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{{Infobox disease
| Name = Ataxia Telangiectasia
| Image =
| Caption =
| DiseasesDB = 1025
| ICD10 = {{ICD10|G|11|3|g|10}}
| ICD9 = {{ICD9|334.8}}
| ICDO =
| OMIM = 208900
| MedlinePlus =
| eMedicineSubj = derm
| eMedicineTopic = 691
| eMedicine_mult = {{eMedicine2|oph|319}}
| MeshID = D001260
}}
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*[[Refsum disease]]
'''[[Ataxia-telangiectasia like disorder]]''' (ATLD) is an extremely rare condition that could be considered in the differential diagnosis of A-T. [[ATLD]] patients are very similar to A-T patients in showing a progressive [[cerebellar ataxia]], hypersensitivity to [[ionising radiation]] and [[genomic instability]].<ref>http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=604391</ref> However, ATLD can be distinguished from A-T by the absence of [[telangiectasias]], normal [[immunoglobulin]] levels, a later onset of the condition and a slower progression of the disease. It is not known whether ATLD individuals are also predisposed to tumours. The gene mutated in ATLD is [[hMre11]] and is located on chromosome 11, section 11q21.
Interestingly, the proteins expressed by the [[hMre11]] (defective in ATLD) and [[Nbs1]] (defective in [[Nijmegen_breakage_syndrome|NBS]]) genes exist in the cell as a complex, along with a third protein expressed by the [[hRad50]] gene. This complex, known as the [[MRN complex]], plays an important role in DNA damage repair and signaling and is required to recruit [[Ataxia telangiectasia mutated|ATM]] to the sites of DNA double strand breaks. [[Mre11]] and [[Nbs1]] are also targets for phosphorylation by the [[ATM kinase]]. Thus, the similarity of the three diseases can be explained in part by the fact that the protein products of the three genes mutated in these disorders interact in common pathways in the cell.
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===Ataxia===
The first indications of A-T usually occur during the toddler years. These first signs indicate difficulty with control of the body posture and body movement ([[truncal ataxia]]). The child may start to walk later than usual (after 18 months), may be reluctant to let go of supporting people or objects, may continue to walk unsteadily for longer than normal, may be unable to stand still without tottering, and may fall frequently.
Walking becomes more strenuous and appears awkward, doors and walls are frequently used for support. Running may, for a time, seem less affected; this is because less balance is needed for quick movements than slower graceful ones. At the beginning of the second decade of their lives most people with A-T begin to use a wheelchair.
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Although people with A-T have an increased sensitivity to ionizing radiation (X-rays and gamma rays), they cope with other forms of radiation normally, i.e. obtaining a suntan from ultraviolet light. Also, the tumors seen in A-T are not thought to be radiation induced. X-ray exposure should be limited only to cases where it is absolutely medically necessary, as exposing an A-T patient to ionizing radiation can mutate cells in such a way that the body can't repair them.
Mental retardation is not seen in A-T. However, many children seem to have slower thinking speed. Some children are placed in special schools while others remain in mainstream schools, even graduating from university. Choreoathetosis, slurred speech, ocular apraxia and cerebellar ataxia are developed over the course of childhood.
A-T patients are often very thin. This may be due to a poor appetite, to the energy expended with involuntary movements, or the inherent characteristics of the disorder. Some people with A-T, both males and females, have a delayed puberty. This seems more common in those who are thin or are prone to infections.
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A-T is caused by mutations in the [[Ataxia telangiectasia mutated|ATM]] gene located on chromosome 11 section 11q22-23.<ref>{{OMIM|209800}}</ref> It was characterised in June 1995 and is made up of 66 exons spread across 150kb of genomic DNA. It encodes a 13kb mature transcript with an open reading frame of 9168 nucleotides. The ATM protein is about 370kDa and is ubiquitously expressed and is localised to the cell nucleus. The ATM protein is a large [[serine-threonine kinase]] thought to play a role in regulating cell cycle checkpoints, repair of double stranded [[DNA]] and [[meiosis]] (similar to the BRCA genes). ATM is also known to play a role in regulating [[p53]], [[BRCA1]] and [[CHEK2]]. Part of ATM’s role in DNA repair is known to be that of [[telomere]] repair as telomeres degrade more rapidly in people affected with A-T.
Mutations in the ATM gene are thought to come in two types:
*[[Null mutation]]s cause complete loss of function of the protein, and are therefore inherited in a recessive manner and cause A-T.
*[[Missense mutations]], which produce stable, full sized protein with reduced function, e.g., substitutions, short [[in-frame]] [[in-frame insertions|insertions]] and [[in-frame deletions|deletions]] etc. These mutations act by dominantly interfering with the normal copy of the protein.
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===ATM Carriers===
Carriers of ATM missense mutations are believed to have a 60% [[penetrance]] by age 70 and a risk of breast cancer 16 times higher that of the normal population, with a 5-8 fold increased risk of cancer. On average carriers die 7–8 years earlier than the normal population, often from heart disease. Some papers state a lifetime risk for people with both null and missense mutations of 10-38%, which is still a hundredfold increase from population risk.
Individuals with a single ATM mutation are also at a higher risk from [[lung cancer|lung]], [[gastric cancer|gastric]] and [[lymphoid tumour]]s, as well as [[breast cancer]]. S707P is known to be particularly common in breast cancer patients and F1463S is known to be associated with [[Hodgkin’s lymphoma]]. If pulmonary infections could be completely eradicated A-T is consistent with survival into the 5th or 6th decade.
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==Pathophysiology==
AT is caused by a defect in the gene responsible for recognizing and correcting errors in duplicating DNA when cells divide. The gene normally repairs double-stranded DNA breaks.
The gene, [[ataxia telangiectasia mutated|ataxia-telangiectasia mutated]] (ATM), discovered in 1995, is on chromosome 11 (11q 22-23)<ref name="Savitsky">{{cite journal |author=Savitsky K, Bar-Shira A, Gilad S, ''et al.'' |title=A single Ataxia-Telangiectasia gene with a product similar to PI-3 kinase |journal=Science |volume=268 |issue=5218 |pages=1749–53 |year=1995 |pmid=7792600 |doi=10.1126/science.7792600}}</ref><ref>{{cite journal |author=Gatti RA, Bick M, Tam CF, ''et al.'' |title=Ataxia-Telangiectasia: a multiparameter analysis of eight families |journal=Clin. Immunol. Immunopathol. |volume=23 |issue=2 |pages=501–16 |year=1982 |pmid=6213343 |doi=10.1016/0090-1229(82)90134-9}}</ref>
Normally, when a cell tries to duplicate damaged DNA, it identifies the damage at several checkpoints in the [[cell cycle|cell division cycle]]. It tries to repair the damage, and, if it can't repair the damage, it commits suicide through [[programmed cell death]] (apoptosis). The ATM gene plays a critical role in this process. It mobilizes several other genes try to repair the DNA damage or destroy the cell if they can't repair it. These downstream genes include tumor suppressor proteins [[p53]] and [[BRCA1]], checkpoint kinase [[CHK2]], checkpoint proteins [[RAD17]] and [[RAD9]], and DNA repair protein [[NBS1]].
In A-T, the pathways that control these processes are defective. This allows cells with damaged DNA to reproduce, resulting in chromosome instability, abnormalities in genetic recombination, and an absence of [[programmed cell death]].<ref>{{cite journal |author=Canman CE, Lim DS |title=The role of ATM in DNA damage responses and cancer |journal=Oncogene |volume=17 |issue=25 |pages=3301–8 |year=1998 |pmid=9916992 |doi=10.1038/sj.onc.1202577}}</ref>
.<ref>Lavin, 2004</ref>
ATM patients are particularly sensitive to X-rays, because X-rays induce double-stranded DNA breaks, which they are unable to repair. They are also particularly susceptible to cancers that result from double-stranded DNA breaks. For example, female ATM patients have a twofold higher risk of developing breast cancer, often before age 50.
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