Tuberous Sclerosis Complex
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- Tuberous sclerosis complex (TSC) is an autosomal dominant, neurocutaneous, multisystem disorder characterized by clinical signs and symptoms that are highly variable and individual.
- Désiré-Magloire Bourneville has been credited with the first detailed description of the neurologic symptoms and neuropathology of TSC and coined the term “tuberous sclerosis of the cerebral convolutions” in 1880. Numerous other clinicians highlighted the clinical features now recognized as diagnostic of TSC.
- Population studies have consistently approximated the prevalence of TSC to be 1 in 6,000 to 9,000 people.
- Noninherited sporadic mutation rates approach 65–75% of those affected with TSC.
- TSC is caused by mutations in two different genes.
- TSC1 identified on 9q34 and TSC2 on 16p13
- Genetic mutations in TSC to account for as many as 80–90% of those affected with identified genetic mutations; however, there remain up to 15% of affected individuals with no identifiable mutation.
- The coating region of TSC2 is 1.5 times larger than that of TSC1. This accounts for several differences in the types of mutations found within these genes. Missense mutations and large deletions and duplications are rare in TSC1, whereas these are relatively common in TSC2. Although there are no specific mutation “hot spots,” individuals with TSC2 have a higher prevalence of cognitive impairment, renal and cardiac lesions compared to TSC1.
- Because TSC is an autosomal dominant disorder, there is full penetrance but variable expressivity. Affected individuals carry a 50% risk of passing the disease on to each prospective progeny.
- Gonadal mosaicism, where only the gonads and their affected gametes is the only affected organ with the TSC mutation, allows for multiple affected offspring from a parent who is otherwise “clinically unaffected.”
- The recurrence risk for all clinically unaffected parents with an affected child is estimated to be <2% due to this mechanism.
- The protein products of TSC1 and TSC2 are hamartin and tuberin respectively. These proteins combine with a third intracellular protein, TBC1D7, to form the TSC protein complex.
- This protein complex in turn serves to regulate multiple cellular processes that includes suppression of the mechanistic target of rapamycin (mTOR) complex 1 (mTORC1). This latter complex is central to cell growth, proliferation, differentiation, metabolism, and cellular organization.
- Consequently, loss of function mutations in either TSC1 or TSC2 results in enhanced mTORC1 activation and increased cellular protein synthesis, anabolic pathways, and the cellular machinery for energy production.