Ataxia telangiectasia: Difference between revisions
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== [[Ataxia telangiectasia pathophysiology|Pathophysiology]] == | == [[Ataxia telangiectasia pathophysiology|Pathophysiology]] == | ||
The responsible [[gene]] in [[AT]], [[ataxia telangiectasia mutated|ataxia-telangiectasia mutated]] ([[ATM]]), was discovered in 1995 by Savitsky et al.,<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> a team led by Yosef Shiloh of Tel Aviv University in Israel. Researchers linked the [[hyper-sensitivity]] of [[AT]] patients to [[ionizing radiation]] ([[IR]]) and [[predisposition]] to [[cancer]], to "[[chromosomal]] [[instability,]] abnormalities in [[genetic recombination]], and [[defective signaling]] to [[programmed cell death]] and several [[cell cycle]] checkpoints activated by [[DNA]] damage".<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> Earlier observations predicted that the gene altered in AT played a role in DNA damage recognition. These predictions were confirmed when a single gene on chromosome 11 (11q 22-23) was discovered.<ref name="Savitsky"> </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> Since its discovery, the [[protein]] product of the [[ATM]] gene has been shown to be a part of [[eukaryotic]] [[cell cycle]] control, [[DNA repair]], and [[DNA]] [[recombination]] (Lavin, 2004). Specifically, the [[AT]] [[gene]] serves as a [[tumor suppressor gene]] by contributing to a network of genes that link double stranded breaks in DNA to cell cycle arrest and [[apoptosis]] ([[programmed cell death]]). Patients with [[ATM]] have a defective [[AT]] [[gene]], which leaves them susceptible to contracting cancer. For example, female [[ATM]] patients have a two-fold higher chance of ever having [[breast cancer]], which often occur before the age of 50. [[ATM]] patients must try avoiding [[x-rays]] at all costs since the [[radiation]] induces double-stranded breaks. | |||
=== Genetics === | |||
[[AT]] is an [[autosomal recessive]] disorder caused by [[mutations]] in the [[ATM]] gene located on [[chromosome]] 11q22-23. <ref>{{OMIM|209800}}</ref> It was characterised in June of 1995 and is made up of 66 exons spread across 150kb of genomic [[DNA]]. It [[encode]]s 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 [[telomere]]s degrade more rapidly in people affected with [[AT]]. | |||
[[Mutation]]s in the [[ATM]] gene are thought to come in two types: | |||
* Null [[mutation]]s are those which cause complete loss of function of the [[protein]] and are therefore [[inherited]] in a [[recessive]] manner and cause [[AT]]. | |||
* ‘[[Missense]]’ [[mutation]]s which produce stable, full sized [[protein]] with reduced function e.g. substitutions, short in-frame insertions and deletions etc. These mutations act by [[dominantly]] interfering with the normal copy of the protein. | |||
The majority of [[AT]] sufferers, 65-70%, have [[truncating]] [[mutations]], with exon skipping [[mutation]]s being particularly common. This results in very low or undetectable levels of [[ATM]] [[protein]]. Missense [[mutations]] are the most common type of [[mutation]] found in carriers with [[breast cancer]]. Individuals with two [[missense]] mutations are believed to have a milder form of AT, which may account for cases of attenuated AT. Therefore it is thought that "subtle constitutional alterations of ATM may impart an increased risk of developing breast cancer and therefore act as a low penetrance, high prevalence gene in the general population" (Maillet et al 2002). | |||
[[Oculo]]-[[cutaneous]] [[telangiectasia]] combined with [[ataxia]] are the defining features of the condition. However, some patients with [[AT]], even those with two null [[mutation]]s who produce no [[ATM]] [[protein]] at all, may never present with [[oculo]]-[[cutaneous]] [[telangiectasia]]. | |||
== [[Ataxia telangiectasia causes|Causes]] == | == [[Ataxia telangiectasia causes|Causes]] == | ||
Revision as of 18:23, 1 August 2021
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Seyed Arash Javadmoosavi, MD[2] Zaida Obeidat, M.D. For patient information, click here
| Ataxia telangiectasia | |
| ICD-10 | G11.3 |
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| ICD-9 | 334.8 |
| OMIM | 208900 |
| DiseasesDB | 1025 |
| MedlinePlus | 001394 |
| MeSH | D001260 |
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Ataxia telangiectasia Microchapters |
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Diagnosis |
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Treatment |
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Case Studies |
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Ataxia telangiectasia On the Web |
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American Roentgen Ray Society Images of Ataxia telangiectasia |
Synonyms and keywords: Louis-bar syndrome, Boder-sedgwick syndrome.
Overview
Ataxia telangiectasia (A-T)is an autosomal recessive disorder caused by mutations in the gene ATM (ataxia-telangiectasia mutated)(11q22.3). This gene is expressed commonly and encodes a protein kinase (ATM kinase) which plays a key role in the control of double-strand-break DNA repair. A-T is a progressive, multisystem disease that has a large number of complex and diverse manifestations that vary with age. The clinical picture of this condition can be very variable and the severity of the pulmonary, immunological and neurological manifestations varies widely between patients and is related to the severity of the underlying mutations and any residual ATM kinase activity. It has been recently suggested that the name A-T should be replaced by ATM syndrome. ATM syndrome represents a neurodegenerative disorder with multisystem involvement due to the absence or reduced levels of ATM protein and kinase activity. The syndrome is characterised by the presence of movement disorders, such as cerebellar ataxia, dystonia, chorea and myoclonus, in association with systemic abnormalities such as immunodeficiency, malignancies, oculocutaneous telangiectasias and an increase in α-fetoprotein levels. The disease most commonly presents with ataxia during the third or fourth year of life. The important first step in the evaluation of young children presenting with ataxia should be α-fetoprotein testing. The diagnosis should then be confirmed by genetic testing to identify the mutations and measure the product of the ATM gene, the protein kinase ATM. This diagnostic test is likely to be available in specialised laboratories only. Patients with A-T die prematurely, the leading causes of death being respiratory diseases and cancer. A minimally estimated annual mortality rate for white patients is 19.5/1000 for ages 15–19 years and reportedly three-fold higher for African-American patients.
Historical Perspective
The term Ataxia-Telangiectasia was initially advanced by Boder and Sedgwick in 1957,in which described eight patients with classical A-T, while in 1958 Centerwall and Miller entitled it Louis-Bar syndrome which relates to Madame Louis-Bar, a Belgian neurologist who published a case report of a 9 year-old boy with cutaneous telangiectasia and progressive cerebellar ataxia. She initially classified this new disease in the group of phacomatosis PPV. In 1993, a case report was published about a 17 year-old boy with cerebellar ataxia concomitant dystonia, myoclonus, pyramidal signs, pulmonary infection, persistent lymphopenia, immunoglobulin deficiency and rising alpha-fetoprotein, termed as ataxia with immune deficiency.[1] In 1995, the responsible gene for A-T(ATM) was identified by Savitsky et al. In 2001, Stewart found a correlation with ATM kinase activity levels in cells and the degree of neurological symptoms in A-T patients.[2]
Classification
- The ataxias can be divided into:[3]
- Genetic (with or without a family history) and those that are acquired/degenerative.
- Sporadic ataxia implies there is no family history.
- Acquired progressive ataxias can be:
- Immune mediated (paraneoplastic spinocerebellar degeneration, gluten ataxia)
- Degenerative (cerebellar variant of multiple systems atrophy (type C))
- Caused by deficiency states (vitamin B12, vitamin E)
- Toxicity (eg, alcohol-related ataxia, phenytoin)
- Associated with infections (HIV, sporadic Creutzfeldt-Jakob disease, progressive multifocal leucoencephalopathy).
- Inherited ataxias can have autosomal dominant, autosomal recessive, X-linked or mitochondrial (maternal) inheritance.
- Metabolic disorders (Niemann-Pick type C, Tay-Sachs disease).
- There is no established system for the classification of Ataxia Telangiectasia.
Pathophysiology
The responsible gene in AT, ataxia-telangiectasia mutated (ATM), was discovered in 1995 by Savitsky et al.,[4] a team led by Yosef Shiloh of Tel Aviv University in Israel. Researchers linked the hyper-sensitivity of AT patients to ionizing radiation (IR) and predisposition to cancer, to "chromosomal instability, abnormalities in genetic recombination, and defective signaling to programmed cell death and several cell cycle checkpoints activated by DNA damage".[5] Earlier observations predicted that the gene altered in AT played a role in DNA damage recognition. These predictions were confirmed when a single gene on chromosome 11 (11q 22-23) was discovered.[4][6] Since its discovery, the protein product of the ATM gene has been shown to be a part of eukaryotic cell cycle control, DNA repair, and DNA recombination (Lavin, 2004). Specifically, the AT gene serves as a tumor suppressor gene by contributing to a network of genes that link double stranded breaks in DNA to cell cycle arrest and apoptosis (programmed cell death). Patients with ATM have a defective AT gene, which leaves them susceptible to contracting cancer. For example, female ATM patients have a two-fold higher chance of ever having breast cancer, which often occur before the age of 50. ATM patients must try avoiding x-rays at all costs since the radiation induces double-stranded breaks.
Genetics
AT is an autosomal recessive disorder caused by mutations in the ATM gene located on chromosome 11q22-23. [7] It was characterised in June of 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 AT.
Mutations in the ATM gene are thought to come in two types:
- Null mutations are those which cause complete loss of function of the protein and are therefore inherited in a recessive manner and cause AT.
- ‘Missense’ mutations which produce stable, full sized protein with reduced function e.g. substitutions, short in-frame insertions and deletions etc. These mutations act by dominantly interfering with the normal copy of the protein.
The majority of AT sufferers, 65-70%, have truncating mutations, with exon skipping mutations being particularly common. This results in very low or undetectable levels of ATM protein. Missense mutations are the most common type of mutation found in carriers with breast cancer. Individuals with two missense mutations are believed to have a milder form of AT, which may account for cases of attenuated AT. Therefore it is thought that "subtle constitutional alterations of ATM may impart an increased risk of developing breast cancer and therefore act as a low penetrance, high prevalence gene in the general population" (Maillet et al 2002).
Oculo-cutaneous telangiectasia combined with ataxia are the defining features of the condition. However, some patients with AT, even those with two null mutations who produce no ATM protein at all, may never present with oculo-cutaneous telangiectasia.
Causes
Differentiating Ataxia telangiectasia from other Diseases
Epidemiology and Demographics
Risk Factors
Screening
Natural History, Complications and Prognosis
Diagnosis
History and Symptoms | Physical Examination | Laboratory Findings | CT | MRI | Other Diagnostic Studies
Treatment
Medical Therapy | Cost Effectiveness of Therapy | Future or Investigational Therapies
Case Studies
Template:Phakomatoses and other congenital malformations not elsewhere classified
Template:Diseases of the nervous system
de:Louis-Bar-Syndrom it:Atassia teleangectasica he:תסמונת אטקסיה טלנגיאקטזיה sr:Атаксија-телеангиектатика
- ↑ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5161405/#R13. Missing or empty
|title=(help) - ↑ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5161405/#R13. Missing or empty
|title=(help) - ↑ de Silva RN, Vallortigara J, Greenfield J, Hunt B, Giunti P, Hadjivassiliou M (2019). "Diagnosis and management of progressive ataxia in adults". Pract Neurol. 19 (3): 196–207. doi:10.1136/practneurol-2018-002096. PMC 6585307 Check
|pmc=value (help). PMID 31048364. - ↑ 4.0 4.1 Savitsky K, Bar-Shira A, Gilad S; et al. (1995). "A single ataxia telangiectasia gene with a product similar to PI-3 kinase". Science. 268 (5218): 1749–53. doi:10.1126/science.7792600. PMID 7792600.
- ↑ Canman CE, Lim DS (1998). "The role of ATM in DNA damage responses and cancer". Oncogene. 17 (25): 3301–8. doi:10.1038/sj.onc.1202577. PMID 9916992.
- ↑ Gatti RA, Bick M, Tam CF; et al. (1982). "Ataxia-Telangiectasia: a multiparameter analysis of eight families". Clin. Immunol. Immunopathol. 23 (2): 501–16. doi:10.1016/0090-1229(82)90134-9. PMID 6213343.
- ↑ Online Mendelian Inheritance in Man (OMIM) 209800