Tuberous sclerosis

Definitions & Key takeaways

Tuberous sclerosis, also known as tuberous sclerosis complex (TSC), is a rare genetic disorder that causes noncancerous tumors to grow in various parts of the body. The condition is caused by mutations in one of two genes, TSC1 or TSC2, which are responsible for regulating cell growth and division.

TSC can affect multiple organs, including the brain, skin, kidneys, heart, and lungs. Symptoms vary widely depending on the location and size of the tumors but may include seizures, intellectual disability, developmental delays, skin lesions, kidney problems, and lung complications.

Diagnosis of TSC typically involves a combination of clinical evaluation, imaging studies, and genetic testing. Treatment may involve a variety of interventions depending on the specific symptoms and organ involvement, such as antiepileptic medications for seizures, surgical removal of tumors, or targeted therapies to block cell growth in affected organs.

Chapters:

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Introduction0:00–0:14

Tuberous sclerosis is a genetic condition that causes growths to form in various body organs. Most commonly affecting the brain, skin, kidneys, lungs, and eyes.

Physiology0:14–1:06

Normally, there are two genes called TSC1 and TSC2 that help control the growth and division of cells in the body. TSC1 encodes the protein hamartin and TSC2 encodes the protein tuberin .
Both of these proteins, are tumor suppressors, meaning they help slow down cell growth and prevent tumors. They do this by combining to form a hamartin-tuberin protein complex, which binds to and inhibits another protein called mechanistic target of rapamycin, or mTOR.
mTOR activity speeds up the cell cycle and increases cell proliferation mainly thanks to its effect on protein synthesis.
So when mTOR is switched off by the hamartin-tuberin protein complex, it slows growth and division of cells throughout the body.

Pathology1:06–3:58

Individuals with tuberous sclerosis have a mutation in either the gene TSC1 or TSC2, and these mutations have an autosomal dominant inheritance pattern.
The mutations lead to an altered hamartin-tuberin protein complex that’s unable to switch off mTOR. Because of that, benign tumors and growths called hamartomas form throughout the body.
Hamartomas are kind of like tumors, but they’re made of a variety of cell types from the tissue where they arise, rather than a single cell type.
In fact, if we think of the tissue like a sheet of fabric, a hamartoma is like a knot in the sheet. Benign tumors and hamartomas can form in any tissue, but the brain and the skin are usually affected the most, along with the kidneys, lungs and eyes.
On top of that the lifetime risk of cancer is increased in individuals with tuberous sclerosis. That’s because the rapidly dividing cells can develop additional mutations that eventually make these growths expand beyond the basement membrane and invade neighboring tissues.
In the brain, the most common growths are glioneural hamartomas, also known as a cortical tubers. They arise from supportive glial cells as well as neurons.
Next most common are subependymal nodules, which are hamartomas that form under the ependyma, the thin membrane that lines the ventricles in the brain.
Individuals are also at an increased risk of developing a subependymal giant cell astrocytoma, or SEGA, which is a type of cancer that can arise from the subependymal nodules.
On the skin, many small growths called angiofibromas appear on the face. Individuals also have many small bumps called fibromas under the nails, known as subungual fibromas.
Light, flat patches also appear on the trunk called ash leaf spots and a distinctive dark, raised patch on the forehead is a common feature.
Another classical feature is a shagreen patch, which is a large, elevated, skin colored patch, that often appears on the lower back.
Individuals with tuberous sclerosis can develop renal tumors called angiomyolipomas. Although benign, they can get really big and put pressure on the kidney.
Because the kidney has a lot of blood vessels, angiomyolipomas do as well, and they can bleed spontaneously. Individuals can also have lymphangioleiomyomatosis in the lungs, which are cysts where the normal lung tissue is gradually replaced by cysts lined by endothelial cells, which are the cells that normally line the blood vessels.
Finally, in the retina, the light sensing part of the eye, hamartomas can form. Symptoms of tuberous sclerosis are often related to the hamartomas in the brain which cause problems like seizures, learning difficulties, and cognitive deficits.

Symptoms3:58–4:20

A large angiomyolipoma can cause flank pain, a lymphangioleiomyomatosis in the lungs, can cause shortness of breath, and a retinal hamartoma can cause vision changes.

Diagnosis4:20–4:42

Diagnosis is usually made on based on the skin lesions and can be confirmed with genetic testing to identify a mutation in TSC1 or TSC2.
A head CT or MRI can identify hamartomas and tumors in the brain, and is usually performed regularly to screen for new lesions.

Treatment4:42–5:01

Treatment of tuberous sclerosis is focused on symptoms. Antiepileptics are used to control seizures.
Brain tumors are managed surgically or with chemotherapy, and behavioral and developmental problems are managed through therapy and psychiatric medications.
All right, as a quick recap… Tuberous sclerosis is a multisystem, autosomal dominant genetic condition caused by mutations in genes TSC1 or TSC2.

Review5:01–5:27

The mutations lead to an altered hamartin-tuberin protein complex that’s unable to switch off mTOR. It causes benign tumors and hamartomas to grow in the brain, the skin, the kidneys, the lungs, and the eyes.