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Diseases » Ataxia Telangiectasia » Wikipedia

Ataxia Telangiectasia in Wikipedia

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This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Ataxia telangiectasia". (Source - Retrieved 2006-09-07 14:19:09 from


Ataxia-telangiectasia (AT) (Boder-Sedgwick syndrome or Louis-Bar syndrome) is a primary immunodeficiency disorder that occurs in an estimated incidence of 1 in 40,000 to 1 in 300,000 births (Lederman, 2000).

Symptoms and prognosis

Telangiectasias are small, red 'spider' veins. These typically appear on the surface of the ears and cheeks or in the corners of the eyes in patients with AT. The 'ataxia' part of the name refers to the difficulty patients with AT have walking. At early age, the child's walking becomes wobbley, at teens handicapped-bound and at the early 20s, it becomes fatal.

AT is characterized by progressive cerebellar ataxia, oculocutaneous telangiectasia, progressive cerebellar dysfunction, and recurrent sinopulmonary infections secondary to progressive immunological and neurological dysfunction (Boder, 1958). AT patients are significantly predisposed to cancer, particularly lymphomas and leukemia. Other manifestations of the disease include sensitivity to ionizing radiation (Taylor et al., 1975), premature aging, and hypogonadism (Regueiro et al., 2000). AT has been a major interest of scientists since the 1960's because it may yield an insight into numerous other major health problems, such as cancer, neurological disease, immunodeficiency, and aging (Lederman, 2000).


The responsible gene in AT, ataxia-telangiectasia mutated (ATM), was discovered in 1995 by Savitsky et al., a team led by Yosef Shiloh of Tel Aviv University in Israel. Researchers linked the hyper-sensitivity of AT patients to ionizing radiation (IR) and predisposition to cancer to "chromosomal instability, abnormalities in genetic recombination, and defective signaling to programmed cell death and several cell cycle checkpoints activated by DNA damage"; (Canman, 1998). Earlier observations predicted that the gene altered in AT played a role in DNA damage recognition. These predictions were confirmed when a single gene on chromosome 11 (11q 22-23) was discovered (Savitsky et al., 1995, Gatti et al., 1982). Since its discovery, the protein product of the ATM gene has been shown to be a part of eukaryotic cell cycle control, DNA repair, and DNA recombination (Lavin, 2004).


AT is characterised by:

  • Early-onset progressive cerebellar ataxia
  • Oculo-cutaneous telangiectasia (dilated blood vessels in the eyes and skin)
  • Immunodeficiency mostly thorough lowering of IgA, IgG and IgE levels.
  • Chromosomal instability
  • Hyper sensitivity to ionising radiation
  • Increased incidence of malignancies primarily lymphoid.
  • Raised alpha-fetoprotein levels.


So far there appear to be three forms of AT:

  1. Pure AT where patients present with all/most of the diagnostic symptoms.
  2. Attenuated AT where sufferers do not possess all of the diagnostic symptoms.
  3. Carrier AT where individuals with a single ATM mutation show an increased risk of cancer (known since the 1970’s).

These are sometimes classified into ‘types’ from I to IV.

  • Type I is the classic syndrome with all manifestations.
  • Type II lacks some of the typical findings but shows radiosensitivity.
  • Type III has the classic clinical findings but is not radiosensitive.
  • Type IV shows only some clinical features and is not radiosensitive.

Differential Diagnosis

Nijmegen syndrome, also known as ataxia telangiectasia variant 1, is a very rare syndrome which could be considered as a differential diagnosis to AT. People with Nijmegen syndrome show the same immunodeficiency, radiosensitivity and risk of cancer as AT but do not have any ataxia or oculo-cutaneous telangiectasia. Nijmegen syndrome sufferers also show microcephaly. The gene associated with Nijmegen syndrome is known to be located on 8q21 and thought to play a similar role to the ATM gene.

In the early, ataxic stages children may be diagnosed with cerebral palsy.

Other differential diagnoses are:

Clinical Description

The outlook for AT sufferers is not good, mainly due to the compromised immune system which results in recurrent respiratory infections. Neurological features are progressive as is deterioration and aging of the skin and hair with ataxia usually seen in the first year of life. Sufferers are usually wheelchair bound by the age of 10 or 11. Telangiectasias are not seen in the early stages of the disease and begin to appear after a few years i.e. between 3-6 years of age, in the corners of the eyes, ears and cheeks. Individuals are also at a 10% risk of developing cancer, usually lymphomas and often breast cancer. However due to sufferers hyper-sensitivity to ionising radiation, radiotherapy and chemotherapy must be used with extreme caution. Oculo-cutaneous telangiectasia is often not obvious in the early stages of the disease. Other features of the disease may include mild diabetes mellitus, premature graying of the hair, difficulty swallowing, and delayed physical and sexual development. Children with A-T usually have normal or above normal intelligence


Treatment is symptomatic and supportive. Physical and occupational therapy may help maintain flexibility. Speech therapy may also be needed. Gamma-globulin injections may be given to help supplement a weakened immune system. High-dose vitamin regimens may also be used. Antibiotics are used to treat infections. Some physicians recommend low doses of chemotherapy to reduce the risk of cancer but this is controversial. It is also recommended that heterozygote family members are regularly monitored for cancers. Recently desferrioxamine was shown to increase the stability of AT cells and may prove to be an effective treatment for the disorder.

Diagnostic Methods

Diagnosis is usually achieved by examination and identification of both ataxia and oculo-cutaneous telangiectasia. This is then followed by laboratory tests for low levels of IgA, Ig2, Ig4, and IgE. Sufferers may also have a low lymphocyte count and other immunological abnormalities. This can then be followed by cytogenetic and molecular testing to confirm the diagnosis. MRI and CT scans may show signs of cerebellar atrophy.


AT is an autosomal recessive disorder caused by mutations in the ATM gene located on chromosome 11q22-23 (OMIM 208900). It was characterised in June of 1995 and is made up of 66 exons spread across 150kb of genomic DNA. It encodes a 13kb mature transcript with an open reading frame of 9168 nucleotides. The ATM protein is about 370kDa and is ubiquitously expressed and is localised to the cell nucleus. The ATM protein is a large serine-threonine kinase thought to play a role in regulating cell cycle checkpoints, repair of double stranded DNA and meiosis (similar to the BRCA genes). ATM is also known to play a role in regulating p53, BRCA1 and CHEK2. Part of ATM’s role in DNA repair is known to be that of telomere repair as telomeres degrade more rapidly in people affected with AT.

Mutations in the ATM gene are thought to come in two types:

  • Null mutations are those which cause complete loss of function of the protein and are therefore inherited in a recessive manner and cause AT.
  • ‘Missense’ mutations which produce stable, full sized protein with reduced function e.g. substitutions, short in-frame insertions and deletions etc. These mutations act by dominantly interfering with the normal copy of the protein.

The majority of AT sufferers, 65-70%, have truncating mutations, with exon skipping mutations being particularly common. This results in very low or undetectable levels of ATM protein. Missense mutations are the most common type of mutation found in carriers with breast cancer. Individuals with two missense mutations are believed to have a milder form of AT, which may account for cases of attenuated AT. Therefore it is thought that ‘subtle constitutional alterations of ATM may impart an increased risk of developing breast cancer and therefore act as a low penetrance, high prevalence gene in the general population’ (Maillet et al 2002).

Clinical Aspects

Oculo-cutaneous telangiectasia combined with ataxia are the defining features of the condition.


The prognosis for AT sufferers is not good. Those with the disease usually die in their teens or early 20s although some individuals have been know to live to over 40. Carriers of ATM missense mutations are believed to have a 60% penetrance by age 70 and a risk of breast cancer 16x that of the normal population. Some papers state a lifetime risk for people with both null and missense mutations of 10-38%, which is still a hundred fold increase from population risk. Carriers of any type of ATM mutation have a 5-8 fold increased risk of cancer and on average die 7-8 years earlier than the normal population, often from heart disease. Individuals with a single ATM mutation are also at a higher risk from lung, gastric and lymphoid tumours, as well as breast cancer. S707P is known to be particularly common in breast cancer patients and F1463S is known to be associated with Hodgkin’s lymphoma. A recent study suggests that the majority of AT sufferers die from pulmonary infections (46%), with 21% dying from malignancies and 28% from malignancies and pulmonary infection. If pulmonary infections could be completely eradicated AT is consistent with survival into the 5th or 6th decade.

Epidemiology/ Prevalence

AT has an incidence of between 1 in 40,000 and 1 in 100,000. Carrier frequency is thought to be 1:100-200. Some mutations are more common than others is certain geographical regions for example, the 7636del9 mutation is a common mutation in European populations which has been shown to increase the risk of breast cancer in carriers.

Molecular Diagnosis

Molecular diagnosis of AT can be carried out by sequencing all 66 exon of the gene or by linkage if there is a significant family history. Protein functionality testing is also available. However AT testing is usually carried out cytogenetically as specific breakpoints and cytogenetic instability are major characteristic features of the disorder. This must be carried out on lymphocytes. 10% of patients with AT show balanced translocations, 2/3rds of which involve the immunoglobulin genes on chromosomes 7 and 14. Some patients show expansions in their immunoglobulin genes which can expand during mitosis resulting in prolymphocyte leukaemia.

Genetic Counselling

All individuals with AT should undergo genetic counselling along with their families. This is especially important due to the increased risk of cancers that heterozygotes have. There is also an associated risk to any other children born to the parents of the affected child.

Antenatal Diagnosis

Antenatal diagnosis can be carried out using microsatellite markers.



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