Question

    Ataxia Telangiectasia

    Ataxia telangiectasia (AT) is a rare neurodegenerative disorder inherited through an autosomal recessive pattern, mainly characterized by a progressive neurologic impairment together with cerebellar ataxia.

    The disorder is related to the following process: hereditary.

    Presentation

    The severity of AT varies between the subjects. Ataxia is undoubtedly one of the most important sings, and among the first ones to appear between 3 and 5 years of age. This is soon followed by oculomotor apraxia, the difficulty in moving head and eye, together with frequent involuntary movements. These later result in more pronounced complications like difficulty in reading, writing, speaking or standing still, that soon end up including difficulty in eating and swallowing (dysphagia). As previously said, telangiectasia tends to appear later in life, between 5 and 8 years of age, especially on the sclera of the eye, making subjects appear bloodshot. This sign never results in bleeding or itching, and never changes or disappears in relation to time, weather or emotions.

    After this first stage the immune-related signs and complications begin to appear, like infections and increased cancer risk. Infections are the result of very low levels of lymphocytes (especially T-cells), and mainly tend to affect the respiratory track. Cancer, instead, tends to manifest itself in the form of lymphomas and leukemia, even though other forms of tumor might occur [17]. AT can also cause many complications in the skin, which mainly involve signs of early aging, vitiligo or chronic inflammatory skin diseases [18].

    Jaw & Teeth
    Drooling
    • Loss of muscle control often leads to drooling.[counsyl.com]
    • Supportive therapy is available to reduce the symptoms of drooling, twitching, and ataxia, but individual responses to specific medications vary.[encyclopedia.com]
    • Uncontrolled drooling is a frequent complaint with AT patients.[themedicalbiochemistrypage.org]
    • Other features of ataxia-telangiectasia that may affect some children are:diabetes mellitus, premature graying of the hair, difficulty swallowing causing choking and/or drooling and slowed growth.[atcp.org]
    • Ataxia is often accompanied by difficulty speaking ( dysarthria ), drooling; and an impaired ability to coordinate certain eye movements (oculomotor apraxia ), including the occurrence of involuntary, rapid, rhythmic motions (oscillations) of the eyes[webmd.com]
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  • Entire body system
    Cerebral Palsy
    • Persons with AT are often initially misdiagnosed as having cerebral palsy.[kennedykrieger.org]
    • Cerebral palsy (CP) describes a non-progressive disorder of motor function stemming from malformation or early damage to the brain.[en.wikipedia.org]
    • The most common early misdiagnosis is that of static encephalopathy — a brain dysfunction, or ataxic cerebral palsy — paralysis due to a birth defect.[encyclopedia.com]
    • Early identification and intervention in cerebral palsy.[ojrd.biomedcentral.com]
    • Cerebral palsy (CP) is a common misdiagnosis among not only A-T patients, but many others with progressive neurological disorders.[forgottendiseases.org]
    Difficulty Walking
    • Signs and symptoms of AT can include: difficulty walking – most children need to use a wheelchair by 10 years of age increasingly slurred, slow and unclear speech (dysarthria) difficulty swallowing (dysphagia) small spider-like clusters of red blood vessels[nhs.uk]
    • Ataxia-telangiectasia (A-T) is a hereditary condition characterized by progressive neurologic problems that lead to difficulty walking and an increased risk of developing various types of cancer.[cancer.net]
    • Affected children typically develop difficulty walking, problems with balance and hand coordination, involuntary jerking movements (chorea), muscle twitches (myoclonus), and disturbances in nerve function (neuropathy).[ghr.nlm.nih.gov]
    • walking, problems with balance and hand coordination, involuntary jerking movements (chorea), muscle twitches (myoclonus), and disturbances in nerve function (neuropathy).[chop.edu]
    Falling
    • Test Your Vocabulary Merriam-Webster's New Words Quiz—Fall 2017 Edition![merriam-webster.com]
    • They have an increased susceptibility to infection and often fall sick with respiratory system related illnesses.[news-medical.net]
    • Signs and symptoms of Friedreich's ataxia can include: problems with balance and co-ordination, often causing wobbliness, clumsiness and frequent falls increasingly slurred, slow and unclear speech (dysarthria) increasing weakness in the legs – many people[nhs.uk]
    • Physical therapy is highly recommended to maintain good muscular strength and avoid ruinous falls, which can be integrated with speech therapy in the attempt of improving the general conditions of the patients.[symptoma.com]
    • In their preschool years, children with A-T begin to stumble and fall, and drooling is frequent.[healthofchildren.com]
    Recurrent Infection
    • Even within families, in which the specific genetic defect should be the same, some children have mostly neurologic problems while others have recurrent infections, and still others have neither neurologic problems nor recurrent infections.[healthofchildren.com]
    • In the United States, where recurrent infections typical of the disorder are usually controlled by antibiotics , patients are at high risk of developing and dying of cancer, particularly leukemias and lymphomas.[cancer.gov]
    • Recurrent infections, particularly sinus and respiratory - due to decreased immunoglobulin A (IgA).[patient.info]
    • Mucociliary clearance is impaired following recurrent infections and aspiration, both commonly seen in A-T.[err.ersjournals.com]
    • Routine follow-up by a physician regarding immune status if an individual experiences recurrent infections.[chop.edu]
    Recurrent Respiratory Infections
    • Recurrent respiratory infections are another common feature of the disease.[dermnetnz.org]
    • This, in association with swallowing problems, makes them susceptible to recurrent respiratory infections.[kennedykrieger.org]
    • Many individuals with A-T have a weakened immune system, making them susceptible to recurrent respiratory infections.[brainfacts.org]
    • For most (about 70 percent) of children with A-T there is another clinical hallmark: immunodeficiency that usually brings recurrent respiratory infections.[atcp.org]
    • Recurrent respiratory infections decreased in frequency, duration and severity [ 12 , 23 ] and all children reported that i.v.[err.ersjournals.com]
    Short Stature
    • stature and delayed puberty) Increased risk to develop leukemia and lymphoma and rarely other cancers The physical features associated with AT can vary in severity among individuals depending upon whether the ATM protein is completely absent or not.[chop.edu]
    • 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.[en.wikipedia.org]
    • Nutritional effects on lung disease and immune function Several small cross-sectional studies have shown that patients with A-T exhibit high rates of malnutrition, short stature and reduced lean body mass [ 56 – 59 ] (E.[err.ersjournals.com]
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  • Face, Head & Neck
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  • neurologic
    Abnormal Gait
    • Most begin walking on time, but as noted, many have abnormal gaits that may be constistently wobbly and unsteady.[forgottendiseases.org]
    Ataxia
    • Ataxia telangiectasia (AT) is a rare neurodegenerative disorder inherited through an autosomal recessive pattern, mainly characterized by a progressive neurologic impairment together with cerebellar ataxia.[symptoma.com]
    • Friedreich's ataxia Friedreich's ataxia is the most common type of hereditary ataxia (caused by genes you've inherited).[nhs.uk]
    • Signs of Ataxia Telangiectasia to Watch for in Children Ataxia or progressive difficulty in coordinating movements is usually the first sign of ataxia telangiectasia.[news-medical.net]
    Delayed Development of Motor Skills
    • The first signs of the disease, which include delayed development of motor skills, poor balance, and slurred speech, usually occur during the first decade of life.[cancer.gov]
    Dysarthria
    • Signs and symptoms of Friedreich's ataxia can include: problems with balance and co-ordination, often causing wobbliness, clumsiness and frequent falls increasingly slurred, slow and unclear speech (dysarthria) increasing weakness in the legs – many people[nhs.uk]
    • Ataxia is often accompanied by difficulty speaking ( dysarthria ), drooling; and an impaired ability to coordinate certain eye movements (oculomotor apraxia ), including the occurrence of involuntary, rapid, rhythmic motions (oscillations) of the eyes[webmd.com]
    • 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.[en.wikipedia.org]
    • Medications can be taken to improve balance, coordination, and dysarthria.[oncofertility.northwestern.edu]
    • Neurological Neurological symptoms of A-T include: progressive cerebellar ataxia (although ataxia may appear static between the ages of two and five) cerebellar dysarthria (slurred speech) difficulty swallowing, causing choking and drooling progressive[encyclopedia.com]
    Neurologic Manifestation
    • This is the first large-scale clinical trial of any drug to treat the neurologic manifestations of AT.[innogest.it]
    • On the contrary, neurological manifestations are very hard to treat, and results remain mostly disappointing, apart from the use of beta-adrenergic blockers that might in some cases improve motor coordination.[symptoma.com]
    • Optimal management of these other changes – many of which are amenable to treatment – may help minimize the neurologic manifestations.[ojrd.biomedcentral.com]
    • TABLE 1 Clinical manifestations of ataxia telangiectasia The clinical picture of this condition can be very variable and the severity of the pulmonary, immunological and neurological manifestations varies widely between patients and is related to the[err.ersjournals.com]
    • A-T was not described as a distinct clinical entity for a further 16 years, when Boder and Sedgwick 2 and Biemond, 27 assisted by autopsies, reported organ developmental abnormalities, neurological manifestations and a third major characteristic of the[doi.org]
    Nystagmus
    • […] of skin areas exposed to sunlight Discoloration of skin (coffee-with-milk-colored spots) Enlarged blood vessels in skin of nose, ears, and inside of the elbow and knee Enlarged blood vessels in the whites of the eyes Jerky or abnormal eye movements ( nystagmus[medlineplus.gov]
    • During an episode, someone with episodic ataxia may experience: problems with balance and co-ordination slurred, slow and unclear speech (dysarthria) muscle spasms involuntary eye movements (nystagmus) vertigo , migraines and tinnitus Episodic ataxia[nhs.uk]
    • […] dysarthria ), drooling; and an impaired ability to coordinate certain eye movements (oculomotor apraxia ), including the occurrence of involuntary, rapid, rhythmic motions (oscillations) of the eyes while attempting to focus upon certain objects (fixation nystagmus[webmd.com]
    • Nystagmus —An involuntary, rhythmic movement of the eyes.[healthofchildren.com]
    Poor Coordination
    • coordination and balance (cerebellar ataxia ), red eyes due to widening of small blood vessels in the conjunctiva ( ocular telangiectasia), and recurrent sinus and lung infections.[medicinenet.com]
    • These two key features compose the general significance or meaning of what this condition is Children with Ataxia-Telangiectasia have poor coordination of movements, problems in maintaining posture, speech difficulties, and spider-like veins on the skin[dovemed.com]
    • The most important symptoms are as follows: Neurologic abnormalities resulting in poor coordination and an unsteady gait (ataxia).[healthofchildren.com]
    • The possible causes of restrictive patterns include suboptimal lung function testing through poor coordination while breathing, muscle fatigue, inspiratory muscle dysfunction, ILD and scoliosis or other chest wall deformity.[err.ersjournals.com]
    • Ataxia refers to poor coordination and telangiectasia to small dilated blood vessels, both of which are hallmarks of the disease.[en.wikipedia.org]
    Slurred Speech
    • Clinical Features Ataxia Telangiectasia (A-T) is characterized by early onset (1-4 years) progressive cerebellar ataxia, telangiectasias of the conjunctivae, oculomotor apraxia, choreoathetosis, immunodeficiency, slurred speech, frequent infections, and[preventiongenetics.com]
    • Their motor skills will develop slower than normal and they will have poor balance and slurred speech.[counsyl.com]
    • Children affected with A-T appear normal at birth; however, the first signs of the disease — usually a lack of balance and slurred speech — often appear between one and two years of age.[encyclopedia.com]
    • Two additional classic symptoms in AT patients is slurred speech and oculomotor apraxia (difficulty in moving the eyes from side to side).[themedicalbiochemistrypage.org]
    • Diazepam or Valium may be prescribed to help slurred speech and muscle contractions that are involuntary in nature.[news-medical.net]
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  • Skin
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  • respiratoric
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  • Workup

    The diagnosis of AT can be made firstly through physical examination, which should evaluate the presence of neurologic features, telangiectasia and infections. These should be confirmed by laboratory tests, through the detection of key abnormalities which include:

    • Elevated alpha-proteins levels, a protein playing a pivotal role in the virilization of female fetuses found in great quantities in the plasma of human fetus and in the plasma of people affected by AT.
    • Immunodeficiency associated with low levels of immunoglobulins and lymphocytes.
    • Increased sensitivity to X-ray exposure due to increased chromosomal breakage and fragility.
    • Cerebellar atrophy, which can be clearly detected by performing an MRI scan.
    • Absence or deficiency of ATM protein in cultured blood cells [19] [20].

    It would also be useful to perform a kinase assay, to detect the absence or deficiency of ATM function, and a genetic test, to detect mutations in both copies of ATM gene, even though these are not essential.

    Test Results

    Skin Test
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  • Laboratory

    Serum
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  • Treatment

    These is not a specific way to treat AT, and its treatment still remains palliative. One of the primary concerns for the patients if the presence of infections, which can be largely reduced by using antibodies. On the contrary, neurological manifestations are very hard to treat, and results remain mostly disappointing, apart from the use of beta-adrenergic blockers that might in some cases improve motor coordination.

    Physical therapy is highly recommended to maintain good muscular strength and avoid ruinous falls, which can be integrated with speech therapy in the attempt of improving the general conditions of the patients. In any case, these activities can only postpone confinement to wheelchair, which surely comes sooner or later.

    Prognosis

    AT is a progressive disease which inexorably degenerates the patient’s conditions. Patients generally find themselves wheelchair-dependent by the age of 15, even though there might be milder forms implying better clinical conditions. Signs tend to appear very early in life which later in life are followed by symptoms of spinocerebellar degeneration, like posterior cord complications or spinal muscular atrophy.

    Although classical treatment of AT might sometime give disappointing results, the new approach of the gene therapy holds great promises for patients in the future [16].

    Complications

    Acute Leukemia
    • Missense mutation and defective function of ATM in a childhood acute leukemia patient with MLL gene rearrangement.[ncbi.nlm.nih.gov]
    • Treatment of acute leukemia in children with ataxia telangiectasia (A-T).[ojrd.biomedcentral.com]
    Ataxia Telangiectasia
    • Tests and Diagnosis of Ataxia Telangiectasia Clinical evaluation is the basis for diagnosis of ataxia telangiectasia.[news-medical.net]
    • ATM and ataxia telangiectasia.[ghr.nlm.nih.gov]
    Bronchiectasis
    • The prevalence of bronchiectasis varied from 10% [ 17 ] to 47% [ 23 ] in these series.[err.ersjournals.com]
    • In children and adults with bronchiectasis, chronic antibiotic therapy should be considered to slow chronic lung disease progression.[en.wikipedia.org]
    • […] sinopulmonary infections, others have repeated infections and the incidence of infections in a third group is no higher than in their unaffected siblings. 29 Infections include otitis and sinusitis as well as recurrent pneumonia, which may progress to bronchiectasis[doi.org]
    Cerebellar Ataxia
    • It is characterised by multiple telangiectasias, cerebellar ataxia, pulmonary infections and immunodeficiency.[radiopaedia.org]
    • Patients with AT develop progressive cerebellar ataxia, abnormal eye movements, other neurologic abnormalities, oculocutaneous telangiectasias, and immune deficiency.[uptodate.com]
    • Description The onset of cerebellar ataxia (unsteadiness and lack of coordination) marks the beginning of progressive degeneration of the cerebellum , the part of the brain responsible for motor control (movement).[encyclopedia.com]
    • ataxia, telangiectasia, IgA deficiency, an enhanced frequency of malignancy and an enhanced level of spontaneous chromosome instability 2 .[nature.com]
    • Symptoms include: Decreased coordination of movements (ataxia) in late childhood that can include ataxic gait (cerebellar ataxia ), jerky gait, unsteadiness Decreasing mental development, slows or stops after age 10 to 12 Delayed walking Discoloration[medlineplus.gov]
    Diabetes Mellitus
    • Other features of the disease may include mild diabetes mellitus, premature aging and graying of the hair and slowed growth.[kennedykrieger.org]
    • Other features can include premature aging (e.g. grey hair) and insulin-resistant diabetes mellitus.[preventiongenetics.com]
    • Some patients may develop mild case of diabetes mellitus, and so glucose levels need to be closely monitored to check for insulin levels.[news-medical.net]
    • Other features of the disease may include mild diabetes mellitus, premature graying of the hair, difficulty swallowing, and delayed physical and sexual development.[brainfacts.org]
    Friedreich Ataxia
    • Friedreich's ataxia Friedreich's ataxia is the most common type of hereditary ataxia (caused by genes you've inherited).[nhs.uk]
    • However, Friedreich ataxia usually has a later onset.[encyclopedia.com]
    • Friedreich ataxia (FRDA) FRDA is a progressive neurological disorder.[forgottendiseases.org]
    • Pulmonary infections Sinus infections Bulbar dysfunction Recurrent aspiration Gonadal atrophy Dystonia Chorea Sensory neuropathy Growth restriction Differential diagnosis There is a need to differentiate from other autosomal recessive ataxias: [ 13 ] Friedreich's[patient.info]
    • Friedreich ataxia (FA) is the most common genetic cause of ataxia in children.[en.wikipedia.org]
    Hyperglycemia
    • […] absent deep tendon reflexes multiple skin changes including eczema and "coffee-with-milk"x colored spots incomplete development of tonsils, lymph nodes, and spleen (hypoplasia) seizures (any type) abnormal ovaries small testes high blood sugar levels (hyperglycemia[healthofchildren.com]
    Leukemia
    • The primary cancer risk in AT is the development of leukemia and lymphoma.[chop.edu]
    • Individuals with AT are predisposed to leukemia and lymphoma and are extremely sensitive to radiation exposure.[kennedykrieger.org]
    • Approximately 35%–40% of AT patients will develop cancers within their shortened life spans and approximately 85% of these cancers are leukemias or lymphomas.[themedicalbiochemistrypage.org]
    • About 20 percent of those with A-T develop cancer, most frequently acute lymphocytic leukemia or lymphoma.[cancer.gov]
    • Cancer, instead, tends to manifest itself in the form of lymphomas and leukemia, even though other forms of tumor might occur.[symptoma.com]
    Malignant Neoplasm
    Mental Retardation
    • Children with A-T usually have normal or above normal intelligence , but some cases of mental retardation have been reported.[healthofchildren.com]
    • Susceptibility to pulmonary infection, presence and degree of mental retardation and predisposition to leukaemia is variable in A-T and represents a tentative means of sub-classifying A-T.[doi.org]
    Recurrent Pneumonia
    • 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.[en.wikipedia.org]
    • Immune dysregulation in A-T can lead to recurrent pneumonia, bronchiectasis and ILD.[ojrd.biomedcentral.com]
    • pneumonia, which may progress to bronchiectasis and pulmonary fibrosis, severe enough to cause clubbing of fingers and toes, and, eventually, to respiratory insufficiency and death. 30 A-T patients are susceptible to common bacterial pathogens and viruses[doi.org]
    Scoliosis
    • Scoliosis varies from mild to severe.[err.ersjournals.com]
    • Early and continued physical therapy has been proven to slow muscle degeneration and minimize contractures and scoliosis (Gatti, R., GeneReviews. 2010; ncbi.nlm.nih.gov/books/NBK26468).[preventiongenetics.com]
    • […] increasingly slurred, slow and unclear speech (dysarthria) increasing weakness in the legs – many people find walking difficult and need to use a wheelchair after around 10 to 20 years difficulty swallowing (dysphagia) abnormal curvature of the spine (scoliosis[nhs.uk]
    • A-T patients do not generally have scoliosis.[forgottendiseases.org]
    • Severe scoliosis is relatively uncommon, but probably does occur more often than in those without A-T.[en.wikipedia.org]
    Sinusitis
    • An increased risk of infections caused by bacteria and viruses is also seen in people with A-T, most commonly affecting the lungs and sinuses.[immunedisease.com]
    • […] and on their cheeks (telangiectasias) very slow eye movements, which may mean the person has to move their head a lot to compensate for this a weakened immune system – children with AT are more vulnerable to infections, particularly infections of the sinuses[nhs.uk]
    • Culturing of the sinuses may be needed to direct antibiotic therapy.[en.wikipedia.org]
    • […] skin condition) Other symptoms Other manifestations of A-T include: susceptibility to neoplasms (tumors or growths) endocrine abnormalities tendency to develop insulin-resistant diabetes in adolescence recurrent sinopulmonary infection (involving the sinuses[encyclopedia.com]
    • Pneumonia is common, as is sinusitis, ear infections, diarrhea, and skin infections.[forgottendiseases.org]
    Strabismus
    Telangiectasis
    • Telangiectasis is not exclusively ocular and may also appear in the butterfly regions of the face and on the ears.[doi.org]
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  • Etiology

    AT is caused by the mutations occurring in the gene of ataxia telangiectasia mutated (ATM) [3], a serine/threonine protein kinase on the chromosome 11. In particular, ATM phosphorylates several key proteins involved in the repair of double-strand DNA breaks, such as p53, CHK2 and H2AX, all examples of tumor suppressors. In other words, ATM plays a pivotal role in regulating cell response to external stressful stimuli, by recognizing the damaged DNA and activating DNA repair machinery and cell cycle checkpoints, to make sure the cell does not replicate the mutated nucleic acid sequences [4].

    Epidemiology

    AT can be seen in all regions of the world, with a probable incidence of 1 case in 100,000 births [5] and a frequency of around 1.4 to 2% in the general population [5] [6]. Death frequently comes from bronchopulmonary infections or malignancy, at the average age of 20 years [6]. AT has been associated with a risk of cancer ranging from 10% to 38% [7] [8] [9], a rate which is about 100 times higher than that of the general population [10].

    No difference has been found in the incidence and prevalence of AT between females and males. Furthermore, AT can been found in all races, even though the mortality ratio varies according to the ethnic group considered, perhaps due to the frequently marked difference in terms of social and economical conditions. In addition, while ataxia usually appears very soon in the first years of life, telangiectasia tends to appear later between 3 and 6 years of age.

    Sex distribution
    Age distribution

    Pathophysiology

    Although the breakpoints on the DNA are randomly distributed, chromosome rearrangements tend to affect chromosomes 7 and 14, especially around the loci of T-cell receptors and heavy-chain immunoglobulin, whose expression therefore is severely affected. This might be the reason for the high frequency of infections and neoplasias among AT subjects, which can easily occur for a marked immunodeficiency. Furthermore ATM targets include well-known tumor suppressors like p53, TP53 or BRCA 1, all plying a pivotal role in the predisposition to cancer. This might explain the consistently reported increased risk of breast cancer among women [11], which however is not associated with a consequent increased frequency for this tumor [12].

    AT has an important role in neurodevelopment, due to its proapoptotic function performed together with BAX [13], another key proapoptotic factor, which is essential during cell differentiation. AT has even been liked to accelerated telomere loss [14] [15], a mechanism believed by experts to be responsible for the other key signs of AT like neurologic disease, thymus aplasia, telangiectasias, and growth retardation. These elements taken together suggest the possible important role of AT in eliminating neurons with severe DNA damages during CNS development.

    Prevention

    Being a genetic condition, no preventive measure can be given for AT. However, families at risk are strongly recommended to have a prenatal test done.

    Summary

    Ataxia refers to the neurological sign consisting of a severe impairment of muscle movement coordination usually coupled with a gait abnormality. This condition occurs as non-specific clinical manifestation indicating serious dysfunctions of the parts of the nervous system that control movements like the cerebellum. Telangiectasia, instead, refers to small dilated blood vessels, 0.5 to 1.0 mm in diameter [1] appearing on the surface of skin, usually on the face, nose, cheeks, and chin. In other words, the subjects affected by ataxia telangiectasia (AT) show motor incoordination together with signs of telangiectasia, especially over the sclera of the eye, both of them seen as hallmarks of this particular disorder [2].

    The signs of AT generally appear during childhood, when children begin to show mobility problems and difficulties in standing still or sitting. They are soon followed by difficulties in speech and in other functions and systems, such as swallowing problems and infections of the respiratory tract, which underline the progressive pattern of this disorder.

    Patient Information

    Ataxia telangiectasia (AT) is a rare inherited neurodegenerative disorder mainly characterized by a progressive neurologic impairment together with motor incoordination. The signs of AT generally appear during childhood, when children begin to show mobility problems and difficulties in standing still or sitting. They are soon followed by difficulties in speech and in other functions and systems, such as swallowing problems and infections to the respiratory track, which underline the progressive pattern of this disorder.

    AT is caused by the mutations occurring in the gene of ataxia telangiectasia mutated (ATM), a molecule which participates in the regulation of several key proteins involved in DNA repair. In other words, ATM plays a pivotal role in regulating cell response to external stressful stimuli, by recognizing the damaged DNA and activating DNA repair machinery, to make sure the cell does not replicate mutated nucleic acid sequences.

    The name of the disorder indicates its two most important signs. Ataxia (difficulty in movement coordination) appears very soon between 3 and 5 years of age, followed by oculomotor apraxia, the difficulty in moving head and eye, together with frequent involuntary movements. These later result in more pronounced symptoms like difficulty in reading, writing, speaking or standing still, that soon end up including difficulty in eating and swallowing. Telangiectasia, that is the appearance of small dilated blood vessels of the surface of the skin, tends to appear later in life, between 5 and 8 years of age, especially on the sclera of the eye, making subjects appear bloodshot. This sign never results in bleeding or itching, and never changes or disappears in relation to time, weather or emotions.

    After this first stage the immune-related signs and complications begin to appear, like infections and increased cancer risk. Infections are the result of very low levels of lymphocytes (especially T-cells), and mainly tend to affect the respiratory track. Cancer, instead, tends to manifest itself in the form of lymphomas and leukemia, even though other forms of tumor might occur. AT is a progressive disease and patients generally find themselves wheelchair-dependent by the age of 15, even though there might be milder forms implying better clinical conditions.

    Being a genetic condition, no preventive measure can be given for AT. However, families at risk are strongly recommended to have a prenatal test done.

    Self-assessment

    References

    1. Goldman MP. Sclerotherapy treatment of varicose and telangiectatic leg veins (2nd ed.). 1995 St. Louis: Mosby. 
    2. Boder E. Ataxia-telangiectasia: an overview. Kroc Foundation series 1985 19: 1–63. 
    3. Savitsky K, Bar-Shira A, Gilad S, Rotman G, Ziv Y, Vanagaite L, et al. A single ataxia telangiectasia gene with a product similar to PI-3 kinase. Science 1995 268 (5218): 1749–53. 
    4. Shiloh Y, Kastan MB. ATM: genome stability, neuronal development, and cancer cross paths. Advances in cancer research 2001 83: 209–54. 
    5. Swift M, Morrell D, Cromartie E, Chamberlin AR, Skolnick MH, Bishop DT. The incidence and gene frequency of ataxia-telangiectasia in the United States. Am J Hum Genet. Nov 1986;39(5):573-83. 
    6. Su Y, Swift M. Mortality rates among carriers of ataxia-telangiectasia mutant alleles. Ann Intern Med. Nov 21 2000;133(10):770-8. 
    7. Morrell D, Chase CL, Swift M. Cancers in 44 families with ataxia-telangiectasia. Cancer Genet Cytogenet. Nov 1 1990;50(1):119-23. 
    8. Olsen JH, Hahnemann JM, Borresen-Dale AL, Brondum-Nielsen K, Hammarstrom L, Kleinerman R, et al. Cancer in patients with ataxia-telangiectasia and in their relatives in the nordic countries. J Natl Cancer Inst. Jan 17 2001;93(2):121-7. 
    9. Spector BD, Filipovich AH, Perry GS, et al. Epidemiology of cancer in ataxia-telangiectasia. In: Bridges BA, Harnden DG, eds. Ataxia-Telangiectasia: A Cellular and Molecular Link Between Cancer, Neuropathology, and Immune Deficiency. New York, NY: Wiley; 1982:103-37. 
    10. Morrell D, Cromartie E, Swift M. Mortality and cancer incidence in 263 patients with ataxia-telangiectasia. J Natl Cancer Inst. Jul 1986;77(1):89-92. 
    11. Lee KM, Choi JY, Park SK, Chung HW, Ahn B, Yoo KY, et al. Genetic polymorphisms of ataxia telangiectasia mutated and breast cancer risk. Cancer Epidemiol Biomarkers Prev. Apr 2005;14(4):821-5. 
    12. Byrd PJ, Srinivasan V, Last JI, Smith A, Biggs P, Carney EF, et al. Severe reaction to radiotherapy for breast cancer as the presenting feature of ataxia telangiectasia. Br J Cancer. Dec 6 2011. 
    13. Frappart PO, McKinnon PJ. Mouse models of DNA double-strand break repair and neurological disease. DNA Repair (Amst). Jul 1 2008;7(7):1051-60. 
    14. Senior K. DNA damage mechanisms in ataxia telangiectasia. Lancet Neurol. 2003;2(3):139. 
    15. Qi L, Strong MA, Karim BO, Armanios M, Huso DL, Greider CW. Short telomeres and ataxia-telangiectasia mutated deficiency cooperatively increase telomere dysfunction and suppress tumorigenesis. Cancer Res. Dec 1 2003;63(23):8188-96. 
    16. Chaudhary MW, Al-Baradie RS. Ataxia-telangiectasia: future prospects. Appl Clin Genet. 2014;7:159-67. 
    17. Reiman A, Srinivasan V, Barone G, Last JI, Wootton LL, Davies,EG, et al. Lymphoid tumours and breast cancer in ataxia telangiectasia; substantial protective effect of residual ATM kinase activity against childhood tumours. British journal of cancer 2011 105 (4): 586–91. 
    18. Paller AS, Massey RB, Curtis MA, et al. Cutaneous granulomatous lesions in patients with ataxia-telangiectasia. The Journal of pediatrics 1991 119 (6): 917–22. 
    19. Chun HH, Sun X, Nahas SA, et al. Improved diagnostic testing for ataxia-telangiectasia by immunoblotting of nuclear lysates for ATM protein expression. Molecular genetics and metabolism 2003 80 (4): 437–43. 
    20. Taylor AM, Byrd PJ. Molecular pathology of ataxia telangiectasia. Journal of clinical pathology 2005 58 (10): 1009–15. 

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