Cerebral cavernous malformations (CCMs)—also known as cavernomas and cavernous angiomas—are abnormal clusters of closely packed, thin-walled blood vessels known as capillaries that form lesions that move tissue in the brain or spinal cord from their normal place and can alter blood flow. Cavernous malformations can be found in the brain, spinal cord, or other parts of the body. The lesions contain slow-moving or clotted blood. Lesions in the brain and spinal cord are particularly fragile and likely to bleed. CCMs in the brain can cause:

• Bleeding in the brain (hemorrhagic stroke)
• Seizures
• Headaches
• Back pain
• Hearing or vision changes
• Paralysis

CCMs are rare. They can occur on their own or be inherited, caused primarily by a mutation in one of three CCM genes: CCM1, CCM2, and CCM3. Some people may have many lesions and some people may have no symptoms.

It is normal for the capillaries to bleed more than once. CCCMs can be fatal, particularly if they cause severe bleeding in the brain. Some CCMs are left untreated. When possible, CCMs are mainly treated surgically. Medications are available to treat other symptoms.

Mutations in at least three genes, KRIT1 (also known as CCM1), CCM2, and PDCD10 (also known as CCM3), cause familial cerebral cavernous malformations.

The precise functions of these genes are not fully understood. Studies show that the proteins produced from these genes are found in the junctions connecting neighboring blood vessel cells. The proteins interact with each other as part of a complex that strengthens the interactions between cells and limits leakage from the blood vessels. Mutations in any of the three genes impair the function of the protein complex, resulting in weakened cell-to-cell junctions and increased leakage from vessels as seen in cerebral cavernous malformations.

Mutations in these three genes account for 85 to 95 percent of all cases of familial cerebral cavernous malformations. The remaining 5 to 15 percent of cases may be due to mutations in unidentified genes or to other unknown causes. Mutations in the KRIT1, CCM2, and PDCD10 genes are not involved in sporadic cerebral cavernous malformations. The cause of this form of the condition is unknown.

Normal Function

The KRIT1 gene (also known as CCM1) provides instructions for making a protein that strengthens the interactions between cells that form blood vessels and limits leakage from the vessels. The KRIT1 protein interacts with a number of other proteins to form a complex that is found in the junctions that connect neighboring cells. As part of this complex, the KRIT1 protein helps turn off (suppress) a signaling molecule known as RhoA-GTPase. This molecule plays a role in regulating the actin cytoskeleton, which is a network of fibers that makes up the cell's structural framework. When turned on, RhoA-GTPase stimulates the formation of actin fibers, which has been linked to weakened junctions between cells and increased leakage from blood vessels.

Health Conditions Related to Genetic Changes

Cerebral cavernous malformation

More than 100 KRIT1 gene mutations have been identified in families with cerebral cavernous malformations, which are collections of blood vessels in the brain that are weak and prone to leakage. Virtually all of these mutations place a premature stop signal in the instructions for making the KRIT1 protein, preventing adequate KRIT1 protein production. A shortage of this protein likely impairs the function of the complex. As a result, RhoA-GTPase signaling is turned on abnormally, weakening cellular junctions and increasing the permeability of blood vessel walls. The increased leakage into the brain can cause health problems such as headaches, seizures, and bleeding in the brain (cerebral hemorrhage) in some people with cerebral cavernous malformations.

Mutations in the KRIT1 gene account for up to 50 percent of all familial cerebral cavernous malformation cases. One particular mutation is responsible for up to 70 percent of cases in people of Hispanic heritage. This mutation changes a single DNA building block (nucleotide) at position 1363 in the KRIT1 gene, written as 1363C>T.

Other Names for This Gene

• ankyrin repeat-containing protein Krit1
• CAM
• CCM1
• cerebral cavernous malformations 1
• krev interaction trapped 1
• KRIT1_HUMAN

Genomic Location

Normal Function

The CCM2 gene provides instructions for making a protein called malcavernin, which strengthens the interactions between cells that form blood vessels and limits leakage from the vessels. Malcavernin interacts with a number of other proteins to form a complex that is found in the junctions that connect neighboring cells. As part of this complex, malcavernin helps turn off (suppress) a signaling molecule known as RhoA-GTPase. This molecule plays a role in regulating the actin cytoskeleton, which is a network of fibers that makes up the cell's structural framework. When turned on, RhoA-GTPase stimulates the formation of actin fibers, which has been linked to weakened junctions between cells and increased leakage from blood vessels.

Malcavernin is also involved in a process called angiogenesis, which is the formation of new blood vessels.

Health Conditions Related to Genetic Changes

Cerebral cavernous malformation

Dozens of mutations in the CCM2 gene have been identified in families with cerebral cavernous malformations, which are collections of blood vessels in the brain that are weak and prone to leakage. Most of these mutations result in an abnormally short or malformed malcavernin protein that does not function. A shortage of this protein likely impairs the function of the complex. As a result, RhoA-GTPase signaling is turned on abnormally, weakening cellular junctions and increasing the permeability of blood vessel walls. The increased leakage into the brain can cause health problems such as headaches, seizures, and bleeding in the brain (cerebral hemorrhage) in some people with cerebral cavernous malformations.

Mutations in the CCM2 gene are involved in approximately 15 percent of all familial cerebral cavernous malformation cases.

Other Names for This Gene

• C7orf22
• CCM2 scaffolding protein
• CCM2_HUMAN
• cerebral cavernous malformation 2
• chromosome 7 open reading frame 22
• MGC4067
• MGC4607
• OSM

Genomic Location

Normal Function

The PDCD10 gene (also known as CCM3) provides instructions for making a protein that appears to play a role in the structure of blood vessels. While the exact function of the PDCD10 protein is unclear, studies suggest that it works with other proteins to help strengthen the interactions between cells and limit leakage from blood vessels. This protein is also thought to be involved in pathways that signal cells to self-destruct (undergo apoptosis) when they have completed a certain number of cell divisions or accumulated errors in their DNA.

Health Conditions Related to Genetic Changes

Cerebral cavernous malformation

More than a dozen mutations in the PDCD10 gene have been identified in families with cerebral cavernous malformations, which are collections of blood vessels in the brain that are weak and prone to leakage. These mutations include a deletion of the entire gene, deletion of small segments of DNA, and changes in single DNA building blocks (nucleotides). These mutations result in an abnormal or absent PDCD10 protein. It is unclear how mutations in the PDCD10 gene lead to the formation of cerebral cavernous malformations.

Mutations in the PDCD10 gene account for approximately 10 percent of familial cerebral cavernous malformation cases.

Other Names for This Gene

• apoptosis-related protein 15
• CCM3
• cerebral cavernous malformation 3
• PDC10_HUMAN
• TFAR15

Genomic Location

This condition has an autosomal dominant pattern of inheritance, which means one copy of the altered gene in each cell is sufficient to cause the disorder. In the familial form, an affected person inherits the mutation from one affected parent.

Most people with cerebral cavernous malformations have the sporadic form of the disorder. These cases occur in people with no history of the disorder in their family.

Yes, genetic testing is available for familial cerebral cavernous malformation. Genetic testing can detect a mutation in one of the three known CCM genes (KRIT1, CCM2 or PDCD10) in 70 percent to 80 percent of individuals from families with CCM. The remaining 20 percent to 30 percent of cases may be due to unidentified genes or to other unknown causes. If no mutation is detected in one of those three genes, research testing may be performed to identify families that demonstrate linkage to a fourth potential location of a CCM gene.

Genetic testing can not be performed on a blood sample from someone with sporadic CCM becuase the gene mutation may be located in tissues other than the blood.