Etiology

There are two recognized genetic loci that produce TSC: the TSC1 gene, found on chromosome 9q34; and the TSC2 gene, found on 16p13.[4] Patients with TSC have mutations in either TSC1 or TSC2, not both genes.

The majority (up to 80%) of affected patients have mutations in the TSC2 gene; however, each genetic locus may produce the same phenotypic expression with individual variation.[4] This genetic heterogeneity is further complicated by variable expressivity, such that family members who inherit the same genetic mutation may express an extreme divergence of signs and symptoms.[4][12] Moreover, in around 10% to 15% of patients with TSC, no pathogenic TSC1 or TSC2 mutation can be detected using conventional testing methods.[1][4][13][14]

As of 2016, over 1500 unique pathogenic TSC1 or TSC2 variants had been identified. A list can be found in the Tuberous Sclerosis Complex Variation Database. LOVD: TSC1 Opens in new window LOVD: TSC2 Opens in new window

Mutations in TSC2 include large deletions, small insertions or deletions, nonsense, and missense mutations. TSC1 mutations are often small insertions or deletions that result in shortened (truncated) protein.[4][12][15] TSC2 mutations are more common in patients with sporadic TSC (with ratios of 3:1 to 7:1 being reported), whereas familial cases are associated almost equally with TSC1 and TSC2 mutations.[4]

TSC2 gene mutations generally produce more severe clinical manifestations overall, although some patients with TSC1 mutations have severe multiorgan system involvement.[4] People harboring TSC2 gene mutations tend to have more hypomelanotic macules and learning disabilities, and male patients have shown more frequent neurologic and eye symptoms, renal cysts, and ungual fibromas.[12]

Pathophysiology

TSC is an autosomal-dominant disorder characterized by cellular hyperplasia, tissue dysplasia, and multiorgan hamartomas.[2][3]

Hamartomas are focal organ malformations that result in faulty organ development and function.[2][3] They are composed of abnormal mixtures or proportions of cellular elements typically found within the tissue, but these elements are hypertrophied, found in excess numbers and in disorganized arrangements.[2][3]

The TSC1 gene codes for the protein product hamartin, and the TSC2 gene codes for the protein product tuberin. These proteins form a hamartin-tuberin complex within the cell that serves as a key negative regulator of cell growth (tumor suppressor). The hamartin-tuberin complex limits the activity of mTOR (mechanistic target of rapamycin) via inhibition of the GTPase Rheb (Ras homolog enhanced in the brain). Therefore TSC1 or TSC2 gene mutations leading to an absent or abnormal hamartin-tuberin protein complex result in inadequately controlled cell growth.

There is also a role for the hamartin-tuberin complex in:[16][17]

  • Protein translation, by modulating the phosphorylation of p70 ribosomal protein S6 kinase-1 through suppression of mTOR kinase activity

  • Cell adhesion, migration, and protein trafficking through its interaction with the ERM (ezrin, radixin, moesin) family of proteins

  • The control of cell proliferation through interaction with MAP (mitogen-activated protein) kinase.

Classification

No formal classification

There is significant variability in symptoms and signs between people with TSC, even those with identical genotypes.​[4]​

The TSC2 gene mutation is more likely to be associated with more severe clinical manifestations.[4]​ People harboring this gene mutation tend to have more hypomelanotic macules and learning disabilities, and male patients have shown more frequent neurologic and eye symptoms, renal cysts, and ungual fibromas.[5] However, there may be significant overlap in disease severity; some patients with TSC1 mutations have severe multiorgan system involvement.​[4]​

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