Tuberous sclerosis complex

Genetics:

TSC is an autosomal dominant disorder caused by a mutation in either the TSC1 or TSC2 genes.^1,2 About 70% of individuals with TSC have a TSC2 mutation, and about 20% have a TSC1 mutation. The remainder typically have somatic mosaicism, meaning one copy of the TSC1 or TSC2 gene is mutated in only a portion of their cells.³ Furthermore, loss of heterozygosity or “second hit” mutations are found in the tumors characteristic of TSC. The variability of timing and location at which the second, functional, copy of the gene is lost contributes to the high person-to-person variability in TSC phenotypes.

The proteins encoded by TSC1 (hamartin) and TSC2 (tuberin) form the TSC protein complex, which regulates mechanistic target of rapamycin (mTOR) complex 1 (mTORC1). mTORC1 is involved in major cellular processes including cell growth, proliferation, protein synthesis, and autophagy.³ When hamartin or tuberin is absent or nonfunctional, the TSC protein complex no longer can inhibit mTORC1 activity. Overactivation of the mTORC1 signaling pathway leads to the tumor growth that is characteristic of TSC.

Symptoms:

The most life-threatening manifestations include epilepsy, brain tumors (subependymal giant cell astrocytomas), and kidney tumors (renal angiomyolipomas). Additionally, for postpubescent women with TSC, there is a high comorbidity with the rare cystic lung disease lymphangioleiomyomatosis (LAM), which is also caused by TSC1 or TSC2 mutations. TSC also causes tumors in the heart, skin, eyes, and teeth.³ However, the manifestations most impactful to daily living are often the neuropsychological ones, including autism spectrum disorder, cognitive impairment, behavioral difficulties, anxiety or depression, and sleep disorders.

The clinical manifestations of TSC occur at different times throughout a person’s life.  For example, epilepsy most commonly begins within the first year or two of life, whereas renal angiomyolipomas generally begin later in childhood or early adulthood, and LAM occurs almost exclusively in adult females.  However, the incidence of these manifestations is highly variable from person-to-person (even between identical twins). Many individuals with milder phenotypes may be genetically mosaic.