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Cerebral cavernous malformations (CCMs) are collections of small blood vessels (capillaries) in the brain that are enlarged and irregular in structure. These capillaries have abnormally thin walls that are prone to leak. They also lack other support tissues, such as elastic fibers, which normally make them stretchy. As a result, when the capillaries fill with blood, they stretch out and may not return to their normal size when the blood vessels empty. Cavernous malformations can occur anywhere in the body, but usually produce serious signs and symptoms only when they occur in the central nervous system (the brain and spinal cord).
Approximately 25 percent of individuals with cerebral cavernous malformations never experience any related medical problems. Other people with cerebral cavernous malformations may experience serious symptoms such as headaches, seizures, paralysis, hearing or vision deficiencies, and bleeding in the brain (cerebral hemorrhage). Severe brain hemorrhages can result in death. The location and number of cerebral cavernous malformations determine the severity of this disorder. These malformations can change in size and number over time, but they do not become cancerous.
Cerebral cavernous malformations affect about 0.5 percent of the population worldwide.
Mutations in the CCM2, KRIT1, and PDCD10 genes cause cerebral cavernous malformation.
The precise functions of these genes are not fully understood, but they most likely play a role in blood vessel formation (angiogenesis) during embryonic development. They may also play a role in maintaining existing blood vessels. Researchers have not determined how mutations in these genes can lead to the abnormal capillaries characteristic of cerebral cavernous malformations.
Mutations in these three genes account for 70 percent to 80 percent of all cases of familial cerebral cavernous malformations. The remaining 20 percent to 30 percent of cases may be due to unidentified genes or to other unknown causes.
This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. In some cases, an affected person inherits the mutation from one affected parent.
Most cases of cerebral cavernous malformation result from a new mutation in the KRIT1, CCM2, or PDCD10 gene. These cases are known as sporadic, and they occur in people with no history of the disorder in their family.
Cerebral cavernous malformations (CCM) is a congenital vascular disorder of the central nervous system that may appear either sporadically or exhibit autosomal dominant inheritance. The incidence in the general population is between 0.1-0.5% and clinical symptoms typically appear between 30 to 50 years of age. This disease is characterized by grossly dilated blood vessels with a single layer of endothelium and an absence of neuronal tissue within the lesions. Blood vessels in patients with CCM can range from a few millimeters to several centimeters in diameter. Clinical symptoms of this disease include recurrent headaches, focal neurological deficits, hemorrahagic stroke, and seizures, but CCM can also be asymptomatic. The lesions can be detected by magnetic resonance imaging (MRI) which can also be used to detect clinically silent lesions. Familial forms of CCM occur at three known genetic loci. The gene for CCM1 encodes KRIT1 and has been found to bind to ICAP1alpha, an integrin cytoplasmic-domain 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 currently unknown. The CCM3 gene was recently identified 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. [ Read More ]