Tuberous Sclerosis Complex

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DESCRIPTION

  • 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 is credited with the first description of the neurologic symptoms of TSC. In 1880, he coined the term tuberous sclerosis of the cerebral convolutions. Numerous other clinicians highlighted the clinical features that are now recognized as diagnostic of TSC.

EPIDEMIOLOGY

  • 1 in 6,000 to 9,000 people
  • Noninherited sporadic mutation rates approach 65–75% of those affected with TSC.

RISK FACTORS

Genetics

  • TSC is caused by mutations in two different genes: TSC1 identified on 9q34 and TSC2 on 16p13. Genetic mutations in these genes account for about 80–90% of those affected with TSC. However, in about 10–20% of patients with this disorder, a pathogenic TSC gene mutation may not be identified with conventional testing, but next-generation sequencing may reveal mosaic and intronic mutations in these genes.
  • 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.

PATHOPHYSIOLOGY

  • 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. 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.

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