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Adam MP, Mirzaa GM, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2023.

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Initial Posting: ; Last Update: October 27, 2016.

Estimated reading time: 35 minutes


Clinical characteristics.

Classic ataxia-telangiectasia (A-T) is characterized by progressive cerebellar ataxia beginning between ages one and four years, oculomotor apraxia, choreoathetosis, telangiectasias of the conjunctivae, immunodeficiency, frequent infections, and an increased risk for malignancy, particularly leukemia and lymphoma. Individuals with A-T are unusually sensitive to ionizing radiation. Non-classic forms of A-T have included adult-onset A-T and A-T with early-onset dystonia.


The diagnosis of A-T is suspected based on suggestive clinical and preliminary laboratory findings and – in some instances – neuroimaging and family history. The diagnosis is established in a proband either by molecular genetic testing to document the presence of biallelic (homozygous or compound heterozygous) ATM pathogenic variants or (when available) by immunoblotting to test for absent or reduced ATM protein.


Treatment of manifestations:

  • Neurologic: supportive therapy and medications (when possible) as well as early and continued physical therapy to reduce the risk for contractures and scoliosis.
  • Immunodeficiency: IVIG replacement therapy as needed for (a) frequent and severe infections and (b) low IgG levels.
  • Pulmonary: multidisciplinary management that emphasizes monitoring of recurrent infection, pulmonary function, swallowing, nutrition, scoliosis, and immune function.
  • Cancer: because of the increased sensitivity of A-T cells, use of ionizing radiation and some chemotherapeutic agents requires careful monitoring.

Prevention of secondary complications: Gastrostomy tube feedings are occasionally needed to prevent pulmonary and nutritional complications of dysphagia. Attention to potential risks of anesthesia including impaired swallowing, increased risk of aspiration, reduced pulmonary function, and infection.

Surveillance: In those with severe recurrent infections or undergoing immunomodulatory therapy: monitoring of pulmonary function and other signs of pulmonary disease and early signs of malignancy (e.g., weight loss, bruising, localized pain or swelling).

Genetic counseling.

A-T is inherited in an autosomal recessive manner. At conception, the sibs of an affected individual have a 25% chance of being affected, a 50% chance of being asymptomatic carriers, and a 25% chance of being unaffected and not carriers. ATM heterozygotes (carriers) are at increased risk of developing cancer. Once the ATM pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible.


Suggestive Findings

Ataxia-telangiectasia (A-T) should be suspected in children who have the following clinical, MRI, and preliminary laboratory findings.

Clinical findings. Progressive cerebellar dysfunction between ages one and four years manifests as:

  • Gait and truncal ataxia;
  • Head tilting;
  • Slurred speech;
  • Oculomotor apraxia and abnormal ocular saccades.
    "If oculomotor apraxia cannot be clearly documented in a cooperative patient, the diagnosis of A-T should be viewed with suspicion" [E Boder, pediatric neurologist and A-T pioneer (1909-1995)].

Note: The diagnosis of A-T is most difficult in very young children: they do not yet exhibit all the characteristic features of A-T and are typically unable to cooperate during neurologic examination.

MRI. The classic cerebellar findings are atrophy of the frontal and posterior vermis and both hemispheres. Note: Although a small cerebellum is not always apparent on MRI in young children, diffusion-weighted MRI allowed quantitation of cerebellar corticomotor pathway pathology in children as young as age three years, suggesting that this imaging may be useful in early confirmation of the diagnosis of A-T when the necessary equipment and expertise are available [Tavani et al 2003, Al-Maawali et al 2012, Sahama et al 2014a, Sahama et al 2014b].

Preliminary laboratory findings

  • Newborn screening (NBS) for severe combined immunodeficiency identifies reduced T-cell receptor excision circle (TREC) levels. This method of NBS most likely identifies the estimated 50% of children with A-T who have lymphopenia; however, it may be less sensitive in older children with A-T (in whom T cell lymphopenias are less severe) [Mallott et al 2013].
  • Serum concentration of alpha-fetoprotein (AFP) is elevated above10 ng/mL in about 95% of individuals with A-T.
    Note: (1) Serum AFP concentration may remain above normal in unaffected children until age 24 months. (2) Persistent elevation of AFP does not necessarily indicate ongoing cerebellar damage or correlate with prognosis.
  • Chromosome analysis. A 7;14 chromosome translocation is identified in 5%-15% of cells in routine chromosome studies of peripheral blood of individuals with A-T. The break points are commonly at 14q11 (the T-cell receptor-alpha locus) and at 14q32 (the B- cell immunoglobulin heavy chain receptor [IGH] locus).

Establishing the Diagnosis

The diagnosis of A-T is established in a proband either by molecular genetic testing to document the presence of biallelic (homozygous or compound heterozygous) ATM pathogenic variants or (when available) by immunoblotting to test for absent or reduced ATM protein.

Molecular genetic testing approaches can include single-gene testing or use of a multigene panel.

Single-gene testing. Sequence analysis of ATM is performed first, followed by gene-targeted deletion/duplication analysis if only one or no pathogenic variant is found.

Targeted analysis for the following ATM pathogenic variants in specific populations can be performed first when appropriate:

A multigene panel that includes ATM and other genes of interest, such as PP2A (see Differential Diagnosis), may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Table 1.

Molecular Genetic Testing Used in Ataxia-Telangiectasia

Gene 1MethodProportion of Probands with Pathogenic Variants 2 Detectable by Method
ATM Sequence analysis 3~90% 4
Deletion/duplication analysis 51%-2% 6

See Molecular Genetics for information on allelic variants detected in this gene.


Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may also include small intragenic deletions/insertions and missense, nonsense, and splice site variants. For issues to consider in interpretation of sequence analysis results, click here.


Some known pathogenic variants, such as the deep intronic Midlands, UK variant, c.5763-1050A>G (formerly known as 5762ins137), will not be detected by routine sequence analysis of ATM exons [McConville et al 1996]; however, targeted sequencing of deep intronic pathogenic variants increases the variant detection rate.


Testing that identifies exon or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Methods used may include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.


Immunoblotting for ATM protein in a lymphoblastoid cell line (LCL) is more than 95% sensitive and more than 98% specific for diagnosing A-T [Chun et al 2003]. This testing may be performed to help interpret sequence variants of uncertain significance or confirm a diagnosis when only one ATM pathogenic variant is identified.

Of individuals with A-T:

  • About 90% have no detectable ATM protein (i.e., <15% of control levels);
  • About 10% have trace amounts to 15% of control levels of ATM protein;
  • About 1% have a near-normal amount of ATM protein that lacks ATM serine/threonine kinase activity (so-called "kinase-dead" protein) [Stewart et al 2001].

Note: The presence of more than 15% ATM protein suggests one of the following:

  • Another diagnosis
  • An ATM pathogenic missense variant
  • A leaky splicing ATM variant
  • An ATM pathogenic variant resulting in "kinase-dead" protein
  • Possibly, a pathogenic variant in a gene encoding an ancillary ATM-activating phosphatase like PP2A. However, to the authors' knowledge, PP2A deficiency results mainly from somatic pathogenic PP2A variants in tumor cells or PP2A inhibitors. To date, a person with PP2A deficiency has not been described.

For more detailed information on the interpretation of the results of ATM protein testing and research testing for ATM, click here (pdf).

Clinical Characteristics

Clinical Description

Classic Ataxia-Telangiectasia

The primary features of classic A-T:

  • Progressive gait and truncal ataxia with onset between ages one and four years
  • Progressively slurred speech
  • Oculomotor apraxia (inability to follow an object across visual fields)
  • Choreoathetosis (writhing movements)
  • Oculocutaneous telangiectasia (usually evident by age 6 years)
  • Frequent infections (with accompanying evidence of serum and cellular immunodeficiencies)
  • Hypersensitivity to ionizing radiation with increased susceptibility to cancer (usually leukemia or lymphoma)

Other features:

  • Premature aging with strands of gray hair
  • Endocrine abnormalities including insulin-resistant diabetes mellitus and premature ovarian failure (i.e., normal menarche followed by irregular menses and loss of ovarian function before age 40 years) [Author, personal observation]

Although the clinical manifestations of A-T in its late stages vary little from family to family, the age of onset and rate of progression can vary considerably even within a family with multiple affected individuals. For clinical reviews, see Boder [1985], Woods & Taylor [1992], Gatti [2001], Taylor & Byrd [2005], and Verhagen et al [2012].

Neurologic. The most obvious characteristic of classic A-T is progressive cerebellar ataxia. Shortly after learning to walk, children with A-T begin to stagger. Although the neurologic status of some children appears to improve from age two to four years, ataxia subsequently progresses. (The transient improvement is probably attributable to the rapid learning curve of young children.)

The ataxia begins as purely truncal but within several years involves peripheral coordination as well. Writing and drawing are affected by age five years.

By age ten years, most children become confined to a wheelchair.

Slurred speech and oculomotor apraxia are noted early. Both horizontal and vertical saccadic eye movements are affected [Farr et al 2002, Onodera 2006, Yakusheva et al 2007]. Drooling is common.

Choreoathetosis is found in almost all individuals with A-T. Myoclonic jerking and intention tremors are present in about 25%.

All teenagers with classic A-T need help with dressing, eating, washing, and toileting.

Muscle strength is normal at first but wanes with disuse, especially in the legs. Contractures in the fingers and toes are common in older individuals. Deep tendon reflexes are decreased or absent in older individuals; plantar reflexes are upgoing or absent

Intelligence is typically normal; however, learning difficulties are common. Slow motor and verbal responses make it difficult for individuals to complete "timed" IQ tests. Many American and British individuals with classic A-T have finished high school with good grades; some have finished college or university, often with the assistance of aides and attentive parents and sibs.

Dystonia and adult-onset spinal muscular atrophy have also been observed (see Non-Classic Forms of Ataxia-Telangiectasia).

Immunodeficiency, present in 60%-80% of individuals with classic A-T, is variable and does not correlate well with the frequency, severity, or spectrum of infections. The most consistent immunodeficiency reported in classic A-T is poor antibody response to pneumococcal polysaccharide vaccines [Sanal et al 1999, Nowak-Wegrzyn et al 2004]. Serum concentration of the immunoglobulins IgA, IgE, and IgG2 is often reduced. NK lymphocyte levels are occasionally elevated, most notably in individuals from Costa Rica [Regueiro et al 2000].

The immunodeficiency is not progressive, and some evidence suggests that T-cell lymphopenia may normalize after age 20 years [Boder 1985, Woods & Taylor 1992, Regueiro et al 2000, Gatti 2001, Pashankar et al 2006, Staples et al 2008].

Of note, immune status was more seriously impaired in 80 individuals with A-T and two null ATM alleles: both T- and B-cell lymphopenia and more frequent recurrent sinopulmonary infections were observed [Staples et al 2008]. Children with lymphopenia tend to have the most deleterious pathogenic variants, lowest (enzymatic) ATM kinase levels, most severe phenotypes, most frequent sinopulmonary infections, and poorest prognosis [Verhagen et al 2012].

Infection. In contrast to the spectrum of infection observed in most immunodeficiency disorders, the spectrum of infection in classic A-T does not include opportunistic infections. The frequency and severity of infections correlate more with ATM kinase levels and general nutritional status than with immune status.

Some individuals with classic A-T develop chronic bronchiectasis.

While individuals with frequent infections may occasionally benefit from prophylactic antibiotics and/or intravenous immunoglobulin (IVIG) replacement therapy [Nowak-Wegrzyn et al 2004], longevity has increased substantially even in those not receiving IVIG.

Pulmonary. In older individuals, pulmonary failure, with or without identifiable infections, is a major cause of failing health and death [Lockman et al 2012]. Life-threatening lymphocytic infiltration of the lung has been reported [Tangsinmankong et al 2001].

Other findings. Liver enzyme levels are often elevated in A-T, without apparent liver pathology. (Thus, liver biopsy is usually not revealing.)

Cancer. The risk for malignancy in individuals with classic A-T is 38%.

Leukemia and lymphoma account for about 85% of malignancies. Younger children tend to have acute lymphocytic leukemia (ALL) of T-cell origin and older children are likely to have an aggressive T-cell leukemia. Lymphomas are usually B-cell types.

As individuals with classic A-T are living longer, other cancers and tumors including ovarian cancer, breast cancer, gastric cancer, melanoma, leiomyomas, and sarcomas have also been observed.

Life expectancy. Over the past 25 years, for reasons that are unclear, the life expectancy of individuals with A-T has increased considerably. Most affected individuals now live beyond age 25 years. Some have survived into their 50s [Dörk et al 2004; Crawford et al 2006; Author, unpublished observations].

Pathology. The cerebellum atrophies early in the course of classic A-T, being visibly smaller on MRI by age seven or eight years, with concomitant loss of Purkinje cells and depletion of granule cells [Sardanelli et al 1995, Tavani et al 2003, Wallis et al 2007, Lin et al 2014].

At autopsy, virtually all affected individuals have a small embryonic-like thymus, lacking Hassall's corpuscles.

Microscopic nucleomegaly (i.e., irregular size and shape of nuclei) is a classic histologic characteristic of A-T cells and is used by pathologists in interpreting tissue changes in organs from persons with A-T. Nucleomegaly is easily appreciated in tissues where the architecture is otherwise very uniform, such as renal tubules and seminal ducts. Nucleomegaly most likely reflects perturbed cell cycle checkpoints and poor fidelity of DNA repair mechanisms and DNA processing.

Non-Classic Forms of Ataxia-Telangiectasia

Other phenotypes associated with biallelic (homozygous or compound heterozygous) ATM pathogenic variants include the following:


The cancer risk of individuals heterozygous for an ATM pathogenic variant is approximately four times that of the general population, primarily because of the increased risk for breast cancer [Swift et al 1991, Stankovic et al 1998, Bretsky et al 2003, Bernstein et al 2006, Renwick et al 2006, Concannon et al 2008, Tavtigian et al 2009, van Os et al 2016].

Cancer risk probably depends on multiple factors including tumor type, age at cancer onset, and whether the individual is heterozygous for a missense or a truncating variant [Gatti 2001, Concannon 2002, Scott et al 2002, Spring et al 2002].

ATM variants associated with breast cancer tend to be missense changes whereas ATM missense variants in individuals with A-T only are uncommon (<10%) [Gatti et al 1999, Bernstein et al 2003, Tavtigian et al 2009]. Meta-analyses estimate a relative risk of three- to fourfold that in comparable general populations.

ATM pathogenic variants have been reported in both tumor cells and germline cells in several types of leukemia and lymphoma, including acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), T-cell prolymphocytic leukemia (T-PLL), and mantle zone lymphoma [Stankovic et al 1998, Stilgenbauer et al 2000, Oguchi et al 2003, Eclache et al 2004].

T-cell ALL-associated ATM pathogenic variants are similar to those seen in individuals with A-T [Liberzon et al 2004, Pylkäs et al 2007].

Genotype-Phenotype Correlations

The c.5762-1050A>G pathogenic variant (formerly referred to as 5762ins137 [Sutton et al 2004]) is associated with a somewhat slower rate of neurologic deterioration, later onset of manifestations, intermediate radiosensitivity, and little or no cancer risk [McConville et al 1996].

The pathogenic variants c.1A>G, c.7271T>G, c.8147T>C, and c.8494C>T have been associated with the following:


Ataxia-telangiectasia was previously referred to as Louis-Bar syndrome.


The prevalence of A-T in the US is 1:40,000-1:100,000 live births. Prevalence varies with the degree of consanguinity in a country.

A-T is the most common cause of progressive cerebellar ataxia in childhood in most countries with low coefficients of inbreeding; Ataxia with oculomotor apraxia type 1 and Ataxia with oculomotor apraxia type 2 may be more prevalent in Portugal and perhaps Japan [Németh et al 2000, Date et al 2001, Moreira et al 2001].

Genetically-Related (Allelic) Disorders

No phenotypes other than those discussed in this GeneReview are known to be associated with germline pathogenic variants in ATM.

Differential Diagnosis

The diagnosis of ataxia telangiectasia (A-T) is questionable when accompanied by severe intellectual disability, seizures, non-progressive ataxia, or microcephaly. Early seizures and microcephaly (especially in an infant of Middle Eastern origin) suggest the diagnosis of microcephaly, seizures, and developmental delay (MCSZ) caused by biallelic pathogenic variants in PNKP (encoding polynucleotide kinase phosphatase) [Shen et al 2010] (OMIM 605610). Cells from these patients have DNA repair deficiencies and are sensitive to ionizing radiation [Shen et al 2010; Gatti RA, unpublished data].

Of note, elevated serum AFP has been described in only four inherited ataxias: A-T; a non-classic form of A-T described as dopa-responsive dystonia observed in three sibs with biallelic ATM pathogenic variants [Charlesworth et al 2013]; ataxia with oculomotor apraxia type 2 (AOA2); and RNF168 deficiency.

ATM is a ubiquitous house-keeping gene, present in every nucleated cell. As a serine-threonine kinase, the ATM protein phosphorylates or activates many proteins/substrates and interacts with many different molecules and protein complexes; thus, clinical phenocopies of A-T are common.

The proteins nibrin, Mre11, and RAD50 interact with ATM to localize the DNA damage and choreograph/coordinate the almost instantaneous repair of double-strand DNA breaks before the next cell replication [Lavin et al 2015]. Without such urgent repair, this commonly occurring DNA damage becomes lethal during the next cell division, leading to more complex lesions such as chromosomal aberrations, cancers, or cell death.

To date, an increased mode of t(7;14) translocations has been observed exclusively in individuals with one of the four disorders: A-T, Nijmegen breakage syndrome, Mre11 deficiency, or RAD50 deficiency; the mechanism is not understood.

It is also clear that DNA double strand breaks are even more devastating to non-dividing neural cells, suggesting that these early steps of DNA repair are still incompletely understood.

  • Nijmegen breakage syndrome (NBS). Biallelic pathogenic variants in NBN (encoding nibrin) are causative. Inheritance is autosomal recessive.
    • Clinical phenotype. Individuals with NBS are immunodeficient and most are intellectually impaired and microcephalic; more than one third develop cancer. Individuals with NBS do not develop ataxia or telangiectasia. Their symptoms overlap with A-TFresno (see Non-Classic Forms of Ataxia-Telangiectasia). NBS also includes the phenotype Berlin breakage syndrome
    • Other. NBS cells are very sensitive to ionizing radiation.
  • Mre11-deficient ataxia (OMIM 604391). Biallelic pathogenic variants in MRE11 are causative. Inheritance is autosomal recessive.
  • RAD50 deficiency (OMIM 604040) has been observed in two unrelated individuals of German descent, a female age 28 years [Waltes et al 2009] and a male age 18 years [Brown et al 2016]. Inheritance is autosomal recessive. Both had different biallelic pathogenic variants in RAD50 and both were also heterozygous for an NBN pathogenic variant.
    • Clinical phenotype. The female had microcephaly, developmental delay, mild spasticity, a slight non-progressive ataxia, and short stature. She had no history of cancer. The male had normal stature and a history of chronic respiratory illness. At age 16 years, he developed T cell acute lymphocytic leukemia (ALL) (Ph+).
    • Other. Cells with translocations of chromosomes 7 and 14 were observed in both. The cells from the male scored as radiosensitive in a colony survival assay [Sun et al 2002, Brown et al 2016].
  • RNF168 deficiency (OMIM 612688) or RIDDLE (radiosensitivity, immunodeficiency, dysmorphic features, and learning difficulties) syndrome (OMIM 611943) is caused by biallelic pathogenic variants in RNF168. Inheritance is autosomal recessive.
    • Clinical phenotype. Ataxia and telangiectasia [Stewart et al 2009]. Devgan et al [2011] described a man with ataxia (without apraxia or dysarthria), growth retardation, microcephaly, immunodeficiency, and an elevated serum AFP who died of respiratory failure at age 30 years.
    • Other. RNF168 protein is absent and ATM protein levels are normal.

Furthermore, virtually without exception, cells in these AT-like phenocopies are hypersensitive to x-rays and DNA damaging agents which are commonly used in cancer treatment. It is now even possible to encounter individuals with XCIND (x-ray sensitivity, cancer, immunodeficiency, neuropathology, and DNA repair deficiency) whose disorder has not yet been causally linked to a specific DNA repair gene or pathway [Gatti et al 2007, Du & Gatti 2009]. Cells from individuals with XCIND scored as "radiosensitive" in a colony survival assay [Sun et al 2002]. Such individuals would be predicted to be cancer prone.

Other disorders with childhood-onset ataxia (see Ataxia Overview for discussion):


Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with ataxia-telangiectasia (A-T), the following evaluations are recommended:

  • Neurologic consultation with attention to ataxia, including assessment of extraocular movement
  • Assessment of speech re communication and swallowing re risk of aspiration
  • Nutrition and feeding assessment
  • Immune status of specific parameters that were previously aberrant (e.g., immunoglobulin levels, B/T cell levels, T cell function)
  • Chest x-ray and pulmonary function for baseline
  • CBC with differential
  • Diabetes screen (urinalysis, fasting blood glucose concentration, Hgb A1C)
  • Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Neurologic. Supportive therapy can minimize drooling, choreoathetosis, myoclonus/tremor, and ataxia. However, individual responses to specific medications (e.g., amantadine and 4-aminopyridine) and to treatments used for myoclonus vary [Perlman et al 2012, Nissenkorn et al 2013, Shaikh et al 2013, van Egmond et al 2015]. Thus, it is recommended that treatment options be discussed with an experienced neurologist.

Early and continued physical therapy can minimize the risk for contractures (which appear in almost all individuals with time and often lead to other problems such as pressure sores and pain) and scoliosis (which can, for example, be the consequence of prolonged sitting in a wheelchair – particularly the tendency to lean on the same elbow).

Although steroids are reported to temporarily improve the neurologic symptoms of A-T in children, the symptoms reappear within days of their discontinuation [Gatti 1985, Buoni et al 2006, Broccoletti et al 2008, Gatti & Perlman 2009]. (See also Therapies Under Investigation.)

Immunodeficiency. IVIG replacement therapy should be considered for individuals with frequent and severe infections and very low IgG levels [Nowak-Wegrzyn et al 2004].

Pulmonary. The European Respiratory Society (ERS) has prepared extensive guidelines for the multidisciplinary respiratory management of A-T, emphasizing the need for monitoring of immune function, recurrent infection, pulmonary function, swallowing, nutrition, and scoliosis, all of which can contribute to increased respiratory morbidity and mortality in persons with A-T [Bhatt et al 2015] (full text).

Cancer. Because cells from individuals with A-T are 30% more sensitive to ionizing radiation than cells from controls, conventional doses of ionizing radiation are potentially lethal in individuals with A-T. Thus, the use of radiotherapy and some radiomimetic chemotherapeutic agents should be administered carefully and monitored closely [Schütte et al 2016].

Doses of some chemotherapeutic agents are often reduced by 25%-50% and longer recovery periods between treatments are considered to allow for the slower DNA repair that occurs in A-T [Schütte et al 2016].

Prevention of Secondary Complications

Pulmonary and nutritional complications of dysphagia are common. Often, gastrostomy tube feedings are recommended to manage these comorbidities. Children with disorders with predictable progression (like A-T) and impaired swallowing may benefit from early rather than late placement of a feeding tube [Lefton-Greif et al 2000].

Anesthesia carries unique potential risks in persons with A-T because of impaired coordination of swallowing, increased risk of aspiration, reduced respiratory capacity, and propensity to infections [McGrath-Morrow et al 2008]. In a recent review, 24% of patients required supplemental oxygen (maximum duration 24 hours) post anesthesia; mild postoperative hypothermia was also relatively common [Lockman et al 2012].


The European Respiratory Society (ERS) has prepared extensive guidelines for the multidisciplinary respiratory management of A-T, emphasizing the need for monitoring of immune function, recurrent infection, pulmonary function, swallowing, nutrition, and scoliosis, all of which could contribute to increased respiratory morbidity and mortality in A-T [Bhatt et al 2015] (full text).

Parents should be counseled to monitor for – and report to a physician – the early warning signs of malignancy (which can occur at any age) including weight loss, bruising, and localized pain or swelling. Periodic CBCs are warranted.

Immune status needs to be monitored if severe recurrent infections occur or immunomodulatory therapy is in progress.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Research suggests the following:

  • Antioxidants (e.g., vitamin E or alpha-lipoic acid) are recommended, although no formal testing for efficacy has been conducted in individuals with A-T. Alpha-lipoic acid has the theoretic advantage of crossing the blood-brain barrier and improving mitochondrial function in A-T cells [Ambrose et al 2007].
  • In culture, certain aminoglycoside antibiotics can induce small amounts of full-length ATM protein and return ATM functions to A-T cells with primary nonsense pathogenic variants [Lai et al 2004, Gatti 2012]. Non-aminoglycoside read-through chemicals, identified by a high-throughput screen of 70,000 compounds, induce ATM protein in A-T cells [Du & Gatti 2009]; and chemical derivatives of those compounds – such as RTC13, RTC14, RTC216, RTC202, RTC204, and RTC219 – have produced encouraging results in other diseases besides A-T (e.g., a mouse model of Duchenne muscular dystrophy [Kayali et al 2012], epidermolysis bullosa keratinocytes, xeroderma pigmentosum [Kuschal et al 2013], and retinal cells from amaurotic congenital blindness [Pillers et al 2015].
    Thus, it is anticipated that in future patients will be candidates for mutation-targeted therapeutic trials, which will be based on the class of pathogenic variants present and not on the specific gene itself. These drugs will be grouped according to the class of pathogenic variants for which they can address/correct the underlying molecular pathogenicity. – rendering them potentially useful for treating a molecular spectrum of genetic diseases based on the class of pathogenic variant rather than the disease itself [Du et al 2007, Hu & Gatti 2008, Du & Gatti 2009, Jung et al 2011, Gatti 2012, Du et al 2013, Lavin 2013].
  • Antisense morpholino oligonucleotides (AMOs) induce substantial corrections of ATM protein in cell lines with certain types of ATM splicing variants [Du et al 2007, Du et al 2009]. AMOs remain active in A-T cells for more than 14 days. In animal studies, they are well tolerated when a cell-penetrating protein moiety is added to the AMO. Groundbreaking clinical trials using AMO to treat spinal muscular atrophy – and a particular splicing variant that causes Duchenne muscular dystrophy – are in progress.
  • Amlexanox (Aphthasol®) is another non-aminoglycoside (similar to ataluren [PTC124]) read-through compound for nonsense pathogenic variants that is being tested. To date, it is approved as an ointment for mouth ulcers and is prescribed primarily by dentists [Loudon 2013].
  • Dexamethasone and betamethasone, but not methylprednisolone, have been reported to decrease neurologic manifestations in A-T [Buoni et al 2006, Broccoletti et al 2008, Gatti & Perlman 2009]. However, the neurologic improvement, which is also accompanied by signs of steroid toxicity, disappears within days of discontinuation of the steroids. Additional studies are in progress. Delivery of the steroids by loading them into erythrocytes affords much better dose control and delivery at 0.001% of previous steroid doses [Leuzzi et al 2015].
    In a formal clinical trial in progress, betamethasone is being delivered within autologous red cells that have been infused with doses 100-1000 times lower than what was previously manageable, thereby mitigating most side effects of chronic steroid therapy.
  • Use of insulin-like growth factor 1(IGF-1) treatment for A-T has been suggested [Fernandez et al 2005]. More recently, Voss et al [2014] showed that the GH/IGF-1 axis was perturbed in 58.3% of individuals with A-T (age range 2 to 9 years). A clinical trial is presently underway.
  • Manganese-containing superoxide dismutase (SOD) mimics have a radioprotective effect on A-T cells [Pollard et al 2009]. A recent report provides compelling evidence that treatment of a transgenic mouse model of amyotrophic lateral sclerosis (ALS) with a copper-chaperone for SOD extends by 500 days the life expectancy of mice that normally die within three months [Williams et al 2016]. This potential advance in treating motor degeneration may be applicable to A-T as well.
  • Mutation-targeted therapy for other rare genetic diseases has been encouraging [Wilschanski et al 2003, Welch et al 2007, Du et al 2009]. The number of potential disease targets for read-through therapy exceeds 8000 [Keeling & Bedwell 2011]. It is also estimated that 10%-15% of human pathogenic variants are nonsense variants [Mort et al 2008], predicting investigation of many millions of potential drug candidates.

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.


Any child younger than age five years with malignancy should be evaluated for A-T before starting chemotherapy and/or radiotherapy since conventional doses of either can be fatal in A-T.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members; it is not meant to address all personal, cultural, or ethical issues that may arise or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Ataxia-telangiectasia (A-T) is inherited an autosomal recessive manner.

Risk to Family Members

Parents of a proband

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% risk of being affected, a 50% risk of being an asymptomatic carrier, and a 25% risk of being unaffected and not a carrier.
  • Heterozygotes (carriers) are at increased risk for cancer and coronary artery disease [Concannon 2002, Spring et al 2002, van Os et al 2016] (see Clinical Description, Heterozygotes).

Offspring of a proband. Although most individuals with A-T do not reproduce, exceptions have been reported [Stankovic et al 1998; Byrd et al 2012; Dawson et al 2015; Blancato et al, unpublished].

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of an ATM pathogenic variant.

Heterozygote Detection

Carrier testing for at-risk relatives requires prior identification of the ATM pathogenic variants in the family.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Testing

Once the ATM pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk for A-T and preimplantation genetic testing are possible.

Note: Prenatal diagnosis by chromosomal breakage studies or by radio-resistant DNA synthesis (RDS) has proven unreliable in at least three instances [Author, unpublished] and should be avoided in favor of molecular genetic testing.


GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Ataxia-Telangiectasia: Genes and Databases

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
ATM 11q22​.3 Serine-protein kinase ATM Ataxia Telangiectasia Mutated (ATM) @ LOVD ATM ATM

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Ataxia-Telangiectasia (View All in OMIM)


Gene structure. The normal gene (NM_000051.3) has 63 exons, 62 of which are coding (the transcription start (ATG) is in exon 2), and 13-kb cDNA.

Pathogenic variants. More than 800 unique pathogenic variants are known (see Table 2 and Table 3 [pdf]). Although a few population-specific pathogenic variants have been identified, most affected individuals in North America inherit different pathogenic variants from each parent; that is, they are compound heterozygotes [Concannon & Gatti 1997, Gatti 2001].

Table 2.

Selected ATM Pathogenic Variants

DNA Nucleotide Change
(Alias 1)
Predicted Protein ChangeReference Sequences
c.1A>Gp.Met1Val NM_000051​.3
See footnote 2
c.6154G>A 3p.Glu2052Lys
c.8147T>Cp.Val2716Ala 4

Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.


Variant designation that does not conform to current naming conventions


Activates a cryptic splice site resulting in a 137-bp insertion and an unstable protein [McConville et al 1996, Stankovic et al 1998, Stewart et al 2001, Sutton et al 2004]


Causes abnormal splicing


For information about founder variants described in specific populations, see Table 3 (pdf).

Normal gene product. The normal serine/threonine protein kinase ATM has 3056 amino acids. It is activated by double-stranded DNA breaks, coordinates cell-cycle checkpoints prior to repair, attaches near damage sites, and recruits other repair proteins to damaged sites [Lavin et al 2008, Lavin 2013].

  • Domains for: PI3 kinase, FAT, leucine zipper, FATC, p53 binding
  • Binding sites for: c-abl, p53, Bloom's protein
  • Other homologies: DNA-PK, ATR/MEC1, MEI41, Rad3, TEL1, FRAP
  • Substrates for phosphorylation: >700, including p53, Chk2, MDM2, 53BP1, SMC1, BRCA1, FANCD2, H2AX, c-abl, nibrin, Mre11, KAP1 [Linding et al 2007, Matsuoka et al 2007].

A growing body of evidence also suggests that ATM kinase deficiency and ATM-specific small molecule inhibitors suppress HIV-1 replication and infection in bench experiments [Lau et al 2005, Ariumi & Trono 2006]; this would probably also apply to other retroviral infections and, eventually, could provide some insight as to a genetic selective advantage for ATM heterozygosity and possibly even for homozygosity in the general population.

Abnormal gene product. Most ATM pathogenic variants result in absence of ATM protein. Serine-protein kinase ATM is absent on immunoblotting in 95% of individuals with A-T. ATM mRNA is present in more than 99% of affected individuals; however, the quantity of mRNA from each allele may not be equal.

About 1% of individuals with A-T have pathogenic variants that permit normal expression of ATM protein, but the protein is lacking in kinase activity (so-called "kinase-dead" ATM protein).

In vitro functional assays showed that selected missense pathogenic variants result in an ATM protein that interferes with the function of normal ATM protein (i.e., a dominant-negative or gain-of-function effect) [Barone et al 2009]. It has been proposed that such effects play a role in the development of breast cancer in ATM heterozygotes [Scott et al 2002].


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Chapter Notes

Revision History

  • 27 October 2016 (bp) Comprehensive update posted live
  • 11 March 2010 (me) Comprehensive update posted live
  • 15 February 2005 (me) Comprehensive update posted live
  • 10 April 2003 (cd) Revision: sequence analysis available
  • 8 October 2002 (me) Comprehensive update posted live
  • 19 March 1999 (pb) Review posted live
  • 13 April 1998 (rg) Original submission
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