October 27, 2022
Years published: 1987, 1990, 1992, 1996, 1997, 1998, 1999, 2000, 2004, 2007, 2022
NORD gratefully acknowledges Rosemary Enright and Kirsten Williams, NORD Editorial Interns from the University of Notre Dame and Sharon McGrath-Morrow, MD, MBA, Associate Chief, Division of Pulmonary & Sleep Medicine, Robert Gerard Morse Endowed Chair and Professor of Pediatrics, Children’s Hospital of Philadelphia
Perelman School of Medicine at The University of Pennsylvania, for assistance in the preparation of this report.
Ataxia telangiectasia (AT) is a complex neurodegenerative disorder. Symptoms associated with AT usually present during the preschool years between one and four years of age. An unsteady gait (ataxia) is often the first sign of AT. Symptoms that distinguish AT from other disorders include an impaired ability to coordinate eye movements (oculomotor apraxia) and episodes of involuntary movements (choreoathetosis). Progression of ataxia is associated with cerebellar degeneration, and many school-age children with AT are dependent on wheelchair assistance.
Telangiectasias, which are dilated blood vessels, may be present in the eye, skin or mucous membranes of children with AT. Ocular telangiectasias are the most common type of telangiectasias and usually present between 4 and 6 years of age. Impaired functioning of the immune system (i.e., cellular and humoral immunodeficiency) is present in many people with AT and many affected individuals have an increased risk of developing infections in the sinuses and lungs. People with AT are also at increased risk for certain cancers, particularly lymphomas and leukemias during the first two decades of life and cancers in solid organs during early adulthood.
AT is caused by changes (mutations) in the ataxia telangiectasia mutated (ATM) gene and is inherited in an autosomal recessive pattern.
The name ataxia telangiectasia refers to two major symptoms associated with AT. One major symptom is diminished muscle coordination and voluntary muscle control (ataxia). Another is the development of red or purple clusters of dilated blood vessels (telangiectasias) on mucous membranes and the sun-exposed areas of the skin, often visible by age six. The severity of symptoms can vary, but AT usually affects coordination of muscle control and immune and pulmonary responses to infection and stress. The symptoms are discussed below.
Impairment of muscle coordination begins in the head and neck, which can affect swallowing and breathing and lead to drooling and choking. An early and defining symptom of AT is reduced ability to control voluntary eye movements (oculomotor apraxia). Eye movement abnormalities are typically present in most patients. Slurred speech (dysarthria) is another early symptom, often resulting in speech that is monotonous, slow and unstable. Shortly after learning to walk, affected children will begin to stagger and require wheelchair assistance by 10-12 years of age. Most affected individuals exhibit episodes of involuntary movements (choreoathetosis) and tremors. Other common muscle impairment symptoms include involuntary, rapid, rhythmic eye movements (nystagmus), muscle stiffness and contractions and/or shortening and hardening (contractures) of fingers and toes. Muscle impairment also reduces ability to read and write, even though most individuals with AT have normal intelligence. Non-classical forms of AT present with milder symptoms and later onset ataxia.
About 60-80% of affected individuals have abnormal functioning of the immune system (immunodeficiencies). Affected individuals have a high risk of infection due to low levels of antibodies (immunoglobulins) including white blood cells (lymphocytes).
Individuals with AT have an increased risk of sinus and pulmonary infections, including pneumonia and chronic bronchitis. Causes for respiratory symptoms are multifactorial and may include an impaired cough preventing clearance of airway secretions, swallowing abnormalities increasing the risk for aspiration and abnormal immune responses to respiratory infections and stress. Lung (pulmonary) failure is one of the greatest health risks for individuals with AT.
Short height and delayed puberty are common symptoms. Other symptoms include underdeveloped adenoids, tonsils, peripheral lymph nodes and sexual organs. Affected females may experience loss of ovarian function. Affected individuals may also demonstrate premature aging of the hair and skin as teenagers.
Other Health Risks
Individuals with AT are at a high risk of cancer, especially cancer in the lymphatic system (lymphomas) or in the blood (leukemia) as well as abnormal tissue growth (neoplasm). During the first 20 years, affected individuals have an increased risk of cancers (malignancies) in the blood. Affected young adults are at an increased risk of cancers/tumors in the solid organs (ex. liver, spleen).
People with one ATM gene mutation do not have AT but have a four times higher risk of cancer than the general population, as well as a higher risk for coronary artery disease.
In some people with AT, type II diabetes mellitus may occur. Diabetes mellitus is a condition characterized by insulin resistance (type II) or insufficient secretion of insulin (type I). Primary symptoms may include abnormally increased thirst and urination (polydipsia and polyuria), weight loss, lack of appetite and fatigue. Recent research suggests that diabetes develops during puberty in individuals with AT. Often type II diabetes in people with AT is associated with metabolic syndrome (a constellation of symptoms including type II diabetes, elevated cholesterol and systemic hypertension).
AT is also characterized by cerebellar degeneration, chromosomal instability and sensitivity to radiation. People with AT should minimize exposure to ionizing radiation (i.e., x-rays) due to their sensitivity to radiation.
AT is caused by pathogenic variants (mutations) in the ATM gene. The ATM gene codes for a serine/threonine protein kinase. A kinase is a biological catalyst (enzyme) that speeds up the addition of phosphate groups to other molecules. The serine/threonine protein kinase belongs to the PI3 kinase-like kinases (PIKKs) family. It is primarily located in the cell nucleus. The ATM kinase activates and interacts with multiple different molecules. Currently, the best-known function of the ATM protein is to coordinate the repair of double strand breaks in DNA, the hereditary material that carries the genetic code. Double strand breaks in DNA can damage the cell. The ATM protein can activate certain enzymes to fix broken strands of DNA. This repair is essential to maintain the stability of the cell’s genetic information.
The ATM protein can also be activated in response to oxidative stress within the cell. In individuals with AT, the ATM gene is mutated in a way that affects the function of the ATM protein and its kinase activity. Therefore, the signaling networks that respond to double strand breaks in the DNA or the reduction of oxidative stress are defective. The mutations in the ATM gene that produce a defective ATM protein cause some of the symptoms associated with AT. For example, without the ATM protein, a cell cannot repair double strand breaks in the DNA. Thus, the cell may die or replicate with damaged DNA, and this can lead to cancer. Cell death in the cerebellum (particularly the Purkinje cells and to a lesser extent the granule neurons), can cause ataxia resulting in difficulties coordinating voluntary movements.
The majority of ATM mutations introduce an early halt (stop codon) to the process of creating the ATM protein (truncating mutation). This results in the shortening of the ATM gene sequence, which creates unstable ATM protein fragments. Truncating mutations correspond to more severe symptoms of AT because the ATM protein is not detected in the body, or it lacks enzymatic activity. ATM mutations can also occur when a base pair is accidentally changed in the DNA (missense mutation) or there is an insertion or deletion of a nucleotide that shifts the reading frame of the DNA (frameshift mutation). With these mutations, the ATM protein is detected and may have some enzymatic activity. Individuals with missense mutations in the ATM gene may experience less severe symptoms.
AT is inherited as an autosomal recessive disorder. Generally, an individual receives two copies of a single gene, one from each parent. Since AT is a recessive disorder, an individual must carry two copies of the abnormal gene to develop the disease.
People who have one mutated gene and one normal gene do not develop AT. These individuals are known as carriers. It is estimated that one in 100 persons may be a carrier for an ATM mutation. Although carriers do not have AT, they are more likely to develop cancer and heart disease compared to those without any ATM gene mutations. Carriers of AT typically do not display any symptoms of the disease; however, they can pass down the altered gene to children. The inheritance pattern for two carrier parents is explained as follows. These individuals have a 25% chance (per pregnancy) of having a child with AT if they both contribute a mutated gene to their offspring. They also have a 25% chance (per pregnancy) of having a child with two normal genes and no AT. Lastly, they have a 50% chance of having a carrier child with one normal gene and one mutated gene who does not develop AT.
In the United States, the prevalence of AT is approximately 1:40,000 to 1:100,000 live births. Males and females are affected in equal numbers. Certain ethnic groups may have a higher prevalence of AT due to a founder effect.
A diagnosis of ataxia telangiectasia is made based upon a detailed patient history, thorough clinical evaluation, identification of characteristic symptoms and a variety of specialized tests including genetic testing, blood tests and magnetic resonance imaging (MRI).
If AT is suspected, then genetic testing should be performed. Genetic testing can be used to show a mutation or duplication/deletion of the ATM gene. When there is a family history of AT, genetic testing may be used to detect ATM gene mutations in a child before the onset of symptoms.
Further testing, referred to as protein assays, can detect the amount of ATM protein. Protein assay tests can be revealing because 90% of individuals with diagnosed AT have no detectable amounts of ATM protein. However, some patients have activity of the ATM gene, which can be associated with milder symptoms.
If there is no family history, the diagnosis of AT may be delayed. Recently however, newborn screening for severe combined immunodeficiency (SCID) has resulted in earlier detection of infants with AT before symptoms are present. Similar to neonates with SCID, some newborns with AT may have low levels of T-cell receptor excision circles (TRECs).
During a brain examination called magnetic resonance imaging (MRI), magnetic fields and radio waves are used to create cross-sectional images of the brain. These images can be helpful in diagnosis because affected individuals often show shrinkage (atrophy) in the cerebellum, the part of the brain responsible for coordinating movement. However, the shrinkage is not always detectable in the MRI scans of young children. While there is limited access to the technology, diffusion weighted MRIs have been able to detect shrinkage in children as young as three years old. Inability to control voluntary eye movement (oculomotor apraxia) is a very specific symptom of AT and can be used to differentiate AT from other related diseases.
Treatment for AT is directed toward the control of symptoms as there is no current cure for the disease. It is recommended that patients diagnosed with AT be treated by physicians with knowledge about the individual’s clinical needs. Optimally, patients should also be seen in a multidisciplinary hospital.
For respiratory infections, some effective treatment options include therapy with an antibiotic when clinically indicated and chest physiotherapy. Some children will benefit from bronchodilator therapy and routine use of a cough assist device to help bring up airway secretions. IVIG replacement therapy is often used to treat chronic infections and/or low IgG levels. IgG levels refer to antibodies in the blood that function to fend off infections. Low levels increase risk of infection. The goal of IVIG replacement therapy is to reduce the risk of infection. Gastrostomy tube (G-tube) feedings are often recommended for affected individuals due to their difficulty swallowing to prevent choking (asphyxiation). Other common treatments include immunoglobulin replacement therapy, antioxidant usage and anti-inflammatory hormone therapy.
Treatments for secondary symptoms of AT, such as cancer, require careful monitoring. Individuals with AT have an increased sensitivity to radiation and chemotherapy. Improper use of these treatments can potentially be lethal or toxic to patients with AT. Doses of chemotherapy can be reduced by 25-50% with longer recovery periods to accommodate the increased sensitivity. Affected individuals can be adversely affected by anesthesia, so careful monitoring during surgery is required, especially in breathing and swallowing.
Careful monitoring for cancer or tumor growth signs is necessary, including signs of weight loss, bruising and/or pain or swelling in a particular area of the body.
Avoidance of undue exposure to sunlight may help control spread and severity of dilated blood vessels (telangiectasias). Other treatments are symptomatic and supportive.
Since recent research suggests that diabetes develops during puberty and early adulthood for individuals with AT, an annual diabetes screening starting from age 12 is recommended.
Genetic counseling is recommended for people with AT and their families.
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