Ataxia telangiectasia
Ataxia telangiectasia (A-T) is a rare, inherited neurodegenerative disorder characterized by a combination of symptoms including lack of motor coordination (ataxia), dilated small blood vessels in the eyes and skin (telangiectasia), and a heightened sensitivity to ionizing radiation. It results from mutations in the ATM gene located on chromosome 11, leading to significant deficiencies in DNA repair mechanisms, immune function, and increased cancer risk. Individuals with A-T often experience developmental delays in motor skills, worsening coordination issues, and increased susceptibility to respiratory infections due to immune system impairments. The condition is typically diagnosed in early childhood, around ages two to seven, often through clinical observation and specific genetic testing. While there is no cure or effective way to slow its progression, symptom management strategies include physical therapy, speech therapy, and antibiotics for infections. Prognosis varies, with many individuals reliant on wheelchairs by age ten, and a typical life expectancy extending into the mid-to-late twenties, though some may live longer. Genetic counseling and prenatal testing are available for families with a history of the condition, providing information on the likelihood of passing on the ATM mutation.
Ataxia telangiectasia
ALSO KNOWN AS: A-T; ATM (ataxia telangiectasia mutated); Louis-Bar syndrome; Boder-Sedgwick syndrome
DEFINITION Ataxia telangiectasia is a rare, autosomal recessive neurodegenerative and immunodeficiency disease caused by mutations in the ATM gene on chromosome 11q22–23. It is characterized by lack of motor coordination (ataxia), dilated small blood vessels in the eyes and skin (telangiectasia), hypersensitivity to ionizing radiation, respiratory infections, and high incidence of cancer.
Risk Factors
According to the National Library of Medicine, the of is estimated to be 1 in 40,000 to 1 in 100,000, as of 2022, and about 1 percent of the population is for an ataxia telangiectasia mutation (carriers). These individuals have an increased risk of cancer.
Etiology and Genetics
The ataxia telangiectasia mutated (ATM) gene is about 150 kilobase pairs (kbp) long, containing sixty-six exons, coding for a 13 kbp mature transcript with a 9,168 nucleotide-long open that translates into a protein of approximately 370 kilodaltons (kDa). The ATM protein is a serine/threonine protein (enzyme that adds a phosphate group to other proteins) with multiple functions and protein targets. Many different proteins are phosphorylated and thereby regulated by the ATM kinase. Lack of functioning ATM protein leads to defects in DNA repair, cancer, and neurodegeneration. ATM kinase activates repair proteins in response to double-stranded breaks in DNA. If there is too much DNA damage for the repair system, then ATM activates p53 and Chk1 to cause cell-cycle arrest or programmed cell death (apoptosis).
Ataxia telangiectasia patients have lack-of-function mutations because of truncated ATM proteins or splice-site mutations that result in short, unstable ATM proteins. Because patients have a decreased ability to repair double-strand DNA breaks, they are very sensitive to ionizing radiation (X-rays and gamma rays). In the normal immune system, rearrangements of DNA occur to create immunoglobins (for example, VDJ in B and T cells). ATM kinase plays a role in the breaks that occur in this rearrangement process. Individuals who lack functioning ATM will have immunodeficiencies. Deficiencies in DNA repair and loss of regulation of the can result in cancer. These deficiencies also lead to degeneration of postmitotic neurons of the cerebellum, the part of the brain that controls voluntary body movements.
Individuals who are carriers for ataxia telangiectasia—that is, who have a single defective copy of the ATM gene—have an increased risk of developing breast, lung, and blood cancers.
Symptoms
Since ataxia telangiectasia may show incomplete penetrance; severity of symptoms or age of occurrence of symptoms varies. Symptoms include developmental delay of motor skills in the young child, difficulty in coordinating movements, and poor balance. As patients age, the problems with motor control progressively worsen and also include lack of control of limb movements. Patients may have slurred speech and difficulty swallowing. Telangiesctasias (visible blood vessels) in the eyes typically occur by age five, though not all patients develop them. The neck and extremities may also develop telangiesctasias. About 60 to 80 percent of ataxia telangiectasia patients have frequent infections, especially of the sinuses and lungs, as a result of immune system defects. Patients have an increased risk of developing cancers, especially lymphomas and leukemias.
Screening and Diagnosis
Patients with ataxia telangiectasia are generally diagnosed between the ages of two and seven. A clinical diagnosis is based on the observation of ataxia and telangiectasia of the eyes. Patients have elevated serum levels of alpha-fetoprotein. Tests include sensitivity of cells to X-ray damage, chromosome instability in the patient’s lymphocytes, an for the protein, and sequencing of the ATM gene. Cerebellar atrophy may be seen in magnetic resonance imaging (MRI) or computed tomography (CT) scans. General indicators of ataxia telangiectasia are increased ionizing radiation sensitivity and lack of the ATM protein.
Treatment and Therapy
There is no cure for ataxia telangiectasia, nor are there treatments that are able to slow the progression of the disease. Symptoms are treated. Antibiotics and gammaglobulins are given to fight recurrent respiratory infections. Physical therapy helps the patient maintain flexibility. Speech therapy may be indicated for individuals who develop slurred speech. Psychological counseling may help individuals with ataxia telangiectasia. Patients generally have normal intelligence but may not perform well on tests that require visual-motor coordination. Because of the hypersensitivity to ionizing radiation, patients should limit exposure to X-rays. Diagnostic X-rays should be used only when there is no alternative to obtain a diagnosis.
Prevention and Outcomes
Patients with ataxia telangiectasia are often confined to wheelchairs by the age of ten but generally survive at least into their mid-to-late twenties, though some even live into their fifties, as reported by pathologist Richard Gatti. According to the National Institute of Neurological Disorders and Stroke, 35 percent develop some form of cancer, especially leukemias and lymphomas. A-T patients often die from recurring respiratory infections and lung failure. Couples with the ATM gene in their families can receive genetic counseling. Prenatal testing can be done to determine if a fetus has a mutated ATM gene. Following a family with the ATM mutation, linkage analysis and microsatellite markers are used to screen the fetus. Direct testing for the mutated gene (from known ataxia telangiectasia patients in the family) is used to determine whether the fetus has A-T.
Bibliography
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