7. Tuberous Sclerosis

Question 1

What causes TSC?

Answer 1

Germline mutations in TSC1/2, followed by second somatic hit of same gene

69% TSC2, 31% TSC1

Question 2

What is the role of the tumberous sclerosis complex?

Answer 2

TSC1 & 2 bind together to form heterodimer - functions as a GTPase activating protein

TSC1/2 complex inhibits activation of mTORC1 - protein kinase that regulates protein synthesis, cell growth and proliferation

Question 3

How is the phenotype of TSC characterised?

Answer 3

Development of multiple benign hamartomas in CNS, skin, kidneys, eyes which can progress to cancerous hamartoblastomas

Question 4

Which different organs are affected in TSC and how?

Answer 4

Neurological - seizures, ID, ADHD
Skin - facial angiofibromas
Kidneys - renal angiomyolipomas
Heart - cardiac rhabdomyoma causing arrhythmia

Question 5

How does the phenotype of TSC2 compare to TSC1?

Answer 5

More severe phenotype, more sporadic cases

Greater risk of renal malignancy and ID/ADHD

Question 6

How is TSC treated?

Answer 6

No cure, early identification of progressive lesions

mTOR inhibitors act as negative regulators in mTOR pathway - replace deficient function of TSC1/2 complex