Cavernous angioma risk factors

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

• 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.

• 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.