Ataxia telangiectasia

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Ataxia telangiectasia
ICD-10 G11.3
ICD-9 334.8
OMIM 208900
DiseasesDB 1025
MedlinePlus 001394
MeSH D001260

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Historical Perspective




Differentiating Ataxia telangiectasia from other Diseases

Epidemiology and Demographics

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Natural History, Complications and Prognosis


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Case #1

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Synonyms and keywords: Louis-bar syndrome, Boder-sedgwick syndrome.


Ataxia telangiectasia (A-T) is an autosomal recessive disorder caused by mutations in the gene ATM (ataxia-telangiectasia mutated)(11q22.3). This gene is expressed commonly and encodes a protein kinase (ATM kinase) which plays a key role in the control of double-strand-break DNA repair. A-T is a progressive, multisystem disease that has a large number of complex and diverse manifestations that vary with age. The clinical picture of this condition can be very variable and the severity of the pulmonary, immunological and neurological manifestations varies widely between patients and is related to the severity of the underlying mutations and any residual ATM kinase activity. It has been recently suggested that the name A-T should be replaced by ATM syndrome. ATM syndrome represents a neurodegenerative disorder with multisystem involvement due to the absence or reduced levels of ATM protein and kinase activity. The syndrome is characterised by the presence of movement disorders, such as cerebellar ataxia, dystonia, chorea and myoclonus, in association with systemic abnormalities such as immunodeficiency, malignancies, oculocutaneous telangiectasias and an increase in α-fetoprotein levels. The disease most commonly presents with ataxia during the third or fourth year of life. The important first step in the evaluation of young children presenting with ataxia should be α-fetoprotein testing. The diagnosis should then be confirmed by genetic testing to identify the mutations and measure the product of the ATM gene, the protein kinase ATM. This diagnostic test is likely to be available in specialised laboratories only. Patients with A-T die prematurely, the leading causes of death being respiratory diseases and cancer. A minimally estimated annual mortality rate for white patients is 19.5/1000 for ages 15–19 years and reportedly three-fold higher for African-American patients.

Historical Perspective

The term Ataxia-Telangiectasia was initially advanced by Boder and Sedgwick in 1957,in which described eight patients with classical A-T, while in 1958 Centerwall and Miller entitled it Louis-Bar syndrome which relates to Madame Louis-Bar, a Belgian neurologist who published a case report of a 9 year-old boy with cutaneous telangiectasia and progressive cerebellar ataxia. She initially classified this new disease in the group of phacomatosis PPV. In 1993, a case report was published about a 17 year-old boy with cerebellar ataxia concomitant dystonia, myoclonus, pyramidal signs, pulmonary infection, persistent lymphopenia, immunoglobulin deficiency and rising alpha-fetoprotein, termed as ataxia with immune deficiency.[1] In 1995, the responsible gene for A-T(ATM) was identified by Savitsky et al. In 2001, Stewart found a correlation with ATM kinase activity levels in cells and the degree of neurological symptoms in A-T patients.[2]



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.


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


  • The disease results from defects in the ataxia telangiectasia mutated (ATM) gene. The ATM gene is involved in making protein that control cell division and DNA repair. The ATM protein helps cells to identify damaged and broken DNA and activates enzymes which fix the broken parts.[8]. Defects in this gene can lead to abnormal cell death in various places of the body, including the part of the brain that helps coordinate movement.
  • Boys and girls are equally affected.

Differentiating Ataxia telangiectasia from other Diseases

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 tumors. 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 breakage syndrome (NBS) 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 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.

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

Other differential diagnoses are:

Ataxia telangiectasia must be differentiated from other diseases that cause neurological manifestations in infants.

Diseases Type of motor abnormality Clinical findings Laboratory findings and diagnostic tests Radiographic findings
Spasticity Hypotonia Ataxia Dystonia
Leigh syndrome - - + +
Niemann-Pick disease type C - - + +
  • Abnormal liver function tests
  • Fibroblast cell culture with filipin staining
Infantile Refsum disease - + + - Elevated plasma VLCFA levels --
Adrenoleukodystrophy + - - -
  • Elevated plasma VLCFA levels
  • Molecular genetic testing for mutations in the ABCD1 gene
Zellweger syndrome - + - - --
Pyruvate dehydrogenase deficiency + + + -
  • Elevated lactate and pyruvate levels in blood and CSF
  • Abnormal PDH enzymatic activity in cultured fibroblasts
Arginase deficiency + - - - --
Holocarboxylase synthetase deficiency - + - - Elevated levels of:
  • Beta-hydroxyisovalerate
  • Beta-methylcrotonylglycine
  • Beta-hydroxypropionate
  • Methylcitrate
  • Tiglylglycine
Glutaric aciduria type 1 - - - + Elevated levels of:
Ataxia telangiectasia - - + - --
Pontocerebellar hypoplasias - + - - Genetic testing for PCH gene mutations
Metachromatic leukodystrophy - + + - --
Pelizaeus-Merzbacher + - + -
Angelman syndrome - - + -
  • Methylation studies and chromosome microarray to detect chromosome 15 anomalies and UBE3A mutations
Rett syndrome + - - +
  • Occurs almost exclusively in females
  • Normal development during first six months followed by regression and loss of milestones
  • Loss of speech capability
  • Stereotypic hand movements
  • Seizures
  • Autistic features
  • Clinical diagnosis
  • Genetic testing for MECP2 mutations
Lesch-Nyhan syndrome + - - + --
Miller-Dieker lissencephaly + + - -
  • Cytogenetic testing for 17p13.3 microdeletion
Dopa-responsive dystonia + - - +
  • Onset in early childhood
  • Symptoms worsen with fatigue and exercise
  • Positive response to a trial of levodopa

Comparison of the clinical features, biomarkers and brain imaging between ataxia telangiectasia (AT), ataxiatelangiectasia-like disorder type 1 (ATLD1) and ataxia telangiectasia-like disorder type 2 (ATLD2)

Clinical Features AT (ATM) ATLD1 (MRE11A) ATLD2 (PCNA)
Ataxia + + +
Dysarthria + + +
Telangiectasia + - +
Eye movement disorders + + -
Photophobia and photosensitivity - - +
Movement disorders (choreoathetosis, dystonia, myoclonus, tremor) + + -
Cognitive dysfunction + + +
Sensorineural hearing loss - - +
Skin abnormalities + - +
Microcephaly - - +
Short stature, developmental delay + + +
Lymphoid tumors predisposition + - Unknown
Recurrent infections + - -
Increased levels of alpha-fetoprotein + - Unknown
Reduced levels of Immunoglobulin + - -
Cerebellar atrophy + + +

AT, ataxia telangiectasia; ATLD1, ataxia telangiectasia-like disorder type 1; ATLD2, ataxia telangiectasia-like disorder type 2.

Epidemiology and Demographics


Ataxia-Telangiectasia prevalence is estimated between 1 in 40,000 and 1 in 100,000.[9] Some studies have shown that the prevalence of A-T among adults younger than age 50 is approximately 1 in 500,000. 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.


Ataxia-Telangiectasia is caused by mutations in the ATM (Ataxia Telangiectasia, Mutated) gene which encodes a protein of the same name. The primary role of the ATM protein is coordination of cellular signaling pathways in response to DNA double strand breaks, oxidative stress and other genotoxic stress.

Risk Factors

  • There are no established risk factors for Ataxia Telangiectasia.
  • Ataxia Telangiectasia patients are at 40% risk of developing cancer, especially leukemia and lymphoma (85%).
  • They are also have increasing risk of developing breast cancer, ovarian, stomach, skin, bone and soft tissue cancers. Lifestyle changes to reduce the risk of cancer are important to A-T patients.
  • A carrier of the ATM gene has been linked to a high rate of breast cancer in some families as per the American Cancer Society.
  • A 2021 review study identified a specific mutation or ATM variant associated with increased breast cancer risk called the V2424G mutation.
  • General risk factors for cancer include:
    • Older age
    • Family history of cancer
    • Tobacco
    • Obesity
    • Alcohol
    • Viral infections, such as human papillomavirus (HPV)
    • Specific chemicals
    • Exposure to radiation, such as ultraviolet radiation (UV)


One of the defective screening test for newborn is severe combined immunodeficiency (SCID), which detect T cells and B cells deficiency or absence from infant dried blood spots. Although there is no modifying therapy or cure for A-T recently, SCID screening test allows for early family education and genetic counseling.
Pre-implantation genetic diagnosis (PGD) can avoid the birth of an affected child. By this screening test, parents who have an affected child (or children) with [[A-T take its advantages.
Antenatal diagnosis can also be performed using haplotype analysis if a diagnosis has been made for the affected child. In this case, DNA polymorphisms within and around the ATM gene can be utilized even if the pathogenic mutations are not known. [10]

Natural History, Complications and Prognosis

Natural History

The outlook for AT patients 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. Patients 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 patients hyper-sensitivity to ionizing 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, dysphagia, and delayed physical and sexual development. People with the disease usually have normal intelligence. Mental retardation is uncommon in people with A-T.[11]


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.


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.


History and Symptoms | Physical Examination | Laboratory Findings | CT | MRI | Other Diagnostic Studies


Medical Therapy | Cost Effectiveness of Therapy | Future or Investigational Therapies

Case Studies

Case #1

Template:Phakomatoses and other congenital malformations not elsewhere classified

Template:Diseases of the nervous system

de:Louis-Bar-Syndrom it:Atassia teleangectasica he:תסמונת אטקסיה טלנגיאקטזיה sr:Атаксија-телеангиектатика



  1. Missing or empty |title= (help)
  2. Missing or empty |title= (help)
  3. de Silva RN, Vallortigara J, Greenfield J, Hunt B, Giunti P, Hadjivassiliou M (2019). "Diagnosis and management of progressive ataxia in adults". Pract Neurol. 19 (3): 196–207. doi:10.1136/practneurol-2018-002096. PMC 6585307 Check |pmc= value (help). PMID 31048364.
  4. 4.0 4.1 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.
  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. doi:10.1016/0090-1229(82)90134-9. PMID 6213343.
  7. Online Mendelian Inheritance in Man (OMIM) 209800
  8. Missing or empty |title= (help)
  9. Rothblum-Oviatt C, Wright J, Lefton-Greif MA, McGrath-Morrow SA, Crawford TO, Lederman HM (2016). "Ataxia telangiectasia: a review". Orphanet J Rare Dis. 11 (1): 159. doi:10.1186/s13023-016-0543-7. PMC 5123280. PMID 27884168.
  10. Template:Https://
  11. ped/2862 at eMedicine