20.06.07 Tuberous Sclerosis

Question 1

Incidence of TS

Answer 1

1 in 6,000 -10,000 (could be higher due to variable penetrance)

Question 2

What is TS

Answer 2

Autosomal dominant condition characterised by a highly variable phenotype and development of multiple hamartoma (benign tumour-like malformation) in multiple organs throughout the body.

Question 3

What neurological symptoms manifest in TS

Answer 3

• Main neurological manifestation is epilepsy (70-90% patients).
• Hamartomas in the CNS
• Mild to severe ID, behavioural problems (ADHD, OCD, ASD)
• Main cause of morbidity and mortality

Question 4

What skin abnormalities are seen in TS

Answer 4

• 96% patients have dermatological problems
• Facial angiofibromas.
• Hypomelanotic macules

Question 5

What renal abnormalities are seen in TS

Answer 5

• Renal angiomyolipomas (common benign tumours) are seen in 80% cases. Can lead to ESRD.
• Second leading cause of death after CNS lesions.

Question 6

What cardiac abnormalities are seen in TS

Answer 6

• Cardiac rhabdomyomas (hamartoma of striated muscle)

- Present in neonatal period but regresses over time. Can lead to arryhthmias

Question 7

What lung abnormalities are seen in TS

Answer 7

• Lymphangiomyomatosis. Loss of alveolar tissue and development of cysts and interstitial fibrosis. Shortness of breath.
• Primarily affects females of child bearing age.
• Lung transplantation often required

Question 8

Diagnostic criteria for TS

Answer 8

Two major features (e.g. cardiac rhabdomyoma, subependymal nodules, hypomelanotic macules), 1 major and 1 minor (renal cysts, non-renal hamartomas) or a pathogenic variant in TSC1/2

Question 9

What genes are involved in TS

Answer 9

• TSC1 and 2
• Autosomal dominant.
• Germline pathogenic variant followed by a second somatic hit in the same gene

Question 10

What are TSC1 and TSC2

Answer 10

Tumour suppressor genes

Question 11

What percentage of TS patients (with a definite diagnostic criteria) have a pathogenic mutation in TSC1 and 2

Answer 11

75-85%

Question 12

What proportion of cases are sporadic with no family history

Answer 12

2/3

Question 13

What does TSC1 encode

Answer 13

• Hamartin

- 31% mutations

Question 14

What does TSC2 encode

Answer 14

• Tuberin

- 69% mutations

Question 15

Function of TSC1 and 2 proteins

Answer 15

• Form a heterodimeric complex that functions as a GTPase activating protein (GAP)
• Catalytic domain is in TSC2, but TSC1 is necessary to stabilise and prevent ubiquitin-mediated degradation.
• TSC1/2 complex inhibits activation of mTORC1 (mammalian target of rapamycin complex 1) by acting on Rheb.

Question 16

What is mTORC1

Answer 16

A protein kinase that regulates protein synthesis, cell growth and proliferation.

Question 17

What percentage of cases have somatic mosaicism

Answer 17

1%

Question 18

What investigations should be undertaken if routine testing of blood DNA does not reveal a pathogenic variant

Answer 18

Test DNA from other tissues (tumour, saliva, skin, hair follicle) to look for somatic mosaicism

Question 19

Reasons for variable expressivity (e.g. in twin studies)

Answer 19

• Random nature of 2nd hit
• TSC1/2 subject to regulation by wide range of environmental and genetic factors.
• TSC1/2 interact with a variety of signalling pathways.

Question 20

Are there genotype-phenotype correlations

Answer 20

• TSC2 mutations are often associated with more severe phenotypes.
• Sporadic cases more often have TSC2 mutations
• Truncating TSC1 pathogenic variant that undergo NMD are associated with less severe LD phenotype.

Question 21

What proportion of mutations are large rearrangements

Answer 21

• TSC1= 3%

- TSC2= 10%

Question 22

Testing strategy for TS

Answer 22

-NGS/sanger and MLPA

Question 23

Recurrence risks

Answer 23

• Parent is a carrier= 50% risk of another affected child

- Due to possible germline mosaicism= 1-2% risk (even if both parents have no variant in leukocytes)

Question 24

Treatment for TS

Answer 24

• No cure
• Treatment= early detection of progressive lesions to minimise complications and relieve symptoms.
• Monitoring= MRI, ultrasound, blood tests, CT scan
• mTOR inhibitors (everolimus)

Question 25

What are mTOR inhibitors

Answer 25

• Drugs that act as negative regulators of mTOR pathway
• E.g. everolimus
• Replace the deficient tuberin-hamartin complex to reverse upregulated cell proliferation and intracellular signalling defects
• Shown to reduce tumour volume and obviates the need for surgical resection