Cerebral Cavernous Malformations (CCM) is a blood vessel disorder typified by the development of vascular lesions with the brain and spinal cord. CCM may occur sporadically or as an inherited genetic disease caused by mutation and the resulting loss of function of one of three genes, CCM1, CCM2, or CCM3.
What are the genetics of lesion development?
Genes are packaged in chromosome pairs. We all have two copies of every gene in our genome, with one inherited from each parent. Germline mutations are those that are inherited from a parent, and therefore present in every cell of the body. By contrast, somatic mutations are randomly acquired over time and not present in all cells.
CCM lesions develop when there is a complete loss of function for one of the CCM genes within a brain endothelial (blood vessel) cell. In familial CCM, this means that the affected individual will have inherited a mutation in one of the CCM genes, then at some point in time, acquired a somatic mutation on the other copy of that gene. When this happens in an endothelial cell, there is a complete loss of function for that gene, and lesion development is the result.
There are two forms of cavernous angioma – familial and sporadic. By contrast to the familial, sporadic CCM is not inherited, individuals do not have germline CCM gene mutations, and typically affected individuals present with single lesions. All CCM lesions look like; there is no structural or histological difference between sporadic and familial lesions, indicating that they may develop following the same mechanism. Recent research shows that this is the case – the formation of sporadic lesions is seeded by the acquisition of two somatic mutations. This likely explains why sporadic CCM patients typically develop solitary lesions – it would be exceedingly rare for an individual to acquire two mutations on both copies of the same gene within a single cell.
Histologically, at the level of the tissue, all CCM lesions look the same – this similarity is regardless of genotype or sporadic lesions. CCM lesions are composed of dilated vessels, a single layer of endothelium, and they lack the normal supportive structures. Within the lesion tissue, there is an increase in cellular proliferation and angiogenesis, as well as a heightened inflammatory response. Signaling and structural aberrations result in defected junctions, leakiness, bleeding, and iron deposits.
Figure Legend: A: Artist rendition of the mulberry-like CA. B: 3D MRI slab of a human lesion, T2 acquisition at 3 Tesla, highlighting the characteristic “popcorn appearance” of a CA with a hemosiderin ring. C: Confocal immunofluorescence photomicrograph with staining (CD31, green) of endothelial cells (ECs) lining the lesion’s vascular spaces (caverns). Red blood cells (red) fill the caverns and extravasate beyond the “leaky” endothelium. Bar = 40 μM. D: Comparative image of normal brain capillaries. Bar = 20 μM.
The above figure is published in Cavernous angiomas: deconstructing a neurosurgical disease, an invited review article in the Journal of Neurosurgery, written by Drs. Issam Awad and Sean Polster. The entirety of the article is freely available and recommended for those who would like to learn more about the biology of cavernous angiomas, clinical features of the illness, and biomarkers.
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