Monitoring and Managing Patients with Tuberous Sclerosis Complex: Current State of Knowledge

Abstract

Tuberous sclerosis complex (TSC) is a rare genetic disease of autosomal dominant transmission that, in most cases, results from the presence of pathogenic variants of the TSC1 or TSC2 genes, encoding hamartin and tuberin, respectively. It is a multisystemic disease, affecting most frequently the brain, skin, kidney, and heart. The wide variety of possible clinical manifestations, given this multisystem dimension, makes the follow-up of patients with TSC an exercise of multidisciplinarity. In fact, these patients may require the intervention of various medical specialties, which thus have to combine their efforts to practice a medicine that is truly holistic. The past few years have witnessed a dramatic leap not only in the diagnosis and management of TSC patients, with standard monitoring recommendations, but also in the therapeutic field, with the use of mTORC1 inhibitors. In this article, we review the clinical manifestations associated with TSC, as well as the treatment and follow-up strategies that should be implemented, from a multidisciplinary perspective.

Keywords: care management; multidisciplinary communications; patient; tuberous sclerosis complex.

Figure 1

Overview of mTOR-TSC regulation and upstream and downstream mediators. Mutations in either TSC1 or TSC2 genes lead to hyperactivation of the downstream mTOR pathway by suppression of Rheb-mediated mTORC1 inhibition. The TSC1-TSC2 protein complex integrates cues such as nutrients, growth factors, hormones, and mitogens to regulate the activity of mTOR. mTOR complexes 1 and 2 are mediators of important cellular functions. Some of the downstream targets of mTORC1 were already clearly identified, including S6K1 and 4E-BP1 proteins, which play a major role in the regulation of cell growth, proliferation, and metabolism. TSC1 and TSC2 proteins have additional roles besides the modulation of mTOR, since inhibition of B-Raf kinase via Rheb is an mTOR-independent function of tuberin. Sirolimus and everolimus are effective inhibitors of mTORC1 via FKBP12.

Figure 2

Small SEGA of the left hemisphere, in a child diagnosed with TSC. The image represents a T1-weighted MRI axial section after intravenous gadolinium administration (arrow points to SEGA).

Figure 3

Large angiomyolipoma adjacent to the right kidney. The image is a sagittal section of a contrast-enhanced Computed Tomography scan obtained from an adult patient diagnosed with TSC, which reveals a lobulated right kidney and a voluminous mass (arrow), consisting essentially of fat, adjacent to it.