Ataxia Telangiectasia/Chromosome Breakage Di... Health Article

Definition

Ataxia telangiectasia (A-T), also called Louis-Bar syndrome or cerebello-oculocutaneous telangiectasia, is a rare, inherited disease that attacks the neurological and immune systems of children. A-T is a recessive disorder, meaning that it affects children who carry two copies of a defective (mutated) A-T gene, one copy from each parent. A-T affects the brain and many parts of the body and causes a wide range of severe disabilities.

Description

Ataxia means poor coordination, and the telangiectasia are tiny, red spider blood vessels which develop in A-T patients, especially on the whites of the eyes and on the surface of the ears. A-T is a progressive disease that affects the cerebellum (the body's motor control center) and, in about 70 percent of cases, weakens the immune system as well, leading to respiratory disorders. The weakening of the immune system (immunodeficiency) resulting from A-T has been traced to defects in both B-cells and T-cells, the specialized white blood cells (lymphocytes) that defend the body against infection, disease, and foreign substances. In A-T children, B-cell responses are very weak, and levels of immunoglobulins, the proteins that B-cells make to fight infection by specific recognition of invading organisms, may also be low. T-cells are few and weak, and the thymus gland is immature. This is why A-T is also considered an immunodeficiency disease. A-T first shows itself in early childhood, usually at the toddler stage. The characteristic symptoms are lack of balance, slurred speech, and perhaps a higher-than-normal number of infections. All children at this age take a little while to develop good walking skills, coherent speech, and an effective immune system, so it often takes a few years before A-T is correctly diagnosed. Other features of the disease may include mild diabetes, premature graying of the hair, difficulty swallowing, and delayed physical and sexual development. Children with A-T usually have normal or above normal intelligence, but some cases of mental retardation have been reported.

Transmission

A-T is genetically transmitted by parents who are carriers of the gene responsible for A-T. The A-T mode of inheritance is autosomal recessive (AR) and requires two copies of the predisposing gene—one from each parent—for the child to have the disease. Parents do not exhibit symptoms, but they each carry a recessive gene that may cause A-T in their offspring. In AR families, there is one chance in four that each child born to the parents will have the disorder. Every healthy sibling of an A-T patient has a 66 percent chance of being a carrier, like the parents.

Demographics

According to the National Cancer Institute, the incidence of A-T is between one out of 40,000 and one out of 100,000 persons worldwide, and for Caucasians it is about three per million, so the disorder is very rare. In the United States, there are about 500 children with A-T with both males and females equally affected. An estimated 1 percent (2.5 million) of the general population carries one of the defective A-T genes. Carriers of one copy of this gene do not develop A-T but have a significantly increased risk of cancer (over 38 percent of children with A-T develop cancer).

Causes and symptoms

A-T is a genetic disorder, meaning that it is caused by a defect in a gene that is present in a person at birth. All people have genes that contain a few mistakes or variations that do not result in a disorder. Disorders result when the gene variations are significant enough to affect the function a gene controls. Variations that cause disease are called mutations and A-T results from a defective gene, the ATM gene (for ataxia telangiectasia, mutated), first identified in 1995. The ATM gene is located on the long arm of chromosome 11 at position 11q22-23. It encodes for (controls) the production of a protein that plays a role in regulating cell division following DNA damage. The various symptoms seen in A-T reflect the main role of this protein, which is to induce several cellular responses to DNA damage. The protein made by the ATM gene is located in the nucleus of the cell and normally functions to control the rate at which the cell grows. The ATM protein does this by sending signals and modifying other proteins in the cell, which then changes the function of the proteins. The ATM protein also interacts with other special proteins when DNA is damaged as a result of exposure to some type of radiation. If the strands of DNA are broken, the ATM protein coordinates DNA repair by activating repair proteins, which helps to maintain the stability of cells. Mutations in ATM prevent cells from repairing DNA damage, which may lead to cancer. Mutations can also signal cells in the brain to die inappropriately, causing the movement and coordination problems associated with A-T.

A-T affects several different organs in the body. The most important symptoms are as follows:

• Neurologic abnormalities resulting in poor coordination and an unsteady gait (ataxia). Shortly after learning to walk, children with A-T begin to stagger. They tend to sway when they stand or sit and wobble when they walk. Jerking and tremors are present in about 25 percent of patients. This symptom results from neurologic abnormalities affecting the cerebellum that controls balance. Writing is affected by seven or eight years of age.
• Dilated blood vessels (telangiectasia). Telangiectasias usually occur on the white portion of the eye or on the ears, neck and extremities.
• Variable immunodeficiency resulting in increased vulnerability to infections. This symptom is a major feature in some individuals. The infections most commonly involve the lungs and sinuses and are usually of bacterial or viral origin. About 10 percent of patients have severe immunodeficiency.
• Predisposition to certain types of cancer. At least 10 percent of all A-T patients, including adults, develop cancer. Most of these are cancers of the lymphoid tissues (leukemias and lymphomas), but one fifth of the cancers occur in the stomach, brain, ovary, skin, liver, larynx, parotid gland, and breast.

Additional clinical symptoms include the following:

• autosomal recessive inheritance of the ATM gene
• involuntary, rapid, rhythmic movement of the eyeball (nystagmus)
• impaired ability to coordinate certain types of eye movements (oculomotor apraxia)
• squint of ocular muscles
• speech defect (dysarthria)
• slow, writhing motions (choreoathetosis)
• lack of T-lymphocytes (thymic aplasia)
• albinism of hair
• decreased to absent deep tendon reflexes
• multiple skin changes including eczema and "coffee-with-milk"x colored spots
• incomplete development of tonsils, lymph nodes, and spleen (hypoplasia)
• seizures (any type)
• abnormal ovaries
• small testes
• high blood sugar levels (hyperglycemia)