Cavernous angioma risk factors: Difference between revisions

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{{Cavernous angioma}}
{{Cavernous angioma}}
{{CMG}}; {{AE}}
{{CMG}}; {{AE}}[[User:Edzelco|Edzel Lorraine Co, D.M.D., M.D.]]


==Overview==
==Overview==
Family history increases the risk of having cavernous angioma. Genetic testing is recommended for the pathogenic variants of cavernous angioma (''KRIT1'', ''CCM2'', and ''PDCD10'').
[[Family history]] increases the [[risk]] of having [[cavernous angioma]]. [[Genetic testing]] is recommended for the [[pathogenic variants]] of [[cavernous angioma]] (''[[KRIT1]]'', ''[[MGC4607]]'', and ''[[PDCD10]]'').


==Risk Factors==
==[[Risk Factors]]==
Familial forms of CCM occur at three known genetic loci. The gene for CCM1 encodes ''KRIT1'' (krev interaction trapped 1) and has been found to bind to ICAP1alpha (integrin cytoplasmic domain associated protein alpha), a beta1 [[integrin]] associated protein. The gene for ''CCM2'' encodes a novel protein named "malcavernin" that contains a phosphotyrosine (PTB) binding domain. The exact biological function of CCM2 is not clear. Recently, it has been shown that CCM1 and CCM2 proteins as well as ICAP1alpha form a macromolecular complex in the cell. In addition, it appears that CCM2 protein may function as a scaffolding protein for [[MAP kinases]] that are essential in p38 activation responding to osmotic stress including MEKK3 and MKK3. It also binds to [[Rac]] and [[actin]]. Therefore, CCM2 protein is also called OSM (osmosensing scaffold for MEKK3). The ''CCM3'' gene was the most recent CCM gene identified. CCM3 was known as PDCD10 (programmed cell death 10), which was initially identified as a gene that is up-regulated during the induction of [[apoptosis]] (cell death) in TF-1, a human [[myeloid]] cell line. The precise role of the PDCD10 protein in the CCM pathway that has been established to this point has not yet been determined. Research is ongoing to determine the function and properties of all three CCM gene products as well as the reaction pathways in which they are involved.


Mutations in these three genes account for 70 to 80 percent of all cases of cerebral cavernous malformations. The remaining 20 to 30 percent of cases may be due to other, still unidentified, genes.
*There are three known [[genetic loci]] for [[cavernous angioma]]. These are [[CCM1]], [[CCM2]], and [[CCM3]].
*[[CCM1]] encodes for [[krev interaction trapped 1]] (''[[KRIT1]]'')  which binds to [[integrin cytoplasmic domain associated protein alpha]] ([[ICAP1alpha|ICAP1-alpha]]), a beta-1 [[integrin]] associated [[protein]]. <ref name="pmid28387823">{{cite journal| author=Akers A, Al-Shahi Salman R, A Awad I, Dahlem K, Flemming K, Hart B | display-authors=etal| title=Synopsis of Guidelines for the Clinical Management of Cerebral Cavernous Malformations: Consensus Recommendations Based on Systematic Literature Review by the Angioma Alliance Scientific Advisory Board Clinical Experts Panel. | journal=Neurosurgery | year= 2017 | volume= 80 | issue= 5 | pages= 665-680 | pmid=28387823 | doi=10.1093/neuros/nyx091 | pmc=5808153 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28387823  }} </ref>
*''[[CCM2]]'' encodes for [[MGC4607]]. <ref name="pmid28387823">{{cite journal| author=Akers A, Al-Shahi Salman R, A Awad I, Dahlem K, Flemming K, Hart B | display-authors=etal| title=Synopsis of Guidelines for the Clinical Management of Cerebral Cavernous Malformations: Consensus Recommendations Based on Systematic Literature Review by the Angioma Alliance Scientific Advisory Board Clinical Experts Panel. | journal=Neurosurgery | year= 2017 | volume= 80 | issue= 5 | pages= 665-680 | pmid=28387823 | doi=10.1093/neuros/nyx091 | pmc=5808153 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28387823  }} </ref> The exact nature of [[CCM2]] is still unclear. However, it has been proven that there is a [[macromolecular]]complex formed by [[CCM1]] and [[CCM2]] [[proteins]] and [[ICAP1alpha|ICAP1 alpha]] inside the [[cell]]. Also, the [[CCM2]] [[protein]] can serve as a [[scaffolding protein]] for [[enzymes]] like [[MAP kinases]] which is essential in [[p38]] [[activation]], responsible for regulation of [[osmotic]] [[stress]] including [[MEKK3]] and [[MKK3]]. It also attaches to [[Rac]] and [[actin]]. Because of these, the [[CCM2]] [[protein]] is oftentimes called [[osmosensing scaffold|osmo-sensing scaffold]] ([[OSM]]) for [[MEKK3]].
*''[[CCM3]]'' [[gene]] is the most recently identified [[CCM gene]]. It was originally known as [[programmed cell death 10]] (''[[PDCD10]]'') , which was thought to be responsible for upregulation of [[apoptosis]] ([[cell death]]) in [[TF-1]], a [[human]] [[myeloid]] [[cell line]]. As of now, the specific role of the [[PDCD10]] [[protein]] and its association with the [[CCM3 gene]] is not yet established.<ref name="pmid28387823">{{cite journal| author=Akers A, Al-Shahi Salman R, A Awad I, Dahlem K, Flemming K, Hart B | display-authors=etal| title=Synopsis of Guidelines for the Clinical Management of Cerebral Cavernous Malformations: Consensus Recommendations Based on Systematic Literature Review by the Angioma Alliance Scientific Advisory Board Clinical Experts Panel. | journal=Neurosurgery | year= 2017 | volume= 80 | issue= 5 | pages= 665-680 | pmid=28387823 | doi=10.1093/neurons/nyx091 | pmc=5808153 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28387823  }} </ref>
 
*The [[mutations]] in the [[CCM1]], [[CCM2]], and [[CCM3]] [[genes]] account for almost 70 to 80 percent of all cases of [[cerebral cavernous malformations]]. The rest has yet to be identified.
 
==[[Genetic Testing]]==
 
===[[Genetic Testing]] and [[Counseling]] Recommendations: <ref name="pmid28387823">{{cite journal| author=Akers A, Al-Shahi Salman R, A Awad I, Dahlem K, Flemming K, Hart B | display-authors=etal| title=Synopsis of Guidelines for the Clinical Management of Cerebral Cavernous Malformations: Consensus Recommendations Based on Systematic Literature Review by the Angioma Alliance Scientific Advisory Board Clinical Experts Panel. | journal=Neurosurgery | year= 2017 | volume= 80 | issue= 5 | pages= 665-680 | pmid=28387823 | doi=10.1093/neuros/nyx091 | pmc=5808153 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28387823  }} </ref>===
 
*A three-[[generation]] [[family history]] should be obtained at the time of [[diagnosis]]. More focus should be given to [[symptoms]] such as [[headache]], [[stroke]], any abnormal [[Magnetic resonance imaging|magnetic resonance]] ([[MRI]]) scan findings, or other [[neurological]] findings.
*In the setting of [[cavernous angioma]], without an association of [[developmental venous anomalies]], [[brain radiation]] history, or a [[family history]] of [[cavernous angioma]], CCM 1-3 [[genes]] by [[Sanger or NextGen sequencing]] followed by [[duplication]]/[[deletion]] analysis should be considered.
*[[Counseling]] for the [[patient]] and [[family]] about [[autosomal dominant inheritance]] should be done when there is a positive [[proband]].


==References==
==References==
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[[Category:Genetic disorders]]
[[Category:Genetic disorders]]
[[Category:Dermatology]]
[[Category:Dermatology]]
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Latest revision as of 13:04, 12 May 2022

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Edzel Lorraine Co, D.M.D., M.D.

Overview

Family history increases the risk of having cavernous angioma. Genetic testing is recommended for the pathogenic variants of cavernous angioma (KRIT1, MGC4607, and PDCD10).

Risk Factors

Genetic Testing

Genetic Testing and Counseling Recommendations: [1]

References

  1. 1.0 1.1 1.2 1.3 Akers A, Al-Shahi Salman R, A Awad I, Dahlem K, Flemming K, Hart B; et al. (2017). "Synopsis of Guidelines for the Clinical Management of Cerebral Cavernous Malformations: Consensus Recommendations Based on Systematic Literature Review by the Angioma Alliance Scientific Advisory Board Clinical Experts Panel". Neurosurgery. 80 (5): 665–680. doi:10.1093/neuros/nyx091. PMC 5808153. PMID 28387823.