Cavernous angioma risk factors: Difference between revisions
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==Overview== | ==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''). | [[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]]== | ||
* | *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]]== | ||
=== 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> === | ===[[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 MRI scan findings, or other neurological findings. | *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, | *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 the patient and | *[[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]] | ||
[[Category: | [[Category:Up to Date]] | ||
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
- 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 (ICAP1-alpha), a beta-1 integrin associated protein. [1]
- CCM2 encodes for MGC4607. [1] The exact nature of CCM2 is still unclear. However, it has been proven that there is a macromolecularcomplex formed by CCM1 and CCM2 proteins and 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 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.[1]
- 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: [1]
- 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 (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
- ↑ 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.