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Ataxia Telangiectasia

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.


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].

Falling
  • Falls, SD 57105, USA david.pearce@sanfordhealth.org.[ncbi.nlm.nih.gov]
  • 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]
  • 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]
  • 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]
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]
  • The most common misdiagnosis was cerebral palsy (29/48 cases). Twenty-one children (4 with AT) were born after the start of symptoms in the index case, but before the establishment of a diagnosis.[ncbi.nlm.nih.gov]
  • The most common misdiagnosis was cerebral palsy (29/48 cases). Twenty-one children (4 with AT) were born after the start of symptoms in the index case, but before the establishment of a diagnosis. Conclusions . [doi.org]
  • 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]
  • 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]
  • 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]
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]
  • BACKGROUND: Ataxia telangiectasia (AT) is a primary immunodeficiency associated with recurrent infections.[ncbi.nlm.nih.gov]
  • Faults in the immune system may lead to recurrent infections.[royalpapworth.nhs.uk]
  • Recurrent infections, particularly sinus and respiratory - due to decreased immunoglobulin A (IgA). Telangiectasias develop from about the age of 3 years and may not be present until the age of 10 years, but will be present in all cases.[patient.info]
  • 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]
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).[ghr.nlm.nih.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]
  • They have more and more difficulty walking and usually need to use a wheelchair for at least part of the day by the age of 10-12 years. They develop an intention tremor, and difficulties with speaking (dysarthria) and swallowing (dysphagia).[primaryimmune.org]
Drooling
  • In contrast, she showed symptoms not generally related to AT, including microcephaly, profound motor and mental retardation, small hands and feet, severely and progressively reduced muscle tone with slackly protruding abdomen and undue drooling, excess[ncbi.nlm.nih.gov]
  • Drooling Drooling of saliva is commonly found in A-T patients.. Drooling Drooling of saliva is commonly found in A-T patients.. Endocrine abnormality Endocrine abnormalities seen in some patients, such as insulin resistant diabetes mellitus..[medicaljoyworks.com]
  • Further features that may affect some children are insulin-resistant diabetes, premature greying of the hair, difficulty swallowing, drooling and slowed growth. The severity and range of symptoms vary in individual patients.[actionforat.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]
  • Loss of muscle control often leads to drooling. While neurological problems may impair their ability to communicate, people with A-T are usually of average or above-average intelligence.[counsyl.com]
Abnormal Eye Movement
  • Poor accommodation and abnormal eye movements may lead to reading difficulty reported by patients with A-T.[ncbi.nlm.nih.gov]
  • 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]
  • eye movements ( nystagmus ) late in the disease Premature graying of the hair Seizures Sensitivity to radiation, including x-rays Severe respiratory infections that keep coming back (recurring) The health care provider will perform a physical exam.[nlm.nih.gov]
  • Other symptoms of A-T include abnormal eye movements and tiny, red, spiderlike veins in the corners of the eyes or on the ears and cheeks when exposed to sunlight. These veins, known as telangiectasias, are harmless.[kidshealth.org]
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]
  • RESULTS: Refractive errors were seen in eight patients and strabismus in three. Major oculomotor findings were fixation abnormalities (6/15), saccadic impairment (15/15), and abnormal smooth pursuit (14/15).[ncbi.nlm.nih.gov]
  • 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]
  • 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.[en.wikipedia.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]
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]
  • Progressive ataxia in childhood with particular reference to ataxia-telangiectasia. Neurology. 1960 Jul. 10:705-15. [Medline]. Biemond A.[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]
  • Although A-T is known to be the most common cause of progressive cerebellar ataxia in childhood, there have been no confirmed cases in Korea.[ncbi.nlm.nih.gov]
  • Cerebellar ataxia was noted in only one of the children and was mild until his death at age eight years. None had severe infections.[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]
  • 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 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]
  • Test Details Technical Information Clinical Significance: Detects sequence variations and deletions to ATM Typical Presentation: Infants and Children: Gait and truncal ataxia, slurred speech, oculomotor apraxia, frequent infections, and oculocutaneous[athenadiagnostics.com]
Dysarthria
  • AT manifests as ataxia, apraxia, telangiectasia, and dysarthria. Common ophthalmologic findings in AT include fine conjunctival telangiectasia.[ncbi.nlm.nih.gov]
  • Prior to cancer therapy, all had non-progressive atypical neurological abnormalities, with onset by age 30 months, including dysarthria, dyskinesia, hypotonia and/or dystonia, without telangiectasias.[ncbi.nlm.nih.gov]
  • Targeted next-generation sequencing (NGS) was performed on an Iranian 5-year-old boy presented with truncal and limb ataxia, telangiectasia of the eye, Hodgkin lymphoma, hyper pigmentation, total alopecia, hepatomegaly, and dysarthria.[ncbi.nlm.nih.gov]
  • CONCLUSIONS Although the literature describes the occurrence of dysarthria and swallowing disorders in patients with AT, little attention has been given to describing which oral motor deficits are responsible for these disorders.[ncbi.nlm.nih.gov]
  • Neurological abnormalities were progressive truncal ataxia, nystagmus, dysarthria, oculomotor apraxia and choreoathetosis. Thirty one patients (34.1%) became dependent on wheelchair at a mean age of 12.1 2.8 years.[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]
  • Hypometric saccades were evident in 48 (76%), pursuit abnormalities in 43 (63%), and nystagmus in 18 (29%). Accommodation was deficient in the 54 patients in whom it was measured. No posterior segment vascular anomalies were detected.[ncbi.nlm.nih.gov]
  • 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]
  • Neurological abnormalities were progressive truncal ataxia, nystagmus, dysarthria, oculomotor apraxia and choreoathetosis. Thirty one patients (34.1%) became dependent on wheelchair at a mean age of 12.1 2.8 years.[ncbi.nlm.nih.gov]
  • […] 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[nlm.nih.gov]

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:

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.

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].

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.

References

Article

  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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Last updated: 2019-07-11 20:55