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Puneet Opal, MD, PhD
Section Editors:
Marc C Patterson, MD, FRACP
Jennifer M Puck, MD
Deputy Editor:
April F Eichler, MD, MPH
Literature review current through: Nov 2022. | This topic last updated: Sep 27, 2022.

INTRODUCTION — Ataxia-telangiectasia (AT; MIM 208900) is an autosomal recessive disorder characterized by progressive cerebellar degeneration, oculocutaneous telangiectasia, immunodeficiency, and susceptibility to cancer as well as radiation toxicity. The disorder is caused by homozygous or compound heterozygous pathogenic variants in the ataxia-telangiectasia mutated (ATM) gene, which lead to defective DNA repair mechanisms and genome instability.

AT is a complex, multisystem disorder that is variably categorized as a genome instability syndrome, chromosomal instability syndrome, DNA repair disorder, DNA damage response syndrome, and neurocutaneous syndrome. Many patients are now diagnosed at birth through newborn screening for hereditary immunodeficiency; in other cases, patients present in mid-childhood with progressive neurologic symptoms and characteristic telangiectasia.

This topic will review the genetics and clinical aspects of AT and related disorders. Other hereditary ataxias are reviewed elsewhere. (See "Overview of the hereditary ataxias".)


Overview — AT is an autosomal recessive genetic disorder caused by pathogenic variants in the ataxia-telangiectasia mutated (ATM) gene on chromosome 11q22 [1,2]. The ATM gene product, ATM kinase, is involved in the detection of DNA damage and plays an important role in cell cycle progression [3]. In most cases, the AT phenotype results from biallelic loss-of-function variants leading to absent or defective ATM kinase. Symptom severity depends on residual ATM activity, which can be gauged by the type of variant.

The majority of ATM pathogenic variants are truncating [4,5]. Such variants lead to unstable protein fragments, undetectable ATM protein on Western blotting, and absent ATM kinase activity. Most patients with these variants have a classic AT phenotype [6].

Certain missense, in-frame, or splice-site pathogenic variants result in residual amounts of functioning ATM protein. The disease course is usually milder in such patients.

Functions of ATM kinase — ATM kinase is involved in a surveillance mechanism that, in the presence of DNA damage, stalls progression of the cell cycle. This delay allows the cell to repair the damage, rather than passing on damaged genetic information to daughter cells.

The cell cycle function of ATM kinase is exerted at the transition between the G1 and S phase, when a cell initiates DNA synthesis in preparation for DNA replication. It also functions at the G2 to M transition, during which the cell begins to divide.

The supervisory function of ATM kinase involves phosphorylation of several key proteins:

p53 – In the presence of DNA damage, ATM kinase phosphorylates the tumor suppressor protein p53 [7]. Phosphorylated p53 serves as a transcriptional activator of genes that cause cell cycle arrest or apoptosis. In the absence of ATM kinase, p53 does not become phosphorylated and cannot prevent the cell from moving into the next phase of the cell cycle.

BRCA1 protein – ATM kinase phosphorylates breast cancer 1 (BRCA1) protein, which is the gene product of the tumor suppressor gene BRCA1 [8,9]. This interaction may explain (at least in part) how inheriting a pathogenic variant in the ATM gene might predispose patients with AT as well as heterozygotes to breast cancer [10-13]. (See 'Heterozygotes' below.)

c-abl tyrosine kinase and nibrin – Phosphorylated c-abl tyrosine kinase and nibrin protein are involved in DNA repair, primarily in response to ionizing radiation [14,15]. The Nijmegen breakage syndrome is an immunodeficiency disorder that is caused by pathogenic variants in the NBN gene that encodes nibrin. (See "Nijmegen breakage syndrome".)

eIF-4E-binding protein 1 – When phosphorylated, the eIF-4E-binding protein 1 releases the translation initiation factor, eIF-4E, and stimulates protein synthesis in the presence of insulin [16]. This interaction may explain the poor growth and insulin resistance that are seen in patients with AT.

Protein phosphatase 2A – Protein phosphatase 2A regulates the nuclear importation of histone deacetylase 4 (HDAC4) [17,18]. Hypophosphorylated HDAC4 translocates to the nucleus of neurons in ATM-deficient mice, resulting in histone deacetylation, altered neuronal gene expression, and neurodegeneration [18].

Defective DNA surveillance and repair — In the absence of the supervisory function of ATM kinase, cells can build up somatic mutations, possibly leading to malignant transformation.

The increased propensity for leukemias and lymphomas in AT may be related to the remarkable number of chromosomal translocations and inversions in lymphocytes that result from the DNA processing defect [19]. These abnormalities predominantly involve the gene loci that generate mature immunoglobulin and T cell receptor genes via genetic rearrangement [19].

The defect in nuclear DNA repair in AT also causes sensitivity of cells to ionizing radiation and radiomimetic chemicals [15,20,21]. Mouse models of AT display many of the features of human disease, including growth retardation, immune system defects, and sensitivity to radiation, although they do not display some of the other features, such as the progressive ataxia [22,23].

In some human heterozygotes, specific missense pathogenic variants result in an abnormal protein (instead of producing no detectable ATM kinase, as is the case with null or truncating variants), which acts by dominantly interfering with the function of the product of the normal allele (a dominant negative effect) [24]. This is proposed to account for the increased risk of solid tumors that is seen in these particular ATM heterozygotes. (See 'Heterozygotes' below.)

Impaired mitochondrial function — Another possible role for ATM is the maintenance of mitochondrial homeostasis [3], in part via regulation of ribonucleotide reductase (RR), which is the rate-limiting enzyme in the synthesis of deoxyribonucleoside triphosphates (dNTP) [25]. RR activity and dNTP synthesis are an important part of the mitochondrial DNA (mtDNA) replication and repair pathway.

Experimental evidence suggests that ATM kinase and RR regulate proper mtDNA copy number and expression, and that mutant ATM results in reduced RR activity or expression. This causes mtDNA depletion and disruption of mitochondrial homeostasis [25]. Impaired mitochondrial activity may contribute to the pathogenesis of AT, leading to clinical features such as ataxia, neurodegeneration, and premature aging [25-27].

Pathology — Both the central and peripheral nervous systems are involved in AT. The central nervous system abnormalities are more severe and are primarily characterized by cerebellar atrophy with particular loss of Purkinje cells [28]. Histologic examination of the peripheral nerves reveals malformed nuclei in Schwann cells. The pathogenesis of neuronal cell death in AT is not well understood but presumably results from impaired protein function due to ATM gene pathogenic variants.

The thymus in patients with AT usually is hypoplastic, with fewer lymphocytes than normal and absence of Hassall corpuscles [29]; these findings are consistent with the associated immune deficiency.

EPIDEMIOLOGY — AT is a rare disorder with an estimated birth prevalence of 1 in 40,000 to 100,000 live births [30,31]. It is reported worldwide and has a higher incidence in populations with increased rates of consanguinity.

The frequency of heterozygosity for a pathogenic ataxia-telangiectasia mutated (ATM) allele is estimated to be as high as 2.8 percent in White Americans [10,30].

CLINICAL MANIFESTATIONS — AT is a complex disease with varying clinical presentations. The phenotypic spectrum is evolving as the diagnosis is now being made at birth in many cases due to widespread newborn screening for immunodeficiency. Three phenotypes are generally recognized:

Classic AT – The classic and most severe form of AT usually presents either at birth, with evidence of partial combined immunodeficiency, or in early childhood, when progressive cerebellar dysfunction and ocular signs become apparent. (See 'Classic AT' below.)

Variant AT – Variant AT presents slightly later, by the age of 10 years in most cases, with milder cerebellar dysfunction. (See 'Variant AT' below.)

AT heterozygotes – Heterozygotes have none of the classic clinical manifestations of AT, but they do have a higher incidence of malignancy at a younger age compared with the general population. (See 'Heterozygotes' below.)

Classic AT — Children with classic AT invariably develop progressive cerebellar ataxia, abnormal eye movements, other neurologic abnormalities, oculocutaneous telangiectasias, and immune deficiency [32-36]. Associated features include pulmonary disease, an increased incidence of malignancy, radiation sensitivity, growth retardation, and diabetes mellitus caused by insulin resistance.

Neurologic manifestations — Neurologic manifestations have historically been the earliest clinical manifestation of classic AT. With newborn screening for severe combined immunodeficiency (SCID), however, it is now recognized that immune manifestations can precede ataxia in some cases. (See 'Immune deficiency' below.)

Ataxia – Ataxia is often the earliest neurologic manifestation of AT [37,38]. Many children appear healthy for the first year of life and begin walking at a normal age but are slow to develop fluidity of gait. Other children will manifest ataxia in infancy, and walking will be delayed. Affected children also have difficulty standing still without wobbling. Unlike most ataxic disorders, individuals with AT walk on an unusually narrow base, and young children often prefer to walk quickly or run. However, they fall less frequently than one might expect.

Gross motor function remains abnormal but relatively stable until school age, and the condition may be misdiagnosed as cerebral palsy because the child seems to have a static or nonprogressive course [39]. When gross and fine motor skills begin to deteriorate in the early school-age period, the provisional diagnosis of cerebral palsy is then appropriately reconsidered.

At approximately the same time as gross and fine motor skills regress, children develop dysarthria and complex disorders of movement. By the second decade of life, most patients must rely on wheelchairs for mobility outside the home.

Eye movement abnormalities – Eye movements are often normal in preschoolers, but children later develop abnormalities of both voluntary and involuntary saccades and have difficulty moving their eyes and heads in smooth, coordinated pursuit of a moving target [40,41]. In addition, there is delay in initiating eye movement, and the eyes move in a series of small jumps rather than in a single smooth motion.

The most obvious early manifestation is oculomotor apraxia: the inability to coordinate head and eye movements naturally when shifting gaze rapidly (saccadic eye movements). The early eye movement problems are primarily related to impaired saccadic initiation, saccadic hypometria, abnormal smooth pursuit, and difficulty suppressing the vestibulo-ocular reflex while tracking an object moving with head rotation [40,41].

Visual performance – Visual performance progressively deteriorates, with signs that include periodic alternating nystagmus and impaired lateral end-gaze fixation, vertical gaze holding, and velocity storage. By the end of their first decade of life, most children with AT stop reading longer passages for content because of these difficulties, even though they are easily able to identify single words and short phrases. Acquired strabismus is also common.

Cognition and speech – Mild to moderate cognitive impairment is frequently present early in the course of AT, and cognitive deficits may become more widespread and severe in the later stages of AT [42,43]. The majority of children with AT never attain normal speech due to problems with articulation, and speech further deteriorates after the age of five to eight years. There is a characteristic delay in the initiation of speech, and the speech is typically slow with inappropriate emphasis placed on single words or syllables.

Progressive difficulty with chewing and swallowing develops over time, and aspiration is common in individuals over the age of 10 years [44].

Movement disorders – Despite the obvious cerebellar pathology, many of the motor difficulties of AT are extrapyramidal in nature (see 'Variant AT' below). These include dystonia, myoclonus, tremor, chorea, delayed reaction time, facial hypomimia, and distal adventitious movements at rest [32,45].

Peripheral neuropathy – Peripheral axonal neuropathy is common [46,47]. However, neuropathy contributes relatively little to functional impairment in AT given the severity of other movement deficits.

In some cases, patients with AT develop a distally predominant pattern of lower motor neuron weakness due to anterior horn cell degeneration [48], though this may be difficult to distinguish from a mixed motor-sensory axonal neuropathy.

Telangiectasias and skin findings — Telangiectasias of blood vessels are seen primarily in the eyes on the bulbar conjunctivae and on exposed areas of the skin, typically the pinnae, nose, face, and neck [49]. In most cases, they first appear when the child reaches three to six years of age.

It is perhaps inaccurate that this disease is named "ataxia-telangiectasia" because the appearance of telangiectasia typically occurs long after the onset of ataxia, and the delayed appearance of telangiectasia often results in a delayed diagnosis [39].

Children with AT frequently have café-au-lait macules (picture 1A-B) [49]. Additional skin lesions that occur with AT include hypopigmented macules, melanocytic nevi, and facial papulosquamous rash.

AT may also result in early features of aging, such as atrophy of facial skin and premature graying of hair [50]. An association with vitiligo has also been reported [51].

Immune deficiency — Immune deficiency, affecting both cellular and humoral immunity, occurs in approximately 70 percent of patients with AT.

With widespread adoption of newborn screening for SCID with a heelstick dried blood spot test, over half of infants with AT are identified in the newborn period as having low T cell numbers [52]. The test uses quantitative polymerase chain reaction (PCR) to measure T cell receptor excision circles (TRECs), which are circular byproducts of T cell receptor gene rearrangement in the thymus. The TREC test flags infants with non-SCID disorders associated with low T cells as well as infants with SCID. (See "Newborn screening for primary immunodeficiencies".)

Because the T cell lymphopenia of AT is quite variable, some infants have very few TRECs (and therefore have a positive newborn screen for SCID), while others have TRECs and T cells in the normal range early in life, with progressive loss over time. Additional laboratory abnormalities are reviewed below. (See 'Laboratory abnormalities' below.)

The clinical manifestations of T cell immunodeficiency are quite variable in patients with AT. The most common complication is recurrent sinopulmonary infections [53,54]. Infections outside of the respiratory tract are generally not increased in frequency, and opportunistic infections rarely occur [53]. Infections may be the result of underlying immunodeficiency and/or dysfunctional swallow with aspiration. (See 'Pulmonary disease' below.)

One particular immune-related phenomenon in AT is the development of cutaneous granulomatous lesions that can become ulcerated and enlarge to several centimeters in size. These were initially described in the 1990s as sarcoid-like lesions and can even be the presenting feature of AT [55], but they are also found in patients with a number of other genetic defects of cellular immunity [56]. The lesions contain nucleic acid from vaccine-strain rubella virus RA27/3 and are a consequence of chronic opportunistic infection following live rubella vaccination [57]. These lesions may not respond to treatment and suggest that live rubella vaccinations should not be given to children with AT [58]. (See 'Vaccinations' below.)

Pulmonary disease — Progressive pulmonary disease is a major cause of morbidity and mortality in patients with AT [53]. Three major types of pulmonary involvement are associated with AT [59]:

Recurrent sinopulmonary infections and bronchiectasis

Interstitial lung disease/pulmonary fibrosis

Neuromuscular abnormalities, including dysphagia, aspiration, and respiratory muscle weakness

Even in the absence of overt infection, patients with AT can develop interstitial lung disease, with symptoms including nonproductive cough, dyspnea, fever, tachypnea, hypoxemia, and crackles [59,60].

Many children with AT have difficulty with coordination of swallowing and may aspirate foods, liquids, and oral secretions [44,61]. Dysphagia often presents in the second decade of life. Neuromuscular weakness can also result in decreased tidal volumes and ineffective cough [62].

Malignancy — Patients with AT are at significantly increased risk for cancer in childhood, especially hematologic malignancies. The best available risk estimates come from a population-based registry study in Germany that identified 160 patients with AT diagnosed between 1973 and 2020 [63]. Among these patients, the rate of cancer by age 18 years was 14 percent, representing a 56-fold increase over the expected rate in the general population. Other studies have estimated a lifetime cancer risk ranging from 10 to 25 percent in patients with AT [64-66].

The majority of childhood cancers in patients with AT are lymphomas and acute leukemias. In the largest individual study, the median age at cancer diagnosis was 9.8 years (range, 3 to 17 years); the most common cancer types were non-Hodgkin lymphoma (58 percent), Hodgkin lymphoma (21 percent), and leukemia (16 percent) [63]. There was one case of medulloblastoma.

Among patients who survive to adulthood (>20 years), there also appears to be an increase in the risk of solid tumors (such as breast cancer) compared with the general population, including breast, liver, gastric, and esophageal cancers [31,67].

Management of cancer in patients with AT requires special care due to an increased risk of toxicities from chemotherapy and radiation. (See 'Cancer management' below.)

Endocrine dysfunction — Poor growth is common in patients with AT and may be multifactorial [33,68]. Contributing factors include nutritional compromise, infections, and alterations in growth hormone.

AT is associated with gonadal dysgenesis and delayed pubertal development, which may be more prominent in females than males [33]. Insulin resistance and type 2 diabetes affect a minority of patients, usually as late events [31].

Laboratory abnormalities — AT is associated with elevation of serum alpha-fetoprotein (AFP) and a range of laboratory abnormalities involving both humoral and cell-mediated immunity.

Importantly, despite the high frequency of immunologic abnormalities, there is a striking lack of opportunistic infections. The risk for infection has never been closely correlated with any single or group of laboratory abnormalities, other than the T cell granulomas that contain vaccine-strain rubella virus. (See 'Immune deficiency' above.)

Elevated AFP – Elevated AFP is the most consistent laboratory abnormality in patients with AT who are over six months of age [69]. Prior to this age, the residual high fetal levels of AFP obscure differences between healthy infants and those affected with AT. In patients older than six months of age, an AFP concentration >30 ng/mL is considered abnormal [70].

AFP is elevated in approximately 90 percent of patients, with levels often >100 micrograms/L [71]. The level does not necessarily rise over time, and it does not correlate with severity of disease. The reason why AFP is elevated in AT is not known.

Several other less common genetic causes of ataxia are also associated with AFP elevation, although usually at lower levels [71]. (See 'Differential diagnosis' below.)

T cell lymphopenia – T cell lymphopenia is present from birth in over half of patients [52]. In the other half, it develops later in childhood or not at all. It is not known why some patients have early T cell lymphopenia while others do not, and genotype/phenotype relationships are not sufficient to explain the variability. (See 'Immune deficiency' above.)

Abnormalities in humoral immunity Patients with AT may have immunoglobulin deficiency, especially absence or marked reduction of immunoglobulin A (IgA), IgG2, and other IgG subclasses [72,73] (see "IgG subclass deficiency"); inability to produce antibodies to polysaccharide antigens such as those forming the capsule of pneumococcal bacteria [74,75]; and oligoclonal gammopathy [76]. Occasional patients have severe panhypogammaglobulinemia or present with a picture compatible with SCID.

In the vast majority of patients with AT, immunodeficiency is not progressive, but humoral immune deficiency becomes more severe with increasing age in 5 to 10 percent of patients [77].

Cytogenetic abnormalities – Spontaneous cytogenetic abnormalities including chromatid gaps, chromosomal breakage, translocations, and rearrangements are common, especially involving the immunoglobulin and T cell receptor gene loci on chromosomes 7 and 14 [78].

Neuroimaging features — Magnetic resonance imaging (MRI) of the brain in children with AT is usually normal, and there are no diagnostic neuroimaging findings. Over time, diffuse cerebellar atrophy may be seen, corresponding to progressive neurodegeneration.

A variety of other findings have been described in older patients with AT, including hemosiderin deposition and deep cerebral telangiectasias, cerebral white matter abnormalities, and degenerative changes in the white matter corticomotor tracts arising from the cerebellum [79-82].

Of note, neuroimaging with MRI is preferred over computed tomography (CT) scans or other methods that involve exposure to x-rays, due to the radiation sensitivity of these patients.

Variant AT — A phenotype referred to as "variant" or "atypical" AT usually has a milder course than classic AT, perhaps on the basis of pathogenic variants that result in expression of residual ataxia-telangiectasia mutated (ATM) protein and kinase activity [45,83-86]. Aside from ataxia, variant AT often presents with extrapyramidal movement disorders such as tremor, dystonia, myoclonus, and choreoathetosis [87-89].

One of the larger studies retrospectively analyzed data from 57 individuals with variant AT [87]. Symptom onset by age 10 years occurred in approximately 80 percent. In a majority, there was a delay in diagnosis of more than 10 years. Presentation with predominant ataxia and little or no extrapyramidal involvement was noted in 33 percent, while a predominant extrapyramidal presentation was found in 18 percent. Disease severity was considered mild (defined by retained ambulation with or without a walking aid and ability to use the arms for most activities without help) in 33 percent, and ambulation was retained for 20 years after disease onset in approximately 40 percent. Extrapyramidal presentations correlated with mild disease severity. A history of malignancy was present in 25 percent.

Due to the milder phenotype and slower course, a diagnosis of malignancy can precede the diagnosis of AT. Compared with classic AT, cancer tends to occur later in life and may include a higher proportion of solid tumor malignancies [31].

Heterozygotes — Individuals who carry a single pathogenic variant in the ATM gene have none of the classic clinical manifestations of AT. However, they are at increased risk for cancer and coronary heart disease compared with the general population [90]. All-cause mortality appears to be increased in carriers up to 60 years of age, primarily due to an excess in cancer deaths [11,90,91].

The spectrum of malignancies observed in ATM heterozygotes is more heavily weighted toward solid tumors compared with that of people with AT [10-12,65,90-94]. In a study of 4607 ATM pathogenic variant carriers, carriers were at moderate-to-high risk for pancreatic cancer (odds ratio [OR] 4.21, 95% CI 3.24-5.47), prostate cancer (OR 2.58, 95% CI 1.93-3.44), gastric cancer (OR 2.97, 95% CI 1.66-5.31), and invasive ductal breast cancer (OR 2.03, 95% CI 1.89-2.19) [95]. Low-to-moderate risk was seen for ductal carcinoma in situ (OR 1.80), male breast cancer (OR 1.72), ovarian cancer (OR 1.57), colorectal cancer (OR 1.49), and melanoma (OR 1.46).

Estimated lifetime cancer risks and implications for screening among ATM heterozygotes are reviewed separately:

Female breast and ovarian cancer (see "Overview of hereditary breast and ovarian cancer syndromes associated with genes other than BRCA1/2", section on 'ATM')

Pancreatic cancer (see "Familial risk factors for pancreatic cancer and screening of high-risk patients", section on 'Ataxia-telangiectasia')

Prostate cancer (see "Genetic risk factors for prostate cancer", section on 'ATM')

Cancer risk among ATM variant carriers differs based on the type of pathogenic variant and may in fact be higher for missense variants (which are uncommon in patients with AT). One explanation for disparate risks (and for the different cancer phenotypes that characterize AT heterozygotes versus homozygotes) may be that heterozygotes who have missense pathogenic variants of ATM (in particular, ones that do not cause AT) could be predisposed to cancer by a different mechanism [24,96,97]. These variants, instead of producing no detectable ATM kinase (as is the case with null or truncating variants), result in an abnormal protein that acts by dominantly interfering with the function of the normal allele (a dominant negative effect). In fact, putative missense pathogenic variants have been reported in a number of studies of breast cancer populations where ATM truncating variants have not been found [98,99].


Clinical suspicion — AT is typically suspected either based on abnormal results of a newborn screen for severe combined immunodeficiency (SCID) or the onset of neurologic abnormalities in early childhood.

Abnormal newborn screening – Since T cell lymphopenia is associated with AT, newborn screening for SCID using T cell receptor excision circle (TREC) quantification will also identify some infants with non-SCID immunodeficiencies, including AT. Not all infants with AT will be detected by TREC screening, but the TREC test will flag those who have a profound decrease in circulating naïve T cells. (See "Newborn screening for primary immunodeficiencies", section on 'Screening for SCID and other T cell defects'.)

When possible, such newborns should undergo confirmatory sequencing of ataxia-telangiectasia mutated (ATM) (see 'Confirmatory testing' below). The ATM gene is very large, however, and sequencing remains expensive or hard to obtain in many parts of the world. In such cases, immunologists typically follow infants with a low TREC and low T cells who do not have SCID or other syndromes (such as DiGeorge) expectantly during the first six months of life. Antibody responses to vaccines and an alpha-fetoprotein (AFP) level can then be checked at seven months of age to raise or lower suspicion for AT. Elevated AFP is an excellent indicator of AT, but only after six months of age. (See 'Laboratory abnormalities' above.)

Childhood-onset ataxia – AT should be suspected when there is childhood onset of progressive cerebellar ataxia or postural instability with abnormalities of eye movements, particularly if associated with telangiectasia, frequent sinopulmonary infections, or laboratory findings such as IgA deficiency, lymphopenia predominantly affecting T lymphocytes, and elevated AFP levels [31]. AT should also be suspected in any child with unexplained ataxia.

In cases of suspected AT, we obtain AFP and IgA levels as a fast and inexpensive screening test. However, genetic testing should still be performed as a confirmatory test.

Confirmatory testing — The diagnosis of AT is established by identification of pathogenic variants on both alleles for the ATM gene. ATM testing is available commercially and is most commonly done as part of an immunodeficiency or autosomal recessive ataxia genetic panel. Whole exome or genome sequencing can also detect ATM variants, but the cost is much higher.

Older clinical and laboratory-based criteria have largely been replaced by genetic testing [100]. Criteria for possible and probable AT in the absence of genetic testing were based on ocular or facial telangiectasia, serum IgA deficiency, elevated AFP, and increased spontaneous and radiation-induced chromosome fragility in cultured cells. Note that telangiectasia usually appears after age five years and that not all patients with AT have elevated levels of AFP. (See 'Classic AT' above.)

Tests for radiation sensitivity are not widely commercially available. They involve radiation of lymphocyte or fibroblast cell lines followed by analysis for chromosomal breaks and fragility. A newer generation of radiation sensitivity testing is performed by flow cytometry [101]. (See "Laboratory evaluation of the immune system", section on 'Chromosomal instability assays for radiation-sensitive patients'.)

Differential diagnosis — AT can be difficult to distinguish clinically from other chronic ataxic syndromes [102]. If ataxia develops early, it may be misdiagnosed as an ataxic variety of cerebral palsy, particularly because cognition is relatively preserved in AT. (See "Cerebral palsy: Classification and clinical features".)

When the onset is delayed, AT most often is mistaken for Friedreich ataxia, a disorder that now is diagnosed by genetic testing of the frataxin gene (see "Friedreich ataxia"). Frataxin, ATM, and the additional genes below are typically tested simultaneously as part of an autosomal recessive ataxia panel.

Several other diseases mirror the neurologic features of AT but result from defects in genes other than ATM. These include the following:

Ataxia-ocular apraxia type 1 (AOA1) – AOA1 is an autosomal recessive disorder characterized by cerebellar ataxia, oculomotor apraxia, cerebellar atrophy, and a severe axonal sensorimotor neuropathy [103-107]. Additional manifestations include hypoalbuminemia and elevation of serum total cholesterol. AOA1 lacks telangiectasia and the other nonneurologic features of AT.

AOA1 is caused by pathogenic variants in the APTX gene that encodes aprataxin [104,105]. Most reported cases are of Portuguese, Italian, and Japanese descent.

A form of ataxia associated with muscle coenzyme Q10 deficiency [108,109] has been linked to the same APTX gene and is probably the same disease as AOA1 [110,111].

Ataxia-ocular apraxia type 2 (AOA2) – AOA2 is associated with a progressive cerebellar ataxia, a variable presence of oculomotor apraxia, distal amyotrophy, sensory and motor axonal neuropathy, and elevations in serum AFP [71,112-116]. Patients have no evidence of chromosomal instability or sensitivity to ionizing radiation. AOA2 is caused by pathogenic variants in the SETX gene on chromosome 9q34 coding for senataxin, a DNA and RNA helicase [113,115].

Other ataxia-ocular apraxias (AOAs) – Additional types of AOA have been described in rare cases. AOA3 (MIM 615217) has been described in a family with homozygous phosphatidylinositol 3-kinase regulatory subunit 5 (PIK3R5) pathogenic variants [117], and AOA4 (MIM 616267) has been described due to homozygous or compound heterozygous pathogenic variants in the polynucleotide kinase 3ꞌ-phosphatase (PNKP) gene, which plays a key role in DNA damage repair [118].

Ataxia-telangiectasia-like disorder (ATLD) – ATLD (MIM 604391) is caused by pathogenic variants of the MRE11A gene, which encodes a protein involved with ATM in double-strand DNA break recognition and repair [31,119,120]. Although ATLD has only been reported in a small number of patients, it is estimated that as many as 5 percent of AT cases may be incorrectly diagnosed and actually have ATLD, given the similarity in clinical manifestations and coding sizes of the two affected genes.

Affected patients have progressive ataxia without telangiectasia [121,122]. The overall neurologic phenotype is similar to that of AT, although the rate of neurodegeneration appears to be slower and most ATLD patients are still ambulatory in their late teens. The laboratory findings in ATLD1 are similar but not identical to those seen in AT. Peripheral blood lymphocytes have chromosomal breaks in the basal state and an increase in chromatid-type damage after exposure to ionizing radiation. However, serum levels of AFP and immunoglobulins are normal.

The diagnosis of ATLD1 can be established with certainty only by finding pathogenic variants in both alleles of the MRE11A gene.

The prognosis of patients with ATLD is unclear, since there are only a few recognized subjects with the disorder. In general, affected patients appear to have a slower pace of neurodegeneration than patients with AT. The risk for development of chronic lung disease or malignancy is unknown. The management of patients with ATLD is otherwise the same as for those with AT.

Another condition, described in one family and tentatively called ataxia-telangiectasia-like disorder 2 (ATLD2), is an autosomal recessive syndrome caused by homozygous pathogenic variants in the proliferating cell nuclear antigen (PCNA) gene [123]. Symptoms include developmental delay, ataxia, and sensorineural hearing loss. Other features include short stature, cutaneous and ocular telangiectasia, hearing loss, premature aging, and photosensitivity.

Others – Other disorders that are characterized by deficiencies in DNA repair pathways and are associated with ataxia include xeroderma pigmentosa, Cockayne syndrome, and Nijmegen breakage syndrome. (See "Xeroderma pigmentosum" and "Neuropathies associated with hereditary disorders", section on 'Cockayne syndrome' and "Nijmegen breakage syndrome".)

MANAGEMENT — Management strategies for patients with AT are symptomatic and supportive based upon disease manifestations [31,124].

Health maintenance

Immunologic evaluation — All patients with AT should have at least one comprehensive immunologic evaluation, typically in consultation with an allergist/immunologist, to measure both humoral and cellular immune function [31]. An evaluation should include measurement of the following:

Complete blood count (CBC) with differential and peripheral blood flow cytometry to measure number and type of T and B lymphocytes.

Antibody levels (IgG, IgA, IgM, and IgE), interpreted using comparison with age-adjusted normal reference ranges. (See "Laboratory evaluation of the immune system", section on 'Measurement of antibody levels'.)

Specific antibody response, typically through an assessment of antibody titers following killed vaccinations. (See "Assessing antibody function as part of an immunologic evaluation".)

Children with abnormal immune function should be followed by an immunology specialist whenever possible. Those with hypogammaglobulinemia or impaired specific antibody production are typically treated with immune globulin replacement and/or prophylactic antibiotics. (See "Primary immunodeficiency: Overview of management".)

Patients with severely compromised T cell function require precautions with blood products to avoid transfusion reactions. (See "Primary immunodeficiency: Overview of management", section on 'Caution with blood products'.)

Vaccinations — Live vaccines are contraindicated in most patients with AT due to partial combined immunodeficiency. In particular, rubella vaccination (or measles/mumps/rubella in the United States) should be avoided due to the risk of chronic T cell granulomatous lesions, unless in an individual case the benefits are judged to outweigh the risks. The approach to immunization in patients with immunodeficiency is reviewed in detail separately. (See "Immunizations in patients with primary immunodeficiency".)

Vaccination of all caregivers of patients with AT is highly encouraged, when possible and safe, as patients with immunodeficiency can significantly benefit from herd immunity.

Vaccinations that are safe and particularly important in patients with AT include:

Pneumococcal vaccination – Children with AT are at increased risk for invasive pneumococcal disease and should receive routine pneumococcal conjugate vaccine (PCV) immunization as well as at least one dose of the 23-valent pneumococcal polysaccharide vaccine (PPSV23). The recommended schedule varies with age and pneumococcal vaccination history. Dosing and schedules for these vaccines in high-risk groups are discussed in detail separately. (See "Pneumococcal vaccination in children", section on 'Immunization of high-risk children and adolescents'.)

Influenza vaccination – All children with AT and members of the household should be immunized with an inactivated influenza vaccine annually. (See "Seasonal influenza in children: Prevention with vaccines", section on 'Target groups' and "Seasonal influenza vaccination in adults" and "Immunizations in patients with primary immunodeficiency".)

Human papilloma virus (HPV) vaccination – HPV vaccination should be considered in all patients with AT due to increased susceptibility to papillomavirus infection. (See "Immunizations in patients with primary immunodeficiency", section on 'Human papilloma virus vaccine'.)

COVID-19 vaccination – Coronavirus disease 2019 (COVID-19) vaccines should be given to all eligible patients with AT and their household contacts. (See "COVID-19: Vaccines".)

Neurologic disability — Physical and occupational therapy are critical for maintaining the maximum possible level of function. There are no therapies known to slow progression of neurologic deficits.

In an eight-week open-label study, amantadine treatment was associated with a modest improvement in motor symptoms (ataxia, involuntary movements, and parkinsonism) in 13 of 17 children with AT [125]. This finding requires confirmation in larger controlled studies.

Infectious complications — Acute infection should be treated with appropriate antibiotics and simple maneuvers such as postural drainage. Antibiotic prophylaxis should be considered in patients with recurrent sinopulmonary bacterial infections. Chest clearance techniques may be helpful in patients with acute or chronic lung infections [59].

Diagnostic tests involving radiographs and ionizing radiation should be avoided when possible to minimize the risk of somatic mutations and subsequent malignancy. However, such studies should not be withheld if they are required to provide optimal management.

Patients who do not tolerate or fail therapy with antibiotics should be given immune globulin infusions. (See "Primary immunodeficiency: Overview of management", section on 'Management of complications'.)

Chronic lung disease — Chronic lung disease is a major cause of morbidity and mortality in patients with AT. (See 'Pulmonary disease' above.)

Monitoring of pulmonary function – Pulmonary function can be measured with spirometry by making minor modifications to standard procedures [62]. Every attempt should be made to test pulmonary function in children with AT who develop chronic respiratory tract symptoms. Pulmonary function should also be part of the risk assessment for elective surgery for patients with AT who are age 10 years and older. Some experts advise regular assessment of lung function in all symptomatic and asymptomatic children with AT who are old enough to cooperate with testing, including yearly spirometry [59].

Early detection of structural damage – Early detection of pulmonary structural damage, particularly bronchiectasis and consolidation, is valuable, resulting in more intensive care and prompt start of treatment. Magnetic resonance imaging (MRI) is a reliable tool in the assessment of pulmonary damage in children and adults with AT [126]. In a study of 15 patients with AT, MRI identified lung abnormalities in all cases, including seven patients without respiratory symptoms. These findings indicate that MRI-detected structural lung damage can precede the appearance of clinical symptoms, and that MRI can lead to earlier diagnosis and thus to better clinical management.

Treatment of interstitial lung disease – A trial of glucocorticoid therapy is an option for patients who have interstitial lung disease [59]. However, only limited observational data support any benefit of this treatment for patients with AT [60]. Other sparse data, including a randomized controlled trial with 13 patients [127] and several small case series [128-130], indicate that short-term treatment with oral betamethasone may help improve ataxia in some patients with AT. Regardless of whether glucocorticoid treatment is directed at interstitial lung disease or ataxia, the optimal dosing regimens and duration of therapy in AT are unknown, as is the safety of long-term treatment. Glucocorticoids can lead to a clinically significant increased risk of infection and insulin resistance in patients with AT and should therefore be used cautiously.

Ventilatory support – Chest clearance techniques and cough assist devices may be helpful for patients with bulbar and respiratory muscle weakness, and noninvasive ventilation is suggested for patients with chronic respiratory failure [59].

Swallowing and nutrition — Many children with AT have difficulty with coordination of swallowing and may aspirate foods, liquids, and oral secretions. Swallowing should be formally evaluated in all patients by an experienced team while minimizing radiation exposure. Children may also aspirate after reflux, and gastroesophageal reflux disease (GERD) should also be investigated and treated as necessary.

Overt or subclinical aspiration contributes to chronic lung injury. Gastrostomy tube placement for enteral feedings should be used to reduce the risk of aspiration and to maintain growth and nutrition in symptomatic children [35].

Cancer surveillance

Patients with AT – Patients with classic AT are at significantly increased risk of malignancy during childhood, with an estimated 25 percent lifetime risk of cancer. Lymphoma and leukemia predominate in patients up to the age of 20 years, and the risk of solid tumors appears to increase in patients who survive into adulthood. (See 'Malignancy' above and 'Variant AT' above.)

Despite known risks, protocols for early detection of hematologic malignancies have not been established [31]. Annual CBC, lactate dehydrogenase (LDH), and comprehensive metabolic panel measurement should be considered, although whether this or other strategies would help to detect cancers earlier and improve outcomes is not known [131]. Clinicians should have heightened suspicion for hematologic malignancy in children with potential signs such as easy bruising, persistently swollen lymph nodes, weight loss, or unexplained fevers.

Due to the risk of breast cancer in females with AT who survive into adulthood, some experts suggest beginning yearly breast MRI at age 25 years and avoiding mammography in order to limit radiation exposure [124].

Heterozygotes – Screening recommendations for solid tumors in carriers of a single ataxia-telangiectasia mutated (ATM) pathogenic variant are discussed separately.

Breast and ovarian cancer (see "Overview of hereditary breast and ovarian cancer syndromes associated with genes other than BRCA1/2", section on 'ATM')

Pancreatic cancer (see "Familial risk factors for pancreatic cancer and screening of high-risk patients", section on 'Candidates for screening')

Prostate cancer (see "Genetic risk factors for prostate cancer", section on 'Guidelines from expert groups')

Cancer management

Patients with AT – Management of hematologic and other malignancies may be challenging due to increased risks of radiation toxicity and cytotoxicity from chemotherapy. AT cells are susceptible to damage by ionizing radiation as well as chemotherapeutic agents that cause double-stranded breaks in DNA. Conventional doses of radiotherapy can cause severe reactions and are potentially lethal in patients with AT [36,132,133], and the incidence of late complications following radiation therapy may be higher in some affected patients [134,135].

Radiotherapy should be performed only in rare circumstances in patients with AT and only with reduced doses and careful monitoring [136]. Alkylating agents and epipodophyllotoxins should be avoided; methotrexate doses should be reduced [137]. Experience with bone marrow transplantation is limited. In case reports, two patients have died, one due to progression of lymphoma [138] and one due to drug toxicity [139], though the diagnosis of AT was made postmortem in the latter patient. Survival of 3.5 years was reported in a single patient with a human leukocyte antigen (HLA)-identical sibling donor after reduced intensity conditioning [138].

Heterozygotes – Risks of cancer therapy in individuals who carry a single ATM pathogenic variant have not been well studied, but limited data do not suggest higher acute toxicity [140]. Experts generally recommend that heterozygous individuals receive whatever is considered the best curative option [31]. Treatment considerations for patients with breast cancer who are ATM heterozygotes are discussed elsewhere. (See "Overview of hereditary breast and ovarian cancer syndromes associated with genes other than BRCA1/2", section on 'ATM'.)

PROGNOSIS — AT is a difficult disease to manage and has a poor prognosis because of its multisystem involvement. No disease-modifying treatment exists for the ataxic syndrome or the progressive cerebellar neurodegeneration.

Many patients with classic AT succumb to progressive pulmonary disease caused by repeated infection or to cancer, and the median age at death is approximately 25 years [141]. Presently no therapies significantly alter the course of the disease.


Clinical features and diagnosis Ataxia-telangiectasia (AT; MIM 208900) is a multisystem autosomal recessive disorder caused by pathogenic variants in the ataxia-telangiectasia mutated (ATM) gene. In most cases, the AT phenotype results from biallelic loss-of-function variants leading to absent or defective ATM kinase. (See 'Genetics and pathogenesis' above and 'Epidemiology' above.)

The phenotypic spectrum of AT is evolving, as the diagnosis is now being made at birth in many cases due to widespread newborn screening for immunodeficiency. Three phenotypes are generally recognized:

Classic AT – Classic AT usually presents either at birth, with partial combined immunodeficiency, or in early childhood, when neurologic abnormalities begin. Young children develop progressive cerebellar ataxia, abnormal eye movements, extrapyramidal motor dysfunction, and oculocutaneous telangiectasias. Progressive pulmonary disease and hematologic malignancy are major causes of morbidity and mortality. (See 'Classic AT' above.)

Variant AT – Variant AT presents slightly later, by the age of 10 years in most cases, with milder cerebellar dysfunction and extrapyramidal movement disorders (eg, tremor, dystonia). Compared with classic AT, cancer tends to occur later in life and may include a higher proportion of solid tumor malignancies. (See 'Variant AT' above.)

AT heterozygotes – AT heterozygotes have none of the classical clinical manifestations of AT, but they do have a higher incidence of coronary heart disease and malignancy at a younger age compared with the general population. (See 'Heterozygotes' above.)

The diagnosis of AT is established by identification of pathogenic variants on both alleles for the ATM gene. ATM testing is available commercially. Supportive laboratory features include elevated serum alpha-fetoprotein (AFP), T cell lymphopenia, and immunoglobulin deficiencies. (See 'Diagnosis' above.)

Management Management of patients with AT is supportive and symptomatic, as there are no disease-modifying treatments available.

Health maintenance – All patients should undergo at least one comprehensive immunologic evaluation to measure both humoral and cellular immune function. Patients with immunodeficiency require additional preventive measures and should be followed by an immunologist whenever possible. (See 'Immunologic evaluation' above.)

Vaccinations – Live vaccines are contraindicated in most patients with AT due to partial combined immunodeficiency. In particular, rubella vaccination (or measles/mumps/rubella in the United States) should be avoided due to the risk of chronic T cell granulomatous lesions, which contain vaccine-strain rubella virus. (See 'Immune deficiency' above and 'Vaccinations' above.)

Vaccinations that are safe and especially important in patients with AT include pneumococcus, inactivated influenza, human papilloma virus (HPV), and coronavirus disease 2019 (COVID-19). (See 'Vaccinations' above.)

Neurologic care – Physical and occupational therapy are critical for maintaining the maximum possible level of function. Swallowing function should be evaluated by an experienced team while minimizing radiation exposure. Swallowing dysfunction contributes to poor nutrition, chronic aspiration, and lung disease. (See 'Neurologic disability' above.)

Infections and lung disease – Patients with AT are at risk for recurrent sinopulmonary infections, respiratory muscle weakness, and chronic lung disease. Management consists of antibiotics for acute infection, routine chest therapy for secretion clearance, and regular monitoring of lung function. Diagnostic tests involving radiation exposure (eg, radiographs, computed tomography [CT]) should be avoided when possible. (See 'Infectious complications' above and 'Chronic lung disease' above.)

Cancer surveillance and treatment – AT poses a significantly increased risk of hematologic malignancy during childhood. Clinicians should maintain heightened awareness for changes on complete blood counts (CBCs), easy bruising, persistently swollen lymph nodes, weight loss, or unexplained fevers. Due to risk of breast cancer in females who survive to adulthood, some experts suggest beginning yearly breast MRI at age 25 years. (See 'Cancer surveillance' above.)

Management of hematologic and other malignancies in patients with AT is challenging due to increased risks of radiation toxicity and cytotoxicity from chemotherapy. Therapeutic radiation should be performed only in rare circumstances and only with reduced doses and careful monitoring. (See 'Cancer management' above.)

Carriers of a single ATM pathogenic variant (AT heterozygotes) are at increased risk for breast cancer, pancreatic cancer, and other solid tumors in adulthood, occurring at younger ages compared with the general population. Enhanced screening protocols are reviewed separately. (See "Overview of hereditary breast and ovarian cancer syndromes associated with genes other than BRCA1/2", section on 'ATM' and "Familial risk factors for pancreatic cancer and screening of high-risk patients", section on 'Candidates for screening' and "Genetic risk factors for prostate cancer", section on 'Guidelines from expert groups'.)

Prognosis – Classic AT is difficult to treat and has a poor prognosis because of its multisystem involvement. Many patients succumb to progressive pulmonary disease or to cancer, and the average lifespan is approximately 25 years. (See 'Prognosis' above.)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges E Richard Stiehm, MD, Howard Lederman, MD, PhD, and Francisco Bonilla, MD, PhD, who contributed to earlier versions of this topic review.

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