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Ataxia telangiectasia

Ataxia telangiectasia
Classification & external resources
ICD-10 G11.3
ICD-9 334.8
OMIM 208900
DiseasesDB 1025
eMedicine derm/691  oph/319
MeSH D001260

Ataxia-telangiectasia (AT) (Boder-Sedgwick syndrome[1] 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 an early age, the child's walking becomes wobbly; at teens, handicapped-bound; and at the early 20s, the condition becomes fatal.

In some cases the victim gets enlarged bowels, and they don't feel like eating. AT is characterized by progressive cerebellar ataxia, oculocutaneous telangiectasia, progressive cerebellar dysfunction, and recurrent sinopulmonary infections secondary to progressive immunological and neurological dysfunction.[2] AT patients are significantly predisposed to cancer, particularly lymphomas and leukemia. Other manifestations of the disease include sensitivity to ionizing radiation,[3] premature aging, and hypogonadism.[citation needed] 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.,[4] 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".[5] 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.[4][6] 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). Specifically, the AT gene serves as a tumor suppressor gene by contributing to a network of genes that link double stranded breaks in DNA to cell cycle arrest and apoptosis (programmed cell death). Patients with ATM have a defective AT gene, which leaves them susceptible to contracting cancer. For example, female ATM patients have a two-fold higher chance of ever having breast cancer, which often occur before the age of 50. ATM patients must try avoiding x-rays at all costs since the radiation induces double-stranded breaks.


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

Ataxia telangiectasia like disorder (ATLD) is an extremely rare condition which could be considered as a differential diagnosis to AT. ATLD patients are very similar to AT patients in showing a progressive cerebellar ataxia, hypersensitivity to ionising radiation and genomic instability. However, ATLD can be distinguished from AT by the absence of telangiectasias, normal immunoglobulin levels, a later onset of the condition and a slower progression of the disease. It is not known whether ATLD individuals are also predisposed to tumours. The gene mutated in ATLD is hMre11 and is located on chromosome 11q21.

Nijmegen breakage syndrome (NBS), 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 breakage syndrome show the same immunodeficiency, radiosensitivity and risk of cancer as AT but do not have any ataxia or oculo-cutaneous telangiectasia. Nijmegen breakage syndrome sufferers also show microcephaly. The gene associated with Nijmegen syndrome (Nbs1) is known to be located on 8q21.

Interestingly, the proteins expressed by the hMre11 and Nbs1 genes exist in the cell as a complex, along with a third protein expressed by the hRad50 gene. This complex, known as the MRN complex, plays an important role in DNA damage repair and signalling and is required to recruit ATM to the sites of DNA double strand breaks. Mre11 and Nbs1 are also targets for phosphorylation by the ATM kinase. Thus, the similarity of the three diseases can be explained in part by the fact that the protein products of the three genes mutated in these disorders interact in common pathways in the cell.

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. People with the disease usually have normal intelligence. Mental retardation is uncommon in people with A-T.[7]


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, IgG2, IgG4, 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. [8] 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. However, some patients with AT, even those with two null mutations who produce no ATM protein at all, may never present with oculo-cutaneous telangiectasia.


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 counseling

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 linkage and microsatellite markers. However, direct gene analysis is more common.


  1. ^ synd/3567 at Who Named It
  2. ^ Boder E, Sedgwick RP (1958). "Ataxia-telangiectasia; a familial syndrome of progressive cerebellar ataxia, oculocutaneous telangiectasia and frequent pulmonary infection". Pediatrics 21 (4): 526-54. PMID 13542097.
  3. ^ Taylor AM, Harnden DG, Arlett CF, et al (1975). "Ataxia telangiectasia: a human mutation with abnormal radiation sensitivity". Nature 258 (5534): 427-9. PMID 1196376.
  4. ^ a b Savitsky K, Bar-Shira A, Gilad S, et al (1995). "A single ataxia telangiectasia gene with a product similar to PI-3 kinase". Science 268 (5218): 1749-53. PMID 7792600.
  5. ^ Canman CE, Lim DS (1998). "The role of ATM in DNA damage responses and cancer". Oncogene 17 (25): 3301-8. doi:10.1038/sj.onc.1202577. PMID 9916992.
  6. ^ Gatti RA, Bick M, Tam CF, et al (1982). "Ataxia-Telangiectasia: a multiparameter analysis of eight families". Clin. Immunol. Immunopathol. 23 (2): 501-16. PMID 6213343.
  7. ^ ped/2862 at eMedicine
  8. ^ Online 'Mendelian Inheritance in Man' (OMIM) 209800
This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Ataxia_telangiectasia". A list of authors is available in Wikipedia.
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