20.06.07 Tuberous Sclerosis Flashcards
Incidence of TS
1 in 6,000 -10,000 (could be higher due to variable penetrance)
What is TS
Autosomal dominant condition characterised by a highly variable phenotype and development of multiple hamartoma (benign tumour-like malformation) in multiple organs throughout the body.
What neurological symptoms manifest in TS
- 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
What skin abnormalities are seen in TS
- 96% patients have dermatological problems
- Facial angiofibromas.
- Hypomelanotic macules
What renal abnormalities are seen in TS
- Renal angiomyolipomas (common benign tumours) are seen in 80% cases. Can lead to ESRD.
- Second leading cause of death after CNS lesions.
What cardiac abnormalities are seen in TS
- Cardiac rhabdomyomas (hamartoma of striated muscle)
- Present in neonatal period but regresses over time. Can lead to arryhthmias
What lung abnormalities are seen in TS
- 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
Diagnostic criteria for TS
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
What genes are involved in TS
- TSC1 and 2
- Autosomal dominant.
- Germline pathogenic variant followed by a second somatic hit in the same gene
What are TSC1 and TSC2
Tumour suppressor genes
What percentage of TS patients (with a definite diagnostic criteria) have a pathogenic mutation in TSC1 and 2
75-85%
What proportion of cases are sporadic with no family history
2/3
What does TSC1 encode
- Hamartin
- 31% mutations
What does TSC2 encode
- Tuberin
- 69% mutations
Function of TSC1 and 2 proteins
- 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.
What is mTORC1
A protein kinase that regulates protein synthesis, cell growth and proliferation.
What percentage of cases have somatic mosaicism
1%
What investigations should be undertaken if routine testing of blood DNA does not reveal a pathogenic variant
Test DNA from other tissues (tumour, saliva, skin, hair follicle) to look for somatic mosaicism
Reasons for variable expressivity (e.g. in twin studies)
- 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.
Are there genotype-phenotype correlations
- 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.
What proportion of mutations are large rearrangements
- TSC1= 3%
- TSC2= 10%
Testing strategy for TS
-NGS/sanger and MLPA
Recurrence risks
- 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)
Treatment for TS
- No cure
- Treatment= early detection of progressive lesions to minimise complications and relieve symptoms.
- Monitoring= MRI, ultrasound, blood tests, CT scan
- mTOR inhibitors (everolimus)
What are mTOR inhibitors
- 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
