Introduction
- Genetic disorder inherited in an autosomal dominant fashion.
- Characterized by increased predisposition to hamartoma formation.
- Mutations in genes TSC1 and TSC2 causing neurological disorders like epilepsy and intellectual disability.
- Other involved organ systems: pulmonary, renal, dermatologic, cardiac.
- Usually diagnosed in childhood/infancy; can be diagnosed earlier or later.
Clinical Manifestations
- Cardiac rhabdomyomas, cortical tubers (prenatal presence possible).
- Renal and pulmonary lesions usually diagnosed in adulthood.
- Skin lesions in 90% patients:
- Hypopigmented macules in early childhood.
- Ungual fibromas near puberty.
- Facial angiofibromas in adolescence.
Etiology
- TSC results from mutations in TSC1 (chromosome 9) and TSC2 (chromosome 16).
- TSC1 mutation affects hamartin protein production.
- TSC2 mutation affects tuberin protein production.
Role in Central Nervous System Development
- TSC1/TSC2 mutations inactivate inhibitory TSC complex, causing mTOR hyperactivation.
- mTOR regulates cell growth and metabolism via complexes mTORC1/mTORC2.
- mTORC1 activation promotes cell proliferation, inhibits autophagy.
- In CNS, abnormalities affect neuronal migration, dendrite arborization, neuronal polarity causing epilepsy, cognitive issues.
- mTOR pathway inhibition reduces melanogenesis causing hypopigmented skin lesions.
Epidemiology
- Affects 1 in 6000 to 1 in 10,000 live births; overall prevalence 1 in 20,000.
- Median age of presentation: 7 months.
- Pulmonary LAM typically diagnosed around age 35 in women.
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