Neurological Disorder:
Ataxia-telangiectasia
Definition
Ataxia-telangiectasia (A-T) is a rare, genetic neurological disorder that progressively affects various systems in the body. Children affected with A-T appear normal at birth; however, the first signs of the disease—usually a lack of balance and slurred speech—often appear between one and two years of age.
Description
The onset of cerebellar ataxia (unsteadiness and lack of coordination) marks the beginning of progressive degeneration of the cerebellum, the part of the brain responsible for motor control (movement). This degeneration gradually leads to a general lack of muscle control, and eventually confines the patient to a wheelchair. Children with A-T become unable to feed or dress themselves without assistance. Because of the worsening ataxia, children with A-T lose their ability to write, and speech also becomes slowed and slurred. Even reading eventually becomes impossible, as eye movements become difficult to control.
Children with A-T usually exhibit another symptom of the disease: telangiectases, or tiny red spider veins (dilated blood vessels). These telangiectases appear in the corners of the eyes—giving the eyes a blood-shot appearance—or on the surfaces of the ears and cheeks exposed to sunlight.
In about 70% of children with A-T, another symptom of the disease is present: an immune system deficiency that usually leads to recurrent respiratory infections. In many patients, these infections can become life threatening. Due to deficient levels of IgA and IgE immunoglobulins—the natural infection-fighting agents in the blood—children with A-T are highly susceptible to lung infections that are resistant to the standard antibiotic treatment. For these patients, the combination of a weakened immune system and progressive ataxia can ultimately lead to pneumonia as a cause of death.
Children with A-T tend to develop malignancies of the blood circulatory system almost 1,000 times more frequently than the general population. Lymphomas (malignant tumors of lymphoid tissues) and leukemias (abnormal overgrowth of white blood cells, causing tumor cells to grow) are particularly common types of cancer, although the risk of developing most types of cancer is high in those with A-T. Another characteristic of the disease is an increased sensitivity to ionizing radiation (high-energy radiation such as x rays), which means that patients with A-T frequently cannot tolerate the radiation treatments often given to cancer patients.
Demographics
Both males and females are equally affected by A-T. Epidemiologists estimate the frequency of A-T as between 1/40,000 and 1/100,000 live births. However, it is believed that many children with A-T, particularly those who die at a young age, are never properly diagnosed. Thus, the disease may occur much more often than reported.
It is also estimated that about 1% (2.5 million) of the American population carry a copy of the defective A-T gene. According to some researchers, these gene carriers may also have an increased sensitivity to ionizing radiation and have a significantly higher risk of developing cancer—particularly breast cancer in female carriers.
Causes and symptoms
Ataxia-telangiectasia is called a recessive genetic disorder because parents do not exhibit symptoms; however, each parent carries a recessive (unexpressed) gene that may cause A-T in offspring. The genetic path of A-T is therefore impossible to predict. The recessive gene may lie dormant for generations until two people with the defective gene have children. When two such A-T carriers have a child together, there is a 1-in-4 chance (25% risk) of having a child with A-T. Every healthy sibling of a child with A-T has a 2-in-3 chance (66% risk) of being a carrier, like his or her parents.
Although there is much variability in A-T symptoms among patients, the signs of A-T almost always include the appearance of ataxia between the ages of two and five. Other, less consistent symptoms may include neurological, cutaneous (skin), and a variety of other conditions.
Neurological
Neurological symptoms of A-T include:
- progressive cerebellar ataxia (although ataxia may appear static between the ages of two and five)
- cerebellar dysarthria (slurred speech)
- difficulty swallowing, causing choking and drooling
- progressive lack of control of eye movements
- muscle weakness and poor reflexes
- initially normal intelligence, sometimes with later regression to mildly retarded range
Cutaneous
Cutaneous symptoms include:
- progressive telangiectases of the eye and skin develop between two to ten years of age
- atopic dermatitis (itchy skin)
- Café au lait spots (pale brown areas of skin)
- cutaneous atrophy (wasting away)
- hypo- and hyperpigmentation (under pigmented and overpigmented areas of skin)
- loss of skin elasticity
- nummular eczema (coin-shaped inflammatory skin condition)
Other symptoms
Other manifestations of A-T include:
- susceptibility to neoplasms (tumors or growths)
- endocrine abnormalities
- tendency to develop insulin-resistant diabetes in adolescence
- recurrent sinopulmonary infection (involving the sinuses and the airways of the lungs)
- characteristic loss of facial muscle tone
- absence or dysplasia (abnormal development of tissue) of thymus gland
- jerky, involuntary movements
- slowed growth
- prematurely graying hair
Diagnosis
For a doctor who is familiar with A-T, the diagnosis can usually be made on purely clinical grounds and often on inspection. But because most physicians have never seen a case of A-T, misdiagnoses are likely to occur. For example, physicians examining ataxic children frequently rule out A-T if telangiectases are not observed. However, telangiectases often do not appear until the age of six, and sometimes appear at a much older age. In addition, a history of recurrent sinopulmonary infections might increase suspicion of A-T, but about 30% of patients with A-T exhibit no immune system deficiencies.
The most common early misdiagnosis is that of static encephalopathy—a brain dysfunction, or ataxic cerebral palsy—paralysis due to a birth defect. Ataxia involving the trunk and gait is almost always the presenting symptom of A-T. And although this ataxia is slowly and steadily progressive, it may be compensated for—and masked—by the normal development of motor skills between the ages of two and five. Thus, until the progression of the disease becomes apparent, clinical diagnosis may be imprecise or inaccurate unless the patient has an affected sibling.
Once disease progression becomes apparent, Friedreich ataxia (a degenerative disease of the spinal cord) becomes the most common misdiagnosis. However, Friedreich ataxia usually has a later onset. In addition, the spinal signs involving posterior and lateral columns along the positive Romberg's sign (inability to maintain balance when the eyes are shut and feet are close together) distinguish this type of spinal ataxia from the cerebellar ataxia of A-T.
Distinguishing A-T from other disorders (differential diagnosis) is ultimately made on the basis of laboratory tests. The most consistent laboratory marker of A-T is an elevated level of serum alpha-fetoprotein (a protein that stimulates the production of antibodies) after the age of two years. Prenatal diagnosis is possible through the measurement of alpha-fetoprotein levels in amniotic fluid and the documentation of increased spontaneous chromosomal breakage of amniotic cell DNA. Diagnostic support may also be offered by a finding of low serum IgA, IgG and/or IgE. However, these immune system findings vary from patient to patient and are not abnormal in all individuals.
The presence of spontaneous chromosome breaks and rearrangements in lymphocytes in vitro (test tube) and in cultured skin fibroblasts (cells from which connective tissue is made) is also an important laboratory marker of A T. And finally, reduced survival of lymphocyte (cells present in the blood and lymphatic tissues) and fibroblast cultures, after exposure to ionizing radiation, will confirm a diagnosis of A-T, although this technique is performed in specialized laboratories and is not routinely available to physicians.
When the mutated A-T gene (ATM) has been identified by researchers, it is possible to confirm a diagnosis by screening the patient's DNA for mutations. However, in most cases the large size of the ATM gene and the large number of possible mutations in patients with A-T seriously limit the usefulness of mutation analysis as a diagnostic tool or method of carrier identification.
Treatment team
The child's primary care physician will likely be the first person to begin evaluating the child for the presence of ataxia-telangiectasia. Other consulting physicians may include a neurologist (to help manage the neurologic complications), a pulmonologist and/or infectious disease specialist (to help manage the lung infections), and a hematologist/oncologist (to help manage lymphoma or leukemia). Physical therapists, occupational therapists, and speech and language therapists should also be consulted.
Treatment
There is no specific treatment for A-T because gene therapy is not yet an available option. Also, the disease is usually not diagnosed until the individual has developed health problems. Treatment is therefore focused on the observed conditions, especially if neoplasms are present. However, radiation therapy must be minimized to avoid inducing further chromosomal damage and tumor growth.
Supportive therapy is available to reduce the symptoms of drooling, twitching, and ataxia, but individual responses to specific medications vary. The use of sunscreens to retard skin changes due to premature aging can be helpful. In addition, early use of pulmonary physiotherapy, physical therapy, and speech therapy is also important to minimize muscle contractures (shortening or tightening of muscles).
Although its use has not been formally tested, some researchers recommend the use of antioxidants (such as vitamin E) in patients with A-T. Antioxidants help to reduce oxidative damage to cells.
Prognosis
A-T is an incurable disease. Most children with A-T depend on wheelchairs by the age of ten because of a lack of muscle control. Children with A-T usually die from respiratory failure or cancer by their teens or early 20s. Although it is extremely rare, some patients with A-T may live into their 40s.
Resources
BOOKS
Vogelstein, Bert, and Kenneth E. Kinzler. The Genetic Basis of Human Cancer. New York: McGraw-Hill, 1998.
PERIODICALS
Brownlee, Shanna. "Guilty Gene." U.S. News and World Report. (July 3, 1995): 16.
Kum Kum, Khanna. "Cancer Risk and the ATM Gene."
Journal of the American Cancer Institute 92, no. 6 (May 17, 2000): 795–802.
Stankovic, Tatjana, and Peter Weber, et al. "Inactivation of Ataxia Tlangiectasia Mutated Gene in B-cell Chronic Lymphocytic Leukaemia." Lancet 353 (January 2, 1999): 26–29.
Wang, Jean. "New Link in a Web of Human Genes." Nature 405, no. 6785 (May 25, 2000): 404–405.
ORGANIZATIONS
A-T Children's Project. 668 South Military Trail, Deerfield Beach, FL 33442. (800) 5-HELP-A-T. http://www.atcp.org.
A-T Medical Research Foundation. 5241 Round Meadow Rd., Hidden Hills, CA 91302. http://pathnet.medsch.ucla.edu/people/faculty/gatti/gatsign.htm.
National Ataxia Foundation. 2600 Fernbrook Lane, Suite 119, Minneapolis, MN 55447. (763) 553-0020. Fax: (763) 553-0167. naf@ataxia.org. http://www.ataxia.org.
National Organization to Treat A-T. 4316 Ramsey Ave., Austin, TX 78756-3207. (877) TREAT-AT. http://www.treat-at.org.
Genevieve T. Slomski, PhD
Rosalyn Carson-Dewitt, MD