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

Ataxia telangiectasia (A-T) (Boder-Sedgwick syndrome[1] or Louis–Bar syndrome[2]:555) is a rare, neurodegenerative, inherited disease that affects many parts of the body and causes severe disability. Ataxia refers to poor coordination and telangiectasia to small dilated blood vessels, both of which are hallmarks of the disease.

A-T affects the cerebellum (the body's motor coordination control center) and also weakens the immune system in about 70% of the cases, leading to respiratory disorders and increased risk of cancer. It first appears in early childhood (the toddler stage) with symptoms such as lack of balance, slurred speech, and increased infections. Because all children at this age take time to develop good walking skills, coherent speech, and an effective immune system, it may be some years before A-T is properly diagnosed.



So far there appear to be three forms of A-T:

  1. Pure A-T where patients present with all/most of the diagnostic symptoms.
  2. Attenuated A-T where sufferers do not possess all of the diagnostic symptoms.
  3. Carrier A-T where individuals with a single ATM mutation show an increased risk of cancer

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

There are several other disorders with similar symptoms that physicians may consider when diagnosing A-T. These include:

Ataxia-telangiectasia like disorder (ATLD) is an extremely rare condition which could be considered in the differential diagnosis of A-T. ATLD patients are very similar to A-T patients in showing a progressive cerebellar ataxia, hypersensitivity to ionising radiation and genomic instability [3]. However, ATLD can be distinguished from A-T 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.

Interestingly, the proteins expressed by the hMre11 (defective in ATLD) and Nbs1 (defective in NBS) 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 signaling 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.

Signs and Symptoms

A-T is characterised by:

Initially it may be hard to be sure that anything is amiss and some children seem to improve from 3 to 5 years, but eventually it becomes obvious that balance control is abnormal. Towards the end of the first decade and the start of the second other problems come to light; these can be as handicapping as the loss of body balance control. Because A-T can have somewhat incomplete penetrance, some patients have a mild form of the disease that starts later and has less severe symptoms. An A-T diagnosis is one of exclusion. Because of the disease's rarity, many doctors aren't familiar with the symptoms, diagnosis methods, or treatment. It may take some time before doctors rule out other possible conditions, such as cancer (a high AFP level can lead doctors in the wrong direction), or Cerebral Palsy.


The first indications of A-T usually occur during the toddler years. These first signs indicate difficulty with control of the body posture and body movement (truncal ataxia). The child may start to walk later than usual (after 18 months), may be reluctant to let go of supporting people or objects, may continue to walk unsteadily for longer than normal, may be unable to stand still without tottering, and may fall frequently.

Walking becomes more strenuous and appears awkward, doors and walls are frequently used for support. Running may, for a time, seem less affected; this is because less balance is needed for quick movements than slower graceful ones. At the beginning of the second decade of their lives most people with A-T begin to use a wheelchair.

Co-ordination of limbs becomes abnormal (peripheral ataxia) later in the disease. Involuntary movements may start in some patients, and generally become worse over time. They may include small jerks of the hands and feet which look like fidgeting (chorea), slower twisting movements of the upper body (athetosis), adoption of stiff and twisted postures (dystonia), occasional uncontrolled jerks (myoclonic jerks), and shaking episodes of a limb which are like shivering (tremors).

Slurring of speech (dysarthria) may develop in the first decade, becoming worse for 5 to 10 years and then remaining a static problem. Patients generally can be understood, although conversation may be a slow process. Eye movements become restricted (vertical and horizontal sacchadic apraxia). Reading and following moving objects becomes difficult.


Prominent blood vessels in the whites of the eyes (telangiesctasias) usually occur by the age of 5 years. These are the ocular telangiectasia of the condition and resemble those vessels seen in the eyes of much older people. They can occasionally be present at birth yet in others may not develop until the teenage years. Although potentially a cosmetic problem they do not bleed or itch. It is their constant nature, not changing with time, weather or emotion, which marks them as different from other eye blood vessels.

Immune problems

About half the people with A-T have immune problems. These usually take the form of repeated colds and runny noses (sinopulmonary infections). The immune system is complex and difficult to assess, but if the child is suffering more than his/her fair share of infections a physician should undertake this assessment. Some people with A-T need additional immunizations (DPT, Hib and Pneumovax), others need continued antibiotics to provide "background cover" and some require injections of Immunoglobulins. Others are not troubled. The impression is that bacterial, rather than viral, cause the most problems. Treatment of infections involve regular administration of IVIg. The doses should be determined by a medical doctor.

Other features

People with A-T have an increased incidence (probably 1% risk per year) of tumors, particularly lymphomas and leukemia. It has been reported that there is a small increased risk of breast cancer in mothers of children with A-T. This finding is the subject of much debate and research at present. Mammography before 50 years however is not recommended unless there is a strong family history of breast cancer.

Although people with A-T have an increased sensitivity to ionizing radiation (X-rays and gamma rays), they cope with other forms of radiation normally, i.e. obtaining a suntan from ultraviolet light. Also, the tumors seen in A-T are not thought to be radiation induced. X-ray exposure should be limited only to cases where it is absolutely medically necessary, as exposing an A-T patient to ionizing radiation can mutate cells in such a way that the body can't repair them.

Mental retardation is not seen in A-T. However, many children seem to have slower thinking speed. Some children are placed in special schools while others remain in mainstream schools, even graduating from university. Choreoathetosis, slurred speech, ocular apraxia and cerebellar ataxia are developed over the course of childhood.

A-T patients are often very thin. This may be due to a poor appetite, to the energy expended with involuntary movements, or the inherent characteristics of the disorder. Some people with A-T, both males and females, have a delayed puberty. This seems more common in those who are thin or are prone to infections.

Thymic hypoplasia may be present.[5] Hypogonadism (ovarian dysgenesis) and extreme sensitivity to ionizing radiation are also part of the clinical picture.


A-T is inherited in an autosomal recessive fashion.

A-T usually runs in families. The mode of inheritance is autosomal recessive, so in a family with two parents who are carriers of the A-T allele, there is 1 chance in 4 that each child born to the parents will have the disorder. Prenatal diagnosis can be carried out in most families, but this is complex and must be arranged before conception.

A-T is caused by mutations in the ATM gene located on chromosome 11q22-23.[6] It was characterised in June 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 A-T.

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 A-T.
  • 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 A-T 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 A-T. 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).

Oculo-cutaneous telangiectasia combined with ataxia are the defining features of the condition. However, some patients with A-T, even those with two null mutations who produce no ATM protein at all, may never present with oculo-cutaneous telangiectasia.

ATM Carriers

Carriers of ATM missense mutations are believed to have a 60% penetrance by age 70 and a risk of breast cancer 16 times higher that of the normal population, with a 5-8 fold increased risk of cancer. On average carriers die 7–8 years earlier than the normal population, often from heart disease. Some papers state a lifetime risk for people with both null and missense mutations of 10-38%, which is still a hundredfold increase from population risk.

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. If pulmonary infections could be completely eradicated A-T is consistent with survival into the 5th or 6th decade.


Diagnosis is usually achieved clinically by examination and identification of both ataxia and oculo-telangiectasia or skin telangiectasia. This is then followed by laboratory tests for serum AFP level, the response of white blood cells to X-rays and measurement of the level of ATM protein. 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. (MRI is the preferred method, as patients should limit exposure to any radiological diagnostic tests that use ionizing radiation)

Molecular diagnosis of A-T 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 A-T 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 A-T 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.

Antenatal diagnosis can be carried out using linkage and microsatellite markers. However, direct gene analysis between known sufferers and the foetus is more common.


The responsible gene in AT, ataxia-telangiectasia mutated (ATM), was discovered in 1995 by Savitsky et al.[7] a team led by Yosef Shiloh of Tel Aviv University in Israel. Researchers linked the hyper-sensitivity of A-T 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".[8] Earlier observations predicted that the gene altered in A-T played a role in DNA damage recognition. These predictions were confirmed when a single gene on chromosome 11 (11q 22-23) was discovered.[7][9] 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 A-T 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 A-T 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.


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 deferoxamine was shown to increase the stability of A-T cells and may prove to be an effective treatment for the disorder.

People with A-T have an increased incidence (probably 1% risk per year) of tumours, particularly lymphomas and leukaemia, but due to sufferers' hyper-sensitivity to ionising radiation, radiotherapy and chemotherapy are rarely used.[10]


Those with A-T usually die in their teens or early 20s although some individuals have been known to live to over 40. Mortality is mainly due to the compromised immune system which results in recurrent respiratory infections, predisposition to cancer, and the high rate of pulmonary problems which are associated with the disease.


The incidence of A-T in Caucasians is about 3 per million so the disorder is very rare, with probably fewer than 200 affected people in the UK.

Society and Culture

All families in the United Kingdom with a child who has A-T have access to a specialist clinic in Nottingham where a multi-disciplinary team (involving a neurologist, a geneticist and therapists) has seen many families with A-T.[11]


The Ataxia Telangiectasia Children's Project, better known as the A-T Children's Project, was founded in late 1993 by a family in Florida with two young sons who have A-T. It is a public, tax-exempt, non-profit organization pursuant to Section 501(c)(3) of the Internal Revenue Code, and all gifts and donations to the Project are tax deductible. The A-T Children's Project was formed to raise funds through events and contributions from corporations, foundations and friends. These funds are then used to accelerate first-rate, international scientific research aimed at finding a cure and improving the lives of all children with ataxia-telangiectasia.


  1. ^ synd/3567 at Who Named It?
  2. ^ James, William; Berger, Timothy; Elston, Dirk (2005). Andrews' Diseases of the Skin: Clinical Dermatology. (10th ed.). Saunders. ISBN 0721629210.
  3. ^
  4. ^ 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. 
  5. ^ "Ataxia-telangiectasia: eMedicine Ophthalmology". 
  6. ^ Online 'Mendelian Inheritance in Man' (OMIM) 209800
  7. ^ 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. doi:10.1126/science.7792600. PMID 7792600. 
  8. ^ 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. 
  9. ^ Gatti RA, Bick M, Tam CF, et al. (1982). "Ataxia-Telangiectasia: a multiparameter analysis of eight families". Clin. Immunol. Immunopathol. 23 (2): 501–16. doi:10.1016/0090-1229(82)90134-9. PMID 6213343. 
  10. ^ Taylor AM, Harnden DG, Arlett CF, et al. (1975). "Ataxia telangiectasia: a human mutation with abnormal radiation sensitivity". Nature 258 (5534): 427–9. doi:10.1038/258427a0. PMID 1196376. 
  11. ^ The A-T society 'Supporting the family, fighting the disease'

External links

raise awareness for A-T


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