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

  Falls, SD 57105, USA [email protected] [ncbi.nlm.nih.gov]

  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]

  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]

• Cerebral Palsy

  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]

  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]

• Recurrent Respiratory Infections

  We report the case of an 8-year-old girl who had experienced recurrent respiratory infection, cutaneous abscesses, and hepatosplenomegaly since the age of 2 years. [ncbi.nlm.nih.gov]

  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]

  Prognosis More than 50% of patients with ataxia-telangiectasia die of recurrent respiratory infections, and many of the remainder develop malignancies, such as leukemia or lymphomas. [emedicine.com]

  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]

• Recurrent Infection

  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]

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

  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]

• Short Stature

  A 9-year-old girl born to healthy parents showed manifestations suggestive of ataxia telangiectasia (AT), such as short stature, sudden short bouts of horizontal and rotary nystagmus, a weak and dysarthric voice, rolling gait, unstable posture, and atactic [ncbi.nlm.nih.gov]

  Patients with A-T exhibit high rates of malnutrition, a short stature and reduced lean body mass [14–17]. [erj.ersjournals.com]

  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]

  The endocrine system can also be involved in growth hormone deficiency, resulting in short stature and failure to grow, and gonadal failure, causing infertility.[13] Both of these symptoms are more frequent in females. [statpearls.com]

• 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. Aspiration is increasingly common. Some, but not all, individuals experience progressive cognitive dysfunction and academic impairments. [now.aapmr.org]

• Eye Movements Abnormal

  Eye movement abnormalities (80% of patients) with characteristic oculomotor apraxia, with nystagmus and various defects in saccade and gaze control (usually, abnormalities in head and neck posturing have been related to gaze impairment, because of an [raredisorders.imedpub.com]

• 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

  Group C ATAXIA-TELANGIECTASIA ATAXIA-TELANGIECTASIA; AT Ataxia Telangiectasia Louis-Bar Syndrome At, Complementation Group E At1 At, Complementation Group a Ataxia-Telangiectasia Variant At, Complementation Group D Immunodeficiency with ataxia telangiectasia [wikidata.org]

  Progressive cerebellar ataxia usually becomes clinically apparent when the child begins to walk. The ataxia affects station, gait, and intention. [emedicine.com]

• Cerebellar Ataxia

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

  Progressive cerebellar ataxia usually becomes clinically apparent when the child begins to walk. The ataxia affects station, gait, and intention. [emedicine.com]

• Slurred Speech

  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]

  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]

  Slurred speech (dysarthria) and drooling: The child with A-T may have slurred speech from very early years, and the speech may worsen at a highly individual rate. [atcp.org]

• Dysarthria

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

• Nystagmus

  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]

  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]

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

  fetoprotein increased levels of carcinoembryonic antigen reduced iga levels reduced ige levels reduced igg levels, particularly the igg2 subclass more Clinical features from OMIM: 208900 UMLS symptoms related to Ataxia-Telangiectasia: seizures, tremor [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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