Clinical manifestations associated with tuberous sclerosis complex (TSC) are due to the involvement of different organs, with central nervous system (CNS) representing the most frequent cause of morbidity; also kidneys, heart, and lungs are commonly involved.1 The appearance of TSC-related lesions and manifestations follows an age-dependent pattern.2 Phenotypic variability in TSC is very high; with some individual presenting a completely asymptomatic disease, and receiving a diagnosis due to an incidental finding or to the detection of the disease in their own child. By contrast, other individuals present very severe manifestations, with early onset of symptoms and complications requiring arduous and sometimes immediate clinical decisions.
After the discovery of the 2 causative genes, TSC1 and TSC2,3, 4 a great progress has been made in understanding the pathophysiology of the disease. It is, in fact, now well known that the genetic mutation leads to an overactivation of the mammalian target of rapamycin (mTOR) pathway, which is a central controller of cell growth and proliferation and plays a significant role in the tumorigenesis of most of TSC-related lesions.5 mTOR also regulates, both directly and indirectly, synaptogenesis and neuronal excitability, thus explaining its role even in determining neurological and neuropsychiatric symptoms, such as epilepsy, autism, and intellectual disability.6
In the last few years everolimus, a selective inhibitor of mTOR pathway, has been licensed both in Europe and in USA for the treatment of TSC-related subependymal giant cell astrocytomas (SEGAs) and renal angiomyolipomas (AMLs). This drug is proving to be effective and safe in these patients, and although specifically administered for SEGA or AML or both, different benefits have been also observed in other manifestations, such as pulmonary lymphangioleiomyomatosis, cardiac rhabdomyomas, and skin lesions.7, 8, 9, 10 In some studies also epileptic seizures appeared to be improved during everolimus treatment, which is therefore candidate to become a potential systemic treatment for TSC.11
The aim of this article is to review what is known on life expectancy and the current causes of death in patients with TSC, and to assess all the main complications and life-threatening events that require an immediate intervention by the clinicians. Furthermore, as mTOR inhibitors have been recently approved, we review the current approach with mTOR inhibitors in all the medical complications and life-threatening conditions associated with the different manifestations of TSC.
Section snippets
Mortality in TSC
Despite there are no specific data in the literature reporting the life expectancy of subjects with TSC, it is well known that they are at increased risk of a series of life-threatening conditions.12 The more comprehensive study performed on this issue was performed at the Mayo Clinic, Rochester, by Shepherd and Gomez12 more than 20 years ago on a large sample of 355 patients, and another retrospective Dutch series by Eijkemans et al13 have been published recently. Shepherd and Gomez found a
Growing Symptomatic SEGAs
SEGAs are mixed cell lineage brain tumors typically growing near the foramen of Monro.21 Although histologically benign, they are highly dynamic lesions, and their location and tendency to grow can determine progressive ventricular dilatation, obstructive hydrocephalus, and severe complications, ultimately causing death.1 In the past, diagnosis of SEGA was delayed until the onset of symptoms of intracranial hypertension; currently the actual follow-up of patients with TSC requires serial
Heart Manifestations
Cardiac rhabdomyomas are the main feature of TSC in the fetus and newborns, and are benign tumors anatomically considered as hamartomas consisting of glycogen myocytes.77, 78, 79 Most commonly they protrude in the ventricles but they can occur in the atria or cava veins as well, less frequently are located within the walls, more often than the septum.80
Cardiac rhabdomyomas, partially or completely, spontaneously regress over time in more than 60% of cases,78, 79, 81, 82 and regression may leave
Current Perspectives and Future Directions
The few epidemiological data available on mortality in TSC seem to show a trend toward a reduction of mortality rate in this complex disease.12, 13 Of course this is partly due to the increasing knowledge of TSC and its manifestations and clinical course, which allow a tailored follow-up with an accurate surveillance plan. This makes clinicians able to early identify life-threatening conditions addressing them in the optimal way, by choosing among the available treatment options.
The last decade
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Mechanistic target of rapamycin (mTOR) signaling in status epilepticus
2019, Epilepsy and BehaviorCitation Excerpt :The time to serum steady state is approximately 5–7 days with a serum half-life of ~ 60 h. Mechanistic target of rapamycin inhibitors as a class of drugs have few drug–drug interactions, although their metabolism is enhanced when coadministered with CYP3A inducers. The side effect profile of mTOR inhibitors ranges from Grade I serious adverse events (aphthous oral ulcers, nausea, diarrhea) to Grade IV events with hyperlipidemia, dysmenorrhea, interstitial pneumonitis, and immunodeficiency [32]. Some of these effects are dose-dependent, while others are idiosyncratic.
Tuberous Sclerosis Complex in Chinese patients: Phenotypic analysis and mutational screening of TSC1/TSC2 genes
2019, SeizureCitation Excerpt :The TSC1 gene contains 23 exons, coding for a 130-kDa protein named Hamartin, while TSC2 consists of 42 exons generating a transcript from which a 200-kDa protein called Tuberin is deriving. Both proteins form a complex that negatively regulates the activation of the mechanistic target of Rapamycin complex 1 (mTORC1), a master serine/threonine kinase that plays role in multiple processes, including translation, ribosome biogenesis, and autophagy [5]. It’s said that patients with TSC2 mutations tend to have more severe manifestation.
Adjunctive everolimus for children and adolescents with treatment-refractory seizures associated with tuberous sclerosis complex: post-hoc analysis of the phase 3 EXIST-3 trial
2018, The Lancet Child and Adolescent HealthCitation Excerpt :Furthermore, community-acquired infections, such as upper respiratory infections, have been estimated to occur 4–6 times per year in children and 2–4 times per year in young adults, and might not be related to everolimus exposure specifically, suggesting that continued surveillance is essential.21 Two deaths that occurred during the reporting period in our study were because of pneumonia and sudden unexplained death due to epilepsy, which is recognised as a life-threatening event related to tuberous sclerosis complex.30 Importantly, however, everolimus was well tolerated in the younger patients during the extended treatment duration (median 1·6 years), with only seven patients discontinuing because of adverse events during the extension phase.
A phase II study of temsirolimus added to low-dose weekly carboplatin and paclitaxel for patients with recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC)
2017, Annals of OncologyCitation Excerpt :One of two patients with a mutation inTSC1, specifically TSC1G305R missense mutation, had a PR and the other patient withTSC1 K820E missense mutation had 24% regression in a target lesion. Given that hyperactivation of mTORC1 is the primary alteration driving the growth ofTSC mutant tumors [13], aTSC1/2 mutation should be predictive of response to temsirolimus. There was no apparent trend in the molecular signatures of patients with >50% regression in a target lesion or on treatment for >6 months.
Everolimus Alleviates Obstructive Hydrocephalus due to Subependymal Giant Cell Astrocytomas
2017, Pediatric NeurologyCitation Excerpt :In all our patients, everolimus was used as an off-label or compassionate therapy because of the risks associated with surgery and the presence of sever systemic comorbidities. SEGAs represent one of the major causes of mortality in TSC, and treatment with everolimus has been recently considered as a possible prevention of life-threatening events.3 Our clinical experience demonstrates that even when symptomatic or asymptomatic hydrocephalus appears, everolimus could still be a valuable option when surgery is too risky because of the large size of lesions and lower chance of complete resection.
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Paolo Curatolo and Romina Moavero received funding from the European Community’s Seventh Framework Programme (FP7/2007-2013) under Grant agreement no. 602391 (www.epistop.eu).