Ataxia-Telangiectasia

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:

• Progressive ataxia (lack of coordination) due to a defect in the cerebellum (the part of the brain involved in coordinating the movement of muscles)
• Oculomotor apraxia (difficulty moving the eyes from side to side)
• Choreoathetosis (abnormal movements such as involuntary jerky movements of the arms, legs and face along with slow, writhing movements of the hands, feet and other body parts)
• Telangiectasias (dilated blood vessels) on the whites of the eyes and the skin
• Weakened immune system resulting in frequent infections
• Sensitivity to ionizing radiation
• Increased risk to develop leukemia (cancer of blood-forming cells) and lymphoma (cancer of immune system cells) and some other cancers

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 acts as a tumor suppressor — the enzyme keeps cells from growing and dividing too quickly and it promotes cell death.
• It interacts with other proteins when DNA damage occurs following exposure to ionizing radiation.
• The ATM enzyme coordinates DNA repair by activating other proteins that are essential for the repair process to occur.

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.

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.

How is Ataxia-telangiectasia inherited?

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 child to be affected with AT.

If both parents carry an ATM mutation, each of their future children would have:

• A 25 percent (or 1 in 4) chance of having AT (i.e. that child would need to inherit a mutation from each parent)
• A  50 percent chance of being an asymptomatic carrier who may be at increased risk for breast cancer if female (i.e. this child would inherit one altered gene copy and one normal copy)
• A 25 percent chance of being unaffected (i.e. this child would inherit two normal gene copies)

Clinical findings

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 :

• Progressive cerebellar dysfunction, such as slurred speech
• Oculomotor apraxia (difficulty moving the eyes from side to side)
• Gait ataxia (unstable walk)
• Truncal ataxia (unable to maintain normal posture)
• A small cerebellum (often observed on magnetic resonance imaging [MRI] examination but may not be as obvious in very young children)

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.

Other clinical features

AT is characterized by additional features, such as:

• Telangiectases on the whites of the eyes and on the skin (usually present by 6 years of age)
• Immunologic defects (present in 60-80 percent of individuals with AT)
• Frequent infections
• Sensitivity to ionizing radiation
• Premature aging with graying of the hair
• Endocrine abnormalities (such as type II diabetes, short stature and delayed puberty)
• Increased risk to develop leukemia and lymphoma and rarely other cancers

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.

Testing for AT

There are several laboratory tests that can be used to support a clinical diagnosis of AT once clinical symptoms have occurred:

• Serum alpha-fetoprotein (AFP) concentration: The level of the AFP protein in the blood is elevated (>10 ng/mL) in more than 95 percent of individuals with AT.
• Chromosome analysis: A translocation (chromosomal abnormalities in which chromosomes break and the fragments reattach to other chromosomes) between chromosomes 7 and 14 is identified in 5-15 percent of cells analyzed in routine chromosomal studies for individuals with AT.
• Assessment of the levels of the ATM protein: Specific tests can be done to determine whether the ATM protein is present within cells, such as white blood cells. About 90 percent of individuals with AT have no detectable ATM protein; approximately 10 percent have trace amounts of the protein in their cells; and 1 percent have a normal amount of ATM protein but this protein cannot function properly.
• Radiosensitivity assay: This test is performed in a lab and measures the DNA repair function within a cell when it has been exposed to radiation. Normal cells that contain a functional ATM protein should be able to repair themselves after being exposed to radiation. The cells from individuals with AT do not survive normally after exposure to radiation due to their defective ability to repair damaged DNA.

Confirming a diagnosis of Ataxia-telangiectasia

Family tree

A detailed review of an child'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.

Genetic testing

In order to confirm on a molecular level that an individual has AT, he or she can undergo the process of genetic testing:

• First, a blood sample is obtained from an affected individual.
• DNA is isolated from the sample and the two copies of the ATM gene are evaluated using a variety of methods and compared to the normal reference sequence for ATM.
• If an alteration in both ATM gene copies is identified, the genetic counselor can next examine whether the alterations have been previously reported in other individuals with AT.

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 a 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.

Reproductive options

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 onto future children:

• Prenatal diagnosis — DNA is isolated from the cells of the developing baby though one of two procedures (chorionic villus sampling [CVS] or amniocentesis) and is analyzed for alterations in both copies of the ATM gene. With appropriate counseling, a parent can then decide whether to carry the pregnancy to term or to end the pregnancy.
• Preimplantation genetic diagnosis (PGD) — For couples using in vitro fertilization to become pregnant, embryos can be tested for genetic disorders before transferring them into the uterus via PGD. Only healthy embryos carrying two working copies of the ATM gene would be implanted.

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:

• Children with AT tend to develop leukemias of T cell origin
• When lymphomas develop, they are usually of B-cell origin

As individuals with AT live longer, other types of cancer have been reported in rare patients:

• Ovarian cancer
• Breast cancer
• Thyroid cancer
• Parotid (salivary) gland tumors
• Gastric (stomach) cancer
• Melanoma
• Leiomyomas (smooth muscle tumors)

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.

Cancer screening protocol for children and adults with Ataxia-telangiectasia

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. 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:

• Periodic medical visits to monitor for early signs of malignancy such as leukemia and lymphoma.
• Routine follow-up by a physician regarding immune status if an individual experiences recurrent infections.
• No other tumors occur at a frequency that warrants surveillance above that offered to members of the general population.

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:

• The type and frequency of breast cancer surveillance should be determined by a physician familiar with AT following review of an individual’s ATM mutation status and family history of cancer. Exposure to surveillance measures using radiation (such as mammograms) should be avoided when possible, but may be necessary if the benefit of this type of surveillance outweighs the risk of developing breast cancer as the result of the procedure
• No other tumors occur at a frequency that warrants surveillance above that offered to members of the general population.
• Carriers of an ATM mutation should also be aware they may have a higher chance of developing coronary artery disease in their lifetime and have proper cardiac surveillance in adulthood.