An essay on Ataxia telangiectasia

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Ataxia telangiectasia is a genetic multisystemic disorder. It is characterized mainly by neurodegeneration and usually cancer predisposition. Presentation usually occurs by the age of 2 years old. Patients show increased sensitivity to ionizing radiation. Such disease usually develops as a result of two truncation mutations in ATM kinase gene found on chromosome 11, other mild cases could develop as a result of missence mutation in the same gene rather than truncating mutations. Diagnosis of this disease is quite clear as characteristic clinical feature appear at the early stage beside other confirmatory test are carried to assure its presence. Currently there is no treatment for this disease but several ways of protection could be performed to avoid having a baby with Ataxia telangiectasia.


Ataxia telangiectasia also known as Louis- Bar syndrome is a genetic multisystemic disorder that affects 1:40 000 - 1:300 000 children (Sandoval N. et al 1998). It is inherited in an autosomal recessive manner, resulting in a cerebellar degeneration (Kirmse B. et al, 2007). It is characterized by: neurologic abnormalities resulting in an unsteady way of walking i.e. uncoordinated movements (ataxia) where such patients are wheel-chair bounded by the age of 10 years old, dilation of eyes' and skin's blood vessels (telangiectasia), mental retardation as the mental development stops after age of 10-12, chromosomal instability and hypersensitivity to ionizing radiation that leads to cancer predisposition specially leukaemia, lymphomas (Tamimi R. Et al 2004). A noticeable immunodeficiency that involves both T-lymphocyte and B-lymphocytes i.e. cellular and humoral immune responses respectively, for the immunodeficiency the patients are divided into three levels the first third of patients have severe immunodeficiency accompanied by severe sino-plumonary infections with non opportunistic organisms, the other third have moderate immunodeficiency while for the last third, they don't show any signs of immunodeficiency (Otabor I. et al 2009).

At the genomic level

As previously mentioned Ataxia telangiectasia is an autosomal recessive disorder. It arises as a result of mutation in ATM tumour suppressor gene, found on the long arm of chromosome 11 at 11 q22-23. It controls the production of a phosphatidylinositol-3-kinase-like enzyme involved in cellular responses to stress, repair of DNA double-strand breaks, controls cell cycle arrests and cellular apoptosis (Tamimi R. Et al 2004) it is also responsible for the regulation of the physiological responses via p53- or Chk1-mediated pathways (Sandoval N. et al 1998). ATM gene is 150 kb long of which 13 kb found on 66 exons are transcribed and expressed into the protein of 350 kDa the nucleotide coding sequence of this gene shows very little diversity among different populations i.e. small number of SNPs has been identified.

Several mutations have been identified in ATM gene leading to development of Ataxia telangiectasia. The most common mutations found were two truncation mutations resulting in the absence of the functional protein kinase (Staples E. et al 2008). Also missesnce substitution and in-frame deletions are commonly found.

When Ataxia telangiectasia patients are exposed to ionizing radiation, the mutations mentioned above start taking place; as those people have genomic instability, because the mutations affect the one of the genes responsible for the DNA repair mechanism. The truncation mutations results in the production of non-functional ATM kinases which are from the components of cell cycle check point pathway in which the removal of damaged DNA takes place before going through the mitosis. In order to start the DNA repair the cell should be induced to start this repair and also should increase the length of G2 phase in its cycle- at which the repair of damaged DNA takes place- and both occur by the action of ATM kinases which are mutated in Ataxia telangiectasia patients.

Functional vs. non-functional ATM protein kinase

Normal ATM kinases induce the repair of double- strand breaks in DNA by the phosphorylation of nibrin Nbs-1 and the formation and activation of

(Mre11/Rad 50/Nbs 1) complex which is responsible for the repair of DNA double strand break. For the occurrence of this repair ATM kinases also increases the time of G2 phase in cell cycle at which the repair takes place before starting the mitosis, this occurs by the phosphorylation and activation of Chk1 and Chk2 kinases which prevent the activation of Cdc42 phosphatse of the mitotic cyclin-dependent kinase. Finally the ATM kinases are also responsible for the activation of the checkpoint protein p53 that in turn induces the synthesis of p21; the physiological inhibitor of most of the cyclin dependent kinases.

When the ATM Kinases are found non-functional i.e. due to ATM gene mutation the double-strand break repair of DNA doesn't occur and the cell enters the mitosis with its damaged DNA, consequently all the newly produced daughter cells will carry this mutation and the non-functional ATM kinases will be the common form (Pincheira J et al 2001). For that reason the Ataxia telangiectasia patients show high ability of cancer predisposition specially lymphomas and leukaemia when they are exposed to ionizing radiation and this is considered the most severe case of Ataxia telangiectasia.

Some Ataxia telangiectasia patients have a milder state of the disease that occurs due to missense mutations rather than a truncation mutation; in which the ATM some of the functional ATM kinases are expressed thus they have a slower neurodegeneration rate and don't show any symptoms of immunodeficiency. So it is clear that the amount of functional ATM kinases produced correlates with the neurodegeneration rate. This correlation is found because the defects in DNA repair mechanisms are found mainly in neural tissue which consequently affects other body functions and systems that's why Ataxia telangiectasia is a mutisystemic disorder.

When the mutation occurs, the neurological degeneration takes place consequently affecting ability to walk (ataxia) and causing dilation of blood vessels (telangiectasia), Patients often lack IgA and IgE immunoglobulin, beside other symptoms that commonly appear in Ataxia telangiectasia patients (Martin L. 2008).

Diagnosis of Ataxia telangiectasia

Clinical symptoms of this disease start to appear at early stages of the patient's life. Together with the clinical symptoms, other laboratory conformation test is performed, simply by the detection of ATM kinases through western blotting. Another confirmatory test could be performed which is "the detection of the chromosomal radio-sensitivity" i.e. measuring the level and rate of cellular damage. At the gene level, analysis of ATM gene length by PCR could be performed where the presence of biallelic truncations proves the presence of Ataxia telangiectasia.

''Laboratory confirmation of the clinical diagnosis of the classic form of ataxia telangiectasia is relatively straightforward'' (Taylor et al 2005)


Currently there is no treatment for Ataxia telangiectasia although some physicians prescribe antibiotics and IV immunoglobulin that may help but actually there is no effective treatment especially for the neurodegenration where the patient usually dies by the age of 30.


It should be taken into consideration that the path of the disease can be quite variable and it is difficult to predict the actual path for a given patient. Even within the same family, there can be great variability in the type and severity of different neurologic problems and immunodeficiency. Most of the patients are wheel-chair bounded in their early stages. Infections of the lungs (bronchitis or pneumonia) and sinuses (sinusitis) are common and may damage the lungs even if treated rapidly. Malignancies are also more common. They can be treated but require modifications of standard therapy protocols i.e. the Ataxia telangiectasia patient must never receive any kind of radiotherapy. (Blaese R. Et al 2007)

Dealing with Ataxia telangiectasia pateints

Patients should be encouraged to participate in several activities as possible. They should attend school on a regular basis, although most will sooner or later need full-time classroom aides. Progressive eye movement abnormalities make reading difficult, so instead they could learn by listening which is unaffected. Learning computer skills are also possible. Now several software programs are available for those having problems in vision. Physical and occupational therapists should be included in the treatment team to prevent the development of inflexibility in muscles and to keep functional mobility.

Special attention should be paid to the lungs. A-T patients have difficulty taking deep breaths and coughing to clear mucus from the airways. They may benefit from daily chest physiotherapy. Many A-T patients develop problems with chewing and swallowing. Those who aspirate (have food and liquids entering their windpipe and lungs) may improve when thin liquids are eliminated from their diet. In some individuals, a tube from the stomach to the outside of the abdomen may be necessary to eliminate the need for swallowing large volumes of liquids and to decrease the risk of aspiration.

Diagnostic X-rays should be banded because of the great risk that the X-rays may cause chromosomal damage.


Ataxia telangiectasia appears when both the father and the mother are carrier to this disease on their autosomes where one quarter of their children will be infected and one quarter will be normal and finally two quarters will be carriers as their parents. To avoid having a baby with Ataxia telangiectasia PGD "preimplantation genetic diagnosis" could be performed; thus allowing the genetic screening of the embryo before it implantation in the mother's uterus thus we could expel those embryos at risk of developing such genetic disease.

Case study

A female was diagnosed with Ataxia telangiectasia syndrome at 3 years of age. She had severe ataxia and was wheelchair bound by 8 years of age. She presented with decreased appetite and a 16 kg weight loss over one year period. A CT scan of the abdomen was performed, a pancreatic mass. On examination, she had notable speech and cognitive delays with scleral telangiectasias, muscle wasting and other features of malnutrition.

Her abdominal examination revealed a soft, nondistended abdomen with no obvious masses. The laboratory studies were remarkable

Pre-albumin level: 15 mg/ dL (normal: 23-48 mg/dL),

an IgG level: 461 mg/dL (normal: 546-1842 mg/dL)

absolute lymphocyte count: 187/cu mm (normal: 1000-4800/cu mm).

IgA: 186 mg/dL

IgM: 70 mg/dL

IgE <1 U/mL

The immunoglobulin levels were within normal limits. (Otabor I. Et al 2009)

From the data shown above we could conclude that this girl has mild Ataxia telangiectasia, with absence of immunodeficiency, other clinical symptoms for Ataxia telangiectasia are quite clear. This could be due to missence mutation rather than truncating mutations in ATM gene.