Ataxia-telangiectasia

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Ataxia-telangiectasia (AT or A-T), also referred to as ataxia-telangiectasia syndrome or Louis-Bar syndrome, is a rare, neurodegenerative, autosomal recessive disease causing severe disability. Ataxia refers to poor coordination and telangiectasia to small dilated blood vessels, both of which are hallmarks of the disease.

A-T affects many parts of the body:

It impairs certain areas of the brain including the cerebellum, causing difficulty with movement and coordination.
It weakens the immune system, causing a predisposition to infection.
It prevents repair of broken DNA, increasing the risk of cancer.

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 their 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 4-5 years of life, but begin to show increasing problems in early school years.

A-T is caused by a defect in the ATM gene, which is responsible for managing the cell's 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. The condition occurs in about 1 in 70,000 people.

Video Ataxia-telangiectasia

Symptoms

There is substantial variability in the severity of features of A-T among 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 5-8 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)
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. 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 coordination 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 5-8 years, but sometimes later or not at all. The absence of telangiectasia does not exclude the diagnosis of A-T. 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.

Immune problems

About two-thirds of people with A-T have abnormalities of the immune system. The most common abnormalities are low levels of one or more classes of immunoglobulins (IgG, IgA or IgM subclasses), not making antibodies in response to vaccines or infections, and having low numbers of lymphocytes (especially T-lymphocytes) 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. 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. 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 auto-immune 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).

Lung disease

Chronic lung disease develops in more than 25% of people with A-T. 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 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, making 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, increasing 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. 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 self-feeding 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
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.
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.

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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). 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.

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.

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, 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.

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. 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).

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. 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.

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. 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.

Neurodegeneration

A-T is one of several DNA repair disorders which result 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). 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 which can lead to
- Failed clearance of genomically damaged neurons during development
- Transcription stress and abortive transcription including topoisomerase 1 cleavage complex (TOP1cc) dependent lesions
- Aneuploidy
Defective response to oxidative stress characterized by elevated ROS and altered cellular metabolism
Mitochondrial dysfunction
Defects in neuronal function:
- Inappropriate cell cycle re-entry of post-mitotic (mature) neurons
- Synaptic/vesicular dysregulation
- HDAC4 dysregulation
- Histone hypermethylation and altered epigenetics
Altered protein turnover

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.

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Genetics and information about A-T carriers

A-T is caused by mutations in the ATM (ATM serine/threonine kinase or ataxia-telangiectasia mutated) gene, which was cloned in 1995. ATM is located on human chromosome 11 (11q22.3) and is made up of 69 exons spread across 150kb of genomic DNA.

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 child's 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.

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 whether 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).

Ataxia-Telangiectasia | Hereditary Ocular Diseases

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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 person's 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:

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)
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, an absence or deficiency of ATM function (kinase assay), or mutations in both copies of the cell's ATM gene. These more specialized tests are not always needed, but are particularly helpful if a child's symptoms are atypical.

Differential diagnosis

There are several other disorders with similar symptoms or laboratory features that physicians may consider when diagnosing A-T. The three most common disorders that are sometimes confused with A-T are:

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. Cogan's 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 5-33 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 differentiation of the two. Individuals with AOA1 have a normal AFP, normal measures of immune function, and after 10-15 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 ataxia, hypersensitivity to ionizing radiation and genomic instability. Those rare individuals with ATLD who are well described differ from 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.

Molecular pathology of ataxia telangiectasia | Journal of Clinical ...

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