Wikipedia - Ataxia Telangiectasia (CHECKED)

Ataxia telangiectasia - Wikipedia, the free encyclopedia
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Ataxia telangiectasia
From Wikipedia, the free encyclopedia
Ataxia telangiectasia (A-T) (also

referred to as LouisBar
syndrome) is a rare,
neurodegenerative, inherited disease
causing severe disability. Ataxia
refers to poor coordination and
telangiectasia to small dilated blood
vessels, both of which are hallmarks
of the disease.[1]
A-T affects many parts of the body:
Ataxia Telangiectasia
Classification and external resources
ICD-10
G11.3
(http://apps.who.int/classifications/icd10/browse/2015/en#/G11.3)
ICD-9
334.8 (http://www.icd9data.com/getICD9Code.ashx?icd9=334.8)
OMIM
208900 (http://omim.org/entry/208900)
DiseasesDB
1025 (http://www.diseasesdatabase.com/ddb1025.htm)
MedlinePlus 001394
It impairs certain areas of the

eMedicine
brain including the
cerebellum, causing difficulty
with movement and
MeSH
coordination.
It weakens the immune
GeneReviews
system causing a
predisposition to infection.
It prevents repair of broken
DNA, increasing the risk of cancer.
(http://www.nlm.nih.gov/medlineplus/ency/article/001394.htm)
derm/691 (http://www.emedicine.com/derm/topic691.htm)
oph/319 (http://www.emedicine.com/oph/topic319.htm#)
D001260 (https://www.nlm.nih.gov/cgi/mesh/2015/MB_cgi?
field=uid&term=D001260)
Ataxia telangiectasia
(http://www.ncbi.nlm.nih.gov/books/NBK26468/)
Symptoms most often first appear in early childhood (the toddler stage) when children begin to walk. Though
they usually start walking at a normal age, they wobble or sway when walking, standing still or sitting, and may
appear almost as if they are drunk. In late pre-school and early school age they develop difficulty moving the
eyes in a natural manner from one place to the next (oculomotor apraxia). They develop slurred or distorted
speech, and swallowing problems. Some have an increased number of respiratory tract infections (ear
infections, sinusitis, bronchitis, and pneumonia). Because not all children develop in the same manner or at the
same rate, it may be some years before A-T is properly diagnosed. Most children with A-T have stable
neurologic symptoms for the first 45 years of life, but begin to show increasing problems in early school years.
A-T is caused by a defect in the ATM gene,[2] which is responsible for managing the cells response to multiple
forms of stress including double-strand breaks in DNA. In simple terms, the protein produced by the ATM gene
recognizes that there is a break in DNA, recruits other proteins to fix the break, and stops the cell from making
new DNA until the repair is complete.[3]
Contents
1 Symptoms
1.1 Ataxia and other neurologic problems
http://en.wikipedia.org/wiki/Ataxia_telangiectasia
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1.2 Telangiectasia
1.3 Immune problems
1.4 Cancer
1.5 Skin
1.6 Lung disease
1.7 Feeding, swallowing, and nutrition
1.8 Eye and vision
1.9 Orthopedics
2 Pathophysiology
2.1 Cancer and radiosensitivity
2.2 Delayed pubertal development/Gonadal dysgenesis
2.3 Immune system defects and immune-related cancers
2.4 Progeric changes
2.5 Telangiectasia
2.6 Increased alpha-fetoprotein (AFP) levels
2.7 Neurodegeneration
2.8 Radiation exposure
3 Genetics and information about A-T Carriers
4 Diagnosis
5 Differential diagnosis
6 Management
6.1 Ataxia and other neurologic problems
6.2 Immune problems
6.3 Lung disease
6.4 Feeding, swallowing and nutrition
6.5 Education and socialization
7 Clinics and support
8 Epidemiology
9 Prognosis
10 Research directions
11 References
12 External links
Symptoms
There is substantial variability in the severity of features of A-T between affected individuals, and at different
ages. The following symptoms or problems are either common or important features of A-T:
Ataxia (difficulty with control of movement) that is apparent early but worsens in school to pre-teen years
Oculomotor apraxia (difficulty with coordination of head and eye movement when shifting gaze from one
place to the next)
Involuntary movements
Telangiectasia (dilated blood vessels) over the white (sclera) of the eyes, making them appear bloodshot.
These are not apparent in infancy and may first appear at age 58 years. Telangiectasia may also appear
on sun-exposed areas of skin.
Problems with infections, especially of the ears, sinuses and lungs
Increased incidence of cancer (primarily, but not exclusively, lymphomas and leukemias)
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Delayed onset or incomplete pubertal development, and very early menopause

Slowed rate of growth (weight and/or height)
Drooling particularly in young children when they are tired or concentrating on activities
Dysarthria (slurred, slow, or distorted speech sounds)
Diabetes in adolescence or later
Premature changes in hair and skin
Many children are initially misdiagnosed as having ataxic cerebral palsy. The diagnosis of A-T may not be
made until the preschool years when the neurologic symptoms of impaired gait, hand coordination, speech and
eye movement appear or worsen, and the telangiectasia first appear. Because A-T is so rare, doctors may not be
familiar with the symptoms, or methods of making a diagnosis. The late appearance of telangiectasia may be a
barrier to the diagnosis. It may take some time before doctors consider A-T as a possibility because of the early
stability of symptoms and signs.
Ataxia and other neurologic problems

The first indications of A-T usually occur during the toddler years.[4][5] Children start walking at a normal age,
but may not improve much from their initial wobbly gait. Sometimes they have problems standing or sitting still
and tend to sway backward or from side to side. In primary school years walking becomes more difficult, and
children will use doorways and walls for support. Children with A-T often appear better when running or
walking quickly in comparison to when they are walking slowly or standing in one place. Around the beginning
of their second decade children with typical forms of A-T start using a wheelchair for long distances. During
school years children may have increasing difficulty with reading because of impaired coordinating of eye
movement. At the same time other problems with fine motor functions (writing, coloring, and using utensils to
eat), and with slurring of speech (dysarthria) may arise. Most of these neurologic problems stop progressing
after the age of about 12 15 years, though involuntary movements may start at any age and may worsen over
time. These extra movements can take many forms, including small jerks of the hands and feet that look like
fidgeting (chorea), slower twisting movements of the upper body (athetosis), adoption of stiff and twisted
postures (dystonia), occasional uncontrolled jerks (myoclonic jerks), and various rhythmic and non-rhythmic
movements with attempts at coordinated action (tremors).
Telangiectasia
Prominent blood vessels (telangiectasia) over the white (sclera) of the
eyes usually occur by the age of 58 years, but sometimes later or not at
all.[6] The absence of telangiectasia does not exclude the diagnosis of AT. Potentially a cosmetic problem, the ocular telangiectasia do not bleed
or itch, though they are sometimes misdiagnosed as chronic
conjunctivitis. It is their constant nature, not changing with time,
weather or emotion, that marks them as different from other visible
blood vessels. Telangiectasia can also appear on sun-exposed areas of
skin, especially the face and ears. They occur in the bladder as a late
complication of chemotherapy with cyclophosphamide, have been seen
deep inside the brain of older people with A-T, and occasionally arise in
the liver and lungs.
Ocular telangiectasia in a person with

A-T
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Immune problems
About two-thirds of people with A-T have abnormalities of the immune system.[7] The most common
abnormalities are low levels of one or more classes of immunoglobulins (IgG, IgA, IgM or IgG subclasses), not
making antibodies in response to vaccines or infections, and having low numbers of lymphocytes (especially Tlymphocytes) in the blood. Some people have frequent infections of the upper (colds, sinus and ear infections)
and lower (bronchitis and pneumonia) respiratory tract. All children with A-T should have their immune
systems evaluated to detect those with severe problems that require treatment to minimize the number or
severity of infections. Some people with A-T need additional immunizations (especially with pneumonia and
influenza vaccines), antibiotics to provide protection (prophylaxis) from infections, and/or infusions of
immunoglobulins (gamma globulin). The need for these treatments should be determined by an expert in the
field of immunodeficiency or infectious diseases.
Cancer
People with A-T have a highly increased incidence (approximately 25% lifetime risk) of cancers, particularly
lymphomas and leukemia, but other cancers can occur.[8] When possible, treatment should avoid the use of
radiation therapy and chemotherapy drugs that work in a way that is similar to radiation therapy (radiomimetic
drugs), as these are particularly toxic for people with A-T. The special problems of managing cancer are
sufficiently complicated that treatment should be done only in academic oncology centers and after consultation
with physicians who have specific expertise in A-T. Unfortunately, there is no way to predict which individuals
will develop cancer. Because leukemia and lymphomas differ from solid tumors in not progressing from solitary
to metastatic stages, there is less need to diagnose them early in their appearance. Surveillance for leukemia and
lymphoma is thus not helpful, other than considering cancer as a diagnostic possibility whenever possible
symptoms of cancer (e.g. persistent swollen lymph glands, unexplained fever) arise.
Women who are A-T carriers (who have one mutated copy of the ATM gene), have approximately a two-fold
increased risk for the development of breast cancer compared to the general population.[9][10] This includes all
mothers of A-T children and some female relatives. Current consensus is that special screening tests are not
helpful, but all women should have routine cancer surveillance.
Skin
A-T can cause features of early aging such as premature graying of the hair. It can also cause vitiligo (an autoimmune disease causing loss of skin pigment resulting in a blotchy bleach-splashed look), and warts which
can be extensive and recalcitrant to treatment. A small number of people develop a chronic inflammatory skin
disease (granulomas).[11]
Lung disease
Chronic lung disease develops in more than 25% of people with A-T.[12] Three major types of lung disease can
develop: (1) recurrent and chronic sinopulmonary infections, (2) lung disease caused by ineffective cough,
swallowing dysfunction, and impaired airway clearance, and (3) restrictive interstitial lung disease. It is
common for individuals with A-T to have more than one of these lung conditions. Chronic lung disease can
occur because of recurrent lung infections due to immunodeficiency. Individuals with this problem are at risk of
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developing bronchiectasis, a condition in which bronchial tubes are permanently damaged, resulting in recurrent
lower airway infections. Gamma globulin for people with antibody deficiency and/or chronic antibiotic
treatment may reduce the problems of infection. Other individuals with A-T have difficulty with taking deep
breaths and may have an ineffective cough, which makes it difficult to clear oral and bronchial secretions. This
can lead to prolonged respiratory symptoms following common viral respiratory illnesses. Techniques that
allow clearance of mucus can be helpful in some individuals during respiratory illnesses. Some people will
develop swallowing problems as they age, which increases their risk of aspiration pneumonia. Recurrent injury
to the lungs caused by chronic infections or aspiration may cause lung fibrosis and scarring. This process may
be enhanced by inadequate tissue repair in ATM-deficient cells. A small number of individuals develop
interstitial lung disease. They have decreased pulmonary reserve, trouble breathing, a need for supplemental
oxygen and chronic cough in the absence of lung infections. They may respond to systemic steroid treatment or
other drugs to reduce inflammation.
Lung function tests (spirometry) should be performed at least annually in children old enough to perform them,
influenza and pneumococcal vaccines given to eligible individuals, and sinopulmonary infections treated
aggressively to limit the development of chronic lung disease.
Feeding, swallowing, and nutrition

Feeding and swallowing can become difficult for people with A-T as they get older.[13] Feeding refers to all
aspects of eating and drinking, including getting food and liquids to the mouth; swallowing refers to ingestion
or what happens after food or liquids enter the mouth. Primary goals for feeding and swallowing are safe,
adequate, and enjoyable mealtimes.
Involuntary movements may make feeding difficult or messy and may excessively prolong mealtimes. It may be
easier to finger feed than use utensils (e.g., spoon or fork). For liquids, it is often easier to drink from a closed
container with a straw than from an open cup. Caregivers may need to provide foods or liquids so that selffeeding is possible, or they may need to feed the person with A-T. In general, meals should be completed within
approximately 30 minutes. Longer meals may be stressful, interfere with other daily activities, and limit the
intake of necessary liquids and nutrients.
If swallowing problems (dysphagia) occur, they typically present during the second decade of life. Dysphagia is
common because of the neurological changes that interfere with coordination of mouth and pharynx (throat)
movements that are needed for safe and efficient swallowing. Coordination problems involving the mouth may
make chewing difficult and increase the duration of meals. Problems involving the pharynx may cause liquid,
food, and saliva to be inhaled into the airway (aspiration). People with dysphagia may not cough when they
aspirate (silent aspiration). Swallowing problems and especially swallowing problems with silent aspiration
may cause lung problems due to inability to cough and clear food and liquids from the airway.
Warning signs of a swallowing problem
Choking or coughing when eating or drinking
Poor weight gain (during ages of expected growth) or weight loss at any age
Excessive drooling
Mealtimes longer than 40 45 minutes, on a regular basis
Foods or drinks previously enjoyed are now refused or difficult
Chewing problems
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Increase in the frequency or duration of breathing or respiratory problems

Increase in lung infections
Eye and vision

Most people develop telangiectasia (prominent blood vessels) in the membrane that covers the white part
(sclera) of the eye.
Vision (ability to see objects in focus) is normal.[14]
Control of eye movement is often impaired affecting visual functions that require fast, accurate eye
movements from point to point (e.g. reading).
Eye misalignments (strabismus) are common, but may be treatable.
There may be difficulty in coordinating eye position and shaping the lens to see objects up close.
Orthopedics
Many individuals with A-T develop deformities of the feet that compound the difficulty they have with walking
due to impaired coordination. Early treatment may slow progression of this deformity. Bracing or surgical
correction sometimes improves stability at the ankle sufficient to enable an individual to walk with support, or
bear weight during assisted standing transfers from one seat to another. Severe scoliosis is relatively
uncommon, but probably does occur more often than in those without A-T. Spinal fusion is only rarely
indicated.
Pathophysiology
How Does Loss of the ATM Protein Create a Multisystem Disorder?
A-T has been described as a genome instability syndrome, a DNA repair
disorder and a DNA damage response (DDR) syndrome. ATM, the gene
responsible for this multi-system disorder, encodes a protein of the same
name which coordinates the cellular response to DNA double strand
breaks (DSBs).[16] Radiation therapy, chemotherapy that acts like
radiation (radiomimetic drugs) and certain biochemical processes and
metabolites can cause DSBs. When these breaks occur, ATM stops the
cell from making new DNA (cell cycle arrest) and recruits and activates
other proteins to repair the damage. Thus, ATM allows the cell to repair
its DNA before the completion of cell division. If DNA damage is too
severe, ATM will mediate the process of programmed cell death
(apoptosis) to eliminate the cell and prevent genomic
instability.[17]
Characteristics of the ATM

protein[15][16][17][18][19][20][21][22][23]
Cancer and radiosensitivity

In the absence of the ATM protein, cell cycle check point regulation and programmed cell death in response to
DSBs are defective. The result is genomic instability which can lead to the development of cancers.[24]
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Irradiation and radiomimetic compounds induce DSBs which are unable to be repaired appropriately when
ATM is absent. Consequently, such agents can prove especially cytotoxic to A-T cells and people with A-T.
Delayed pubertal development/Gonadal dysgenesis

Infertility is often described as a characteristic of A-T. Whereas this is certainly the case for the mouse model of
A-T,[25] in humans it may be more accurate to characterize the reproductive abnormality as gonadal atrophy or
dysgenesis characterized by delayed pubertal development. Because programmed DSBs are generated to initiate
genetic recombinations involved in the production of sperm and eggs in reproductive organs (a process known
as meiosis), meiotic defects and arrest can occur when ATM is not present.[25][26][27]
Immune system defects and immune-related cancers

As lymphocytes develop from stem cells in the bone marrow into mature
lymphocytes in the periphery, they rearrange special segments of their
DNA [V(D)J recombination process]. This process requires them to
make DSBs, which are difficult to repair in the absence of
ATM.[32][33][34][35] As a result most people with A-T have reduced
numbers of lymphocytes and some impairment of lymphocyte function
(such as an impaired ability to make antibodies in response to vaccines
or infections). In addition, broken pieces of DNA in chromosomes
involved in the above-mentioned rearrangements have a tendency to
recombine with other genes (translocation), making the cells prone to
the development of cancer (lymphoma and leukemia).
ATM and the immune system

[28][29][30][31]
Progeric changes
Cells from people with A-T demonstrate genomic instability, slow growth and premature senescence in culture,
shortened telomeres and an ongoing, low level stress response.[3][36] These factors may contribute to the
progeric (signs of early aging) changes of skin and hair sometimes observed in people with A-T. For example,
DNA damage and genomic instability cause melanocyte stem cell (MSC) differentiation which produces
graying. Thus, ATM may be a stemness checkpoint protecting against MSC differentiation and premature
graying of the hair.[37]
Telangiectasia
The cause of telangiectasia or dilated blood vessels in the absence of the ATM protein is not yet known.
Increased alpha-fetoprotein (AFP) levels

Approximately 95% of people with A-T have elevated serum AFP levels after the age of two, and measured
levels of AFP appear to increase slowly over time.[38] AFP levels are very high in the newborn, and normally
descend to adult levels over the first year to 18 months. The reason for why individuals with A-T have elevated
levels of AFP is not yet known.
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Neurodegeneration
A-T is one of several DNA repair disorders which results in neurological abnormalities or degeneration.
Arguably some of the most devastating symptoms of A-T are a result of progressive cerebellar degeneration,
characterized by the loss of Purkinje cells and, to a lesser extent, granule cells (located exclusively in the
cerebellum).[4] The cause of this cell loss is not known, though many hypotheses have been proposed based on
experiments performed both in cell culture and in the mouse model of A-T. Current hypotheses explaining the
neurodegeneration associated with A-T include the following:
Defective DNA damage response in neurons[18][39] which can lead to
Failed clearance of genomically damaged neurons during development[40][41]
Abortive transcription including topoisomerase 1 cleavage complex (TOP1cc) dependent
lesions[42][43]
Aneuploidy[44]
Oxidative stress[45][46]
Inappropriate cell cycle re-entry of post-mitotic (mature) neurons[47]
Synaptic/vesicular dysregulation[48] and HDAC4 dysregulation[49][50]
These hypotheses may not be mutually exclusive and more than one of these mechanisms may underlie
neuronal cell death when there is an absence or deficiency of ATM. Further, cerebellar damage and loss of
Purkinje and granule cells do not explain all of the neurologic abnormalities seen in people with A-T. The
effects of ATM deficiency on the other areas of the brain outside of the cerebellum are being actively
investigated.
Radiation exposure
People with A-T have an increased sensitivity to ionizing radiation (X-rays and gamma rays). Therefore, X-ray
exposure should be limited to times when it is medically necessary, as exposing an A-T patient to ionizing
radiation can damage cells in such a way that the body cannot repair them. The cells can cope normally with
other forms of radiation, such as ultraviolet light, so there is no need for special precautions from sunlight
exposure.
Genetics and information about A-T Carriers

A-T is caused by mutations in the ATM (Ataxia Telangiectasia Mutated) gene which was cloned in 1995.[2]
ATM is located on human chromosome 11 (11q22.3) and is made up of 69 exons spread across 150kb of
genomic DNA.[51]
The mode of inheritance for A-T is autosomal recessive. Each parent is a carrier, meaning that they have one
normal copy of the A-T gene (ATM) and one copy which is mutated. A-T occurs if a child inherits the mutated
A-T gene from each parent, so in a family with two carrier parents, there is 1 chance in 4 that a child born to the
parents will have the disorder. Prenatal diagnosis (and carrier detection) can be carried out in families if the
errors (mutation) in an affected childs two ATM genes have been identified. The process of getting this done
can be complicated and as it requires time should be arranged before conception.
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Looking for mutations in the ATM gene of an unrelated person (for example, the spouse of a known A-T
carrier) presents significant challenges. Genes often have variant spellings (polymorphisms) which do not affect
function. In a gene as large as ATM, such variant spellings are likely to occur and doctors cannot always predict
if a specific variant will or will not cause disease. Genetic counseling can help family members of an A-T
patient understand what can or cannot be tested, and how the test results should be interpreted.
Carriers of A-T, such as the parents of a person with A-T, have one mutated copy of the ATM gene and one
normal copy. They are generally healthy, but there is an increased risk of breast cancer in women. This finding
has been confirmed in a variety of different ways, and is the subject of current research. Standard surveillance
(including monthly breast self-exams and mammography at the usual schedule for age) is recommended, unless
additional tests are indicated because the individual has other risk factors
(e.g., family history of breast cancer).
Diagnosis
The diagnosis of A-T is usually suspected by the combination of
neurologic clinical features (ataxia, abnormal control of eye movement,
and postural instability) with telangiectasia and sometimes increased
infections, and confirmed by specific laboratory abnormalities (elevated
alpha-fetoprotein levels, increased chromosomal breakage or cell death
of white blood cells after exposure to X-rays, absence of ATM protein in
white blood cells, or mutations in each of the persons ATM genes).
A variety of laboratory abnormalities occur in most people with A-T,
allowing for a tentative diagnosis to be made in the presence of typical
clinical features. Not all abnormalities are seen in all patients. These
abnormalities include:
A-T is inherited in an autosomal

recessive fashion
Elevated and slowly increasing alpha-fetoprotein levels in serum

after 2 years of age
Immunodeficiency with low levels of immunoglobulins (especially IgA, IgG subclasses, and IgE) and
low number of lymphocytes in the blood
Chromosomal instability (broken pieces of chromosomes)
Increased sensitivity of cells to x-ray exposure (cells die or develop even more breaks and other damage
to chromosomes)[52]
Cerebellar atrophy on MRI scan
The diagnosis can be confirmed in the laboratory by finding an absence or deficiency of the ATM protein in
cultured blood cells,[53][54] an absence or deficiency of ATM function (kinase assay), or mutations in both
copies of the cells ATM gene. These more specialized tests are not always needed, but are particularly helpful
if a childs symptoms are atypical.
Differential diagnosis
There are several other disorders with similar symptoms or laboratory features that physicians may consider
when diagnosing A-T.[55] The three most common disorders that are sometimes confused with A-T are:
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Cerebral palsy
Friedreich ataxia
Cogan oculomotor apraxia.
Each of these can be distinguished from A-T by the neurologic exam and clinical history.
Cerebral palsy (CP) describes a non-progressive disorder of motor function stemming from malformation or
early damage to the brain. CP can manifest in many ways given the different manner in which brain can be
damaged; in common to all forms is the emergence of signs and symptoms of impairment as the child develops.
However, milestones that have been accomplished and neurologic functions that have developed do not
deteriorate in CP as they often do in children with A-T in the late pre-school years. Most children with ataxia
caused by CP do not begin to walk at a normal age, whereas most children with A-T start to walk at a normal
age even though they often wobble from the start. Pure ataxia is a rare manifestation of early brain damage or
malformation, however, and the possibility of an occult genetic disorder of brain should be considered and
sought for those in whom ataxia is the chief manif estation of CP. Children with ataxic CP will not manifest the
laboratory abnormalities associated with A-T.
Cogan occulomotor apraxia is a rare disorder of development. Affected children have difficulty moving their
eyes only to a new visual target, so they will turn their head past the target to drag the eyes to the new object
of interest, then turn the head back. This tendency becomes evident in late infancy and toddler years, and mostly
improves with time. This contrasts to the oculomotor difficulties evident in children with A-T, which are not
evident in early childhood but emerge over time. Cogans oculomotor apraxia is generally an isolated problem,
or may be associated with broader developmental delay.
Friedreich ataxia (FA) is the most common genetic cause of ataxia in children. Like A-T, FA is a recessive
disease, appearing in families without a history of the disorder. FA is caused by mutation in the frataxin gene,
most often an expansion of a naturally occurring repetition of the three nucleotide bases GAA from the usual 533 repetitions of this trinucleotide sequence to greater than 65 repeats on each chromosome. Most often the
ataxia appears between 10 and 15 years of age, and differs from A-T by the absence of telangiectasia and
oculomotor apraxia, a normal alpha fetalprotein, and the frequent presence of scoliosis, absent tendon reflexes,
and abnormal features on the EKG. Individuals with FA manifest difficulty standing in one place that is much
enhanced by closure of the eyes (Romberg sign) that is not so apparent in those with A-T even though those
with A-T may have greater difficulty standing in one place with their eyes open.
There are other rare disorders that can be confused with A-T, either because of similar clinical features, a
similarity of some laboratory features, or both. These include:
Ataxia oculomotor apraxia type 1 (AOA1)
Ataxia oculomotor apraxia type 2 (AOA2 also known as SCAR1)
Ataxia telangiectasia like disorder (ATLD)
Nijmegen breakage syndrome (NBS)
Ataxia oculomotor apraxia type 1 (AOA1) is an autosomal recessive disorder similar to A-T in manifesting
increasing problems with coordination and oculomotor apraxia, often at a similar age to those having A-T. It is
caused by mutation in the gene coding for the protein aprataxin. Affected individuals differ from those with A-T
by the early appearance of peripheral neuropathy, early in their course manifest difficulty with initiation of gaze
shifts, and the absence of ocular telangiectasia, but laboratory features are of key importance in the
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differentiation of the two. Individuals with AOA1 have a normal AFP, normal measures of immune function,
and after 1015 years have low serum levels of albumin. Genetic testing of the aprataxin gene can confirm the
diagnosis. There is no enhanced risk for cancer.
Ataxia oculomotor apraxia type 2 (AOA2) is an autosomal recessive disorder also similar to A-T in manifesting
increasing problems with coordination and peripheral neuropathy, but oculomotor apraxia is present in only half
of affected individuals. Ocular telangiectasia do not develop. Laboratory
abnormalities of AOA2 are like A-T, and unlike AOA1, in having an
elevated serum AFP level, but like AOA1 and unlike A-T in having
normal markers of immune function. Genetic testing of the senataxin
gene (SETX) can confirm the diagnosis. There is no enhanced risk for
cancer.
Ataxia-telangiectasia like disorder (ATLD) is an extremely rare
condition, caused by mutation in the hMre11 gene, that could be
considered in the differential diagnosis of A-T. Patients with ATLD are
very similar to those with A-T in showing a progressive cerebellar
Comparison of clinical and laboratory
ataxia, hypersensitivity to ionizing radiation and genomic instability.
features of rare genetic disorders than
Those rare individuals with ATLD who are well described differ from
can be confused with A-T
those with A-T by the absence of telangiectasia, normal immunoglobulin
levels, a later onset, and a slower progression of the symptoms. Because of its rarity, it is not yet known whether
or not ATLD carries an increased risk to develop cancer. Because those mutations of Mre11 that severely impair
the MRE11 protein are incompatible with life, individuals with ATLD all have some partial function of the
Mre11 protein, and hence likely all have their own levels of disease severity.
Nijmegen breakage syndrome (NBS) is a rare genetic disorder that has similar chromosomal instability to that
seen in people with A-T, but the problems experienced are quite different. Children with NBS have significant
microcephaly, a distinct facial appearance, short stature, and moderate cognitive impairment, but do not
experience any neurologic deterioration over time. Like those with A-T, children with NBS have enhanced
sensitivity to radiation, disposition to lymphoma and leukemia, and some laboratory measures of impaired
immune function, but do not have ocular telangiectasia or an elevated level of AFP.
Interestingly, the proteins expressed by the hMre11 (defective in ATLD) and Nbs1 (defective in NBS) genes
exist in the cell as a complex, along with a third protein expressed by the hRad50 gene. This complex, known as
the MRN complex, plays an important role in DNA damage repair and signaling and is required to recruit ATM
to the sites of DNA double strand breaks. Mre11 and Nbs1 are also targets for phosphorylation by the ATM
kinase. Thus, the similarity of the three diseases can be explained in part by the fact that the protein products of
the three genes mutated in these disorders interact in common pathways in the cell.
Differentiation of these disorders is often possible with clinical features and selected laboratory tests. In cases
where the distinction is unclear, clinical laboratories can identify genetic abnormalities of ATM, aprataxin and
senataxin, and specialty centers can identify abnormality of the proteins of potentially responsible genes, such
as ATM, MRE11, nibrin, TDP1, aprataxin and senataxin as well as other proteins important to ATM function
such as ATR, DNA-PK, and RAD50.
Management
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Ataxia and other neurologic problems

There is no treatment known to slow or stop the progression of the neurologic problems. Treatment of A-T is
symptomatic and supportive. Physical, occupational and speech therapies and exercise may help maintain
function but will not slow the course of neurodegeneration. Therapeutic exercises should not be used to the
point of fatigue and should not interfere with activities of daily life. Certain anti-Parkinson and anti-epileptic
drugs maybe useful in the management of symptoms, but should be prescribed in consultation with a
neurologist.
Immune problems
All individuals with A-T should have at least one comprehensive immunologic evaluation that measures the
number and type of lymphocytes in the blood (T-lymphocytes and B-lymphocytes), the levels of serum
immunoglobulins (IgG, IgA, and IgM) and antibody responses to T-dependent (e.g., tetanus, Hemophilus
influenzae b) and T-independent (23-valent pneumococcal polysaccharide) vaccines. For the most part, the
pattern of immunodeficiency seen in an A-T patient early in life (by age five) will be the same pattern seen
throughout the lifetime of that individual Therefore, the tests need not be repeated unless that individual
develops more problems with infection. Problems with immunity sometimes can be overcome by immunization.
Vaccines against common bacterial respiratory pathogens such as Hemophilus influenzae, pneumococci and
influenza virus (the flu) are commercially available and often help to boost antibody responses, even in
individuals with low immunoglobulin levels. If the vaccines do not work and the patient continues to have
problems with infections, gamma globulin therapy (IV or subcutaneous infusions of antibodies collected from
normal individuals) may be of benefit. A small number of people with A-T develop an abnormality in which
one or more types of immunoglobulin are increased far beyond the normal range. In a few cases, the
immunoglobulin levels can be increased so much that the blood becomes thick and does not flow properly.
Therapy for this problem must be tailored to the specific abnormality found and its severity.
If an individual patients susceptibility to infection increases, it is important to reassess immune function in case
deterioration has occurred and a new therapy is indicated. If infections are occurring in the lung, it is also
important to investigate the possibility of dysfunctional swallow with aspiration into the lungs (see above
sections under Symptoms: Lung Disease and Symptoms: Feeding, Swallowing and Nutrition.)
Most people with A-T have low lymphocyte counts in the blood. This problem seems to be relatively stable
with age, but a rare number of people do have progressively decreasing lymphocyte counts as they get older. In
the general population very low lymphocyte counts are associated with an increased risk for infection. Such
individuals develop complications from live viral vaccines (measles, mumps, rubella and chickenpox), chronic
or severe viral infections, yeast infections of the skin and vagina, and opportunistic infections (such as
pneumocystis pneumonia). Although lymphocyte counts are often as low in people with A-T, they seldom have
problems with opportunistic infections. (The one exception to that rule is that problems with chronic or
recurrent warts are common.) The number and function of T-lymphocytes should be re-evaluated if a person
with A-T is treated with corticosteroid drugs such as prednisone for longer than a few weeks or is treated with
chemotherapy for cancer. If lymphocyte counts are low in people taking those types of drugs, the use of
prophylactic antibiotics is recommended to prevent opportunistic infections.
If the tests show significant abnormalities of the immune system, a specialist in immunodeficiency or infectious
diseases will be able to discuss various treatment options. Absence of immunoglobulin or antibody responses to
vaccine can be treated with replacement gamma globulin infusions, or can be managed with prophylactic
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antibiotics and minimized exposure to infection. If antibody function is normal, all routine childhood
immunizations including live viral vaccines (measles, mumps, rubella and varicella) should be given. In
addition, several special vaccines (that is, licensed but not routine for otherwise healthy children and young
adults) should be given to decrease the risk that an A-T patient will develop lung infections. The patient and all
household members should receive the influenza (flu) vaccine every fall. People with A-T who are less than two
years old should receive three (3) doses of a pneumococcal conjugate vaccine (Prevnar) given at two month
intervals. People older than two years who have not previously been immunized with Prevnar should receive
two (2) doses of Prevnar. At least 6 months after the last Prevnar has been given and after the child is at least
two years old, the 23-valent pneumococcal vaccine should be administered. Immunization with the 23-valent
pneumococcal vaccine should be repeated approximately every five years after the first dose.
In people with A-T who have low levels of IgA, further testing should be performed to determine if the IgA
level is low or completely absent. If absent, there is a slightly increased risk of a transfusion reaction. Medical
Alert bracelets are not necessary, but the family and primary physician should be aware that if there is elective
surgery requiring red cell transfusion, the cells should be washed to decrease the risk of an allergic reaction.
People with A-T also have an increased risk of developing autoimmune or chronic inflammatory diseases. This
risk is probably a secondary effect of their immunodeficiency and not a direct effect of the lack of ATM protein.
The most common examples of such disorders in A-T include immune thrombocytopenia (ITP), several forms
of arthritis, and vitiligo.
Lung disease
Recurrent sinus and lung infections can lead to the development of chronic lung disease.[12] Such infections
should be treated with appropriate antibiotics to prevent and limit lung injury. Administration of antibiotics
should be considered when children and adults have prolonged respiratory symptoms (greater than 7 days), even
following what was presumed to have been a viral infection. To help prevent respiratory illnesses from common
respiratory pathogens, annual influenza vaccinations should be given and pneumococcal vaccines should be
administered when appropriate. Antibiotic treatment should also be considered in children with chronic coughs
that are productive of mucous, those who do not respond to aggressive pulmonary clearance techniques and in
children with muco-purulent secretions from the sinuses or chest. A wet cough can also be associated with
chronic aspiration which should be ruled out through proper diagnostic studies, however aspiration and
respiratory infections are not necessarily exclusive of each other. In children and adults with bronchiectasis,
chronic antibiotic therapy should be considered to slow chronic lung disease progression.
Culturing of the sinuses may be needed to direct antibiotic therapy. This can be done by an Ear Nose and Throat
(ENT) specialist. In addition, diagnostic bronchoscopy may be necessary in people who have recurrent
pneumonias, especially those who do not respond or respond incompletely to a course of antibiotics.
Clearance of bronchial secretions is essential for good pulmonary health and can help limit injury from acute
and chronic lung infections. Children and adults with increased bronchial secretions can benefit from routine
chest therapy using the manual method, an a cappella device or a chest physiotherapy vest. Chest physiotherapy
can help bring up mucous from the lower bronchial tree, however an adequate cough is needed to remove
secretions. In people who have decreased lung reserve and a weak cough, use of an insufflator-exsufflator
(cough-assist) device may be useful as a maintenance therapy or during acute respiratory illnesses to help
remove bronchial secretions from the upper airways. Evaluation by a Pulmonology specialist however, should
first be done to properly assess patient suitability.
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Children and adults with chronic dry cough, increased work of breathing (fast respiratory rate, shortness of
breath at rest or with activities) and absence of an infectious process to explain respiratory symptoms should be
evaluated for interstitial lung disease or another intrapulmonary process. Evaluation by a Pulmonologist and a
CT scan of the chest should be considered in individuals with symptoms of interstitial lung disease or to rule
other non-infectious pulmonary processes. People diagnosed with interstitial lung disease may benefit from
systemic steroids.
Feeding, swallowing and nutrition

Oral intake may be aided by teaching persons with A-T how to drink, chew and swallow more safely. The
propriety of treatments for swallowing problems should be determined following evaluation by an expert in the
field of speech-language pathology. Dieticians may help treat nutrition problems by recommending dietary
modifications, including high calorie foods or food supplements.
A feeding (gastrostomy) tube is recommended when any of the following occur:[56]
A child cannot eat enough to grow or a person of any age cannot eat enough to maintain weight;
Aspiration is problematic;
Mealtimes are stressful or too long, interfering with other activities.
Feeding tubes can decrease the risk of aspiration by enabling persons to avoid liquids or foods that are difficult
to swallow and provide adequate calories without the stress and time commitment of prolonged meals.
Gastrostomy tubes do not prevent people from eating by mouth. Once a tube is in place, the general goal should
be to maintain weight at the 10-25th percentile.
Education and socialization

Most children with A-T have difficulty in school because of a delay in response time to visual, verbal or other
cues, slurred and quiet speech (dysarthria), abnormalities of eye control (oculomotor apraxia), and impaired fine
motor control. Despite these problems, children with A-T often enjoy school if proper accommodations to their
disability can be made. The decision about the need for special education classes or extra help in regular classes
is highly influenced by the local resources available. Decisions about proper educational placement should be
revisited as often as circumstances warrant. Despite their many neurologic impairments, most individuals with
A-T are very socially aware and socially skilled, and thus benefit from sustained peer relationships developed at
school. Some individuals are able to function quite well despite their disabilities and a few have graduated from
community colleges.
Many of the problems encountered will benefit from special attention, as problems are often related more to
input and output issues than to intellectual impairment. Problems with eye movement control make it difficult
for people with A-T to read, yet most fully understand the meaning and nuances of text that is read to them.
Delays in speech initiation and lack of facial expression make it seem that they do not know the answers to
questions. Reduction of the skilled effort needed to answer questions, and an increase of the time available to
respond, is often rewarded by real accomplishment. It is important to recognize that intellectual disability is not
regularly a part of the clinical picture of A-T although school performance may be suboptimal because of the
many difficulties in reading, writing, and speech. Children with A-T are often very conscious of their
appearance, and strive to appear normal to their peers and teachers. Life within the ataxic body can be tiring.
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The enhanced effort needed to maintain appearances and increased energy expended in abnormal tone and extra
movements all contribute to physical and mental fatigue. As a consequence, for some a shortened school day
yields real benefits.
General recommendations:
All children with A-T need special attention to the barriers they experience in school. In the United
States, this takes the form of a formal IEP (Individualized Education Program).
Children with A-T tend to be excellent problem solvers. Their involvement in how to best perform tasks
should be encouraged.
Speech-language pathologists may facilitate communication skills that enable persons with A-T to get
their messages across (using key words vs. complete sentences) and teach strategies to decrease
frustration associated with the increase time needed to respond to questions (e.g., holding up a hand and
others about the need to allow more time for responses). Rarely helpful are traditional speech therapies
that focus on the production of specific sounds and strengthening of the lip and tongue muscles.
Classroom aides may be appropriate, especially to help with scribing, transportation through the school,
mealtimes and toileting. The impact of an aide on peer relationships should be monitored carefully.
Physical therapy is useful to maintain strength and general cardiovascular health. Horseback therapy and
exercises in a swimming pool are often well-tolerated and fun for people with A-T. However, no amount
of practice will slow the cerebellar degeneration or improve neurologic function. Exercise to the point of
exhaustion should be avoided.
Hearing is normal throughout life. Books on tape may be a useful adjunct to traditional school materials.
Early use of computers (preschool) with word completion software should be encouraged.
Practicing coordination (e.g. balance beam or cursive writing exercises) is not helpful.
Occupational therapy is helpful for managing daily living skills.
Allow rest time, shortened days, reduced class schedule, reduced homework, modified tests as necessary.
Like all children, those with A-T need to have goals to experience the satisfaction of making progress.
Social interactions with peers are important, and should be taken into consideration for class placement.
For everyone long-term peer relationships can be the most rewarding part of life; for those with A-T
establishing these connections in school years can be helpful.
Clinics and support

The US, UK, Australia, Israel, The Netherlands, Germany, Poland, Norway and Japan have specialized clinics
for patients with A-T. These clinics house multidisciplinary medical teams, including neurologists,
immunologists, pulmonologists and therapists, capable of dealing with the many facets of this disease.
Epidemiology
Individuals of all races and ethnicities are affected equally. The incidence world-wide is estimated to be
between 1 in 40,000 and 1 in 100,000 people.[3][57]
Prognosis
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The life expectancy of people with A-T is highly variable. The average is approximately 25 years, but continues
to improve with advances in care. The two most common causes of death are chronic lung disease (about onethird of cases) and cancer (about one-third of cases).
Research directions
An open-label Phase II clinical trial studying the use of red blood cells (erythrocytes) loaded with
dexamethasone sodium phosphate found that this treatment improved symptoms and appeared to be well
tolerated.[58] This treatment uses a unique delivery system for medication by using the patient's own red blood
cells as the delivery vehicle for the drug.[59] Given the other immunologic deficits present in individuals with
A-T, there remains a need to evaluate the therapeutic potential of steroids further, particularly with respect to the
duration of any benefit and its long-term safety.
References
1. Boder, E (1985). "Ataxia-telangiectasia: an overview.". Kroc Foundation series 19: 163. PMID 2415689
(https://www.ncbi.nlm.nih.gov/pubmed/2415689).
2. Savitsky, K; Bar-Shira, A, Gilad, S, Rotman, G, Ziv, Y, Vanagaite, L, Tagle, DA, Smith, S, Uziel, T, Sfez, S, Ashkenazi,
M, Pecker, I, Frydman, M, Harnik, R, Patanjali, SR, Simmons, A, Clines, GA, Sartiel, A, Gatti, RA, Chessa, L, Sanal, O,
Lavin, MF, Jaspers, NG, Taylor, AM, Arlett, CF, Miki, T, Weissman, SM, Lovett, M, Collins, FS, Shiloh, Y (Jun 23,
1995). "A single ataxia telangiectasia gene with a product similar to PI-3 kinase.". Science 268 (5218): 174953.
doi:10.1126/science.7792600 (https://dx.doi.org/10.1126%2Fscience.7792600). PMID 7792600
3. Shiloh, Y; Kastan, MB (2001). "ATM: genome stability, neuronal development, and cancer cross paths.". Advances in
cancer research 83: 20954. doi:10.1016/s0065-230x(01)83007-4 (https://dx.doi.org/10.1016%2Fs0065230x%2801%2983007-4). PMID 11665719 (https://www.ncbi.nlm.nih.gov/pubmed/11665719).
4. Crawford, TO (December 1998). "Ataxia telangiectasia.". Seminars in pediatric neurology 5 (4): 28794.
doi:10.1016/s1071-9091(98)80007-7 (https://dx.doi.org/10.1016%2Fs1071-9091%2898%2980007-7). PMID 9874856
5. Crawford, TO; Mandir, AS, Lefton-Greif, MA, Goodman, SN, Goodman, BK, Sengul, H, Lederman, HM (Apr 11,
2000). "Quantitative neurologic assessment of ataxia-telangiectasia.". Neurology 54 (7): 15059.
doi:10.1212/wnl.54.7.1505 (https://dx.doi.org/10.1212%2Fwnl.54.7.1505). PMID 10751267
6. Cabana, MD; Crawford, TO; Winkelstein, JA; Christensen, JR; Lederman, HM (July 1998). "Consequences of the
delayed diagnosis of ataxia-telangiectasia.". Pediatrics 102 (1 Pt 1): 98100. doi:10.1542/peds.102.1.98
(https://dx.doi.org/10.1542%2Fpeds.102.1.98). PMID 9651420 (https://www.ncbi.nlm.nih.gov/pubmed/9651420).
7. Nowak-Wegrzyn, A; Crawford, TO; Winkelstein, JA; Carson, KA; Lederman, HM (April 2004). "Immunodeficiency and
infections in ataxia-telangiectasia". The Journal of pediatrics 144 (4): 50511. doi:10.1016/j.jpeds.2003.12.046
(https://dx.doi.org/10.1016%2Fj.jpeds.2003.12.046). PMID 15069401
8. Reiman, A; Srinivasan, V, Barone, G, Last, JI, Wootton, LL, Davies, EG, Verhagen, MM, Willemsen, MA, Weemaes,
CM, Byrd, PJ, Izatt, L, Easton, DF, Thompson, DJ, Taylor, AM (Aug 9, 2011). "Lymphoid tumours and breast cancer in
ataxia telangiectasia; substantial protective effect of residual ATM kinase activity against childhood tumours."
(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3170966). British journal of cancer 105 (4): 58691.
doi:10.1038/bjc.2011.266 (https://dx.doi.org/10.1038%2Fbjc.2011.266). PMC 3170966
(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3170966). PMID 21792198
9. Thompson, D; Duedal, S; Kirner, J; McGuffog, L; Last, J; Reiman, A; Byrd, P; Taylor, M; Easton, DF (Jun 1, 2005).
"Cancer risks and mortality in heterozygous ATM mutation carriers.". Journal of the National Cancer Institute 97 (11):
Page 16 of 22
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
6/1/15, 1:59
"Cancer risks and mortality in heterozygous ATM mutation carriers.". Journal of the National Cancer Institute 97 (11):
81322. doi:10.1093/jnci/dji141 (https://dx.doi.org/10.1093%2Fjnci%2Fdji141). PMID 15928302
Renwick, A; Thompson, D, Seal, S, Kelly, P, Chagtai, T, Ahmed, M, North, B, Jayatilake, H, Barfoot, R, Spanova, K,
McGuffog, L, Evans, DG, Eccles, D, Breast Cancer Susceptibility Collaboration, (UK), Easton, DF, Stratton, MR,
Rahman, N (August 2006). "ATM mutations that cause ataxia-telangiectasia are breast cancer susceptibility alleles.".
Nature Genetics 38 (8): 8735. doi:10.1038/ng1837 (https://dx.doi.org/10.1038%2Fng1837). PMID 16832357
Paller, AS; Massey, RB, Curtis, MA, Pelachyk, JM, Dombrowski, HC, Leickly, FE, Swift, M (December 1991).
"Cutaneous granulomatous lesions in patients with ataxia-telangiectasia.". The Journal of pediatrics 119 (6): 91722.
doi:10.1016/s0022-3476(05)83043-4 (https://dx.doi.org/10.1016%2Fs0022-3476%2805%2983043-4). PMID 1960607
McGrath-Morrow, SA; Gower, WA, Rothblum-Oviatt, C, Brody, AS, Langston, C, Fan, LL, Lefton-Greif, MA,
Crawford, TO, Troche, M, Sandlund, JT, Auwaerter, PG, Easley, B, Loughlin, GM, Carroll, JL, Lederman, HM
(September 2010). "Evaluation and management of pulmonary disease in ataxia-telangiectasia.". Pediatric pulmonology
45 (9): 84759. doi:10.1002/ppul.21277 (https://dx.doi.org/10.1002%2Fppul.21277). PMID 20583220
Lefton-Greif, MA; Crawford, TO, Winkelstein, JA, Loughlin, GM, Koerner, CB, Zahurak, M, Lederman, HM (February
2000). "Oropharyngeal dysphagia and aspiration in patients with ataxia-telangiectasia.". The Journal of pediatrics 136
(2): 22531. doi:10.1016/s0022-3476(00)70106-5 (https://dx.doi.org/10.1016%2Fs0022-3476%2800%2970106-5).
PMID 10657830 (https://www.ncbi.nlm.nih.gov/pubmed/10657830).
Farr, AK; Shalev, B; Crawford, TO; Lederman, HM; Winkelstein, JA; Repka, MX (December 2002). "Ocular
manifestations of ataxia-telangiectasia.". American journal of ophthalmology 134 (6): 8916. doi:10.1016/s00029394(02)01796-8 (https://dx.doi.org/10.1016%2Fs0002-9394%2802%2901796-8). PMID 12470759
Savitsky, K; Bar-Shira, A, Gilad, S, Rotman, G, Ziv, Y, Vanagaite, L, Tagle, DA, Smith, S, Uziel, T, Sfez, S, Ashkenazi,
M, Pecker, I, Frydman, M, Harnik, R, Patanjali, SR, Simmons, A, Clines, GA, Sartiel, A, Gatti, RA, Chessa, L, Sanal, O,
Lavin, MF, Jaspers, NG, Taylor, AM, Arlett, CF, Miki, T, Weissman, SM, Lovett, M, Collins, FS, Shiloh, Y (Jun 23,
1995). "A single ataxia telangiectasia gene with a product similar to PI-3 kinase.". Science 268 (5218): 174953.
doi:10.1126/science.7792600 (https://dx.doi.org/10.1126%2Fscience.7792600). PMID 7792600
Derheimer, FA; Kastan, MB (Sep 10, 2010). "Multiple roles of ATM in monitoring and maintaining DNA integrity."
(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2950315). FEBS Letters 584 (17): 367581.
doi:10.1016/j.febslet.2010.05.031 (https://dx.doi.org/10.1016%2Fj.febslet.2010.05.031). PMC 2950315
Kurz, EU; Lees-Miller, SP (AugSep 2004). "DNA damage-induced activation of ATM and ATM-dependent signaling
pathways.". DNA repair 3 (8-9): 889900. doi:10.1016/j.dnarep.2004.03.029
(https://dx.doi.org/10.1016%2Fj.dnarep.2004.03.029). PMID 15279774
Dar, I; Biton, S; Shiloh, Y; Barzilai, A (Jul 19, 2006). "Analysis of the ataxia telangiectasia mutated-mediated DNA
damage response in murine cerebellar neurons.". The Journal of neuroscience : the official journal of the Society for
Neuroscience 26 (29): 776774. doi:10.1523/JNEUROSCI.2055-06.2006
(https://dx.doi.org/10.1523%2FJNEUROSCI.2055-06.2006). PMID 16855104
Gorodetsky, E; Calkins, S; Ahn, J; Brooks, PJ (November 2007). "ATM, the Mre11/Rad50/Nbs1 complex, and
topoisomerase I are concentrated in the nucleus of Purkinje neurons in the juvenile human brain."
(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2797317). DNA repair 6 (11): 1698707.
doi:10.1016/j.dnarep.2007.06.011 (https://dx.doi.org/10.1016%2Fj.dnarep.2007.06.011). PMC 2797317
Valentin-Vega, YA; Maclean, KH, Tait-Mulder, J, Milasta, S, Steeves, M, Dorsey, FC, Cleveland, JL, Green, DR, Kastan,
MB (Feb 9, 2012). "Mitochondrial dysfunction in ataxia-telangiectasia."
(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3286212). Blood 119 (6): 1490500. doi:10.1182/blood-2011-08-
Page 17 of 22
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
6/1/15, 1:59
(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3286212). Blood 119 (6): 1490500. doi:10.1182/blood-2011-08373639 (https://dx.doi.org/10.1182%2Fblood-2011-08-373639). PMC 3286212

Guo, Z; Kozlov, S; Lavin, MF; Person, MD; Paull, TT (Oct 22, 2010). "ATM activation by oxidative stress.". Science
330 (6003): 51721. doi:10.1126/science.1192912 (https://dx.doi.org/10.1126%2Fscience.1192912). PMID 20966255
Bakkenist, CJ; Kastan, MB (Jan 30, 2003). "DNA damage activates ATM through intermolecular autophosphorylation
and dimer dissociation.". Nature 421 (6922): 499506. doi:10.1038/nature01368
(https://dx.doi.org/10.1038%2Fnature01368). PMID 12556884 (https://www.ncbi.nlm.nih.gov/pubmed/12556884).
Kanu, N; Behrens, A (Nov 15, 2008). "ATMINistrating ATM signalling: regulation of ATM by ATMIN.". Cell cycle
(Georgetown, Tex.) 7 (22): 34836. doi:10.4161/cc.7.22.7044 (https://dx.doi.org/10.4161%2Fcc.7.22.7044).
Shiloh, Y (March 2003). "ATM and related protein kinases: safeguarding genome integrity.". Nature Reviews Cancer 3
(3): 15568. doi:10.1038/nrc1011 (https://dx.doi.org/10.1038%2Fnrc1011). PMID 12612651
Barlow, C; Hirotsune, S, Paylor, R, Liyanage, M, Eckhaus, M, Collins, F, Shiloh, Y, Crawley, JN, Ried, T, Tagle, D,
Wynshaw-Boris, A (Jul 12, 1996). "Atm-deficient mice: a paradigm of ataxia telangiectasia.". Cell 86 (1): 15971.
doi:10.1016/S0092-8674(00)80086-0 (https://dx.doi.org/10.1016%2FS0092-8674%2800%2980086-0). PMID 8689683
Plug, AW; Peters, AH, Xu, Y, Keegan, KS, Hoekstra, MF, Baltimore, D, de Boer, P, Ashley, T (December 1997). "ATM
and RPA in meiotic chromosome synapsis and recombination.". Nature Genetics 17 (4): 45761. doi:10.1038/ng1297457 (https://dx.doi.org/10.1038%2Fng1297-457). PMID 9398850 (https://www.ncbi.nlm.nih.gov/pubmed/9398850).
Barchi, M; Roig, I, Di Giacomo, M, de Rooij, DG, Keeney, S, Jasin, M (May 23, 2008). "ATM promotes the obligate XY
crossover and both crossover control and chromosome axis integrity on autosomes."
(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2374915). PLoS genetics 4 (5): e1000076.
doi:10.1371/journal.pgen.1000076 (https://dx.doi.org/10.1371%2Fjournal.pgen.1000076). PMC 2374915
Lumsden, JM; McCarty, T, Petiniot, LK, Shen, R, Barlow, C, Wynn, TA, Morse HC, 3rd, Gearhart, PJ, Wynshaw-Boris,
A, Max, EE, Hodes, RJ (Nov 1, 2004). "Immunoglobulin class switch recombination is impaired in Atm-deficient mice."
(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2211853). The Journal of experimental medicine 200 (9): 111121.
doi:10.1084/jem.20041074 (https://dx.doi.org/10.1084%2Fjem.20041074). PMC 2211853
Franco, S; Alt, FW; Manis, JP (Sep 8, 2006). "Pathways that suppress programmed DNA breaks from progressing to
chromosomal breaks and translocations.". DNA repair 5 (9-10): 103041. doi:10.1016/j.dnarep.2006.05.024
Calln, E; Jankovic, M, Wong, N, Zha, S, Chen, HT, Difilippantonio, S, Di Virgilio, M, Heidkamp, G, Alt, FW,
Nussenzweig, A, Nussenzweig, M (May 15, 2009). "Essential role for DNA-PKcs in DNA double-strand break repair
and apoptosis in ATM-deficient lymphocytes." (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2709792). Molecular
Cell 34 (3): 28597. doi:10.1016/j.molcel.2009.04.025 (https://dx.doi.org/10.1016%2Fj.molcel.2009.04.025).
PMC 2709792 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2709792). PMID 19450527
Bagley, J; Singh, G; Iacomini, J (Apr 15, 2007). "Regulation of oxidative stress responses by ataxia-telangiectasia
mutated is required for T cell proliferation.". Journal of Immunology (Baltimore, Md. : 1950) 178 (8): 475763.
doi:10.4049/jimmunol.178.8.4757 (https://dx.doi.org/10.4049%2Fjimmunol.178.8.4757). PMID 17404255
Bredemeyer, AL; Sharma, GG, Huang, CY, Helmink, BA, Walker, LM, Khor, KC, Nuskey, B, Sullivan, KE, Pandita,
TK, Bassing, CH, Sleckman, BP (Jul 27, 2006). "ATM stabilizes DNA double-strand-break complexes during V(D)J
recombination.". Nature 442 (7101): 46670. doi:10.1038/nature04866 (https://dx.doi.org/10.1038%2Fnature04866).
Page 18 of 22
6/1/15, 1:59
33. Bredemeyer, AL; Huang, CY; Walker, LM; Bassing, CH; Sleckman, BP (Aug 15, 2008). "Aberrant V(D)J recombination
in ataxia telangiectasia mutated-deficient lymphocytes is dependent on nonhomologous DNA end joining.". Journal of
Immunology (Baltimore, Md. : 1950) 181 (4): 26205. doi:10.4049/jimmunol.181.4.2620
(https://dx.doi.org/10.4049%2Fjimmunol.181.4.2620). PMID 18684952
34. Bredemeyer, AL; Helmink, BA, Innes, CL, Calderon, B, McGinnis, LM, Mahowald, GK, Gapud, EJ, Walker, LM,
Collins, JB, Weaver, BK, Mandik-Nayak, L, Schreiber, RD, Allen, PM, May, MJ, Paules, RS, Bassing, CH, Sleckman,
BP (Dec 11, 2008). "DNA double-strand breaks activate a multi-functional genetic program in developing lymphocytes."
(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2605662). Nature 456 (7223): 81923. doi:10.1038/nature07392
(https://dx.doi.org/10.1038%2Fnature07392). PMC 2605662 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2605662).
35. Calln, E; Jankovic, M, Difilippantonio, S, Daniel, JA, Chen, HT, Celeste, A, Pellegrini, M, McBride, K, Wangsa, D,
Bredemeyer, AL, Sleckman, BP, Ried, T, Nussenzweig, M, Nussenzweig, A (Jul 13, 2007). "ATM prevents the
persistence and propagation of chromosome breaks in lymphocytes.". Cell 130 (1): 6375.
doi:10.1016/j.cell.2007.06.016 (https://dx.doi.org/10.1016%2Fj.cell.2007.06.016). PMID 17599403
36. Shiloh, Y; Tabor, E; Becker, Y (July 1982). "Colony-forming ability of ataxia-telangiectasia skin fibroblasts is an
indicator of their early senescence and increased demand for growth factors.". Experimental cell research 140 (1): 191
9. doi:10.1016/0014-4827(82)90169-0 (https://dx.doi.org/10.1016%2F0014-4827%2882%2990169-0). PMID 6213420
37. Inomata, K; Aoto, T, Binh, NT, Okamoto, N, Tanimura, S, Wakayama, T, Iseki, S, Hara, E, Masunaga, T, Shimizu, H,
Nishimura, EK (Jun 12, 2009). "Genotoxic stress abrogates renewal of melanocyte stem cells by triggering their
differentiation.". Cell 137 (6): 108899. doi:10.1016/j.cell.2009.03.037
(https://dx.doi.org/10.1016%2Fj.cell.2009.03.037). PMID 19524511 (https://www.ncbi.nlm.nih.gov/pubmed/19524511).
38. Stray-Pedersen, A; Borresen-Dale, AL, Paus, E, Lindman, CR, Burgers, T, Abrahamsen, TG (November 2007). "Alpha
fetoprotein is increasing with age in ataxia-telangiectasia.". European journal of paediatric neurology : EJPN : official
journal of the European Paediatric Neurology Society 11 (6): 37580. doi:10.1016/j.ejpn.2007.04.001
(https://dx.doi.org/10.1016%2Fj.ejpn.2007.04.001). PMID 17540590
39. Biton, S; Dar, I; Mittelman, L; Pereg, Y; Barzilai, A; Shiloh, Y (Jun 23, 2006). "Nuclear ataxia-telangiectasia mutated
(ATM) mediates the cellular response to DNA double strand breaks in human neuron-like cells.". The Journal of
Biological Chemistry 281 (25): 1748291. doi:10.1074/jbc.M601895200
(https://dx.doi.org/10.1074%2Fjbc.M601895200). PMID 16627474 (https://www.ncbi.nlm.nih.gov/pubmed/16627474).
40. Herzog, KH; Chong, MJ; Kapsetaki, M; Morgan, JI; McKinnon, PJ (May 15, 1998). "Requirement for Atm in ionizing
radiation-induced cell death in the developing central nervous system.". Science 280 (5366): 108991.
doi:10.1126/science.280.5366.1089 (https://dx.doi.org/10.1126%2Fscience.280.5366.1089). PMID 9582124
41. Lee, Y; Chong, MJ; McKinnon, PJ (Sep 1, 2001). "Ataxia telangiectasia mutated-dependent apoptosis after genotoxic
stress in the developing nervous system is determined by cellular differentiation status.". The Journal of neuroscience :
the official journal of the Society for Neuroscience 21 (17): 668793. PMID 11517258
42. Sordet, O; Redon, CE, Guirouilh-Barbat, J, Smith, S, Solier, S, Douarre, C, Conti, C, Nakamura, AJ, Das, BB, Nicolas,
E, Kohn, KW, Bonner, WM, Pommier, Y (August 2009). "Ataxia telangiectasia mutated activation by transcription- and
topoisomerase I-induced DNA double-strand breaks." (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2726680).
EMBO Reports 10 (8): 88793. doi:10.1038/embor.2009.97 (https://dx.doi.org/10.1038%2Fembor.2009.97).
PMC 2726680 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2726680). PMID 19557000
43. Das, BB; Antony, S; Gupta, S; Dexheimer, TS; Redon, CE; Garfield, S; Shiloh, Y; Pommier, Y (Dec 2, 2009). "Optimal
function of the DNA repair enzyme TDP1 requires its phosphorylation by ATM and/or DNA-PK."
(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2790489). The EMBO Journal 28 (23): 366780.
doi:10.1038/emboj.2009.302 (https://dx.doi.org/10.1038%2Femboj.2009.302). PMC 2790489
Page 19 of 22
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
6/1/15, 1:59
Iourov, IY; Vorsanova, SG; Liehr, T; Kolotii, AD; Yurov, YB (Jul 15, 2009). "Increased chromosome instability
dramatically disrupts neural genome integrity and mediates cerebellar degeneration in the ataxia-telangiectasia brain.".
Human Molecular Genetics 18 (14): 265669. doi:10.1093/hmg/ddp207
(https://dx.doi.org/10.1093%2Fhmg%2Fddp207). PMID 19414482 (https://www.ncbi.nlm.nih.gov/pubmed/19414482).
Barzilai, A; Biton, S; Shiloh, Y (Jul 1, 2008). "The role of the DNA damage response in neuronal development,
organization and maintenance.". DNA repair 7 (7): 101027. doi:10.1016/j.dnarep.2008.03.005
Biton, S; Barzilai, A; Shiloh, Y (Jul 1, 2008). "The neurological phenotype of ataxia-telangiectasia: solving a persistent
puzzle.". DNA repair 7 (7): 102838. doi:10.1016/j.dnarep.2008.03.006
Yang, Y; Herrup, K (Mar 9, 2005). "Loss of neuronal cell cycle control in ataxia-telangiectasia: a unified disease
mechanism.". The Journal of neuroscience : the official journal of the Society for Neuroscience 25 (10): 25229.
doi:10.1523/JNEUROSCI.4946-04.2005 (https://dx.doi.org/10.1523%2FJNEUROSCI.4946-04.2005). PMID 15758161
Li, J; Han, YR; Plummer, MR; Herrup, K (Dec 29, 2009). "Cytoplasmic ATM in neurons modulates synaptic function."
(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2805770). Current biology : CB 19 (24): 20916.
doi:10.1016/j.cub.2009.10.039 (https://dx.doi.org/10.1016%2Fj.cub.2009.10.039). PMC 2805770
"Nuclear accumulation of HDAC4 in ATM deficiency promotes neurodegeneration in ataxia telangiectasia.". Nat Med 18
(5): 78390. May 2012. doi:10.1038/nm.2709 (https://dx.doi.org/10.1038%2Fnm.2709). PMID 22466704
"ATM and the epigenetics of the neuronal genome.". Mech Ageing Dev 134 (10): 4349. Oct 2013.
doi:10.1016/j.mad.2013.05.005 (https://dx.doi.org/10.1016%2Fj.mad.2013.05.005). PMID 23707635
Gatti, R.A.; Berkel I, Boder E, Braedt G, Charmley P, Concannon P, Ersoy F, Foroud T, Jaspers NG, Lange K, et al.
(1988). "Localization of an ataxia-telangiectasia gene to chromosome 11q22-23". Nature 336 (6199): 577580.
doi:10.1038/336577a0 (https://dx.doi.org/10.1038%2F336577a0). PMID 3200306
Sun, X; Becker-Catania, SG, Chun, HH, Hwang, MJ, Huo, Y, Wang, Z, Mitui, M, Sanal, O, Chessa, L, Crandall, B,
Gatti, RA (June 2002). "Early diagnosis of ataxia-telangiectasia using radiosensitivity testing.". The Journal of pediatrics
140 (6): 72431. doi:10.1067/mpd.2002.123879 (https://dx.doi.org/10.1067%2Fmpd.2002.123879). PMID 12072877
Chun, HH; Sun, X; Nahas, SA; Teraoka, S; Lai, CH; Concannon, P; Gatti, RA (December 2003). "Improved diagnostic
testing for ataxia-telangiectasia by immunoblotting of nuclear lysates for ATM protein expression.". Molecular genetics
and metabolism 80 (4): 43743. doi:10.1016/j.ymgme.2003.09.008
(https://dx.doi.org/10.1016%2Fj.ymgme.2003.09.008). PMID 14654357
Taylor, AM; Byrd, PJ (October 2005). "Molecular pathology of ataxia telangiectasia."
(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770730). Journal of clinical pathology 58 (10): 100915.
doi:10.1136/jcp.2005.026062 (https://dx.doi.org/10.1136%2Fjcp.2005.026062). PMC 1770730
Anheim, M; Tranchant, C; Koenig, M (Feb 16, 2012). "The autosomal recessive cerebellar ataxias.". The New England
Journal of Medicine 366 (7): 63646. doi:10.1056/NEJMra1006610 (https://dx.doi.org/10.1056%2FNEJMra1006610).
Lefton-Greif, MA; Crawford, TO; McGrath-Morrow, S; Carson, KA; Lederman, HM (May 15, 2011). "Safety and
caregiver satisfaction with gastrostomy in patients with Ataxia Telangiectasia."
(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3116459). Orphanet journal of rare diseases 6: 23. doi:10.1186/17501172-6-23 (https://dx.doi.org/10.1186%2F1750-1172-6-23). PMC 3116459
Page 20 of 22
6/1/15, 1:59

57. Swift, M; Morrell, D; Cromartie, E; Chamberlin, AR; Skolnick, MH; Bishop, DT (November 1986). "The incidence and
gene frequency of ataxia-telangiectasia in the United States." (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1684065).
American Journal of Human Genetics 39 (5): 57383. PMC 1684065
58. Chessa, L; Leuzzi, V; Plebani, A; Soresina, A; Micheli, R; D'Agnano, D; Venturi, T; Molinaro, A; Fazzi, E; Marini, M;
Ferremi Leali, P; Quinti, I; Cavaliere, FM; Girelli, G; Pietrogrande, MC; Finocchi, A; Tabolli, S; Abeni, D; Magnani, M
(Jan 9, 2014). "Intra-erythrocyte infusion of dexamethasone reduces neurological symptoms in ataxia teleangiectasia
patients: results of a phase 2 trial.". Orphanet journal of rare diseases 9 (1): 5. doi:10.1186/1750-1172-9-5
(https://dx.doi.org/10.1186%2F1750-1172-9-5). PMID 24405665 (https://www.ncbi.nlm.nih.gov/pubmed/24405665).
59. Yousefpour, P; Chilkoti, A (Sep 2014). "Co-opting biology to deliver drugs.". Biotechnology and Bioengineering 111 (9):
1699716. doi:10.1002/bit.25307 (https://dx.doi.org/10.1002%2Fbit.25307). PMID 24916780
External links
The A-T Children's Project (http://www.atcp.org)
Wobbly Feet Foundation, Inc. (http://www.wobblyfeet.org)
The UK AT Society (http://www.atsociety.org.uk)
Action for A-T Charity (http://www.actionforAT.org)
Asociacion Espanola Familia Ataxia-Telangiectasia (AEFAT) (http://www.aefat.es)
BrAshA-T, Australia (http://brashat.org.au)
Projeto AT/Brasil (http://www.projetoatbrasil.org.br)
Association Pour la Recherche sur l'A-T (APRAT) (http://www.aprat.fr)
AT Europe (http://www.ateurope.org/en)
AT Info, Germany (http://www.info-at.de)
Un Vero Sorriso Onlus (A-True Smile Association) (http://www.unverosorriso.it)
Gli Amici di Valentina (Friends of Valentina) (http://www.gliamicidivalentina.eu/HOME.html)
Team A-T, Japan (http://www.tmd.ac.jp/med/ped/atcp)
Stichting A-T, Netherlands (http://www.stichting-at.org)
Twan Foundation, Netherlands (http://www.twanfoundation.nl)
Razem Zdazymy (Together We are in Time) (http://www.razemzdazymy.org.pl)
FEAT (http://www.featmovie.com) An independent documentary to raise awareness for A-T
About A-T from the NINDS (http://www.ninds.nih.gov/disorders/a_t/a-t.htm)
Orphanet for A-T (http://www.orpha.net/consor/cgi-bin/OC_Exp.php?Lng=GB&Expert=100)
GeneReviews for Ataxia-Telangiectasia (http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?
book=gene&part=ataxia-telangiectas)
Replication-Independent Double-Strand Breaks (DSBs) (http://www.ncbi.nlm.nih.gov/books/bv.fcgi?
rid=eurekah.section.17952) Discusses importance of the ATM kinase
Cancer.Net: Ataxia-Telangiectasia (http://www.cancer.net/cancer-types/ataxia-telangiectasia)
Retrieved from "http://en.wikipedia.org/w/index.php?title=Ataxia_telangiectasia&oldid=654918883"
Categories: Chromosome instability syndromes Genodermatoses
Systemic atrophies primarily affecting the central nervous system Neurodegenerative disorders
IUIS-PID table 3 immunodeficiencies DNA replication and repair-deficiency disorders
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Ataxia telangiectasia - Wikipedia, the free encyclopedia

Ataxia telangiectasia (A-T) (also

It impairs certain areas of the

Ataxia telangiectasia - Wikipedia, the free encyclopedia

Ataxia telangiectasia - Wikipedia, the free encyclopedia

Delayed onset or incomplete pubertal development, and very early menopause

Ataxia and other neurologic problems

Ocular telangiectasia in a person with

Ataxia telangiectasia - Wikipedia, the free encyclopedia

Ataxia telangiectasia - Wikipedia, the free encyclopedia

Feeding, swallowing, and nutrition

Ataxia telangiectasia - Wikipedia, the free encyclopedia

Increase in the frequency or duration of breathing or respiratory problems

Eye and vision

Characteristics of the ATM

Cancer and radiosensitivity

Ataxia telangiectasia - Wikipedia, the free encyclopedia

Delayed pubertal development/Gonadal dysgenesis

Immune system defects and immune-related cancers

ATM and the immune system

Increased alpha-fetoprotein (AFP) levels

Ataxia telangiectasia - Wikipedia, the free encyclopedia

Genetics and information about A-T Carriers

Ataxia telangiectasia - Wikipedia, the free encyclopedia

A-T is inherited in an autosomal

Elevated and slowly increasing alpha-fetoprotein levels in serum

Ataxia telangiectasia - Wikipedia, the free encyclopedia

Ataxia telangiectasia - Wikipedia, the free encyclopedia

Ataxia telangiectasia - Wikipedia, the free encyclopedia

Ataxia and other neurologic problems

Ataxia telangiectasia - Wikipedia, the free encyclopedia

Ataxia telangiectasia - Wikipedia, the free encyclopedia

Feeding, swallowing and nutrition

Education and socialization

Ataxia telangiectasia - Wikipedia, the free encyclopedia

Clinics and support

Ataxia telangiectasia - Wikipedia, the free encyclopedia

Ataxia telangiectasia - Wikipedia, the free encyclopedia

Ataxia telangiectasia - Wikipedia, the free encyclopedia

(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3286212). Blood 119 (6): 1490500. doi:10.1182/blood-2011-08373639 (https://dx.doi.org/10.1182%2Fblood-2011-08-373639). PMC 3286212

Ataxia telangiectasia - Wikipedia, the free encyclopedia

Ataxia telangiectasia - Wikipedia, the free encyclopedia

Ataxia telangiectasia - Wikipedia, the free encyclopedia

(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3116459). PMID 21569628

Ataxia telangiectasia - Wikipedia, the free encyclopedia

This page was last modified on 4 April 2015, at 15:01.

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