Ataxia-Telangiectasia (AT) is a rare inherited condition that affects the nervous system, the immune system and other body systems. It is characterized by the presence of:
AT occurs in one in 40,000 to 100,000 live births in the United States and it affects males and females of all races equally.
AT is a hereditary condition in which a person must inherit two non-working copies of a gene known as ATM in order to be affected with the condition. Individuals who inherit only one non-working gene copy are known as “carriers." Carriers of an alteration in one copy of the ATM gene do NOT have AT or the clinical features associated with this disease, though they may have a higher chance of developing coronary artery disease. Female carriers may have a higher chance of developing breast cancer. A non-working gene can be passed from generation to generation, but unless an individual inherits a non-working copy of the ATM gene from both parents who are each carriers for the condition, he or she will not have AT.
AT is caused by alterations (mutations) at specific areas within an individual’s genetic information. Each of us has a large amount of genetic information that is organized into smaller segments known as “genes." Genes provide the necessary instructions that our cells need to perform different functions within our bodies.
AT develops when there are alterations in a specific gene known as ATM, located on chromosome 11 at position q22.3. The ATM gene has the ability to produce an enzyme called a “serine/threonine kinase" that has several important functions:
It is believed that through a combination of these mechanisms, the ATM enzyme aids in the prevention of specific types of cancer, such as leukemia and lymphoma.
With the exception of egg and sperm cells, each cell of the body normally has two working copies of the ATM gene. Patients with AT carry an alteration in both copies of the ATM gene in all the cells of their body. When both copies of the ATM gene are altered within the cells of an individual with AT, the altered gene copies will make less of the ATM protein or an ATM protein that does not function properly. As a result, cells are hypersensitive to radiation and instead of repairing damaged DNA, the defective ATM proteins allow for alterations to accumulate in other genes because effective DNA repair is unable to occur. When this happens, individuals with AT are at an increased risk to develop leukemia and lymphoma. Additionally, altered ATM genes may allow cells to die inappropriately, particularly in the cerebellum. This can result in the neurological symptoms that occur in AT.
Individuals who have two non-working copies of a gene that results in the manifestation of disease are said to have an “autosomal recessive” condition. AT is an example of an autosomal recessive condition. Since AT is inherited in an autosomal recessive manner, both parents carry one normal copy of the ATM gene and one altered copy of the ATM gene. An altered ATM gene must then be passed on from each parent in order for the offspring to be affected with AT.
If both parents carry an ATM mutation, each of their future children would have:
The diagnosis of AT relies primarily on the presence of certain clinical findings.
Children with AT between ages 1 and 4 may show signs of :
Over time, affected children typically develop difficulty walking, problems with balance and hand coordination, involuntary jerking movements (chorea), muscle twitches (myoclonus), and disturbances in nerve function (neuropathy). The movement problems typically cause people to require wheelchair assistance by adolescence.
AT is characterized by additional features, such as:
The physical features associated with AT can vary in severity among individuals depending upon whether the ATM protein is completely absent or not. Affected individuals with no ATM protein activity have a more severe course of disease, with more frequent infections, lower immunoglobulin levels, and a higher prevalence of B-cell lymphoma as compared to patients with some residual ATM activity. However, the clinical findings of AT vary little from family to family in the late stages of disease.
People with AT typically have normal intelligence, but they often have slow motor and verbal responses. Occasionally, learning difficulties or mild intellectual disability can be present. While life expectancy is reduced, most individuals live beyond 25 years of age, with some surviving into their 40s and 50s.
There are several laboratory tests that can be used to support a clinical diagnosis of AT once clinical symptoms have occurred:
A detailed review of an individual’s medical, developmental and family history is important in diagnosing AT. A doctor or genetic counselor may construct a pedigree, or a multi-generation family tree, that indicates which members of the family have developed cancer, the types of cancer and their ages at onset, as well as the presence of any clinical manifestations of AT. If the pattern of clinical features and/or cancers is suggestive of AT, the physician or counselor may recommend that genetic testing be performed.
In order to confirm on a molecular level that an individual has AT, he or she can undergo the process of genetic testing:
This information can strengthen the conclusion that the ATM alterations are the cause of the clinical findings in the individual. In patients carrying a clinical diagnosis of AT, approximately 90 percent will have mutations involving ATM. However, it is important to remember that not all patients with AT carry detectable alterations in ATM. Therefore, the failure to identify alterations in the ATM gene does not exclude the diagnosis of AT.
ATM genetic test results can also provide important information for other family members. Knowing the specific alterations in the ATM gene in an individual with AT allows other family members to undergo testing to determine whether or not they are carriers of one of the two ATM mutations identified in the affected individual, if desired.
Individuals with AT typically do not have children. However, reproductive options exist for individuals who are both carriers of an identified ATM gene alteration who do not wish to pass these alterations on to future children:
The primary cancer risk in AT is the development of leukemia and lymphoma. The risk to develop malignancy is 38 percent, with leukemia and lymphoma accounting for 85 percent of malignancies:
As individuals with AT live longer, other types of cancer have been reported in rare patients:
Some research has shown that individuals who are carriers of an ATM mutation may be at an increased risk for breast cancer. The cancer risk of individuals who are carriers for AT disease-causing mutations is estimated to be moderately increased compared to that of the general population (approximately 2-4 times greater than the general population risk); however the definitive risk is uncertain. There is no consistent evidence that carriers are at an increased risk for any other type of cancer besides breast cancer.
Regardless of whether one decides to pursue genetic testing for ATM mutations, it is recommended that an individual with AT or a carrier of an ATM mutation consider the following evaluation and surveillance recommendations, some of which are listed on the Genetests website. It is important to note that these are only recommendations. There is no current medical consensus regarding the optimal surveillance for the development of cancer in individuals with AT or in carriers of an ATM gene alteration.
For individuals with AT:
In addition to following these guidelines, children and adults with AT should be encouraged to follow-up with physicians familiar with this disease. They should lead as healthy a lifestyle as possible with avoidance of exposure to the sun and ionizing radiation, as their cells are hypersensitive to the effects of radiation. Therefore the use of radiotherapy and radiomimetic chemotherapeutic agents (chemical drugs that imitate the effects of radiation) should be avoided if possible or used only after careful consideration.
For individuals who are carriers of an ATM mutation:
Ataxia Telangiectasia Society
Phone: +44 (0) 1582 760733
AT Children’s Project
5300 W. Hillsboro Blvd. #105
Coconut Creek, FL 33073
Phone: 954-481-6611 or
Toll free: 1-800-5-HELP-A-T (800-543-5728)
Reviewed by: Kim Nichols, MD, Kristin Zelley, MS
Date: September 2012