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Ataxia-telangiectasia

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 diseaseusually a lack of balance and slurred speechoften 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 eyesgiving the eyes a blood-shot appearanceor 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 immunoglobulinsthe natural infection-fighting agents in the bloodchildren 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 cancerparticularly 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 encephalopathya brain dysfunction, or ataxic cerebral palsyparalysis 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 forand maskedby 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): 795802.

Stankovic, Tatjana, and Peter Weber, et al. "Inactivation of Ataxia Tlangiectasia Mutated Gene in B-cell Chronic Lymphocytic Leukaemia." Lancet 353 (January 2, 1999): 2629.

Wang, Jean. "New Link in a Web of Human Genes." Nature 405, no. 6785 (May 25, 2000): 404405.

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

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"Ataxia-telangiectasia." Gale Encyclopedia of Neurological Disorders. . Encyclopedia.com. 21 Oct. 2017 <http://www.encyclopedia.com>.

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"Ataxia-telangiectasia." Gale Encyclopedia of Neurological Disorders. . Retrieved October 21, 2017 from Encyclopedia.com: http://www.encyclopedia.com/science/encyclopedias-almanacs-transcripts-and-maps/ataxia-telangiectasia

Ataxia-Telangiectasia

Ataxia-Telangiectasia

Definition

Ataxia-telangiectasia (A-T), also called Louis-Bar syndrome, is a rare, genetic neurological disorder of childhood that progressively destroys part of the motor control area of the brain, leading to a lack of balance and coordination. A-T also affects the immune system and increases the risk of leukemia and lymphoma in affected individuals.

Description

The disorder first appeared in the medical literature in the mid-1920s, but was not named specifically until 1957. The name is a combination of two recognized abnormalities: ataxia (lack of muscle control) and telangiectasia (abnormal dilatation of capillary vessels that often result in tumors and red skin lesions ). However, A-T involves more than just the sum of these two findings. Other associated A-T problems include immune system deficiencies, extreme sensitivity to radiation, and blood cancers.

Medical researchers initially suspected that multiple genes (the units responsible for inherited features) were involved. However, in 1995, mutations in a single large gene were identified as causing A-T. Researchers named the gene ATM for A-T, mutated. Subsequent research revealed that ATM has a significant role in regulating cell division. The symptoms associated with A-T reflect the main role of the AT gene, which is to induce several cellular responses to DNA damage, such as preventing damaged DNA from being reproduced. When the AT gene is mutated into ATM, the signaling networks are affected and the cell no longer responds correctly to minimize the damage.

A-T is very rare, but it occurs in every population world wide, with an estimated frequency of between 1/40,000 and 1/100,000 live births. But it is believed that many A-T cases, particularly those who die at a young age, are never properly diagnosed. Therefore, this disease may actually be much more prevalent. According to the A-T Project Foundation, an estimated 1% (2.5 million in the United States) of the general population carries defective A-T genes. Carriers of one copy of this gene do not develop A-T, but have a significantly increased risk of cancer. This makes the A-T gene one of the most important cancer-related genes identified to date.

Causes and symptoms

The ATM gene is autosomal recessive, meaning the disease occurs only if a defective gene is inherited from both parents. Infants with A-T initially often appear very healthy. At around age two, ataxia and nervous system abnormalities becomes apparent. The root cause of A-T-associated ataxia is cell death in the brain, specifically the large branching cells of the nervous system (Purkinje's cells) which are located in the cerebellum. A toddler becomes clumsy, loses balance easily and lacks muscle control. Speech becomes slurred and more difficult, and the symptoms progressively worsen. Between ages two and eight, telangiectases, or tiny, red "spider" veins, appear on the cheeks and ears and in the eyes.

KEY TERMS

Angioma A tumor (such as a hemangioma or lymphangioma) that mainly consists of blood vessels or lymphatic vessels.

Antibody Any of a large number of proteins produced by specialized blood cells after stimulation by an antigen and that act specifically against the antigen in an immune response.

Antigen Any substance (such as a toxin or enzyme) capable of stimulating an immune response in the body.

Ataxia The inability to control voluntary muscle movement, most frequently resulting from disorders in the brain or spinal cord.

Autosomal Relating to any of the chromosomes except for X and Y, the sex chromosomes.

Cerebellum The part of the brain responsible for coordination of voluntary movements.

Gamma-globulin An extract of human blood that contains antibodies.

Immune response A response from the body to an antigen that occurs when the antigen is identified as foreign and that induces the production of antibodies and lymphocytes capable of destroying the antigen or making it harmless.

Immunoglobulin A protein in the blood that is the component part of an antibody.

Leukemia A cancer of blood cells characterized by the abnormal increase in the number of white blood cells in the tissues. There are many types of leukemias and they are classified according to the type of white blood cell involved.

Lymphoma A blood cancer in which lymphocytes, a variety of white blood cells, grow at an unusually rapid rate.

Mutation Any change in the hereditary material of genes.

Purkinje's cells Large branching cells of the nervous system.

Recessive Producing little or no phenotypic effect when occurring in heterozygous condition with a contrasting allele.

Telangiectases Spidery red skin lesions caused by dilated blood vessels.

Telangiectasia Abnormal dilation of capillary blood vessels leading to the formation of telangiectases or angiomas.

Thymus A gland located in the front of the neck that coordinates the development of the immune system.

By age 10-12, children with A-T can no longer control their muscles. Immune system deficiencies become common, and affected individuals are extremely sensitive to radiation. Immune system deficiencies vary between individuals but include lower-than-normal levels of proteins that function as antibodies (immunoglobulins) and white blood cells (blood cells not containing "iron" proteins). The thymus gland, which aids in development of the body's immune system, is either missing or has developed abnormally. Intelligence is normal, but growth may be retarded owing to immune system or hormonal deficiencies. Individuals with A-T are also sometimes afflicted with diabetes, prematurely graying hair, and difficulty swallowing. As the children grow older, the immune system becomes weaker and less capable of fighting infection. In the later stages, recurrent respiratory infections and blood cancers, such as leukemia or lymphoma, are common.

Diagnosis

Diagnosis relies on recognizing the hallmarks of A-T: progressive ataxia and telangiectasia. However, this may be difficult as ataxia symptoms do appear prior to telangiectasia symptoms by several years. Other symptoms can vary between individuals; for example, 70% of individuals with A-T have a high incidence of respiratory infection, 30% do not. The identification of the ATM gene raises hopes that screening, and perhaps treatment, may be possible.

Treatment

There is currently no cure for A-T, and treatment focuses on managing the individual's multiple symptoms. Physical therapy and speech therapy can help the patient adjust to ataxia. Injections of gamma globulin, or extracts of human blood that contain antibodies, are used to strengthen the weakened immune system. High-dose vitamin administrations may also be prescribed. Research continues in many countries to find effective treatments. Individuals and families living with this disorder may benefit from attending support groups.

Prognosis

A-T is a fatal condition. Children with A-T become physically disabled by their early teens and typically die by their early 20s, usually from the associated blood cancers and malignancies. In very rare cases, individuals with A-T may experience slower progression and a slightly longer life span, surviving into their 30s. A-T carriers have a five-fold higher risk than non-carriers of developing certain cancers, especially breast cancer.

Prevention

Medical researchers are investigating methods for screening individuals who may be carriers of the defective gene. Prenatal testing for A-T is possible but not done routinely, because commercial screening tests have yet to be developed.

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"Ataxia-Telangiectasia." Gale Encyclopedia of Medicine, 3rd ed.. . Encyclopedia.com. 21 Oct. 2017 <http://www.encyclopedia.com>.

"Ataxia-Telangiectasia." Gale Encyclopedia of Medicine, 3rd ed.. . Encyclopedia.com. (October 21, 2017). http://www.encyclopedia.com/medicine/encyclopedias-almanacs-transcripts-and-maps/ataxia-telangiectasia

"Ataxia-Telangiectasia." Gale Encyclopedia of Medicine, 3rd ed.. . Retrieved October 21, 2017 from Encyclopedia.com: http://www.encyclopedia.com/medicine/encyclopedias-almanacs-transcripts-and-maps/ataxia-telangiectasia