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].

• Falling

  Given that complementation analysis has demonstrated the genetic heterogeneity of A-T, the A-T heterozygote frequency will probably fall between 0.68% and 7.7%, with 2.8% being the most likely estimate. [ncbi.nlm.nih.gov]

  All household members should receive an influenza vaccination every fall. [primaryimmune.org]

  They have an increased susceptibility to infection and often fall sick with respiratory system related illnesses. Tests and Diagnosis of Ataxia Telangiectasia Clinical evaluation is the basis for diagnosis of ataxia telangiectasia. [news-medical.net]

  Das sludged blood-Phänomen an den Bindehautgefäßen von Fall 2 wird im Zusammenhang mit dem Louis-Bar-Syndrom erstmals mitgeteilt. Als außergewöhnlich muß bei Fall 3 die Diagnosestellung im Alter von nur 12 Monaten gelten. [link.springer.com]

• Recurrent Respiratory Infections

  Symptoms Uncoordinated movements (ataxia) Poor balance Slurred speech Feeding and swallowing problems Spider veins (telangiectasia) on the whites of the eyes Stunted physical growth and sexual development Immunodeficiency Recurrent respiratory infections [hopkinsmedicine.org]

  Many patients have recurrent respiratory infections. Leukemia or lymphomas are seen in 10-15% of patients and may be the presenting finding. Some patients are not recognized to have AT until the second decade of life. [esid.org]

  This, in association with swallowing problems, makes them susceptible to recurrent respiratory infections. Other features of the disease may include mild diabetes mellitus, premature aging and graying of the hair and slowed growth. [kennedykrieger.org]

  Many individuals with A-T have a weakened immune system, making them susceptible to recurrent respiratory infections. [ninds.nih.gov]

  Ataxia-telangiectasia is a rare inherited multisystem disorder that is characterised by: Ataxia (lack of co-ordination) Telangiectases on the skin and eyes Severe combined immunodeficiency resulting in recurrent respiratory infections A predisposition [dermnetnz.org]

• Cerebral Palsy

  Persons with AT are often initially misdiagnosed as having cerebral palsy. Individuals with AT are predisposed to leukemia and lymphoma and are extremely sensitive to radiation exposure. Many individuals with AT have a weakened immune system. [kennedykrieger.org]

  Dystonic/dyskinetic cerebral palsy was diagnosed at the age of 3 years. At age 6 he was diagnosed with asthma based on recurrent wheezing episodes. [ncbi.nlm.nih.gov]

  View Article PubMed Google Scholar Sleigh G, Brocklehurst P: Gastrostomy feeding in cerebral palsy: a systematic review. Arch Dis Child. 2004, 89: 534-539. [doi.org]

• Recurrent Infection

  Some of the complications of A-T include cancer (typically leukemia or lymphoma), recurrent infections and chronic lung disease. [hopkinsmedicine.org]

  Ataxia-telangiectasia (A-T) is an autosomal recessive primary immunodeficiency disease characterized by progressive cerebellar ataxia, telangiectasia, sinopulmoner recurrent infections, and cancer susceptibility. [ncbi.nlm.nih.gov]

  A total of 71 children (90%) initially presented with ataxia, 16% presented with recurrent infections, and 5% presented with ocular telangiectasias. [pediatrics.aappublications.org]

  Faults in the immune system may lead to recurrent infections. [royalpapworth.nhs.uk]

• Difficulty Walking

  Most patients begin to have difficulty walking at the end of the first year of life and are wheelchair bound by the teenage years. Ocular or facial telangiectasia are usually noted at 4-8 years of life. [esid.org]

  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). [medlineplus.gov]

  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. Signs of A-T often develop in childhood. [cancer.net]

  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]

  The first indication generally is difficulty walking (gait ataxia). The condition typically progresses to the arms and trunk. Muscles weaken and waste away over time, causing deformities, particularly in your feet, lower legs and hands. [medtransacademy.com]

• Abnormal Eye Movement

  A clinical diagnosis of A‐T in early childhood can be made based on the presence of ataxia of both upper and lower limbs, ocular telangiectasia, and abnormal eye movements. [onlinelibrary.wiley.com]

  Onset usually occurs between 1 and 2 years of age with abnormal head movements and loss of balance, followed by slurred speech and abnormal eye movements. [orpha.net]

  […] 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 [nlm.nih.gov]

• Strabismus

  Twenty-four of 63 patients (38%) had strabismus. Esodeviations were the most common, seen in 15 individuals. Apraxia of horizontal gaze was observed in 19 of 63 patients (30%). [ncbi.nlm.nih.gov]

  Ocular signs are prominent and in addition to bulbar conjunctival telangiectasia include nystagmus, ocular motor apraxic movements, strabismus, frequent loss of optokinetic responses, and poor convergence ability. [jamanetwork.com]

  Strabismus and nystagmus may also be present. Telangiectasia of the conjunctiva develops between the ages of 3 and 5 years. In one study, 91% of AT patients had conjunctival telangiectasia. [aao.org]

  Acquired strabismus may be seen and aspiration is increasingly common. [now.aapmr.org]

• Cutaneous Manifestation

  We present an unusual case of a child in whom the primary cutaneous manifestation of AT was noninfectious cutaneous caseating granulomas. [ncbi.nlm.nih.gov]

  S.: Ataxia-Telangiectasia: A syndrome with characteristic cutaneous manifestations. Arch. Derm. 82, 927 (1960). Google Scholar 56. Young, R. R., Austen, K. F., Moser, H. W.: Ataxia-Telangiectasia and the thymus. Trans. Amer. neurol. [link.springer.com]

• Cafe-Au-Lait Spots

  30%) HP:0000819 32 neurological speech impairment 58 Very frequent (99-80%) 33 abnormality of eye movement 58 Very frequent (99-80%) 34 cafe-au-lait spot 31 HP:0000957 35 myoclonus 31 HP:0001336 36 immunodeficiency 58 Very frequent (99-80%) 37 abnormality [malacards.org]

• Ataxia

  Tests and Diagnosis of Ataxia Telangiectasia Clinical evaluation is the basis for diagnosis of ataxia telangiectasia. [news-medical.net]

  By adolescence, many people with ataxia-telangiectasia will require a wheelchair. What causes ataxia-telangiectasia? Ataxia-telangiectasia is caused by changes in a gene known as ATM. [stjude.org]

• Cerebellar Ataxia

  Definitive Male or female patient with either increased radiation induced chromosomal breakage in cultured cells, or progressive cerebellar ataxia, who has disabling mutations on both alleles of ATM. [esid.org]

  Hallmarks of the disease comprise progressive cerebellar ataxia, oculocutaneous telangiectasiae, cancer susceptibility, and variable humoral and cellular immunodeficiency. [ncbi.nlm.nih.gov]

  Ataxia-telangiectasia results from a DNA repair defect that frequently results in humoral and cellular deficiency; it causes progressive cerebellar ataxia, oculocutaneous telangiectasias, and recurrent sinopulmonary infections. [msdmanuals.com]

  It is characterized by multiple telangiectasias, cerebellar ataxia, pulmonary infections, and immunodeficiency. [radiopaedia.org]

• Slurred Speech

  Symptoms Uncoordinated movements (ataxia) Poor balance Slurred speech Feeding and swallowing problems Spider veins (telangiectasia) on the whites of the eyes Stunted physical growth and sexual development Immunodeficiency Recurrent respiratory infections [hopkinsmedicine.org]

  Symptoms include slurred speech, poor balance, lack of muscle control, and tiny red spider veins in the corners of the eyes or on the ears and cheeks. There is no cure. It is managed by treating the symptoms. [cedars-sinai.org]

  Symptoms may include: Poor balance and slurred speech Lack of muscle control (ataxia). This causes an awkward gait when walking. Tiny red “spider” veins (telangiectasias) in the corners of the eyes or on the ears and cheeks. [stanfordchildrens.org]

  We describe a 17-year-old boy with slurred speech, mild motor delays and learning disability diagnosed with atypical A-T in the setting of T-cell acute lymphoblastic leukemia. [ncbi.nlm.nih.gov]

  Slurred speech Slurred speech is also found in early stage of the disease.. Occurs due to involvement of cerebellum.. Slurred speech Slurred speech is also found in early stage of the disease.. Occurs due to involvement of cerebellum.. [medicaljoyworks.com]

• Nystagmus

  Less striking elements of ataxia-telangiectasia include familial occurrence, choreoathetosis, hyporeflexia, drooling, dysarthric speech, retardation of statural growth, pseudo-ophthalmoplegia, and fixation nystagmus.5 In the present study, three siblings [jamanetwork.com]

  Abnormal ocular movements were seen in 13/15 (saccadic intrusion in 8 and nystagmus in 5). Using ICARS scale, 13/15 children presented gaze-evoked nystagmus, 4/15 a clearly saccadic pursuit, and 11/15 dysmetria of saccades. [ncbi.nlm.nih.gov]

  Clinical examination revealed bilateral ataxia with wide-based gait, downbeat nystagmus, mild dysarthria, and brisk reflexes. Brain MRI showed moderate to severe bilateral cerebellar atrophy (figure, A). [ng.neurology.org]

  Speech becomes slurred, choreoathetoid movements and nystagmus develop, and muscle weakness usually progresses to muscle atrophy. [msdmanuals.com]

• 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]

  AT manifests as ataxia, apraxia, telangiectasia, and dysarthria. Common ophthalmologic findings in AT include fine conjunctival telangiectasia. [ncbi.nlm.nih.gov]

  By 5 to 15 years, increased falling and overt dysmetria are usually present, and oropharyngeal dysphagia, dysarthria, and oculocutaneous telangiectasias first notable in the bulbar conjunctivae usually develop. [now.aapmr.org]

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.

• Alpha Fetoprotein Increased

  Affected individuals tend to have high amounts of a protein called alpha-fetoprotein (AFP) in their blood. [malacards.org]

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.

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].

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].

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.

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.

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.

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.

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.

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