Ataxia-Telangiectasia

[Louis-Bar Syndrome]
Initial Posting: March 19, 1999.
Last Update: March 11, 2010.
Prevalence
The prevalence of A-T in the US is 1:40,000-1:100,000 live births.
A-T is the most common cause of progressive cerebellar ataxia in childhood in most countries; ataxia with oculomotor
apraxia (AOA) may be more prevalent in Portugal and perhaps Japan [Nemeth et al 2000, Date et al 2001, Moreira et al
2001]. (See Ataxia with Oculomotor Apraxia Type 1 and Ataxia with Oculomotor Apraxia Type 2.)
Prevalence varies with the degree of consanguinity in a country.
Clinical Description
Natural History
Classic Ataxia-Telangiectasia
The primary features of classic A-T include 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); and hypersensitivity to ionizing radiation with
increased susceptibility to cancer (usually leukemia or lymphoma).
Other features include premature aging with strands of gray hair and endocrine abnormalities, such as insulin-resistent
diabetes mellitus.
The A-T syndrome varies little from family to family in its late stages. For clinical reviews, see Boder [1985], Gatti [2002],
Perlman et al [2003], Chun & Gatti [2004], Nowak-Wegrzyn et al [2004], and Taylor & Byrd [2005]. However, the time of
onset and rate of progression of symptoms can vary considerably even in a family with multiple affected individuals.
Cerebellar ataxia. The most obvious and troubling characteristic of classic A-T is the progressive cerebellar ataxia. Shortly
after learning to walk, children with A-T begin to stagger. The neurologic status of some children appears to improve from
age two to four years, then ataxia begins to progress again; 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. By age ten years, most children become confined to a wheelchair for the remainder of their lives.
Slurred speech and oculomotor apraxia are noted early. Both horizontal and vertical saccadic eye movements are affected
[Lewis et al 1999, Farr et al 2002, Onodera 2006, Yakusheva et al 2007].
Choreoathetosis is found in almost all individuals with A-T. Myoclonic jerking and intention tremors are present in about
25% of individuals.
Deep tendon reflexes are decreased or absent in older individuals; plantar reflexes are upgoing or absent. Three siblings
with A-T presented with lower motor neuron degeneration [Larnaout et al 1998].
Drooling is common.
Writing is affected by age seven or eight years.
All teenagers with classic A-T need help with dressing, eating, washing, and using the toilet. Because swallowing is not well
coordinated, eating should be slow and deliberate to avoid aspirating food [Lefton-Greif et al 2000]. 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 but may be minimized by rigorous exercise.
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.
Immunodeficiency. Immunodeficiencies are present in 60% to 80% of individuals with classic A-T; they are variable and
do not correlate well with the frequency, severity or spectrum of infections. The immunodeficiency is not progressive
[Boder 1985, Woods & Taylor 1992, Gatti 2002, Nowak-Wegrzyn et al 2004, Pashankar et al 2006].
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
may be reduced. Approximately 30% of individuals with classic A-T who have immunodeficiency have T-cell deficiencies.
At autopsy, virtually all individuals have a small embryonic-like thymus.
Infection. In contrast to the spectrum of infection in most immunodeficiency disorders, the spectrum of infection in classic
A-T does not include opportunistic infections. Some individuals with classic A-T develop chronic bronchiectasis. The
frequency and severity of infections correlates more with general nutritional status than with the immune status. Although
individuals with frequent and severe classic A-T infections appear to occasionally benefit from intravenous immunoglobulin

(IVIG) replacement therapy [Nowak-Wegrzyn et al 2004], longevity has increased substantially even in affected individuals
not receiving IVIG.
Cancer risk. 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 span. Over the past 20 years, the expected life span of individuals with A-T has increased considerably; most affected
individuals now live beyond age 25 years. Some have survived into their 50s [Dork et al 2004; Crawford et al 2006,
unpublished]. In older individuals, pulmonary failure, with or without identifiable infections, is a major cause of failing
health and death. Life-threatening lymphocytic infiltration of the lung has been reported [Tangsinmankong et al 2001].
Pathology. The cerebellum atrophies early in the course of classic A-T, being visibly smaller on MRI examination 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, Lin et al 2006, Wallis et al 2007].
Microscopic nucleomegaly also occurs in the cells of tissues throughout the body.
Non-Classic Forms of Ataxia-Telangiectasia
Phenotypes other than classic A-T associated with homozygosity or compound heterozygosity for two deleterious ATM
mutations include:
Milder A-T phenotypes including adult-onset A-T [McConville et al 1996, Stankovic et al 1998, Trimis et al 2004, Alterman
et al 2007, Saviozzi et al 2002, Mitui et al 2009].
Adult-onset spinal muscular atrophy [Hiel et al 2006]. This phenotype is also associated with reduced levels of ATM
protein.
A-TFresno, a phenotype that combines features of both Nijmegen breakage syndrome (NBS) and A-T [Curry et al 1989, Gilad
et al 1998]
Progressive dystonia as the presenting symptom in individuals later diagnosed as having A-T [Bodensteiner et al 1980,
Woods & Taylor 1992, Goyal & Behari 2002]; however, these reports antedated the use of molecular genetic testing to
confirm the diagnosis of A-T.
Early-onset dystonia or hypotonia in some individuals with classic A-T and adult-onset mild ataxia in others associated with
homozygosity for the ATM mutation, c.6200C>A, seen in the Mennonite population [Yanofsky et al 2009]
A-T variants. Sometimes the A-T-like findings in individuals with diagnostic changes in ATM serine/threonine kinase
activity and ATM mutations do not meet A-T diagnostic criteria for example, the combination of progressive ataxia,
absence of telangiectasias, normal serum AFP concentration, and normal immune function (see Saunders-Pullman & Gatti
[2009], Verhagen et al [2009], and Alterman et al [2007]).
Heterozygotes. The cancer risk of individuals heterozygous for ATM disease-causing mutations 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, Geoffroy-Perez et al 2001, Olsen et al 2001, Teraoka et al 2001, Sommer et al 2002, Bernstein et al 2003, Bretsky et
al 2003, Sommer et al 2003, Thorstenson et al 2003, Ahmed & Rahman 2006, Bernstein et al 2006, Einarsdottir et al 2006,
Renwick et al 2006, Pylks et al 2007, Concannon et al 2008].
ATM mutations have been reported in both tumor cells and germline cells in several forms of leukemia and lymphoma,
including acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), T-cell prolymphocytic leukemia (TPLL), and mantle zone lymphoma [Stankovic et al 1998, Stilgenbauer et al 2000, Fang et al 2003, Oguchi et al 2003,
Yamaguchi et al 2003, Eclache et al 2004].
Cancer risk probably depends on multiple factors including tumor type, age at cancer onset, and whether the heterozygote
carries a missense or a truncating mutation [Gatti et al 2001, Concannon 2002, Scott et al 2002, Spring et al 2002].
Breast cancer-associated ATM mutations tend to be missense mutations whereas missense mutations are uncommon in
individuals with A-T, even in the same host population [Bernstein et al 2003].
T-cell ALL-associated ATM mutations are similar to those seen in individuals with A-T [Liberzon et al 2004, Pylks et al
2007].
Epidemiologic studies suggest that A-T carriers are also at an increased risk for heart disease [Swift 1985, Swift et al 1991].
Genotype-Phenotype Correlations
A mutation commonly referred to as 5762ins137 is associated with a somewhat slower rate of neurologic deterioration, later
onset of symptoms, intermediate radiosensitivity, and little or no cancer risk [McConville et al 1996]. This mutation is
formally designated as c.5762-1050A>G [Sutton et al 2004].
The mutations c.7271T>G, c.8147T>C, and c.8494C>T have been associated with a milder phenotype and longer life span
[Stankovic et al 1998, Verhagen et al 2009]. However, the limited number of individuals with these mutations and the lack
of individuals homozygous for these mutations preclude making statistically significant correlations.
Nomenclature
A-T complementation groups (A-E) were defined when fibroblasts (from different individuals with A-T) that fused to form
heterodikaryons did not complement the radiosensitive phenotype of any other A-T cells as assayed in several laboratories

by several different methods. Later, groups A and B were thought to be the same (i.e., group AB) and together they
accounted for more than half of the families tested worldwide.
Complementation group Variant 1 of A-T (V1) included individuals with Nijmegen breakage syndrome (NBS), a rather
different phenotype, now known to be caused by mutations in NBS1. NBS was named Variant 1 of A-T because the cellular
phenotype and chromosome abnormalities observed were similar to those of A-T.
Complementation group Variant 2 of A-T (V2) included individuals with Berlin breakage syndrome (BBS), a phenotype
similar to NBS, now known to be caused by mutations in NBS1 [Gatti 2002].
ATFresno was considered yet another clinical variant of A-T, and in limited studies appeared to complement group V1 cells
[Gatti 1991]. It is now known that ATFresno is caused by ATM mutations [Gilad et al 1998, Chun et al 2004].
Because NBS and BBS resemble A-T in various ways, use of the term AT-like disorder (ATLD) has appeared often in the
old and new literature.
More recently, the term AT-like disorder was used to describe a form of ataxia associated with Mre11 deficiency [Stewart et
al 1999], which is more appropriately designated as Mre11-deficient ataxia. The Mre11 protein is encoded by the MRE11A
gene. Use of the latter term avoids confusion, not only for Mre11-deficient ataxia but for other A-T-like phenotypes that are
neither A-T nor Mre11 deficiency [Bakheet et al 2008].
Molecular Genetics
Table A. Ataxia-Telangiectasia: Genes and Databases
Gene
Chromosomal Locus Protein Name
Locus Specific
HGMD
Symbol
ATM
11q22.3
Serine-protein kinase ATM Ataxia Telangiectasia Mutated (ATM) @ LOVD ATM
Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name,
critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus
Specific, HGMD) linked to, click here.
Normal allelic variants. The normal gene has 66 (62 coding) exons and a 13-kb cDNA.
Pathologic allelic variants. More than 500 unique mutations are known (see Table 2 and Table 3). No common mutations
(hot spots) have been identified. Most affected individuals in North America inherit different mutations from each parent,
i.e., they are compound heterozygotes [Concannon & Gatti 1997, Gatti et al 2001]. Most mutations result in absence of
ATM protein.
Table 2. Selected ATM Pathologic Allelic Variants
DNA Nucleotide
Reference
Change
Protein Amino Acid Change
Sequences
1
(Alias )
c.7271T>G
p.Val2424Gly
c.8147T>C
p.Val2716Ala 2
c.8494C>T
p.Arg2832Cys
NM_000051.3
NP_000042.3
c.6200C>A
p.Ala2067Asp
c.5762-1050A>G
See footnote 3
(5762ins137)
See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the
Human Genome Variation Society (www.hgvs.org).
1. Variant designation that does not conform to current naming conventions
2. Verhagen et al [2009], Saunders-Pullman & Gatti [2009]
3. Activates a cryptic splice site resulting in a 137-bp insertion and a truncated protein [McConville et al 1996, Stewart et al
2001, Sutton et al 2004]
Normal gene product. The normal serine-protein kinase ATM has 3056 amino acids. It senses double-stranded DNA
breaks, coordinates cell-cycle checkpoints prior to repair, attaches near damage sites, and recruits other repair proteins to
damaged sites [Lavin 2008].
Domains for: PI3 kinase, FAT, leucine zipper, FATC, p53 binding
Binding sites for: c-abl, p53, Blooms 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].
Abnormal gene product. Serine-protein kinase ATM is absent on immunoblotting in 95% of individuals. ATM mRNA is
present in more than 99% of affected individuals; however, the quantity of mRNA from each mutant allele may not be
equal. About 1% of individuals with A-T have mutations 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
mutations result in an ATM protein that interferes with the function of normal ATM protein (i.e., a dominant negative 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].
Diagnosis
Clinical Diagnosis
Ataxia-telangiectasia (A-T) is suspected in children who show progressive cerebellar dysfunction between ages one and
four years. This can present as:
Gait and truncal ataxia
Head tilting
Slurred speech
Oculomotor apraxia and uneven (interrupted or bumpy) tracking across a visual field
A small cerebellum, often observed on MRI, is not usually apparent in young children.
Testing
Serum concentration of alpha-fetoprotein (AFP). Serum AFP concentration is elevated above 10 ng/mL in more than
95% of individuals with A-T.
Note: Serum AFP concentration may remain above normal in unaffected children until age 24 months.
Immunoblotting for ATM protein. Intracellular ATM protein is severely depleted in most patients with A-T. To date, this
is the most sensitive and specific clinical test for establishing a diagnosis of A-T. Small amounts of ATM protein have been
occasionally associated with a milder prognosis, although there are many exceptions to this and the association needs
further validation.
Of individuals with A-T:
About 90% have no detectable ATM protein.
About 10% have trace amounts of ATM protein.
About 1% have a normal amount of ATM protein that lacks ATM serine/threonine kinase activity (so-called "kinase-dead").
Note: Immunoblotting assays are not easily quantified and thus the determination of "trace amounts" and "undetectable
amounts" of ATM protein often overlap. The results of immunoblotting are influenced by the following:
The amount of cell lysate loaded. Optimal results are obtained by loading nuclear lysate prepared from at least five million
cells, or 25 g of lysate protein [Chun et al 2003]. This is most reliably achieved by first establishing a lymphoblastoid cell
line (LCL) on each test sample [Author, personal observation], a procedure requiring a minimum of four to six weeks;
The titer of the developing antibody to ATM;
The time and method of exposure of the autoradiogram;
The technique used to compare the band density of observed ATM protein;
The range of sensitivity of the radiographic film or chemiluminescence reader.
Butch et al [2004] described a rapid immunoassay to measure ATM protein that is both sensitive and specific for the
diagnosis of A-T. Note: This method requires a reliable and renewable source of purified ATM protein [Chun et al 2004] and
requires that a daily control be included to insure that a result of very low ATM protein is not caused by poor specimen
handling.
ATM-dependent phosphorylation of ATM substrates. Recent reports describe rapid flow cytometric methods that
measure ATM-dependent phosphorylation of ATM substrates, such as ATM itself [Porcedda et al 2008], H2AX (encoded by
the H2AFX gene) [Honda et al 2009], and SMC1 [Nahas et al 2009]. Studies comparing this method to ATM
immunoblotting remain to be completed.
Radiosensitivity assay. The colony survival assay (CSA) is an in vitro assay that determines the survival of patient-derived
lymphoblastoid cells following irradiation with 1.0 Gy [Sun et al 2002]. The CSA was abnormal in 103 of 104 individuals
(99%) who had at least one identifiable ATM mutation; however, seven of 104 individuals scored in an intermediate
radiosensitivity range that overlaps with the normal range [Sun et al 2002].
Note: (1) Exposure of the lymphoblastoid cells of such individuals to several radiation doses (1.0, 1.5, and 2.0 Gy) can
produce a dose-response curve. (2) The test takes approximately three months to complete. Dose-response testing requires
additional time.
ATM serine/threonine kinase activity. The serine/threonine kinase activity of ATM protein can be assessed using
immunoblotting of cell lysates and commercial antibodies to many phosphorylated ATM target substrates. Frequently used
substrates include p53-serine15 (encoded by TP53 gene), ATM-serine1981, KAP1 (encoded by TRIM28 gene) and SMC1serine966 (encoded by SMC1A gene). Cells are first irradiated to create double-strand DNA breaks which activate ATM
serine/threonine kinase. If evaluated within 30 minutes after irradiation, ATM serine/threonine kinase activity is
undetectable in all situations in which ATM protein levels are undetectable.
Note: (1) Cell lysates prepared from patient-derived cell lines established for immunoblot testing for ATM protein or for the
radiosensitivity assay are also used to evaluate ATM protein serine/threonine kinase activity [Chun et al 2003, Nahas et al
2005]. (2) Although ATM serine/threonine kinase activity is difficult to quantify, as a quantitative assay, the kinase activity
constitutes a very important test for evaluating ATM function and identifies rare individuals with A-T with normal or nearnormal amounts of ATM protein that lacks kinase function.

In individuals with kinase-dead ATM protein (such as when associated with the c.7271T>G mutation) ATM
serine/threonine kinase activity is markedly reduced [Stewart et al 2001].
Chromosome analysis. A 7;14 chromosome translocation is identified in 5%-15% of cells in routine chromosomal studies
of peripheral blood of individuals with A-T in which lymphocytes have been stimulated with phytohemagglutinin (PHA)
and harvested at 72 hours. The break points are commonly at 14q11 (the T-cell receptor-alpha locus) and at 14q32 (the Bcell receptor [IGH] locus).
Note: Routine karyotyping may be difficult in individuals with A-T because lymphocytes are decreased in number and do
not respond well to PHA, resulting in no metaphases observed. The difficulty may be partially overcome by adding more
PHA and harvesting the cells at 72 hours instead of 48 hours. Unless interpreted by an experienced cytogeneticist, routing
karyotyping is unreliable for diagnosing A-T and is superfluous to molecular testing.
Heterozygotes (carriers). The new FC-pSMC1 assay utilizes flow cytometry to measure the intranuclear phosphorylation
of SMC1 protein (encoded by SMC1A gene). This assay reports a clear distinction of ATM heterozygotes from normal
individuals and homozygotes [Nahas et al 2009].
Molecular Genetic Testing
Gene. ATM is the only gene known to be associated with ataxia-telangiectasia. Greater than 99% of individuals with classic
A-T have mutations in ATM.
Clinical testing
Sequence analysis. Sequence analysis of the ATM coding region detects about 90% of ATM sequence variants; however,
the functional consequences of variants are often very difficult to interpret. Sequencing may be performed on genomic DNA
or cDNA made from mRNA purified from a lymphoblastoid cell line of the patient; the latter is less costly but not always
available. In general, DNA sequencing for diagnosis of A-T is of lower sensitivity than immunoblotting and is several times
more expensive. Furthermore, intronic mutations and heterozygous deletions of an exon(s) or whole gene are not detected.
Note: The author has experience with one or two individuals in whom neither mutation can be identified despite the absence
of ATM protein [Author, personal observation]. It is estimated that about 10% of persons with A-T have only one ATM
mutation identified using sequence analysis [Author, personal observation]; however, these data are no longer of publication
interest and thus cannot be confirmed.
Deletion/duplication analysis
Of the 600 unique mutations reported, approximately 14 large genomic deletions have been described. By convention,
these are genomic deletions larger than 500 bp and not those involving single exons only.
Only one partial (41-kb) duplication within the ATM gene has been described to date [Cavalieri et al 2006, Cavalieri et al
2008].
It is unknown how many affected individuals in whom only one ATM mutation has been identified by sequence analysis
have actually been tested for deletions or duplications by either array CGH or MLPA.
Targeted mutation analysis is offered for pathologic alleles common in specific ethnic populations (e.g., c.103C>T).
Linkage analysis/ethnic haplotype analysis. Linkage analysis involves testing DNA sequence polymorphisms (normal
variants such as short tandem repeats, [STR]) that are near or within a gene of interest in order to track within a family the
inheritance of a disease-causing mutation in the given gene. In specific well-studied ethnic groups (e.g., Amish, Mennonite,
Costa Rican, Spanish, Brazilian, Polish, British, Russian, Italian, Turkish, Iranian, Israeli), STR analysis at 11q23.1 can be
used to rapidly identify founder haplotypes that are in linkage disequilibrium with known or unknown pathogenic mutations
[Campbell et al 2003, Mitui et al 2003, Coutinho et al 2004]. See Table 2. For previously identified mutations, direct
sequencing from DNA is possible.
Table 1. Summary of Molecular Genetic Testing Used in Ataxia-Telangiectasia
Gene
Mutations
Mutation Detection Frequency by Test
Test Method
Symbol
Detected
Test Method 1
Availability
Sequence analysis gDNA
Sequence analysis cDNA 2
ATM

Deletion/duplication analysis 4

Sequence variants
Sequence variants
Large genomic
deletions
c.103C>T

~90%
~95% 3
Perhaps 1%-2%

Clinical

Targeted mutation analysis

>99% for the c.103C>T mutation
Linkage analysis/ethnic haplotype
See footnote 5
(Not applicable)
analysis
Test Availability refers to availability in the GeneTests Laboratory Directory. GeneReviews designates a molecular genetic
test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed
laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any
aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify
information.
1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. cDNA scanning by PCR amplification of large segments, followed by sequence confirmation on cDNA and then gDNA.
By first scanning cDNA, it is possible to not only detect but to identify the consequences of splicing mutations.
3. Detection frequencies are for the detection of at least one mutant allele per haplotype.
4. Testing that identifies deletions/duplications not readily detectable by sequence analysis of genomic DNA; a variety of
methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or
targeted array GH (gene/segment-specific) may be used. A full array GH analysis that detects deletions/duplications across
the genome may also include this gene/segment. See array GH.
5. A mutation is not detected directly.
Interpretation of test results
For issues to consider in interpretation of sequence analysis results, click here.
Significant difficulties exist in distinguishing polymorphisms from disease-causing missense mutations [Richards et al
2008, Tavtigian et al 2009, Mitui et al 2009].
Testing Strategy
To establish the diagnosis in a proband
1. Assay of ATM protein level. If the ATM protein level by immunoblotting is:
Absent or seen only in trace amounts, a diagnosis of A-T is made.
Greater than trace amounts and the radiosensitivity is normal, a diagnosis of A-T is usually excluded.
Normal and the radiosensitivity assay is abnormal, the ATM serine/threonine kinase activity is tested to determine if a nonfunctional (kinase-dead) ATM protein is present (<1% of individuals with A-T).
Note: The radiosensitivity assay is also informative for identifying those individuals who do not have A-T but may have
another DNA repair disorder.
2. Molecular genetic testing of ATM to identify both disease-causing mutations
Carrier testing for at-risk relatives presently requires prior identification of the disease-causing mutations in the family.
Nahas et al [2009] described a new rapid method for carrier detection using functional flow cytometry that is expected to
become a clinically available test.
Note: Carriers are heterozygotes for this autosomal recessive disorder. Heterozygotes are not at increased risk of developing
A-T neurologic manifestations, but are at a fourfold increased risk of developing breast cancer through mechanisms that are
not understood [Scott et al 2002, Gatti et al 1999].
Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require a firm laboratory
diagnosis of a prior affected family member and either prior identification of the disease-causing mutations in the family or
haplotyping with short tandem repeat (STR) markers if the proband is available to identify the affected haplotype or the
haplotype has been previously identified through family studies.
Genetically Related (Allelic) Disorders
No phenotypes other than classic and non-classic A-T are known to be associated with homozygous or compound
heterozygous mutations in ATM.
Differential Diagnosis
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory
Directory. ED.
Establishing the diagnosis of ataxia-telangiectasia is most difficult in very young children, primarily because all
characteristic features are not yet present.
The most common misdiagnosis is cerebral palsy.
The diagnosis of A-T is questionable when accompanied by severe mental retardation, seizures, non-progressive ataxia, or
microcephaly.
Other disorders with childhood-onset ataxia are discussed in the Ataxia Overview.
A-T-like disorders to consider in the differential diagnosis include:
Nijmegen breakage syndrome (NBS), caused by mutations in NBS1. Note: NBS also includes the phenotype Berlin
breakage syndrome.
Mre11 deficiency, characterized by normal serum AFP concentration, increased radiosensitivity, and ataxia [Stewart et al
1999, Pitts et al 2001]
Ataxia with oculomotor apraxia type 1 (AOA1 or aprataxin deficiency) [Date et al 2001, Moreira et al 2001]
Ataxia with oculomotor apraxia type 2 (AOA2 or senataxin deficiency) [Moreira et al 2004]. Like A-T, AOA2 is associated
with an elevated serum concentration of alpha-fetoprotein.
ADCK3 (aarF-domain-containing kinase 3) childhood-onset gait ataxia with cerebellar atrophy, associated with CoQ10
deficiency [Lagier-Tourenne et al 2008]
Infantile-onset spinocerebellar ataxia (IOSCA) caused by mutations in C10orf2 (previously PEO1) [OMIM 271245]
Sensory ataxic neuropathy with dysarthria and ophthalmoparesis (SANDO), caused by mutations in POLG [OMIM 607459]
X-linked sideroblastic anemia/ataxia, caused by mutations in ABCB7 [OMIM 301310]

Lymphoblastoid cells from individuals with Friedreich ataxia, ataxia with oculomotor apraxia type 1 (AOA1), and ataxia
with oculomotor apraxia type 2 (AOA2) are not typically radiosensitive by CSA [Nemeth et al 2000, Moreira et al 2001,
Nahas et al 2007]. Thus, CSA can be used to distinguish these disorders from A-T.
Although radiosensitivity, as measured by CSA, is often used in the diagnosis of A-T, radiosensitivity is also seen in
Nijmegen breakage syndrome; RAD50 deficiency; X-linked agammaglobulinemia; Fanconi anemia syndrome [Sun et al
2002, Nahas et al 2005, Waltes et al 2009]; ligase IV deficiency [O'Driscoll et al 2001]; and severe combined
immunodeficiency with Cernunnos, Artemis deficiency, DNA-PKcs deficiency, or RNF168 deficiency [Buck et al 2006a,
Buck et al 2006b, Gatti et al 2007, Stewart et al 2007, Stewart et al 2009, van der Burg et al 2009]. Although none of these
disorders is characterized by ataxia or elevated serum concentration of AFP, two individuals with RNF168 deficiency have
recently been described with a syndrome that includes mild ataxia and elevated serum concentration of alphafetoprotein.
The diagnosis of this disorder can be established by identification of microscopic 53BP1 irradiation-induced nuclear foci
[Devgan et al, submitted].
Management
Evaluations Following Initial Diagnosis
To establish the extent of disease in an individual diagnosed with ataxia-telangiectasia (A-T), the following evaluations are
recommended:
Serum alpha-fetoprotein (AFP)
MRI of cerebellum
Chest x-ray and pulmonary function for baseline
Neurologic consultation, including ocular coordination
Karyotype for characteristic t7;14 translocations and leukemic clones
CBC with differential as baseline for screening for leukemia
Diabetes screen (urinalysis, fasting blood glucose concentration, Hgb A1C)
Immune work-up (Immunoglobulin levels, B/T cell levels, T cell function)
Immunoblot for approximate level of ATM protein in nuclear lysates and as an aid in prognosis, family counseling, and
possible later therapy
Note: Liver enzyme levels are often elevated in A-T, without apparent liver pathology. Liver biopsy is usually not necessary.
Treatment of Manifestations
IVIG replacement therapy should be considered for individuals with frequent and severe infections and very low IgG levels
[Nowak-Wegrzyn et al 2004].
Individuals with chronic bronchiectasis require aggressive pulmonary hygiene. However, these therapeutic attempts are
often to no avail in the final stages of the disease [Tangsinmankong et al 2001].
Supportive therapy is available to minimize drooling, choreoathetosis, and ataxia; individual responses to specific
medications vary [Perlman et al 2003].
A wheelchair is usually necessary by age ten years.
Although steroids can 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].
Prevention of Secondary Complications
Early and continued physical therapy minimizes contractures, which appear in almost all individuals with time and lead to
other physical problems.
Prolonged time in a wheelchair, especially the tendency to lean on the same elbow, can produce serious scoliosis, which can
be mitigated by aggressive physical therapy.
Surveillance
Parents should be counseled to monitor for and report to a physician the early warning signs of malignancy (which can
occur at any age), such as weight loss, bruising, and localized pain or swelling.
Immune status needs to be monitored if severe recurrent infections occur or immunomodulatory therapy is in progress.
Agents/Circumstances to Avoid
Because cells from individuals with A-T are 30% more sensitive to ionizing radiation than cells from controls, conventional
doses are potentially lethal in individuals with A-T and the use of radiotherapy and some radiomimetic chemotherapeutic
agents in treatment should be monitored carefully. 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 these
individuals. Before finalizing a therapeutic protocol for cancer in individuals with A-T, the A-T professional community
recommends a consultation with St. Judes Hospital, Department of Oncology [Lavin et al 1999].
Anesthesia carries unique risks in persons with A-T because of the impaired coordination of swallowing, the increased risk
of aspiration, the reduced respiratory capacity, and the propensity to infections [McGrath-Morrow et al 2008].
Testing of Relatives at Risk
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
Therapies Under Investigation
New research suggests the following:

Iron chelators, such as the antioxidant epigallocatechin-3-gallate (EGCG), improve genomic stability of atm-deficient mice
[Shackelford et al 2004].
Although N-acetyl cysteine has also been reported to be effective in atm-deficient mice [Reliene & Schiestl 2006], an
informal clinical trial in patients with A-T showed no improvement [Author, unpublished].
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 theoretical advantage of crossing the blood-brain barrier and
improving mitochondrial function in A-T cells [Ambrose et al 2007].
Maganese-containing superoxide dismutase mimics have a radioprotective effect on A-T cells [Pollard et al 2009].
In culture, aminoglycoside antibiotics can induce small amounts of full-length ATM protein and return of ATM functions to
A-T cells with nonsense mutations [Lai et al 2004]. Non-aminoglycoside readthrough chemicals also induce ATM protein in
A-T cells [Du & Gatti 2009].
Antisense morpholino oligonucleotides (AMOs) induce substantial corrections of ATM protein in patients with certain types
of ATM splicing mutations [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 (CPP) moiety is added to the AMO.
Betamethasone, but not methylprednisilone, has been reported to decrease neurologic symptoms [Buoni et al 2006,
Broccoletti et al 2008]. However, the neurologic improvement, which is accompanied by signs of steroid toxicity,
disappears within days of discontinuation of the steroids. Additional studies are in progress [Gatti 1985, Gatti & Perlman
2009].
Use of insulin-like growth factor 1 treatment for A-T has been suggested [Fernandez et al 2005].
Recent efforts at mutation-targeted therapy have been encouraging [Du et al 2009]. Thus, identifying ATM mutations may
provide new therapeutic opportunities in the near future [Bedwell et al 1997, Wilschanski et al 2003, Lai et al 2004, Du et al
2007, Welch et al 2007, Hu & Gatti 2008, Du & Gatti 2009].
Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.
Other
Any child under 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.
Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural
history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available
consumer-oriented resources. See the GeneTests Clinic Directory.
See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations
have been established for individuals and families to provide information, support, and contact with other affected
individuals.
Genetic Counseling
Mode of Inheritance
Ataxia-telangiectasia is inherited an autosomal recessive manner.
Risk to Family Members
Parents of a proband
The parents are both obligate carriers of an ATM gene mutation.
Heterozygotes (carriers) appear to be at increased risk for cancer and coronary artery disease [Concannon 2002, Spring et al
2002] (see Non-classic forms of ataxia-telangiectasia, Heterozygotes).
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.
Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
Offspring of a proband. Most individuals with A-T do not reproduce.
Other family members of a proband. Each sib of the proband's parents is at a 50% risk of being a carrier.
Carrier Detection
Carrier testing is possible if the disease-causing mutations in the family have been identified. This can also be accomplished
by linkage analysis (i.e., segregation of affected haplotypes) if an affected family member has also been haplotyped.
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 testing is before pregnancy.
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, mutations, and diseases will improve in the future, consideration
should be given to banking DNA of affected individuals. See
for a list of laboratories offering DNA banking.
Prenatal Testing
Prenatal diagnosis for pregnancies at 25% risk is possible by analysis of DNA extracted from fetal cells obtained by
amniocentesis usually performed at about 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at about ten to 12

weeks' gestation. Both disease-causing alleles in the family must be identified or linkage established before prenatal testing
can be performed.
Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual
period or by ultrasound measurements.
Prenatal diagnosis by chromosomal breakage studies or by radio-resistent DNA synthesis (RDS) has proven unreliable in at
least three instances [Author, unpublished] and should be avoided in favor of recent molecular genetic testing approaches.
Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutations have been
identified. For laboratories offering PGD, see