Ataxia Telangiectasia Genetic Testing Basics - Medicine and Health

Ataxia Telangiectasia

What is ataxia telangiectasia?
Ataxia telangiectasia (A-T) is a rare but deadly childhood disease that primarily affects the brain and immune system. A-T is a degenerative disease, meaning it gets progressively worse over time. Children with A-T often require a wheelchair by age 10. In the United States, most people with A-T live well beyond 20 years. This is a major change from just a few years ago. Survival for patients in other parts of the world is not as good, perhaps due to lack of good nutrition and therapy.

Symptoms of A-T usually develop in the first 10 years of life, and can include:

Neurological problems, such as a staggering and unsteady pattern of walking, poor coordination, poor balance, slurred speech, uncoordinated eye movements and hearing loss. These develop slowly during childhood as certain nerve cells deteriorate over time.
Skin spots (like birthmarks) or bumps caused by an abnormal pattern of dilated capillaries. They appear as tiny red "spider" veins, commonly on the white part of the eye or on the ears and cheeks.
An increased risk of cancer. About 40% of people with A-T develop some type of cancer in his or her lifetime.
A weakened immune system, which causes frequent infections, such as respiratory infections and pneumonia
Increased sensitivity to X-rays and radiation for cancer treatment. People with A-T and carriers of A-T who receive radiation for cancer treatment should receive lower doses. Other types of radiation, such as CT scans and X-rays, should also be minimized.
Type 2 diabetes can develop in some patients with A-T in their late teens. Type 2 diabetes is the adult-onset form of the disease.
Prematurely gray hair
Difficulty swallowing
Delayed physical and sexual development
Children with A-T usually have normal intelligence.

How common is ataxia telangiectasia
A-T occurs in about 1 of 40,000 live births in the United States. The chance of carrying one change in the gene responsible for the disease is about 1 in 100.

Who is at risk of ataxia telangiectasia?
A-T affects people from all different ethnic groups. People are not at increased risk based on their ethnic background. Someone is typically at increased risk due to his or her family history.

Is there a cure?
No. And there are no standards of treatment. However, there are methods aimed at prolonging survival and improving a person's quality of life:

Antioxidants, such as vitamin E or alpha-lipoic acid, are recommended as a general anti-cancer regimen.
Physical therapy helps to prevent stiff muscles.
Speech therapy may help to maintain communication skills.
Some patients need infusions of gamma globulin (antibodies) to help prevent severe infections.
The Gene For Ataxia Telangiectasia Disease

What goes wrong with this gene?
The gene that causes A-T is called ataxia-telangiectasia mutated (ATM). This gene tells the body how to make an essential protein. If someone inherits two changes (one from mother and one from father) in the ATM gene, the child will not be able to make enough of the ATM protein, which is critical for proper growth and maintenance of the body.

This protein plays an important role in cellular division in the brain during development. If brain cells do not develop correctly, the child will eventually have motor and neurological problems — the very symptoms of A-T.

In addition, the protein acts as a sensor to detect breaks in the DNA. DNA is like a chain of letters. Something like radiation can damage the DNA by breaking that chain of letters, causing a gap between two parts of the chain that are supposed to be connected. Gaps in DNA can cause a change in one of the genes. Normally, when the body notices a break in the DNA, it tells the cell to stop dividing (that is, growing). People with A-T lack this quality-control measure. In fact, telangiectasias (which looks like a birthmark) results when the cells that make capillaries grow out of control. A similar type of abnormal cell growth often leads to cancer in A-T patients.

Should You Be Tested?

What is my risk of being an ataxia-telangiectasia carrier?
Your chances of being a carrier depend on your family history. If someone in your immediate family has A-T or is an A-T carrier, you too could be a carrier. If you have a brother or sister with A-T disease, you have a two-thirds chance of being a carrier. If one of your parents is a carrier, and the other one is not, you have a 50% chance of being a carrier. If your child has A-T disease, it means you and your partner are both carriers of the altered ATM gene.

Understanding Test Results and Options

How Do You Make Sense Of The Results?

If I test positive as a carrier, what does that mean for my family and me?
If your child has ataxia-telangiectasia disease, you and your partner are both carriers of the altered ATM gene. If you have a close family member with A-T, you might be a carrier. Carriers do not have the full disease; they have one normal copy of the gene and one altered copy. You only need one "working" copy to avoid the full disease. If you're a carrier, one or both of your parents must have been a carrier too. This means your brothers and sisters have at least a 50% chance of having inherited the gene from one of your parents.

Could I get a positive test result, but not carry the disease gene (a "false positive")?
The DNA test for A-T is based on reading the DNA sequence of the gene, and is very specific. If your family includes someone affected by A-T, and this person has a change in the DNA sequence, the lab can look for that same DNA change in you and other family members. In this case, the test will or will not see the same DNA change. There are essentially no false positives.

Sometimes the lab will see a change in the sequence that has never been seen before. It may not be clear if this change causes A-T or not. In this case, they would not tell you that the test is definitely positive, so this would not be a false positive either.

Could I get a negative test result, but actually have the disease (a "false negative")?
False negatives occur in less than 5% of cases tested by sequencing and in about 20% to 25% of cases tested by mutation scanning. This means you could have the disease even though the lab was not able to find a change in the gene. Instead, the disease could be due to a change in an untested part of the gene. In such cases, the lab might be able to use another test called linkage analysis to look for evidence of a genetic change.

Personal Questions

How will I cope if the test shows I am an A-T carrier?
Keep in mind that a carrier does not have the full disease. Carriers, however, may be more sensitive to X-rays and radiation therapy for cancer. It is possible that A-T carriers have an increased risk of developing cancer, but the exact risk is not known. If you are an A-T carrier, each of your children has a 50% chance of inheriting the ATM gene from you.

If I have the A-T gene, can I have children who don't have the gene?
Yes, but you need to "do the math" to understand the risks of passing on the mutated gene.

If you're an A-T carrier and your partner is not, you have a 50% chance of passing the gene to each child. In other words, even if your child inherits your copy of the ATM gene, the child will NOT have A-T, but will be a carrier, like you.

If you and your partner are both A-T carriers, your child has a:

25% chance of inheriting A-T (two copies of the ATM gene)
50% chance of being a carrier (one ATM gene and one normal gene)
25% chance of not being a carrier (two normal genes)
While pregnant, can I determine the risk my baby has of developing ataxia-telangiectasia disease?
To discover whether your unborn child has inherited A-T, you and your partner can seek prenatal testing. Prenatal testing for A-T is only available if you already have a family member with the disease.

The lab looks for changes in the ATM gene in the affected family member. If the affected family member has two identifiable changes in the gene, the lab will look for those same changes in you and your partner. If one or both of you are NOT carriers of these same changes, then your fetus will not inherit A-T from you. If you are both carriers, then your fetus might have the disease, and the lab can look for the same changes in your fetus.

If the affected family member has only one identifiable change in the gene, they must have another change that is undetectable. In this case, your family member would need to have another test called linkage analysis. Linkage analysis can also be used for prenatal testing.

Early in the pregnancy, a doctor can use either chorionic villus sampling or amniocentesis to get a sample of tissue from the fetus. A lab tests the tissue to determine if the fetus has inherited the change in the A-T gene. A baby that inherits only one changed A-T gene will be a carrier. A baby that inherits two changed A-T genes will have the disease.

It's best to plan genetic testing prior to, or early in, the pregnancy. Talk to an obstetrician or a genetic counselor about your options.

If I DON'T have the A-T gene, can I have children who DO have it?
If you're not a carrier, your children cannot inherit the gene from you. They could still get the gene from your partner, if he or she is a carrier, but your children would not get A-T because they would only have one altered gene.

Is there any harm in finding out if I carry the gene?
You may feel upset if you learn that you carry a gene that could potentially cause a disease in your future children.

Test Details

How does the test work?
There are three types of DNA tests for A-T. All require a blood sample, chorionic villus sample or amniotic fluid sample. Testing is used to confirm the presence of A-T in a person who has some or all of the symptoms of the disease, or to test family members to see if they are A-T carriers.

Direct DNA Sequencing
DNA sequencing "reads" the letters of DNA code within the ATM gene. The DNA sequence of any gene is like the ingredients in a recipe. In DNA sequencing, the lab "reads" the sequence to look for typos.

Mutation Scanning
This looks at one letter at a time in the DNA code. Some labs take a shortcut by breaking the gene into pieces and testing each piece for changes. If it looks like a particular piece of the gene carries a change, the lab will examine that piece to find where the change is located. This saves money by not examining the pieces that look normal. The trade-off is that mutation scanning is more likely to miss a change in the gene as compared to sequencing.

Linkage Analysis
Linkage analysis tracks a change in the ATM gene within a family. The test is generally used to detect carriers or for prenatal testing. Typically, you would have linkage analysis done only after someone in your family has been diagnosed with A-T.

The test looks at four representative pieces ("markers") of DNA, two within the ATM gene and two bordering the gene on each side. A lab uses these markers to "find" a change in the gene. For example, imagine a family with one member affected with A-T. While DNA sequencing did not detect a change in the ATM gene, the affected person inherited DNA marker 1. (Family members who do not have A-T have inherited DNA marker 2.) A-T and DNA marker 1 are considered linked because they always go together. Therefore, when testing other members in the same family, the lab will assume a person has a change in the ATM gene if they inherit marker 1 (which is always linked to A-T) and not marker 2 (which is not linked to A-T).

What do the tests cost?
DNA sequencing costs about $4,000. Mutation scanning costs about $1,000. If more than one family member is being tested, the lab will usually charge the full price for the first person and significantly less for each additional person. The cost is highest for the first person because the lab must look at the whole gene. Once the lab finds the changes in the gene for that person, the lab can then look specifically for just those changes in other family members, usually for a cost of about $250 per additional person.

Does insurance pay for the tests?
Most health-insurance companies pay 80% or more of the cost. Some companies pay all the cost; others won't pay any portion. If you are considering this test, call your insurance company and ask about its coverage.

How long does it take to get results?
The sequencing test takes about two to three months; if the lab has already tested someone in your family the results will arrive sooner. Mutation scanning takes up to four months. The lab sends results to the medical center that ordered the test. You will need to return to the center to learn your results.

Can a health-insurance company raise my rates or drop me from coverage if I test positive?
Not usually, though this may depend on whether or not you have group insurance or are self-employed. People with group insurance are usually covered by both federal and state laws, while people who are self-employed are covered only by state laws. Also, the Federal Health Insurance Portability and Accountability Act (HIPAA) of 1996 prohibits health-insurance discrimination based on any "health-status-related factor" (including genetic information) by group health plans. Unfortunately, this act does not apply to the self-employed.

Some states have enacted legislation to cover the gaps. Thirty-four states prohibit health-insurance companies from using genetic information to deny coverage. Other states require specific justification for the use of genetic information in denying a claim. Texas bans the use of genetic information by any group health plans, and Alabama prohibits discrimination based upon predisposition to cancer.

These laws generally do not cover life insurance, long-term care and disability insurance. People with life and disability coverage provided by their employers are unlikely to have this insurance affected by a genetic test result.