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].

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.

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.

Self-assessment

References

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  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. 
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  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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Self-assessment