Ataxia-telangiectasia

Definitions & Key takeaways

Ataxia-telangiectasia (A-T) also called Louis-Bar Syndrome, is an autosomal recessive condition characterized by progressive cerebellar atrophy and oculocutaneous telangiectasia (small dilated vessels under the skin). People with A-T often have high rates of cancer and immunodeficiency disorders. It is caused by a mutation of the ataxia telangiectasia mutated (ATM) gene, and it is characterized by poor muscle coordination or ataxia (often needing a wheelchair by the age of 10), dysarthria, and telangiectasia on the skin and eyes.

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Introduction0:00–0:31

With ataxia telangiectasia, ataxia refers to poor coordination and telangiectasia refers to dilated blood vessels, which are the two key symptoms of this disease.
Ataxia telangiectasia develops when a genetic mutation causes the lack of a protein called ataxia telangiectasia mutated serine-threonine kinase, or just ATM for short, which normally fixes up damaged DNA.
DNA of every cell gets damaged over and over again from various environmental factors like radiation and chemical toxins.

Physiology0:31–2:11

Now, one of the most severe types DNA damage is a double-strand break, where both strands of the DNA’s double helix are severed, damaging the genetic information that was stored there.
To help with this sort of repair, there’s a protein called ATM. ATM is primarily located in the cell's nucleus, and you can sort of think of ATM as like a manager of the DNA’s repair.
It’s protein kinase, which means that it uses it’s managing skills to activate other proteins through phosphorylation, which is the addition of a phosphoryl or -PO32− group.
So at the site of the double strand break, ATM phosphorylates proteins like the tumor suppressor protein p53, that stop the cell from reproducing.
ATM also phosphorylates additional proteins which will either fix the DNA or kill the faulty cell through a process of apoptosis - controlled cell death.
This way we don't end up with a bunch of defective cells trying to reproduce. That's the main role of ATM, but it also plays a role in the development of immune cells, especially T lymphocytes.
T lymphocytes need to be able to recognize a wide variety of antigens, and to do this, they purposefully create double strand breaks in their DNA during development.
That way parts of their DNA can get rearranged, and code for new and unique antigen receptors. Once again, ATM helps to fix these breaks - and that keeps the T-cells functioning normally.

Pathology2:11–4:03

In ataxia telangiectasia, there's an autosomal recessive mutation of the ATM gene. This leads to a decrease in the amount of functioning ATM protein, and as a result, cells that undergo a double-strand break don't have sufficient ATM to repair the break.
As a result, some of the damaged cells might survive and continue to proliferate despite the damage, but most ultimately die off.
Now, if cells start dying off left-right-and-center that’s a big problem. This can especially impact the nervous system.
When the cerebellum’s affected, it atrophies, and since the cerebellum coordinates movement, this degeneration is what causes the ataxia, or or difficulty with coordination and movement, inbb lots of individuals with the disease.
In many cases, the ataxia can lead to the muscles in the mouth and throat not coordinating, which can cause aspiration pneumonia.
That’s where bits of food, liquid, and body secretions are able to enter the airways, and cause direct damage as well as infection in the lungs.
Meanwhile in the immune system, a decrease in functioning ATM causes improper repair of T-cells as they go through their maturation process.
This can result in T-cells that don't function properly, or simply die off. Since T-cells are critical in activating B-cells that produce immunoglobulins, it can also lead to lower immunoglobulin levels in the body.
Insufficient T-cell activity and decreased immunoglobulin levels puts individuals with ataxia telangiectasia at higher risk for infections.
Finally, remember what we said about some cells surviving and proliferating despite DNA damage? Well it's thought that this can make people with ataxia telangiectasia prime candidates for cancers, especially leukemias and lymphomas, both of which involve immune cells.

Symptoms4:03–4:35

Symptoms for people with ataxia telangiectasia often develop ataxia, as a result of cerebellar degeneration. This can cause frequent stumbling or unsteady gait, and trouble with fine motor movements like those needed for eating, writing, or speaking.
It's also common to see recurrent infection because of the weakened immune system, and telangiectasias, which are dilated blood vessels visible especially on the white of the eyes, for reasons we don't really know.

Diagnosis4:35–5:04

The diagnosis of ataxia telangiectasia is based on a person having severe ataxia together with mutations on ATM genes, which can be identified through genetic testing.
There's usually a low level of serum immunoglobulins, and a high level of a protein called alpha-fetoprotein. Alpha-fetoprotein levels are usually high in infants, but then fall after that, and the reason that it’s high in individuals with ataxia telangiectasia is a bit of a mystery.

Treatment5:04–5:31

The underlying genetic mutation in ataxia telangiectasia can’t be treated, so the medications are really aimed at symptoms and complications.
For reducing the risk of infections, immunoglobulin supplements and antibiotics can be used. For ataxia, In some cases, beta blockers can be used.
And finally for cancer development, individuals usually have increased surveillance. All right, as a quick recap...Ataxia telangiectasia is an autosomal recessive disorder where a defective ATM gene causes an absence of the protein ATM, which is used to repair damage to cellular DNA.

Review5:31–6:04

As a result, patients experience progressive damage to cells across the body, especially those in the cerebellum, which causes ataxia.
Ataxia telangiectasia can also can a decrease in T-cells and decreased immunoglobulin levels, causing a weakened immune response, as well as an increased risk of developing cancers.