Ataxia-telangiectasia Health Article

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.

Soon after the onset of the ataxia, an individual usually exhibits 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.

Genetic profile

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.

The A-T gene (called ATM, or A-T Mutated) was discovered by Tel Aviv researchers in 1995. The ATM protein is thought to prevent damaged DNA from being reproduced. However, the cells of patients with A-T lack the ATM protein, although the cells of those with the mild form of the disorder contain small amounts of it. It is thought that ATM is involved in sending messages to several other regulating proteins in the body. The absence of ATM severely disrupts the transmission of these messages, thereby affecting many different systems of the body.

Scientists have found that the ATM gene is often found with the p53 gene, which is defective in the majority of cancerous tumors. Tumor biologists, therefore, view A-T as one of the most explicit human models for studying inherited cancer susceptibility. In children who have A-T, the defective A-T gene blocks the normal development of the thymus, the organ most important for the development of the immune response. Understanding how immunodeficiencies develop in children with A-T may have relevance to research on other immunodeficiency disorders.

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.