Received: 4 November 2018 | Revised: 29 December 2018 | Accepted: 30 December 2018

DOI: 10.1111/pai.13020

REVIEW ARTICLE

Ataxia‐telangiectasia: A review of clinical features and

molecular pathology

Parisa Amirifar1 | Mohammad Reza Ranjouri2 | Reza Yazdani3,4 |

Hassan Abolhassani3,4,5 | Asghar Aghamohammadi3,4

1
Medical Genetics Department, School of
Medicine, Tehran University of Medical Abstract
Sciences, Tehran, Iran Ataxia‐telangiectasia (A‐T) is an autosomal recessive primary immunodeficiency (PID)
2
Molecular Medicine and Genetics
disease that is caused by mutations in ataxia‐telangiectasia mutated (ATM) gene en‐
Department, School of Medicine, Zanjan
University of Medical Sciences, Zanjan, Iran coding a serine/threonine protein kinase. A‐T patients represent a broad range of
3
Research Center for clinical manifestations including progressive cerebellar ataxia, oculocutaneous telan‐
Immunodeficiencies, Pediatrics Center
of Excellence, Children's Medical Center,
giectasia, variable immunodeficiency, radiosensitivity, susceptibility to malignancies,
Tehran, Iran and increased metabolic diseases. This congenital disorder has phenotypic heteroge‐
4
University of Medical Science, Tehran, Iran neity, and the severity of symptoms varies in different patients based on severity of
5
Division of Clinical Immunology,
mutations and disease progression. The principal role of nuclear ATM is the coordina‐
Department of Laboratory
Medicine, Karolinska Institute at Karolinska tion of cellular signaling pathways in response to DNA double‐strand breaks, oxida‐
University Hospital Huddinge, Stockholm,
tive stress, and cell cycle checkpoint. The pathogenesis of A‐T is not limited to the
Sweden
role of ATM in the DNA damage response (DDR) pathway, and it has other functions
Correspondence
mainly in the hematopoietic cells and neurons. ATM adjusts the functions of orga‐
Asghar Aghamohammadi, Children’s Medical
Center Hospital, Tehran, Iran. nelles such as mitochondria and peroxisomes and also regulates angiogenesis and
Email: [email protected]
glucose metabolisms. However, ATM has other functions in the cells (especially cell
Edited by: Philippe Eigenmann viability) that need further investigations. In this review, we described functions of
ATM in the nucleus and cytoplasm, and also its association with some disorder forma‐
tion such as neurologic, immunologic, vascular, pulmonary, metabolic, and dermato‐
logic complications.

KEYWORDS
ataxia‐telangiectasia, ATM, double‐strand breaks repair, primary immunodeficiency

1 | I NTRO D U C TI O N (1,262 in North America, 251 in Latin America, 696 in Europe, 199
patients in Asia and Oceania, 106 patients in Africa).5
Ataxia‐telangiectasia (A‐T) is an autosomal recessive primary immu‐ A‐T patients represent a broad range of clinical manifestations,
nodeficiency (PID) disease that is caused by mutations in ataxia‐tel‐ including progressive cerebellar ataxia, oculocutaneous telangiec‐
angiectasia mutated (ATM) gene encoding a serine/threonine protein tasia, variable immunodeficiency, radiosensitivity, susceptibility to
kinase. 1,2
ATM is a large protein (∼350 KDa) with critical roles in DNA malignancies, and metabolic disorders.6,7 Other abnormalities such
double‐strand breaks (DBS) repair, genomic stability, cell cycle reg‐ as growth failure, poor pubertal development, insulin resistant di‐
3
ulation, and cell survival. Ataxia‐telangiectasia is reported all over abetes, gonadal atrophy, lung disease, cutaneous abnormality, and
the world with an estimated prevalence of 1:40 000 to 1:100 000. 4 cardiovascular disease have been also reported in A‐T patients.6,8-10
ATM deficiency is the second most common monogenic PID after A‐T patients have a poor prognosis, and their survival time is ap‐
familial Mediterranean fever with 2,514 globally reported patients proximately 25 years. The two most common causes of death in

Pediatr Allergy Immunol. 2019;30:277–288. wileyonlinelibrary.com/journal/pai

© 2019 EAACI and John Wiley and Sons A/S. | 277
Published by John Wiley and Sons Ltd.
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278 | AMIRIFAR et al.

these patients are chronic pulmonary diseases and malignancy.10,11

A‐T patients clinically and para‐clinically (based on laboratory, im‐
Key Message
aging, pathology) manifest remarkable variations, which reflect the
presence of a genotype‐phenotype correlation in these patients Complication of Ataxia‐telangiectasia pathogenesis:
or other genetic/environmental modifying factors. The majority of 1. Nuclear function of ataxia-telangiectasia mutated (ATM)
ATM mutations lead to a truncated protein, while some missense 2. The cytoplasmic function of ATM
and splicing site variations cause milder phenotypes. 12 3. Association of defective ATM with some disorder forma‐
In previous years, several studies have investigated the mecha‐ tion such as neurological, immunological, vascular, pul‐
nisms and pathogenesis of A‐T disease, but there is no comprehen‐ monary, metabolic and dermatological complications
sive article to describe these issues. The aim of this review article
was to describe different mechanisms of ATM in different cell types
and its relationship with corresponding clinical manifestations that is However, DSB repair is regulated based on cell cycle stage and
helpful for better diagnosing and managing A‐T patients. chromatin environment rather than to the nature of the lesion. Such
processes involve mechanisms that transiently or locally modify
chromatin structure to promote DNA repair. DNA DSB occurs at
2 | FU N C TI O N A L M EC H A N I S M S O F ATM heterochromatin, and ATM is crucial for unfolding heterochromatin
due to the accessibility of DNA repair machinery to DSB point. 22
Ataxia‐telangiectasia mutated is the main known gene that is related Ataxia‐telangiectasia mutated facilitates entry of DNA repair
to A‐T clinical phenotype. This gene contains 66 exons (62 of them machinery into heterochromatin by phosphorylation of transcrip‐
are coding) within 150 kb of genomic DNA localized to chromosome tional corepressor Kruppel‐associated box (KRAB)‐associated
11q22‐23. Expression levels of the mRNA and protein have been re‐ protein‐1 (KAP1). 23 KAP‐1 involves in compaction of chromatin by
ported in high level ubiquitously in majority of human organs (mainly interacting with heterochromatin protein 1 (HP1). 24 Therefore, it
detected in nucleoplasm) and cell types, but it is documented in a seems that ATM signaling is necessary to increase DNA repair ma‐
lower status in liver, adipose, and soft tissues.13 chinery access to heterochromatin through transiently or locally
Up to now, more than 500 unique mutations have been known.14 changing its conformation. 22 Furthermore, ATM involves in spe‐
ATM plays a key role in repair of DNA double‐strand breaks. It en‐ cialized DSB repair mechanisms in physiologic conditions such as
codes a large protein that belongs to the phosphatidylinositol (PI) meiotic recombination, the assembly of the T‐cell receptor, and im‐
3/4‐kinase family. The ATM‐ and Rad3‐related kinase (ATR), the munoglobulin (Ig) genes by V(D)J recombination and efficient class
DNA‐dependent protein kinase (DNA‐PK), ATX/SMG‐1, and mTOR/ switch recombination (CSR) in mature B cells. These processes are
FRAP (mammalian target of rapamycin/FKBP‐rapamycin–associated related to important perspectives of A‐T pathogenesis including
protein) are other proteins of this family that has significantly similar immune dysfunction, lymphoma predisposition, and sterility. 25,26
3,15
sequence and functions with ATM. These mammalian PI3K‐like Some studies show that A‐T patients’ cells have short telo‐
protein kinases are known to be involved in responding to DNA dam‐ meres. In these cells, chromosome end‐to‐end association (known
age, except for mTOR/FRAP.16 DNA‐PK is a serine/threonine protein as telomere associations) results in telomere instability, mimicking
kinase composed of a catalytic subunit (DNA‐PKcs) and a targeting cancerous state. It is not clear how telomere stability and ATM are
subunit (the Ku70‐Ku80 heterodimer). This enzyme plays a role in related. However, it has been reported that ectopic expression of
DSBs repair through non‐homologous end‐joining (NHEJ).17,18 human telomerase reverse transcriptase (hTERT) in ATM‐deficient
cells does not improve telomere length, highlighting that ATM
pathway is necessary for telomere maintenance. 27 Telomeric re‐
3 | N U C LE A R FU N C TI O N O F ATM peat‐binding factor 1 (TRF1) is an important downstream substrate
of ATM‐dependent phosphorylation in the telomere maintenance
Ataxia‐telangiectasia mutated is a nuclear serine/threonine protein system. 28 Generally, radiation hypersensitivity of A‐T cells is asso‐
kinase which activates checkpoint signaling upon DSB, apoptosis, ciated with their short telomeres. 29 A study by Kishi et al reported
and genotoxic stresses such as ionizing radiation, thereby acting that Pin2/TRF1 negatively regulates telomere elongation and its
as a DNA damage sensor.19 Generally, an early event during the phosphorylation by ATM following DNA damage appears to sup‐
DNA‐damage response is the monomerization and activation of press apoptosis and decreases the radiosensitivity of cells. These
ATM, leading to rapid phosphorylation of several proteins involved results suggest that ATM phosphorylates Pin2/TRF1 and probably
in DNA repair, cell cycle checkpoint, and transcription. H2AX, as a negatively regulates its function in DNA damage response. 30
molecule involved in DNA repair mechanism, binds to the mediator Nevertheless, most of the clinical manifestations of A‐T patients
of DNA‐damage checkpoint protein‐1 (MDC1) and acts as a scaffold such as telangiectasia, insulin resistance, cardiovascular disease, and
for DDR complex at the breakpoint of DNA. Afterward, MRN com‐ pulmonary diseases with DDR pathway deficiency and nuclear ge‐
plex (MRE11, RAD50, and NBS1) binds to MDC1 and recruits BRCA1 nomic instability are not easily interpretable indicating other func‐
and BRCA2 to the DNA breakpoint. 20,21 tions of ATM (Figure 1).31,32
 13993038, 2019, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/pai.13020 by Universidad De Santiago De Chile, Wiley Online Library on [05/04/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
AMIRIFAR et al. | 279

F I G U R E 1 The role of the ATM signaling in nucleus and cytoplasm. The main role of nuclear ATM is to get involved in the response
to DDR pathway and cell cycle checkpoint. There is an evidence that the ATM pathway is necessary for telomere maintenance and
chromatin compaction change in the nucleus. Moreover, ATM is present as a soluble protein in the cytoplasm that manages the functions
of peroxisomes and mitochondria during oxidative stress response as well as regulating angiogenesis, glucose metabolism, mitochondrial
homeostasis, and autophagy of peroxisomes. ATM, ataxia-telangiectasia mutated; GLUT4, glucose transporter 4; VEGF, vascular endothelial
growth factor; HIF1, hypoxia‐inducible factor‐1; AMPK, AMP‐activated protein kinase; LKB1, liver kinase B1; 4E‐BP1, eukaryotic translation
initiation factor 4E; TSC2, tuberous sclerosis complex 2; mTORC1, mammalian target of rapamycin complex 1; PEX5, peroxisomal biogenesis
factor 5; TRF1, telomeric repeat‐binding factor 1; KAP1, KRAB‐associated protein‐1; HP1, heterochromatin protein 1; H2AX, H2A histone
family member X; MDC1, mediator of DNA damage checkpoint 1; NBS1, Nijmegen breakage syndrome; MRE11, meiotic recombination 11
homolog A

The ATM in accordance with ATR can regulate cell cycle by ex‐ in the DSB repair pathway and cell cycle checkpoint.34,35 However,
erting cell cycle delay, in part, by phosphorylating Checkpoint kinase there is insufficient evidence regarding cytoplasmic ATM function,
(CHK) 1, CHK 2, and p53. The activation of this pathway occurs both which exists in peroxisome and endosome. Peroxisomes get involved
after physiologic and pathologic DNA damages. Phosphorylation on in beta‐oxidation of very‐long‐chain fatty acids (VLCFAs), which
CHK1 (p.S345), CHK2 (p.T68), and p53 (p.S15) following oxidative generate reactive oxygen species (ROS).36 Recently, Zhang et al re‐
damage involved both kinases, and cells exposed can exhibit growth ported a significant new role for ATM in metabolism. They reported
delay in G1, S, and G2 in response to damage and providing time for that ATM signaling at the peroxisome participates in pexophagy
DNA repair.33 (selective autophagy of peroxisomes) through two pathways: First,
ATM is localized at peroxisome by specific import receptors, such as
peroxisomal biogenesis factor 5 (PEX5). In response to excess ROS,
4 | C Y TO PL A S M I C FU N C TI O N O F ATM PEX5 can be phosphorylated and ubiquitinated by ATM. Then, au‐
tophagy adapter p62 recognize ubiquitinated PEX5 and recruit the
Although ATM locates on nuclear protein, there is evidence that in‐ autophagosome to peroxisomes to induce pexophagy. Second, ATM
dicates its presence in the cytoplasm (ranging 10%‐20% in differ‐ activates tuberous sclerosis complex 2 (TSC2) tumor suppressor
ent cells with ATM expression).3 The principal role of nuclear ATM is via the LKB1‐AMPK metabolic pathway in the cytoplasm leading to
 13993038, 2019, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/pai.13020 by Universidad De Santiago De Chile, Wiley Online Library on [05/04/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
280 | AMIRIFAR et al.

suppression of mTORC1 (inhibitor of autophagy) and targeting per‐ 5 | A S S O C I ATE D CO M PLI C ATI O N S I N A‐T
oxisomes for pexophagy (Figure 1). 35
PATI E NT S
One of the characteristics of A‐T patients’ cells is related to
pathways responsive to oxidative DNA damage and ROS are which 5.1 | Neurologic features
always active due to continuous oxidative stress. Therefore, other
In patients with ATM mutations, neurodegenerative processes are
targets of ATM are those involved in oxidative stress metabolism.
the main aspect of clinical manifestation. The progressive neurode‐
In a study on A‐T patients’ cells, lacking ATM function, exhibit
generation and spinocerebellar neurodegeneration usually manifest
alterations in mitochondrial homeostasis. 37,38 In addition, it has
between 6 and 18 months of age. Ataxia often is the first diagnos‐
been demonstrated that in vivo loss of ATM function results in
tic sign that occurs during the toddler years. Beyond the age of
mitochondrial dysfunction in thymocytes and consequently leads
10 years, the movement problems typically cause a child to be con‐
in increased mitochondrial number and mitochondrial ROS pro‐
fined to a wheelchair.47 A‐T patients manifest hallmarks of cerebellar
duction. 39 In fact, mitochondrial dysfunction is related to aging
dysfunction such as truncal swaying, gait ataxia, dyssynergia, muscle
and progressive neurodegenerative disorders such as Alzheimer,
hypotonia, and sudden falls,48 and may have abnormal involuntary
Parkinson, Huntington disease, and Friedreich ataxia.40 There
movements, including chorea, dystonia, dysphagia, athetosis, myo‐
are few studies on how ATM deficiency results in mitochondrial
clonic jerks, or various tremors. Generally, a severe form of chorea
dysfunction. Ambrose et al reported that the level of mitochon‐
and dystonia are observed in 90% of the patients.49,50
drial targeted transcripts in A‐T cells is lower than that of normal
Cerebellar degenerations in A‐T originate from atrophy of the cer‐
cells. The results indicated that the expression of SOD2, POLG,
ebellar vermis and hemispheres involving the dendrites and axons of
TOP1mt, and PRX3, which play a part in mtDNA repair and ROS
Purkinje cells and granule neurons. However, microcephaly is usually not
metabolism, was increased in A‐T cells compared to normal cells,
common in A‐T patients since it is due to progressive accelerated aging
while the expression of CYB5B (an integral outer mitochondrial
process. Magnetic resonance imaging (MRI) studies support the patho‐
membrane electron carrier) was decreased. Elevated expression
logical finding of progressive and diffuse cerebellar degeneration.47,51
of mitochondrial targeted repair proteins may be resulted from a
Intellectual disability is not a common sign in A‐T; however, it occasionally
compensating mechanism in A‐T cells. Because ROS relates mito‐
occurs.52 Abnormal eye movements and visual disturbances caused by
chondrial DNA damaged in A‐T patients, ATM should be consid‐
degeneration of the cerebellar cortex manifesting in A‐T including oculo‐
ered as an important sensor of ROS in human cells. 38 In addition,
motor apraxia, periodic alternating nystagmus (PAN), gaze‐evoked nys‐
Eaton et al presented evidence on the role of ATM in regulating ri‐
tagmus, strabismus, and vestibulo‐ocular (VOR) abnormalities.23,53,54
bonucleotide reductase (related in the de novo synthesis of dNTP)
Up to now, the correlation of neurodegenerative phenotype and ATM
and mitochondrial homeostasis. 37 Considering these results, it can
deficiency remained unsolved, but the hypothesis suggested that ATM
be concluded that ATM has a key role in mitochondrial stability.
is the main player in maintaining cellular homeostasis and preventing dis‐
It has been reported that ATM phosphorylates AKT to regulate
ease in the nervous system. Normal ATM protein may allow neurons to
insulin‐mediated glucose uptake by GLUT4.41,42 In addition, ATM in‐
repair damaged DNA, or initiate apoptosis pathway.55,56 On the other
directly regulates insulin function and glucose metabolism through a
hand, neurodegeneration may be attributable to deficient‐ROS homeo‐
p53‐dependent pathway. Guo et al found that, in human cells, ATM
stasis following dysfunction of ATM in neurons.47 The elevated serum
is activated in the presence of H2O2 and phosphorylates p53.43 It has
alpha fetoprotein (AFP) concentration is a diagnostic marker for diagno‐
been reported that in mouse cells when p53 is not phosphorylated
sis of A‐T patients which have been linked to the mechanism of the neu‐
by ATM, glucose intolerance, and insulin resistance increase.44 One
rodegenerative process (and in parallel the liver). AFP is a plasma protein
other study has demonstrated that ATM phosphorylates Ser111 of a
normally made by the embryonic yolk sac and the fetus hepatocytes. Its
cytoplasmic translational regulatory protein, eIF‐4E‐binding protein
main expression time is during the first three months of development
1 (4E‐BP1), which is necessary for insulin treatment.31
and it subsequently decreases by first years. AFP levels in adult vary for
Additionally, Ousset et al45 showed that lack of ATM results in
age but mostly range from 0 to 40 ng/m.57 The serum AFP level is lower
increased expression of both subunits of hypoxia‐inducible factor 1
in patients with A‐T than with yolk sac‐derived tumors and liver cancers,
(HIF‐1). HIF‐1 is a transcription factor that, in hypoxic condition, in‐
and more similar to the levels observed in hepatitis, but their liver is al‐
creases the expression of vascular endothelial growth factor (VEGF)
most always intact. Therefore, neurologic disease in A‐T patients and a
and glucose transporter type 4 (GLUT‐4) and therefore is involved
decrease in suppressor TP53 (which repress AFP gene expression) are
in angiogenesis and cell metabolism, respectively.46 Subsequently,
the main playmakers for this laboratory indicator.58
overexpression of HIF‐1 in ATM‐deficient cells can explain vascular
Currently, there is no cure for stopping the progression of the
abnormalities like cardiovascular disease, telangiectasia, and tumor
neurologic deficits in patients with A‐T, but clinical trials on glucocor‐
development in A‐T patients. Given ATM multifunctionality, it is
ticoids have recently suggested some promising results. Generally,
necessary to consider every aspect of the disease especially mito‐
the use of physical, occupational, and speech therapies can be help‐
chondrial function during clinical evaluation since the administration
ful to maintain function in the patients, but will not slow the process
of antioxidant adjuvant therapy results in reduced oxidative stress
of neurologic degeneration.59
originating from mitochondrial dysfunction in A‐T patients.
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AMIRIFAR et al. | 281

profile or IgA deficiency manifest minor respiratory infections, while

5.2 | Telangiectasia
A‐T patients with CSRD present severe infections such as otitis
Causes of telangiectasia are related to dilated blood vessels that are media, pneumonia, and mucocutaneous infections along with au‐
manifest primarily in the ocular sclerae, and on sun‐exposed areas toimmunity, hepatosplenomegaly, lymphadenopathy, and neutro‐
of skin (with accelerated levels of pathogenic DSB), especially the penia.66 Furthermore, A‐T patients with CSRD have a more severe
face and ears, but mainly eyes.60 The bulbar telangiectasia findings course of the disease leading to a lower quality of life and shorter
become more prominent by increasing age as well as other ocular survival in earlier ages than other A‐T patients.77
complications strabismus, nystagmus, and poor convergence abil‐ A major problem in A‐T patients is an increased risk of devel‐
ity in A‐T. The ocular telangiectasia does not affect vision though oping autoimmune and/or chronic inflammatory diseases that are
it is sometimes misdiagnosed due to chronic conjunctivitis or al‐ associated with selective IgA deficiency. Interestingly, low levels
lergy in context of immunodeficiency and immunodysregulation.61 of IgA have been reported as a risk factor or biomarker for the
Telangiectasia within the bulbar conjunctiva over the exposed development of lymphoid cancers in A‐T.73 These risks in pa‐
sclera of the eyes mainly appear before 10 years old, but sometimes tients with A‐T are likely a secondary effect of their immune de‐
60
it may be appeared later or not at all. The pathophysiologic basis ficiency and not directly related to the lack of ATM protein, as
of telangiectasia in A‐T patients has not fully understood. However, early onset cancer is organ‐specific. Defective cell cycle control
it has been postulated that oculocutaneous telangiectasias in A‐T and increased rate of infection (oncogenic viruses such as EBV in‐
patients are associated with vascular abnormalities due to HIF‐1 fection) can increase the susceptibility of ATM patients to cancer,
overexpression. As it has been mentioned, ATM dysfunction is as‐ and vice versa, chemotherapy for cancer treatment can deteriorate
sociated with an increased expression of HIF‐1 protein. In hypoxic immunodeficiency.78
condition, the HIF‐1 overexpression leads to increase the expres‐ The mechanism that ATM dysfunction leads to immunodefi‐
sion of HIF‐1 target genes such as VEGF that is a potent angiogenic ciency is not entirely understood, and there are probably multiple
factor.45 mechanisms involved in. Fundamentally, A‐T is a PID disease involv‐
ing both cellular and humoral immune systems. This defect can be
explained by the role of ATM protein in DNA damage responses.79,80
5.3 | Immunodeficiency
It has been recognized that ATM plays a critical role in DNA DSB
PID is observed in approximately 70% of individuals with A‐T due to recognition and repair during rearrangement of T‐cell receptor and
impaired antigen receptor recombination and CSR. Generally, B‐ or immunoglobulin CSR.82,83 On the other hand, it has been postulated
T‐cell lymphopenia, decreased CD8+ and/or CD4+ T cells, deficiency that chromosomal translocation in the regions of chromosomes 7
of antibody production, selective IgA deficiency, hypogammaglobu‐ and 14 that are associated with T‐cell receptors and heavy‐chain im‐
linemia, and IgG subclass deficiency are frequent findings in A‐T pa‐ munoglobulin coding regions may be involved in immunodeficiency
tients.62 Defective cell‐mediated immunity is found in almost all A‐T in A‐T patients.82
63
patients, whereas deficiency in humoral immunity is more variable. In addition, defects in thymic structure and a reduction in naive
The most common deficiencies of cellular immunity are lymphope‐ CD4+ T‐cell numbers have also been observed in A‐T patients.84
nia with reduced number and function of CD4+ T lymphocytes.64 The Since ATM regulates the response to oxidative stress and protects
most common abnormalities in humoral immunity of AT patients are thymocytes against apoptosis, thymic dysfunction may be caused
related to decreased or absent of serum IgA, IgE, IgG2 and IgG4 lev‐ by oxidative stress effects following the loss of ATM function. It has
els, deficiency of specific antibody responses, and gammopathy65 A‐T been demonstrated that naive T cells may be more susceptible than
patients based on serum immunoglobulin (Ig) profile are classified into other T cells in this condition.85
normal immunoglobulin level, selective IgA deficiency, hypogamma‐ It has been reported that low levels of ROS may be involved in
globulinemia, and hyper‐IgM.66 The most frequent defect in immu‐ amplifying signaling in activated T cells, as high levels of ROS are
noglobulin profile is related to IgA and IgG2 deficiencies, which are critical for activation‐induced cell death.86,87 Moreover, previous an‐
diminished in 50% and 80% of cases, respectively.67,68 However, sev‐ imal model research suggested that ATM plays a critical role in T‐cell
eral A‐T cases were reported in whom immunoglobulin class switch proliferation by controlling responses to ROS due to T‐cell activa‐
recombination defect (CSRD) was indicated.69,70 In our previous study tion. Thus, ROS production leads to the induction of apoptosis in
performed in 2017, we showed that 21.2% of AT patients revealed the absence of ATM function. Accordingly, the molecular basis of
66
immunoglobulin CSRD. Since some clinical features of A‐T such immunodeficiency in A‐T might be caused by defective responses to
as ataxic gait and dysarthric speech might not be present in infancy, ROS production in ATM‐deficient T cells.85
the diagnosis of these patients can become misclassify as hyper‐IgM
syndrome.73
5.4 | Pulmonary disease
It has been estimated that almost 80% of A‐T patients suffer from
infections.74,75 Generally, the most common manifestation of immu‐ Pulmonary diseases are manifested in more than 70% of patients
nodeficiency in A‐T is sinopulmonary infections that often be mani‐ with A‐T and mostly progress by increasing age and neurologic de‐
fested early in the life.8,67 A‐T patients with normal immunoglobulin terioration. Respiratory diseases are the major cause of morbidity
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282 | AMIRIFAR et al.

and mortality among A‐T patients,8,11 as 50% of patients die in ado‐ esophageal carcinomas. 59 B‐cell non‐Hodgkin lymphoma (NHL)
lescence from respiratory failure.88 The pathogenic mechanisms of and Hodgkin lymphoma (HL) have also been reported frequently
lung diseases in these patients are rather ambiguous. It has been in A‐T patients.98,99 Another factor that may contribute to malig‐
postulated that combined immunodeficiency, abnormal injury repair, nancies (such as HL and B‐cell NHL) is Epstein‐Barr virus (EBV).
premature aging, systemic inflammation, and oxidative stress are A‐T populations demonstrate a pattern of anti‐EBV antibodies
89
related to the pathophysiology of lung disease. Several of these that may be associated with a perturbed regulation of EBV la‐
mechanisms related to disease progression due to recurrent infec‐ tency in B cells. EBV rate is higher in A‐T patients due to cel‐
tions,67 emphysema, cough ineffectiveness, and abnormal airway lular immunodeficiency and pronounced DNA repair defects via
clearance and oropharyngeal dysphagia.90,91 Generally, there are viral nuclear antigen interference on the remaining DNA repair
three major types of lung diseases in A‐T patients, including recur‐ machinery components.100 Despite the poor prognosis of cancer
rent sinopulmonary infections and bronchiectasis, interstitial lung in A‐T, some reports suggest that patients achieving a major re‐
disease (ILD)/pulmonary fibrosis, and neuromuscular disorders af‐ sponse to treatment may have an increased survival. However, it
fecting respiratory function.8,67,91 should be noted that because of the high sensitivity of A‐T's cells,
Recurrent sinopulmonary manifestations are associated with use of some chemotherapeutic agents and ionizing radiation can
both immunologic and neurologic manifestations, but there is no di‐ prove especially cytotoxic in A‐T patients who require careful and
rect correlation between the severity of neurodegeneration and pul‐ cautious monitoring.73
80
monary disease. It has been demonstrated that defective cellular It has been indicated that heterozygous ATM mutations lead to
and humoral immune system lead to increased susceptibility of A‐T an increased risk of developing breast cancer, with an estimated risk
patients to recurrent sinopulmonary infections.88 The most related of 5.1 over that in the general population and without any evidence
humoral immunodeficiencies in patients with respiratory infections for an increased risk of lymphoid malignancies.101,102 Recent reports
92
are decreased or absent serum IgG2 and defect in CSR. As above suggest that the breast cancer risk in carriers of ATM mutation by
mentioned, ATM involves in assembly of the T‐cell receptor and im‐ the age of 50 years is about 6%‐9% and by the age of 80 years is
munoglobulin (Ig) genes by V(D)J recombination and efficient class about 33%.103,104 Moreover, some results demonstrated that ATM
switch recombination (CSR) in mature B cells. Thus, ATM dysfunc‐ monoallelic defects are breast cancer susceptibility markers, with
tion can lead to pulmonary complications through immunodeficien‐ an estimated relative risk of ~3%.105,106 Although there is insuffi‐
cies like hypogammopathies. cient evidence that demonstrates ATM heterozygotes could increase
Children and young adults with A‐T are at increased risk for sec‐ the risk of other cancers, there are some studies suggesting an in‐
ondary pulmonary lymphoma, and may clinically and radiographically creased risk of stomach and colorectal cancers.107 Nevertheless,
93
imitate ILD. Also, chemotherapy for the management of malignancy additional researches are needed to elucidate the risk of malignan‐
in A‐T patients leads to an increased risk of developing pulmonary cies and other conditions among ATM mutation carriers. Up to now,
fibrosis.94 Some clinical aspects of pulmonary diseases in A‐T pa‐ an association of ATM mutations with breast cancer susceptibility
tients can be related to progressive neuromuscular deficits. Bulbar has been not universally accepted by immunologists and oncolo‐
muscle dysfunction can result in dysphagia (swallowing difficulties) gists. Furthermore, most large cancer cohort studies have recog‐
91
and chronic aspiration that can cause or deteriorate lung disease. nized mainly missense mutations and few nonsense mutations (15%
Pulmonary function tests (PFTs) would be useful in detecting nonsense vs 85% missense), whereas ATM missense variants in
early lung failure in A‐T. The identification of strategies that limit the patients with A‐T only are uncommon (90% nonsense vs 10% mis‐
development and progression of lung diseases can also ameliorate sense).108,109 Previous studies suggest that the heterozygous ATM
the quality of life (QOL) and increase life expectancy until discovery mutation identified in breast cancer patients shares few variants
and development of therapeutic interventions.90 with A‐T patients.105,108 Therefore, long‐term follow‐up of carriers in
relatives of A‐T patients can indicate the role of these truncating mu‐
tations compared with less severe variants in breast cancer patients.
5.5 | Cancer predisposition
Cancer screening guidelines are developing for ATM mutation carri‐
A‐T is categorized as genomic instability syndrome, disorders ers. Recently, the National Comprehensive Cancer Network (NCCN)
that often result in a heightened predisposition to malignancy. recommended that ATM mutation carrier women should start breast
A‐T patients show potentially an increased risk of cancer, ranging cancer screening with yearly breast MRI and mammogram and also
from 10% to 25% mainly due to the immunodeficiency described that both male and female ATM mutation carriers should start colon
above.73,95,96 The most prevalent types of malignancy in A‐T pa‐ cancer screenings with a colonoscopy (every 3‐5 years compared to
tients with a lower age of 20 years are leukemia and lymphoma every 10 years for the general population).112
(most notably T‐cell acute lymphoblastic leukemias [ALLs] and
T‐cell prolymphocytic leukemia [T‐PLL]). These two types of can‐
5.6 | Cutaneous abnormality
cers account for 85% of all malignancy in childhood,97 but adults
are susceptible to both lymphoid tumors and different types of Non‐infectious cutaneous granulomas with unknown pathogen‐
solid tumors including breast, gastric, liver, parotid gland, and esis occur uncommonly in various PID disorders like A‐T.113 Chronic
 13993038, 2019, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/pai.13020 by Universidad De Santiago De Chile, Wiley Online Library on [05/04/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
AMIRIFAR et al. | 283

cutaneous granulomas manifest in almost 10% of A‐T patients. These A‐T is associated with dysglycemia and reduced insulin sensitivity.122
lesions have not been related to a specific pathogen, but some‐ Based on these observations, it is likely that ATM is directly related
times can be associated with painful ulceration and bleeding.114 to glucose and insulin metabolic pathways.
Dermal wound healing is a complex biological process that involves
inflammation, migration of keratinocytes, and tissue remodeling. T
5.8 | Other complications
cells, B cells, and various growth factors work together for healing
process.115 The vascular disease could be manifested with high risk in patients
A recent report suggests that a subset of A‐T patients with hyper‐ with ATM homozygotes mutation, while this risk is lower in patients
IgM phenotype is more likely to develop cutaneous granulomas. These with ATM heterozygotes. Beside telangiectasia in ATM homozygotes
findings show that all A‐T patients with the cutaneous granulomas had (with key features of premature aging and impaired ROS signaling
a significantly reduced CD19+ B‐cell and CD3+CD4+CD45RA+ naive forming of aberrant vascular structures due to increase pro‐angio‐
T‐cell counts in the presence of normal total NK and T cells.114 CD19, genic factors), it has been demonstrated that patients with ATM
a critical positive‐response regulator of B cells, plays a fundamental heterozygotes mutations have increased the risk of death associated
role in wound healing as is shown by the observation that CD19 defi‐ with cardiovascular disease.10 This may be related also to mitochon‐
116
ciency in mice stopped cutaneous wound healing. Other common drial dysfunction and/or other basic defects due to ATM dysfunction
skin abnormalities associated with A‐T include seborrheic dermatitis such as angiogenesis pathway.
and skin and hair pigmentation changes.117 Hair greying is caused by Infertility is described as one of the features of A‐T mouse mod‐
127,128
the incomplete maintenance of melanocyte stem cells (MSCs) with els. In humans, infertility is gonadal atrophy, early menopause,
age. Astonishingly, DNA damage and genomic instability cause MSC and premature ovarian failure. It has been postulated that defect in
differentiation which produces greying. Furthermore, deficiency of DSB repair system due to loss of ATM can induce meiotic defects
ATM sensitizes MSCs to ectopic differentiation, demonstrating that and arrest that probably be associated with gonadal dysgenesis.129
ATM acts as a “stemness checkpoint” protecting against MSC differ‐ Some A‐T patients suffer from bladder and/or bowel inconti‐
entiation and premature greying of the hair.114 nence, recurrent vomiting especially in the morning, and decreased
Non‐infectious cutaneous granulomatous might hardly be treated. sleep efficiency and dizziness that may connect with neurologic
Nonetheless, high potency topical corticosteroids and cyclosporine A complications.59 These patients can also have an increased preva‐
can be used for healing of small superficial ulceration.59 In addition, lence of vitiligo, and warts, may be due to impairment of the immune
more considerable non‐infectious granulomas may respond to fuma‐ system, that can be extensive and recalcitrant to treatment.67
118
ric acid esters (FAE), systemic inhibitors of tumor necrosis factor
(TNF‐alpha),119 direct injection of steroids into the site of the granu‐
lomatous ulceration,120 and combination therapy such as topical ste‐ 6 | D I FFE R E NTI A L D I AG N OS I S
roids with concurrent immunoglobulin replacement therapy.121
There are some rare disorders that can be misdiagnosis with A‐T
based on similar clinical and laboratory features. Other disorders
5.7 | Insulin resistance and metabolic disorders
with childhood‐onset ataxia include ataxia‐telangiectasia‐like dis‐
A minority of A‐T patients suffer from insulin resistant diabetes during order 2 (ATLD2), ataxia oculomotor apraxia type 1 (AOA1), ataxia
disease progression. However, increased glycaemia and decreased in‐ oculomotor apraxia type 2 (AOA2), RIDDLE syndrome (RNF168
sulin sensitivity may be observed in patients with A‐T who do not have deficiency), and spinocerebellar ataxia with axonal neuropathy
122
diabetes. It has been demonstrated that insulin signaling leads to (SCAN1). In children, it is important to distinguish ataxia from an
ATM‐dependent phosphorylation of 4E‐BP1 that is an insulin‐respon‐ unsteady gait because of immaturity or muscle weakness. Of note,
sive cytoplasmic protein.31 Other studies have been reported that the immune deficiency is one of the common symptoms of Nijmegen
lack of ATM in Atm‐deficient mice and in patients with A‐T effect on breakage syndrome (NBS, with birds like face and microcephaly)
insulin and insulin‐like growth factor 1 (IGF‐1), demonstrating a signifi‐ and ataxia‐telangiectasia‐like disorder 1 (ATLD1, due to MRE11 de‐
cant role of functional protein in glucose and insulin metabolism.123,124 ficiency) that can be confused with A‐T. Regarding similar laboratory
Therefore, the use of insulin‐like growth factor 1 (IGF‐1) treatment has features, increased serum AFP has been observed in A‐T, AOA2, and
been recommended for A‐T patients.125 RIDDLE syndrome. Thus, knowing gene mutation along with the
Metformin (oral antihyperglycemic medication) is suggested presence of ataxia, immunodeficiency, telangiectasia, radiosensitiv‐
as the first‐line therapy for patients with type 2 diabetes mellitus. ity, and increased AFP could differentiate A‐T from other disorders
Interestingly, the results of the genome‐wide association study iden‐ with childhood‐onset ataxia. However, ESID criteria clarify the di‐
tified an association between the single nucleotide polymorphism agnosis of A‐T disorder based on ataxia and at least two of the fol‐
(SNP) of ATM gene and metformin glycemic response in diabetic pa‐ lowing: oculocutaneous telangiectasia, elevated alpha fetoprotein,
tients.126 In one recent study, the role of ATM in glucose metabo‐ and lymphocyte AT karyotype with t (7;14) and hypoplasia on MRI. A
lism was investigated by performing an oral glucose tolerance test in comparison of the clinical and laboratory features of these disorders
participants with A‐T and healthy controls. This report suggests that is shown in Table 1.
 13993038, 2019, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/pai.13020 by Universidad De Santiago De Chile, Wiley Online Library on [05/04/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
284 | AMIRIFAR et al.

TA B L E 1 Clinical and laboratory features of some genetic disorders that can be misdiagnosed with A‐T (reviewed in Ref. 58 and 134)

Disorders Gene Ataxia Immunodeficiency Telangiectasia Radiosensitivity Malignancy Alpha fetoprotein

A‐T ATM Yes Yes Yes Yes Yes High

ATLD1 MRE11 Yes No No Yes Unknown Normal
ATLD2 PCNA Yes No Yes ‐ Yes Normal
AOA1 APTX Yes No No Yes No Normal
AOA2 SETX Yes No No No No High
NBS NBS1 No Yes No Yes Yes Normal
RIDDLE RNF168 Yes Yes Yes Yes ‐ High

7 | M A N AG E M E NT A N D TR E ATM E NT randomized phase II clinical trial examining the efficacy of olaparib for
gastric cancer with improving the level of ATM expression suggesting
Hematopoietic stem cell transplantation (HSCT) showed a success‐ a modality for heterozygous carriers predisposing with malignancy.144
ful preliminary outcome on lymphoma and even neurologic condition
of Atm‐deficient animal models.130,131 Nonetheless, allogeneic HSCT
7.4 | Mitochondrial abnormality
and pre‐emptive alloHSCT have been performed as potential thera‐
peutic modality in few A‐T patients132,133 resulting in a poor survival Nutritional antioxidants (eg, vitamin E and alpha‐lipoic acid) have
rate of 25% during 3‐year follow‐up.135,136 Furthermore, the most de‐ been recommended for A‐T patients because of improving mito‐
bilitating feature of A‐T is the progressive neurodegeneration due to chondrial function.38
loss of Purkinje cells and malfunction of other neuronal cells, but the‐
oretically HSCT is unable to cure neurodegenerative phenotype of
this disorder.137 Although no effective treatment is available for A‐T, 8 | CO N C LU S I O N S
some medications may be useful in the management of symptoms.
Reviewing clinical complications of A‐T, including progressive neuro‐
degenerative, oculocutaneous telangiectasia, radiosensitivity, vari‐
7.1 | Immunodeficiency
able immunodeficiency with increased predisposition to infections,
More than 50% of PIDs are due to impaired antibody production. Life and susceptibility to malignancies, indicate DNA repair pathway and
expectancy is reduced, and recurrent infections cause significant mor‐ ROS signaling as two main functions of ATM. Generally, this con‐
bidity and disability because of complications from chronic pulmonary genital disorder has phenotypic heterogeneity, and the severity of
disease and autoimmune disorders. The life span of A‐T patients could symptoms varies in different patients and in different ages. On the
potentially be prolonged by immunoglobulin replacement therapy and other hand, deciphering ATM's functions in nucleus and cytoplasm
antibiotic treatment.138 Also, vaccination against common bacterial res‐ can help researchers better understand the pathogenesis of A‐T and
piratory pathogens such as hemophilus influenzae, influenza viruses, other ATM‐related diseases such as cancers.
and pneumococci improves the status of immunity in these patients.67 The current evidence could no strongly relevant result of exper‐
imental contexts to what happens in a living cell/tissue/organism
due to the largely unexplained nature of the pathogenesis of A‐T.
7.2 | Neurologic problems
Findings identified in vitro provide first step in the development of
Use of pharmacotherapeutic interventions including amantadine, medical hypothesis and scientific breakthroughs and subsequently
fluoxetine, buspirone, trihexyphenidyl,137,139 baclofen,140 and clon‐ may help in clarification of the role of ATM in presenting clinical
azepam141 can decrease neurologic manifestations in A‐T. Also, glu‐ complications. Understanding different roles of defective ATM in
cocorticoids (especially dexamethasone and betamethasone) have clinical manifestations in AT patients could be helpful in determining
been reported to improve neurologic symptoms in A‐T.142 However, better diagnosis and also treatment of the patients.
this type of drugs can increase the frequency of infections in reduc‐
ing inflammatory and immune responses.
C O N FL I C T O F I N T E R E S T S

The authors declare that there was no conflict of interest.

7.3 | Cancer
Radiation therapy and chemotherapeutic agents utilized for treating
AU T H O R S ' C O N T R I B U T I O N
A‐T patients with cancer. However, since these treatments are cy‐
totoxic143; thus, the use of this therapeutic must be monitored very PA conceived of the presented idea. PA and MRR. participated in the
carefully. Recently, poly (ADP‐ribose) polymerase inhibitor has passed collection of information. PA and MRR. contributed to the writing
 13993038, 2019, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/pai.13020 by Universidad De Santiago De Chile, Wiley Online Library on [05/04/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
AMIRIFAR et al. | 285

of the manuscript. HA and RY contributed to the final version of the 21. O'Neill T, Dwyer AJ, Ziv Y, et al. Utilization of oriented peptide
manuscript. AA supervised the project. libraries to identify substrate motifs selected by ATM. J Biol Chem.
2000;275:22719‐22727.
22. Goodarzi AA, Jeggo P, Lobrich M. The influence of heterochroma‐
tin on DNA double strand break repair: getting the strong, silent
ORCID
type to relax. DNA Repair. 2010;9:1273‐1282.
Asghar Aghamohammadi http://orcid.org/0000-0002-9454-1603 23. Lewis RF, Lederman HM, Crawford TO. Ocular motor abnormali‐
ties in ataxia telangiectasia. Ann Neurol. 1999;46:287‐295.
24. Matsuda E, Agata Y, Sugai M, Katakai T, Gonda H, Shimizu A.
Targeting of Kruppel‐associated box‐containing zinc finger pro‐
REFERENCES
teins to centromeric heterochromatin. Implication for the gene
1. Chaudhary MW, Al‐Baradie RS. Ataxia‐telangiectasia: future pros‐ silencing mechanisms. J Biol Chem. 2001;276:14222‐14229.
pects. Appl Clin Genet. 2014;7:159‐167. 25. Alvarez‐Quilon A, Serrano‐Benitez A, Lieberman JA, et al. ATM
2. Gatti RA, Berkel I, Boder E, et al. Localization of an ataxia‐telangiec‐ specifically mediates repair of double‐strand breaks with blocked
tasia gene to chromosome 11q22‐23. Nature. 1988;336:577‐580. DNA ends. Nat Commun. 2014;5:3347.
3. Lavin MF. Ataxia‐telangiectasia: from a rare disorder to a paradigm 26. Bednarski JJ, Sleckman BP. Lymphocyte development: in‐
for cell signalling and cancer. Nat Rev Mol Cell Biol. 2008;9:759‐769. tegration of DNA damage response signaling. Adv Immunol.
4. Swift M, Morrell D, Cromartie E, Chamberlin AR, Skolnick MH, 2012;116:175‐204.
Bishop DT. The incidence and gene frequency of ataxia‐telangiec‐ 27. Simonsen JL, Rosada C, Serakinci N, et al. Telomerase expression
tasia in the United States. Am J Hum Genet. 1986;39:573‐583. extends the proliferative life‐span and maintains the osteogenic
5. Modell V, Orange JS, Quinn J, Modell F. Global report on pri‐ potential of human bone marrow stromal cells. Nat Biotechnol.
mary immunodeficiencies: 2018 update from the Jeffrey Modell 2002;20:592‐596.
Centers Network on disease classification, regional trends, treat‐ 28. Kishi S, Lu KP. A critical role for Pin2/TRF1 in ATM‐dependent reg‐
ment modalities, and physician reported outcomes. Immunol Res. ulation. Inhibition of Pin2/TRF1 function complements telomere
2018;66:367‐380. shortening, radiosensitivity, and the G(2)/M checkpoint defect of
6. Nissenkorn A, Levy‐Shraga Y, Banet‐Levi Y, Lahad A, Sarouk I, ataxia‐telangiectasia cells. J Biol Chem. 2002;277:7420‐7429.
Modan‐Moses D. Endocrine abnormalities in ataxia telangiectasia: 29. Metcalfe JA, Parkhill J, Campbell L, et al. Accelerated telomere
findings from a national cohort. Pediatr Res. 2016;79:889‐894. shortening in ataxia telangiectasia. Nat Genet. 1996;13:350‐353.
7. Teive HA, Moro A, Moscovich M, et al. Ataxia‐telangiectasia ‐ A 30. Kishi S, Zhou XZ, Ziv Y, et al. Telomeric protein Pin2/TRF1 as an
historical review and a proposal for a new designation: ATM syn‐ important ATM target in response to double strand DNA breaks. J
drome. J Neurol Sci. 2015;355:3‐6. Biol Chem. 2001;276:29282‐29291.
8. Bott L, Lebreton J, Thumerelle C, Cuvellier J, Deschildre A, 31. Yang DQ, Kastan MB. Participation of ATM in insulin signalling
Sardet A. Lung disease in ataxia‐telangiectasia. Acta Paediatr. through phosphorylation of eIF‐4E‐binding protein 1. Nat Cell Biol.
2007;96:1021‐1024. 2000;2:893‐898.
9. Schalch DS, McFarlin DE, Barlow MH. An unusual form of 32. Schneider JG, Finck BN, Ren J, et al. ATM‐dependent suppres‐
diabetes mellitus in ataxia telangiectasia. New Engl J Med. sion of stress signaling reduces vascular disease in metabolic syn‐
1970;282:1396‐1402. drome. Cell Metab. 2006;4:377‐389.
10. Su Y, Swift M. Mortality rates among carriers of ataxia‐telangiec‐ 33. Helt CE, Cliby WA, Keng PC, Bambara RA, O'Reilly MA. Ataxia
tasia mutant alleles. Ann Intern Med. 2000;133:770‐778. telangiectasia mutated (ATM) and ATM and Rad3‐related protein
11. Crawford TO, Skolasky R, Fernandez R, Rosquist K, Lederman exhibit selective target specificities in response to different forms
H. Survival probability in ataxia telangiectasia. Arch Dis Child. of DNA damage. J Biol Chem. 2005;280:1186‐1192.
2006;91:610‐611. 34. Watters D, Kedar P, Spring K, et al. Localization of a portion of extra‐
12. Gilad S, Chessa L, Khosravi R, et al. Genotype‐phenotype rela‐ nuclear ATM to peroxisomes. J Biol Chem. 1999;274:34277‐34282.
tionships in ataxia‐telangiectasia and variants. Am J Hum Genet. 35. Zhang J, Tripathi DN, Jing J, et al. ATM functions at the peroxi‐
1998;62:551‐561. some to induce pexophagy in response to ROS. Nat Cell Biol.
13. Uhlen M, Fagerberg L, Hallstrom BM, et al. Proteomics. Tissue‐based 2015;17:1259‐1269.
map of the human proteome. Science. 2015;347:1260419‐1260419. 36. Reddy JK, Hashimoto T. Peroxisomal beta‐oxidation and peroxi‐
14. Gatti RA, Becker‐Catania S, Chun HH, et al. The pathogenesis of some proliferator‐activated receptor alpha: an adaptive metabolic
ataxia‐telangiectasia. Clin Rev Allergy Immunol. 2001;20:87‐108. system. Annu Rev Nutr. 2001;21:193‐230.
15. Shiloh Y. ATM and related protein kinases: safeguarding genome 37. Eaton JS, Lin ZP, Sartorelli AC, Bonawitz ND, Shadel GS. Ataxia‐tel‐
integrity. Nat Rev Cancer. 2003;3:155‐168. angiectasia mutated kinase regulates ribonucleotide reductase and
16. Durocher D, Jackson SP. DNA‐PK, ATM and ATR as sensors mitochondrial homeostasis. J Clin Investig. 2007;117:2723‐2734.
of DNA damage: variations on a theme? Curr Opin Cell Biol. 38. Ambrose M, Goldstine JV, Gatti RA. Intrinsic mitochondrial dys‐
2001;13:225‐231. function in ATM‐deficient lymphoblastoid cells. Hum Mol Genet.
17. Smith GC, Jackson SP. The DNA‐dependent protein kinase. Genes 2007;16:2154‐2164.
Dev. 1999;13:916‐934. 39. Valentin‐Vega YA, MacLean KH, Tait‐Mulder J, et al. Mitochondrial
18. Gottlieb TM, Jackson SP. The DNA‐dependent protein kinase: dysfunction in ataxia‐telangiectasia. Blood. 2012;119:1490‐1500.
requirement for DNA ends and association with Ku antigen. Cell. 40. Kwong JQ, Beal MF, Manfredi G. The role of mitochondria in inher‐
1993;72:131‐142. ited neurodegenerative diseases. J Neurochem. 2006;97:1659‐1675.
19. Bakkenist CJ, Kastan MB. DNA damage activates ATM through in‐ 41. Summers SA, Birnbaum MJ. A role for the serine/threonine ki‐
termolecular autophosphorylation and dimer dissociation. Nature. nase, Akt, in insulin‐stimulated glucose uptake. Biochem Soc Trans.
2003;421:499‐506. 1997;25:981‐988.
20. Kim ST, Lim DS, Canman CE, Kastan MB. Substrate specificities 42. Viniegra JG, Martinez N, Modirassari P, et al. Full activation of
and identification of putative substrates of ATM kinase family PKB/Akt in response to insulin or ionizing radiation is mediated
members. J Biol Chem. 1999;274:37538‐37543. through ATM. J Biol Chem. 2005;280:4029‐4036.
 13993038, 2019, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/pai.13020 by Universidad De Santiago De Chile, Wiley Online Library on [05/04/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
286 | AMIRIFAR et al.

43. Guo Z, Kozlov S, Lavin MF, Person MD, Paull TT. ATM activation by 66. Ghiasy S, Parvaneh L, Azizi G, et al. The clinical significance of
oxidative stress. Science (New York, NY). 2010;330:517‐521. complete class switching defect in Ataxia telangiectasia patients.
44. Armata HL, Golebiowski D, Jung DY, Ko HJ, Kim JK, Sluss HK. Exp Rev Clin Immunol. 2017;13:499–505.
Requirement of the ATM/p53 tumor suppressor pathway for glu‐ 67. Nowak‐Wegrzyn A, Crawford TO, Winkelstein JA, Carson KA,
cose homeostasis. Mol Cell Biol. 2010;30:5787‐5794. Lederman HM. Immunodeficiency and infections in ataxia‐telan‐
45. Ousset M, Bouquet F, Fallone F, et al. Loss of ATM positively regu‐ giectasia. J Pediatr. 2004;144:505–511.
lates the expression of hypoxia inducible factor 1 (HIF‐1) through 68. Stray‐Pedersen A, Jonsson T, Heiberg A, et al. The impact of an
oxidative stress: role in the physiopathology of the disease. Cell early truncating founder ATM mutation on immunoglobulins, spe‐
cycle (Georgetown, Tex). 2010;9:2814‐2822. cific antibodies and lymphocyte populations in ataxia‐telangiecta‐
46. Schofield CJ, Ratcliffe PJ. Oxygen sensing by HIF hydroxylases. sia patients and their parents. Clin Exp Immunol. 2004;137:179–186.
Nat Rev Mol Cell Biol. 2004;5:343. 69. Etzioni A, Ben‐Barak A, Peron S, Durandy A. Ataxia‐telangiectasia
47. Hoche F, Seidel K, Theis M, et al. Neurodegeneration in ataxia in twins presenting as autosomal recessive hyper‐immunoglobulin
telangiectasia: what is new? What is evident? Neuropediatrics. M syndrome. Isr Med Assoc J. 2007;9:406–407.
2012;43:119‐129. 70. Noordzij JG, Wulffraat NM, Haraldsson A, et al. Ataxia‐telangiec‐
48. Boder E, Sedgwick RP. Ataxia‐telangiectasia. (Clinical and immuno‐ tasia patients presenting with hyper‐IgM syndrome. Arch Dis Child.
logical aspects). Psychiatr Neurol Med Psychol Beih. 1970;13‐14:8‐16. 2009;94:448–449.
49. Shaikh AG, Zee DS, Mandir AS, Lederman HM, Crawford TO. 71. Aghamohammadi A, Imai K, Moazzami K, et al. Ataxia‐telangiec‐
Disorders of upper limb movements in ataxia‐telangiectasia. PLoS tasia in a patient presenting with hyper‐immunoglobulin M syn‐
ONE. 2013;8:e67042. drome. J Investig Allergol Clin Immunol. 2010;20:442–445.
50. Pearson TS. More than ataxia: hyperkinetic movement disorders 72. Mohammadinejad P, Abolhassani H, Aghamohammadi A, et
in childhood autosomal recessive ataxia syndromes. Tremor Other al. Class switch recombination process in ataxia telangiecta‐
Hyperkinet Mov (NY). 2016;6:368. sia patients with elevated serum levels of IgM. J Immunoassay
51. Sahama I, Sinclair K, Pannek K, Lavin M, Rose S. Radiological imag‐ Immunochem. 2015;36:16–26.
ing in ataxia telangiectasia: a review. Cerebellum (London, England). 73. Suarez F, Mahlaoui N, Canioni D, et al. Incidence, presentation, and
2014;13:521–530. prognosis of malignancies in ataxia‐telangiectasia: a report from
52. Chun HH, Gatti RA. Ataxia‐telangiectasia, an evolving phenotype. the French national registry of primary immune deficiencies. J Clin
DNA Repair. 2004;3:1187–1196. Oncol. 2015;33:202–208.
53. Shaikh AG, Marti S, Tarnutzer AA, et al. Ataxia telangiectasia: a 74. Waldmann T. Immunological abnormalities in ataxia‐telangiec‐
"disease model" to understand the cerebellar control of vestibular tasia. In: BA Bridges & DG Harnden eds. Ataxia‐telangiectasia:
reflexes. J Neurophysiol. 2011;105:3034–3041. A Cellar and Molecular Link between Cancer Neuropthology and
54. Shaikh AG, Marti S, Tarnutzer AA, et al. Gaze fixation deficits Immune Deficiency (Vol. 21). Chichester, UK; Wiley;1982:475‐479.
and their implication in ataxia‐telangiectasia. J Neurol Neurosurg 75. Ament M. Respiratory complications of ataxia‐telangiectasia. N
Psychiatry. 2009;80:858–864. Engl J Med. 1969;281:1019.
55. Kruman II, Wersto RP, Cardozo‐Pelaez F, et al. Cell cycle activation 76. Bobba N, Kaplan MS. Immunodeficiency and Infections in Ataxia‐
linked to neuronal cell death initiated by DNA damage. Neuron. Telangiectasia. Pediatrics. 2005;116:568–668.
2004;41:549–561. 77. Chen L, Guo L, Tian J, Zheng B, Han S. Deficiency in activa‐
56. Lee Y, McKinnon PJ. Responding to DNA double strand breaks in tion‐induced cytidine deaminase promotes systemic autoim‐
the nervous system. Neuroscience. 2007;145:1365–1374. munity in lpr mice on a C57BL/6 background. Clin Exp Immunol.
57. Adigun OO, Bhimji SS. Alpha Fetoprotein (AFP, Maternal Serum Alpha 2010;159:169–175.
Fetoprotein, MSAFP). StatPearls. Treasure Island, FL: StatPearls 78. Meyts I, Weemaes C, De Wolf‐Peeters C, et al. Unusual and severe
Publishing StatPearls Publishing LLC; 2018. disease course in a child with ataxia‐telangiectasia. Pediatr Allergy
58. Stray‐Pedersen A, Borresen‐Dale AL, Paus E, Lindman CR, Burgers Immunol. 2003;14:330–333.
T, Abrahamsen TG. Alpha fetoprotein is increasing with age in 79. Moin M, Aghamohammadi A, Kouhi A, et al. Ataxia‐telangiecta‐
ataxia‐telangiectasia. Eur J Paediat Neurol. 2007;11:375–380. sia in Iran: clinical and laboratory features of 104 patients. Pediatr
59. Rothblum‐Oviatt C, Wright J, Lefton‐Greif MA, McGrath‐Morrow Neurol. 2007;37:21–28.
SA, Crawford TO, Lederman HM. Ataxia telangiectasia: a review. 80. Nissenkorn A, Ben‐Zeev B. Ataxia telangiectasia. Handb Clin
Orphanet J Rare Dis. 2016;11:159. Neurol. 2015;132:199–214.
60. Cabana MD, Crawford TO, Winkelstein JA, Christensen JR, 81. Micol R, Ben Slama L, Suarez F, et al. Morbidity and mortality from
Lederman HM. Consequences of the delayed diagnosis of ataxia‐ ataxia‐telangiectasia are associated with ATM genotype. J Allergy
telangiectasia. Pediatrics. 1998;102:98–100. Clin Immunol. 2011;128:382‐389.e1.
61. Farr AK, Shalev B, Crawford TO, Lederman HM, Winkelstein JA, 82. Kojis TL, Gatti RA, Sparkes RS. The cytogenetics of ataxia telangi‐
Repka MX. Ocular manifestations of ataxia‐telangiectasia. Am J ectasia. Cancer Genetics. 1991;56:143–156.
Ophthalmol. 2002;134:891–896. 83. Bredemeyer AL, Sharma GG, Huang CY, et al. ATM stabilizes DNA
62. Buckley RH. Pulmonary complications of primary immunodefi‐ double‐strand‐break complexes during V(D)J recombination.
ciencies. Paediatr Respir Rev. 2004;5:S225–S233. Nature. 2006;442:466–470.
63. Driessen GJ, Ijspeert H, Weemaes CM, et al. Antibody deficiency 84. Peterson RD, Kelly WD, Good RA. Ataxia‐telangiectasia. Its as‐
in patients with ataxia telangiectasia is caused by disturbed B‐ and sociation with a defective thymus, immunological‐deficiency dis‐
T‐cell homeostasis and reduced immune repertoire diversity. J ease, and malignancy. Lancet (London, England). 1964;1:1189–1193.
Allergy Clin Immunol. 2013;131:1367‐1375.e9. 85. Bagley J, Singh G, Iacomini J. Regulation of oxidative stress re‐
64. Fiorilli M, Businco L, Pandolfi F, Paganelli R, Russo G, Aiuti F. sponses by ataxia‐telangiectasia mutated is required for T cell pro‐
Heterogeneity of immunological abnormalities in ataxia‐telangiec‐ liferation. J Immunol. 2007;178:4757–4763.
tasia. J Clin Immunol. 1983;3:135–141. 86. Gatti RA, Vinters HV. Cerebellar pathology in ataxia‐telangiectasia:
65. Sanal O, Ersoy F, Yel L, et al. Impaired IgG antibody production to the significance of basket cells. Kroc Found Ser. 1985;19:225–232.
pneumococcal polysaccharides in patients with ataxia‐telangiec‐ 87. Goldowitz D, Hamre K. The cells and molecules that make a cere‐
tasia. J Clin Immunol. 1999;19:326–334. bellum. Trends Neurosci. 1998;21:375–382.
 13993038, 2019, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/pai.13020 by Universidad De Santiago De Chile, Wiley Online Library on [05/04/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
AMIRIFAR et al. | 287

88. Canny GJ, Roifman C, Weitzman S, Braudo M, Levison H. A pulmo‐ 110. Telatar M, Wang Z, Udar N, et al. Ataxia‐telangiectasia: mutations
nary infiltrate in a child with ataxia telangiectasia. Annals of allergy. in ATM cDNA detected by protein‐truncation screening. Am J Hum
1988;61(422–3):66–68. Genet. 1996;59:40–44.
89. Pagano G, Korkina LG, Brunk UT, et al. Congenital disorders shar‐ 111. Telatar M, Wang S, Castellvi‐Bel S, et al. A model for ATM het‐
ing oxidative stress and cancer proneness as phenotypic hallmarks: erozygote identification in a large population: four founder‐effect
prospects for joint research in pharmacology. Med Hypotheses. ATM mutations identify most of Costa Rican patients with ataxia
1998;51:253–266. telangiectasia. Mol Genet Metab. 1998;64:36–43.
90. McGrath‐Morrow SA, Gower WA, Rothblum‐Oviatt C, et al. 112. Hall MJ, Forman AD, Pilarski R, Wiesner G, Giri VN. Gene
Evaluation and management of pulmonary disease in ataxia‐telan‐ panel testing for inherited cancer risk. J Natl Compr Canc Netw.
giectasia. Pediatr Pulmonol. 2010;45:847–859. 2014;12:1339–1346.
91. Lefton‐Greif MA, Crawford TO, Winkelstein JA, et al. 113. Lehman H. Skin manifestations of primary immune deficiency. Clin
Oropharyngeal dysphagia and aspiration in patients with ataxia‐ Rev Allergy Immunol. 2014;46:112–119.
telangiectasia. J Pediatr. 2000;136:225–231. 114. Chiam LY, Verhagen MM, Haraldsson A, et al. Cutaneous granu‐
92. Umetsu DT, Ambrosino DM, Quinti I, Siber GR, Geha RS. Recurrent lomas in ataxia telangiectasia and other primary immunodeficien‐
sinopulmonary infection and impaired antibody response to bac‐ cies: reflection of inappropriate immune regulation? Dermatology
terial capsular polysaccharide antigen in children with selective (Basel, Switzerland). 2011;223:13–19.
IgG‐subclass deficiency. N Engl J Med. 1985;313:1247–1251. 115. Takamiya M, Fujita S, Saigusa K, Aoki Y. Simultaneous detection of
93. Yalcin B, Kutluk MT, Sanal O, et al. Hodgkin's disease and eight cytokines in human dermal wounds with a multiplex bead‐
ataxia telangiectasia with pulmonary cavities. Pediatr Pulmonol. based immunoassay for wound age estimation. Int J Legal Med.
2002;33:399–403. 2008;122:143–148.
94. Chen RL, Wang PJ, Hsu YH, Chang PY, Fang JS. Severe lung fibrosis 116. Iwata Y, Yoshizaki A, Komura K, et al. CD19, a response regulator
after chemotherapy in a child with ataxia‐telangiectasia. J Pediatr of B lymphocytes, regulates wound healing through hyaluronan‐
Hematol Oncol. 2002;24:77–79. induced TLR4 signaling. Am J Pathol. 2009;175:649–660.
95. Reiman A, Srinivasan V, Barone G, et al. Lymphoid tumours and 117. Cohen LE, Tanner DJ, Schaefer HG, Levis WR. Common and un‐
breast cancer in ataxia telangiectasia; substantial protective effect common cutaneous findings in patients with ataxia‐telangiectasia.
of residual ATM kinase activity against childhood tumours. Br J J Am Acad Dermatol. 1984;10:431–438.
Cancer. 2011;105:586–591. 118. Breuer K, Gutzmer R, Volker B, Kapp A, Werfel T. Therapy of non‐
96. Morrell D, Cromartie E, Swift M. Mortality and cancer incidence infectious granulomatous skin diseases with fumaric acid esters. Br
in 263 patients with ataxia‐telangiectasia. J Natl Cancer Inst. J Dermatol. 2005;152:1290–1295.
1986;77:89–92. 119. Mitra A, Gooi J, Darling J, Newton‐Bishop JA. Infliximab in the
97. Taylor A, Metcalfe J, Thick J, Mak Y. Leukemia and lymphoma in treatment of a child with cutaneous granulomas associated with
ataxia telangiectasia. Blood. 1996;87:423–438. ataxia telangiectasia. J Am Acad Dermatol. 2011;65:676–677.
98. Ben Arush MW. Treatment of lymphoid malignancies in patients 120. Pinzon‐Charry A, Kimble R, Peake J. Intralesional steroids for the
with ataxia‐telangiectasia. Med Pediatr Oncol. 1999;32:479–480. treatment of cutaneous granulomas in ataxia telangiectasia. Intern
99. Sandoval C, Swift M. Hodgkin disease in ataxia‐telangiectasia pa‐ Med J. 2013;43:25.
tients with poor outcomes. Med Pediatr Oncol. 2003;40:162–166. 121. Privette ED, Ram G, Treat JR, Yan AC, Heimall JR. Healing of gran‐
100. Kulinski JM, Leonardo SM, Mounce BC, Malherbe L, Gauld ulomatous skin changes in ataxia‐telangiectasia after treatment
SB, Tarakanova VL. Ataxia telangiectasia mutated ki‐ with intravenous immunoglobulin and topical mometasone 0.1%
nase controls chronic gammaherpesvirus infection. J Virol. ointment. Pediatr Dermatol 2014;31:703–707.
2012;86:12826–12837. 122. Connelly PJ, Smith N, Chadwick R, Exley AR, Shneerson JM,
101. Olsen JH, Hahnemann JM, Borresen‐Dale AL, et al. Cancer in pa‐ Pearson ER. Recessive mutations in the cancer gene Ataxia
tients with ataxia‐telangiectasia and in their relatives in the nordic Telangiectasia Mutated (ATM), at a locus previously associated
countries. J Natl Cancer Inst. 2001;93:121–127. with metformin response, cause dysglycaemia and insulin resis‐
102. Swift M, Morrell D, Massey RB, Chase CL. Incidence of cancer tance. Diabet Med. 2016;33:371–375.
in 161 families affected by ataxia‐telangiectasia. N Engl J Med. 123. Yang DQ, Halaby MJ, Li Y, Hibma JC, Burn P. Cytoplasmic
1991;325:1831–1836. ATM protein kinase: an emerging therapeutic target for diabe‐
103. Marabelli M, Cheng SC, Parmigiani G. Penetrance of ATM gene tes, cancer and neuronal degeneration. Drug Discovery Today.
mutations in breast cancer: a meta‐analysis of different measures 2011;16:332–338.
of risk. Genet Epidemiol. 2016;40:425–431. 124. Ditch S, Paull TT. The ATM protein kinase and cellular redox sig‐
104. Antoniou AC, Pharoah PP, Smith P, Easton DF. The BOADICEA naling: beyond the DNA damage response. Trends Biochem Sci.
model of genetic susceptibility to breast and ovarian cancer. Br J 2012;37:15–22.
Cancer. 2004;91:1580–1590. 125. Fernandez AM, Carro EM, Lopez‐Lopez C, Torres‐Aleman I.
105. Pippard EC, Hall AJ, Barker DJ, Bridges BA. Cancer in homozy‐ Insulin‐like growth factor I treatment for cerebellar ataxia: ad‐
gotes and heterozygotes of ataxia‐telangiectasia and xeroderma dressing a common pathway in the pathological cascade? Brain Res
pigmentosum in Britain. Can Res. 1988;48:2929–2932. Brain Res Rev. 2005;50:134–141.
106. Renwick A, Thompson D, Seal S, et al. ATM mutations that cause 126. Zhou K, Bellenguez C, Spencer CC, et al. Common variants near
ataxia‐telangiectasia are breast cancer susceptibility alleles. Nat ATM are associated with glycemic response to metformin in type
Genet. 2006;38:873–875. 2 diabetes. Nat Genet. 2011;43:117–120.
107. Perlman S, Becker‐Catania S, Gatti RA. Ataxia‐telangiectasia: diag‐ 127. Elson A, Wang Y, Daugherty CJ, et al. Pleiotropic defects in ataxia‐
nosis and treatment. Semin Peadiatr Neurol. 2003;10:173–182. telangiectasia protein‐deficient mice. Proc Natl Acad Sci USA.
108. Gatti RA, Tward A, Concannon P. Cancer risk in ATM heterozygotes: 1996;93:13084–13089.
a model of phenotypic and mechanistic differences between mis‐ 128. Xu Y, Ashley T, Brainerd EE, Bronson RT, Meyn MS, Baltimore D.
sense and truncating mutations. Mol Genet Metab. 1999;68:419–423. Targeted disruption of ATM leads to growth retardation, chromo‐
109. Gilad S, Khosravi R, Shkedy D, et al. Predominance of null muta‐ somal fragmentation during meiosis, immune defects, and thymic
tions in ataxia‐telangiectasia. Hum Mol Genet. 1996;5:433–439. lymphoma. Genes Dev. 1996;10:2411–2422.
 13993038, 2019, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/pai.13020 by Universidad De Santiago De Chile, Wiley Online Library on [05/04/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
288 | AMIRIFAR et al.

129. Lange J, Pan J, Cole F, Thelen MP, Jasin M, Keeney S. ATM 138. van Os N, Jansen A, van Deuren M, et al. Ataxia‐telangiectasia:
controls meiotic double‐strand‐break formation. Nature. immunodeficiency and survival. Clin Immunol. 2017;178:45–55.
2011;479:237–240. 139. Nissenkorn A, Hassin‐Baer S, Lerman SF, Levi YB, Tzadok M, Ben‐
130. Bagley J, Cortes ML, Breakefield XO, Iacomini J. Bone marrow Zeev B. Movement disorder in ataxia‐telangiectasia: treatment
transplantation restores immune system function and prevents with amantadine sulfate. J Child Neurol. 2013;28:155–160.
lymphoma in Atm‐deficient mice. Blood. 2004;104:572–578. 140. Marmolino D, Manto M. Past, present and future therapeutics for
131. Pietzner J, Baer PC, Duecker RP, et al. Bone marrow transplan‐ cerebellar ataxias. Curr Neuropharmacol. 2010;8:41–61.
tation improves the outcome of Atm‐deficient mice through 141. van Egmond ME, Elting JW, Kuiper A, et al. Myoclonus in child‐
the migration of ATM‐competent cells. Hum Mol Genet. hood‐onset neurogenetic disorders: The importance of early iden‐
2013;22:493–507. tification and treatment. Eur J Paediat Neurol. 2015;19:726–729.
132. Ussowicz M, Musial J, Duszenko E, Haus O, Kalwak K. Long‐term 142. Broccoletti T, Del Giudice E, Amorosi S, et al. Steroid‐induced im‐
survival after allogeneic‐matched sibling PBSC transplantation provement of neurological signs in ataxia‐telangiectasia patients.
with conditioning consisting of low‐dose busilvex and fludarabine Eur J Neurol. 2008;15:223–228.
in a 3‐year‐old boy with ataxia‐telangiectasia syndrome and ALL. 143. Schoenaker MH, Suarez F, Szczepanski T, Mahlaoui N, Loeffen JL.
Bone Marrow Transplant. 2013;48:740–741. Treatment of acute leukemia in children with ataxia telangiectasia
133. Beier R, Sykora KW, Woessmann W, et al. Allogeneic‐matched (A‐T). Eur J Med Genet. 2016;59:641–646.
sibling stem cell transplantation in a 13‐year‐old boy with ataxia 144. Lee SY, Oh SC. Ataxia telangiectasia mutated (ATM), could it be an‐
telangiectasia and EBV‐positive non‐Hodgkin lymphoma. Bone other useful biomarker for the successful treatment with the poly
Marrow Transplant. 2016;51:1271–1274. (ADP‐ribose) polymerase inhibitor? Transl gastroenterol Hepatol.
134. Bakhtiar S, Woelke S, Huenecke S, et al. Pre‐emptive allogeneic 2016;1:3.
hematopoietic stem cell transplantation in ataxia telangiectasia.
Front Immunol. 2018;9:2495.
135. Buckley RH. Bone marrow and thymus transplantation in ataxia‐
How to cite this article: Amirifar P, Ranjouri MR, Yazdani R,
telangiectasia. Birth Defects Orig Artic Ser. 1975;11:421–424.
136. Slack J, Albert MH, Balashov D, et al. Outcome of hematopoietic
Abolhassani H, Aghamohammadi A. Ataxia‐telangiectasia: A
cell transplantation for DNA double‐strand break repair disorders. review of clinical features and molecular pathology. Pediatr
J Allergy Clin Immunol. 2018;141:322‐328.e10. Allergy Immunol. 2019;30:277–288. https://doi.org/10.1111/
137. Lavin MF, Gueven N, Bottle S, Gatti RA. Current and potential pai.13020
therapeutic strategies for the treatment of ataxia‐telangiectasia.
Br Med Bull. 2007;81‐82:129‐147.