Ataxia telangiectasia (AT) is a complex genetic neurodegenerative disorder that may become apparent during infancy or early childhood. The disorder is characterized by progressively impaired coordination of voluntary movements (ataxia), the development of reddish lesions of the skin and mucous membranes due to permanent widening of groups of blood vessels (telangiectasia), and impaired functioning of the immune system (i.e., cellular and humoral immunodeficiency), resulting in increased susceptibility to upper and lower respiratory infections (sinopulmonary infections). Individuals with AT also have an increased risk of developing certain malignancies, particularly of the lymphatic system (lymphomas), the blood-forming organs (e.g., leukemia), and the brain.
In those with AT, progressive ataxia typically develops during infancy and may initially be characterized by abnormal swaying of the head and trunk. As the disease progresses, the condition leads to an inability to walk (ambulation) by late childhood or adolescence. Ataxia is often accompanied by difficulty speaking (dysarthria), drooling; and an impaired ability to coordinate certain eye movements (oculomotor apraxia), including the occurrence of involuntary, rapid, rhythmic motions (oscillations) of the eyes while attempting to focus upon certain objects (fixation nystagmus). Affected children may also develop an unusually stooped posture and irregular, rapid, jerky movements that may occur in association with relatively slow, writhing motions (choreoathetosis). In addition, telangiectasias may develop by mid-childhood, often appearing on sun-exposed areas of the skin, such as the bridge of the nose, the ears, and certain regions of the extremities, as well as the mucous membranes of the eyes (conjunctiva).
AT is inherited as an autosomal recessive trait. The disorder is caused by changes (mutations) of a gene known as ATM (for "AT mutated") that has been mapped to the long arm (q) of chromosome 11 (11q22.3). The ATM gene controls (encodes for) the production of an enzyme that plays a role in regulating cell division following DNA damage.
An early symptom of ataxia telangiectasia is diminished muscle coordination usually noticed when a child begins to walk. Coordination (especially in the head and neck area) becomes impaired, and tremors (involuntary muscle contractions) can occur. In most cases, mental functioning is not affected and most children exhibit normal or above average intelligence.
The telangiectasias (visible dilated blood vessels) usually begin in the eyes (the eyes look “bloodshot”) between three and six years of age, although they can occur earlier. These discolorations may spread to the eyelids, face, ears, roof of the mouth and possibly other areas of the body. Rapid eye blinking and movements, and turning of the head may develop gradually. Occasional nosebleeds may also occur. The adenoids, tonsils and peripheral lymph nodes may develop abnormally or fail to develop. Muscle coordination in the head and neck area may be gradually impaired causing poor cough reflexes and problems with swallowing, breathing, drooling, and choking. Slurred speech and variable jerking, writhing and tic-like movements also be noticed.
Growth retardation can be linked to a growth hormone deficiency. Premature aging occurs in approximately ninety percent of affected individuals and is characterized by gray hair with dry, thin, wrinkled or discolored skin during adolescence. A variety of other skin or hair problems may develop in some cases. Abnormalities of hormone producing (endocrine) glands may be accompanied by incomplete sexual development in both males and females.
Because of an impaired immune response, affected individuals may be more susceptible to chronic sinus and/or lung infections, recurring cases of pneumonia and chronic bronchitis.
Persons with this disorder may be affected by a high incidence of carcinoma and lymphoma usually beginning during early adulthood. Approximately one in three affected individuals develop cancer, usually cancer of certain malignancies, particularly of the lymphatic system (lymphomas) or of the blood (leukemia). Exposure to x-rays seems to increase the incidence of possible tumors. In addition, individuals with one ataxia telangiectasia gene (carriers) also appear to have an elevated risk for cancer. Close relatives of persons with ataxia telangiectasia may be at a higher risk of developing certain types of cancer than the general population.
In some cases, a mild form of diabetes mellitus may occur. Diabetes mellitus is a condition in which there is insufficient secretion of the hormone insulin. Primary symptoms may include abnormally increased thirst and urination (polydipsia and polyuria), weight loss, lack of appetite, and fatigue.
Ataxia telangiectasia is inherited as an autosomal recessive trait. Genetic diseases are determined by two genes, one received from the father and one from the mother.
Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%.
The disease gene that causes ataxia telangiectasia, known as the ATM gene, is located on the long arm (q) of chromosome 11 (11q22.3). Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males and two X chromosomes for females. Each chromosome has a short arm designated as “p” and a long arm identified by the letter “q”. Chromosomes are further subdivided into bands that are numbered.
Researchers have determined that the ATM gene encodes a protein that plays a role in regulating cell division after DNA damage. (DNA or deoxyribonucleic acid is the carrier of the genetic code.) The protein, which is known as ATM for “A-T mutated”, is an enzyme (protein kinase) that normally responds to DNA damage by triggering the accumulation of a protein (p53) that prevents cells from dividing (tumor suppressor protein). However, in individuals with ataxia telangiectasia, abnormal changes (mutations) of the ATM gene cause an absence or defect of the ATM protein and delayed accumulation of the p53 protein. As a result, cells with DNA damage continue dividing (replicating) without appropriate repair of their DNA, causing an increased risk of cancer development. Approximately half of human cancers are thought to be characterized by abnormalities affecting the activity of the p53 tumor suppressor protein. Exposure to ionizing radiation (such as x-rays) normally enhances the p53-directed activity of the ATM protein; however, in individuals with ataxia telangectasia, deficient activity of the ATM protein results in extreme sensitivity to such radiation.
Ataxia telangiectasia usually begins during infancy (between one and three years of age) and often affects more than one child in a family. Males and females may be affected in equal numbers. In the United States, the prevalence is approximately one in 40,000-100,000 live births.
A diagnosis of ataxia telangiectasia is made based upon a detailed patient history, a thorough clinical evaluation, identification of characteristic symptoms, and a variety of specialized tests including blood tests, magnetic resonance imaging (MRI), and karyotyping.
Blood tests may detect elevated levels of serum alpha-fetoprotein, which occurs in approximately 85 percent of cases. However, in unaffected children this protein may remain elevated until 2 years of age. Blood tests may also reveal elevated liver enzymes. During an MRI, magnetic field and radio waves are used to create cross-sectional images of the brain, which can show progressive cerebellar atrophy. Karyotyping is a specialized test that detects chromosomal abnormalities. Affected individuals have an increased frequency of such chromosomal abnormalities.
Treatment for AT is directed toward control of symptoms. For respiratory infections, therapy with an antibiotic drug, postural drainage (with the head lower than the rest of the body) of the bronchial tubes and lungs, and gammaglobulin injections in some cases may be effective.
Avoidance of undue exposure to sunlight may help control spread and severity of dilated blood vessels (telangiectasias). Vitamin E therapy has in some cases been reported to provide temporary relief of some symptoms, but should only be tried under advice and supervision of a physician to avoid toxicity. The drug Diazepam (Valium) may be useful in some cases to help slurred speech and involuntary muscle contractions. Physical therapy may help maintain muscle strength and prevent limb contractures. Care should be taken to ward off infections.
Other treatment is symptomatic and supportive. Genetic counseling may be of benefit to persons with AT and their families.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
For information about clinical trials sponsored by private sources, contact:
Research on ataxia telangiectasia concerning immunology and endocrinology is underway at this time. Developing laboratory procedures for earlier diagnoses and specific therapies are priorities of these research projects.
Trials of the experimental drug levamisole (used to heighten the immune response) are underway to test effectiveness on Ataxia Telangiectasia and other disorders involving impaired immune responses. Other trials involve the effects of interleukin-2, interferon and chemotherapeutic agents such as cyclophosphamide. Complications or side effects of these drugs (such as toxicity) have not been fully documented and more extensive research is being pursued.
Clinical trials of the orphan drug physostigmine salicylate (Antilirium) for treatment of ataxia telangiectasia and other inherited forms of ataxia are underway. For additional information, physicians can contact:
2510 Metro Blvd.
Maryland Heights, MO 64043
Dr. Peter McKinnon at St. Jude Children’s Research Hospital is studying the function of the ataxia telangiectasia gene and the cause of brain cell death. For more information, contact the ataxia telangiectasia Children’s Project listed in the Resources Section of this report.
Researchers at the Children’s Hospital of Philadelphia are conducting clinical studies on a nutritional intervention, myo-Inositol, as a treatment for ataxia telangiectasia. More studies are needed to determine the long-term safety and effectiveness of this treatment for ataxia telangiectasia. For more information, contact:
Dr. Gerard Berry, Principal Investigator
Children’s Hospital of Philadelphia
34th Street & Civic Center Blvd
Philadelphia, PA 19104-4399
Tel: (215) 590-3372
Michelle Bergman, R.N.
Clinical Research Center Coordinator
Tel: (215) 590-1399
Researchers at the University of Texas are conducting clinical studies on the nutritional and metabolic status of human lymphocytes. More studies are needed to determine the long-term safety and effectiveness of this research. For more information, contact:
Flora Pettit, Ph.D.
Elaine Hrissikopoulos- Administrative Associate
Biochemical Institute, University of Texas
Austin, TX 78712-1096
Tel: (512) 471-3662
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Behrman RE, et al., eds. Nelson Textbook of Pediatrics. 15th ed. Philadelphia, PA; W.B. Saunders Company; 1996:576, 1709.
Buyse ML. Birth Defects Encyclopedia. Dover, MA; Blackwell Scientific Publications, Inc.; 1990:205-207.
Gorlin RJ, et al., eds. Syndromes of the Head and Neck. 3rd ed. New York, NY; Oxford University Press; 1990:469-471.
Canman CE, et al. Activation of the ATM kinase by ionizing radiation and phosphorylation of p53. Science. 1998;281:1677-1679.
Banin S, et al. Enhanced phosphorylation of p53 by ATM in response to DNA damage. Science. 1998;281:1674-1677.
Watts GD, et al. Construction of a transcription map around the gene for ataxia telangiectasia: identification of at least four novel genes. Genomics. 1997;40:267-276.
Jung M, et al. Regulation of p53 in response to ionizing radiation in ataxia telangiectasia fibroblasts. Int J Radiat Oncol Biol Phys. 1997;37:417-422.
Dork T, et al. A frequent polymorphism of the gene mutated in ataxia telangiectasia. Mol Cell Probes. 1997;11:71-73.
Fritz E, et al. Overexpression of a truncated human topoisomerase III partially corrects multiple aspects of the ataxia-telangiectasia phenotype. Proc Natl Acad Sci USA. 1997; 94:4538-4542.
Savitsky K, et al. A single ataxia telangiectasia gene with a product similar to PI-3 kinase. Science. 1995;268:1749-1753.
Swift M, et al. Cancer incidences in families with ataxia telangiectasia. New Engl J Med. 1991;325:1831-1836.
Conerly SL, et al. Ataxia-telangiectasia or Louis-bar syndrome. J Am Acad Dermatol. 1985;12;681-696.
Dooley DM, et al. Treatment of patients with degenerative diseases of the central nervous system by electrical stimulation of the spinal cord. Confin Neurol. 1981;44;71-76.
FROM THE INTERNET
Online Mendelian Inheritance in Man, OMIM (TM). John Hopkins University, Baltimore, MD. MIM Number 208900; 1/3/00. Available at: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?208900.
National Institute of Neurological Disorders and Stoke. Ataxia Telagiectasia Information Page. October 29, 2003. Available at: http://www.ninds.nih.gov/health_and_medical/disorders/a-t.htm?format=printable
Ataxia Telangiectasia: fact Sheet-National Cancer Institute
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