Mammalian Target of Rapamycin Inhibitors and Life-Threatening Conditions in Tuberous Sclerosis Complex

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Tuberous sclerosis complex (TSC) is a multisystem disease associated with an overall reduction in life expectancy due to the possible occurrence of different life-threatening conditions. Subjects affected by TSC are, in fact, at risk of hydrocephalus secondary to the growth of subependymal giant cell astrocytomas, or of sudden unexpected death in epilepsy. Other nonneurological life-threatening conditions include abdominal bleeding owing to renal angiomyolipomas rupture, renal insufficiency due to progressive parenchymal destruction by multiple cysts, pulmonary complications due to lymphangioleiomyomatosis, and cardiac failure or arrhythmias secondary to rhabdomyomas. In the last decades, there has been a great progress in understanding the pathophysiology of TSC-related manifestations, which are mainly linked to the hyperactivation of the so-called mammalian target of rapamycin (mTOR) pathway, as a consequence of the mutation in 1 of the 2 genes TSC1 or TSC2. This led to the development of new treatment strategies for this disease. In fact, it is now available as a biologically targeted therapy with everolimus, a selective mTOR inhibitor, which has been licensed in Europe and USA for the treatment of subependymal giant cell astrocytomas and angiomyolipomas in subjects with TSC. This drug also proved to benefit other TSC-related manifestations, including pulmonary lymphangioleiomyomatosis, cardiac rhabdomyomas, and presumably epileptic seizures. mTOR inhibitors are thus proving to be a systemic therapy able to simultaneously address different and potentially life-threatening complications, giving the hope of improving life expectation in individuals with TSC.

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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    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).

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