By Cornelia Lee, PsyD, Judith Gault, PhD, Emily Crocker, MS, and Tracey Leedom, MS
Cerebral cavernous malformations (cavernous angiomas) can form through several different mechanisms. The major differences lie in whether you have a sporadic cavernous malformation or familial cavernous malformations.
A gene is the basic unit of heredity. Genes are made from DNA, the building block of life, and carry the information for creating the proteins which lead to a particular characteristic or function. When a gene mutates, it changes from its natural state and can cause an illness. With a sporadic cavernous malformation, it is believed that a genetic mutation has occurred in just one cell in your body. With familial cavernous malformations, a mutation of a specific gene has occurred in every cell of your body.
You may have one cavernous malformation and have no other family members with the illness. It is believed that a majority of those diagnosed with the illness fall into this category. The cause of sporadic cavernous malformations is not known. However, it is thought that a solitary cavernous malformation can be formed when a single cell has two specific mutations, or changes in both copies of a particular gene. As the cell replicates and divides, it goes on to form the cavernous malformation.
A solitary cavernous malformation may be present at birth or may form later. If you have a sporadic cavernous malformation, it is likely that your children would have no greater chance of having the illness than anyone in the general population.
In certain instances, individuals with the sporadic form of the illness have more than one cavernous malformation. This can be true if the individual has a venous malformation (also known as a venous anomaly or venous angioma) or if they have undergone radiation treatments in the brain or spinal cord. As MRI technology has improved, there are also more cases in which small blood vessel leakage associated with aging is interpreted as the development of a new cavernous malformation when it is not. If you have more than one cavernous malformation and don't appear to have a family history of the illness, a knowledgeable physician possibly combined with genetic testing is an appropriate approach to determining if you have the hereditary form.
Familial cavernous malformations are caused by a genetic mutation found in every cell in your body, rather than a mutation in a single cell. This illness may run in your family or you may be the first in your family to have the illness. You may have just one cavernous malformation, but are likely to have multiple cavernous malformations.
Familial cavernous malformation is a hereditary illness that is an autosomal dominant condition. This means that only one parent must have the illness for it to be passed on to offspring. Statistically, if you have the familial form of the illness and you have a child with someone who does not, your child will have a 50% chance of having the illness.
If you are the first in your family to have multiple cavernous malformations, you are likely to be the first in your family to have a familial mutation. This puts your risk of passing on the illness to your children at 50%.
Familial cavernous malformations are caused by a single gene mutation in any one of at least three different genes. A mutation on any one of these genes can cause the illness.
We each have two copies of any gene. When one copy mutates, the other is a backup that will perform the same function. However, the backup must work perfectly to avoid any problems caused by the original mutation. This is almost never the case for every cell in the body.
One theory is that in the case of familial cavernous malformation, a mutation on the first gene causes it to stop functioning. Intermittent but naturally occurring problems with the backup gene in some cells cause the formation of cavernous malformations. Wherever the backup gene fails, a cavernous malformation develops. As a result, if you have familial cavernous malformations you are likely to have more than one malformation. It is thought that almost everyone with the familial form will eventually have multiple cavernous malformations.
To date, three genes have been linked to the familial form of the illness and have been precisely located. The first is called CCM1 (for cerebral cavernous malformation 1) and is located on chromosome 7, at 7q11.2-q21. It is also known as KRIT1, for the protein created by the gene. This is the gene responsible for most of the cases of familial multiple cavernous malformation in Hispanic families, and in a number of other families. In fact, most Hispanics with the CCM1 mutation are thought to share a common ancestor. 40% of familial cavernous malformation can be linked to a CCM1 genetic mutation.
CCM1 is responsible for creating KRIT1 protein, or Krev interaction-trapped 1 protein. This protein is considered to be important for basic life development. The exact function of KRIT1 protein is not known but it is believed to play a role in determining the structure of endothelial cells in blood vessels in the brain. When the first copy of the CCM1 gene mutates, only the backup copy can produce KRIT1 protein. If there are problems with the second copy of the gene, the KRIT1 protein can not function and cavernous malformations form.
The second gene is called CCM2. It is located at 7p15-p13 and controls the production of a protein named malcavernin. The malcavernin protein is believed to play a role in determining where in a vascular endothelial cell (nucleus versus cytoplasm) KRIT1 will be active. When it mutates, too much KRIT1 is in the nucleus of the cell and not enough is in the cytoplasm. 20% of familial cavernous malformation can be linked to a CCM2 mutation. Another 20% of a familial cavernous malformation in the United States can be linked to a deletion of a section of this gene.
The third gene, CCM3, is on the 3rd chromosome at 3q26.1. CCM3 is responsible for creating a protein called Programmed Cell Death 10 or PDCD10. The function of this protein in the formation of cavernous malformations is not known.
For more information on these three genes, please visit the Genetics Home Reference. Genetics Home Reference is a service of the National Library of Medicine. These are the links:
CCM1 (KRIT1): http://ghr.nlm.nih.gov/gene=krit1
CCM2 (malcavernin): http://ghr.nlm.nih.gov/gene=ccm2
CCM3 (PDCD10): http://ghr.nlm.nih.gov/gene=pdcd10
Clinical genetic testing, the only kind of testing that can be used for diagnosis, is available for all three currently known genes. See our Genetic Testing page to find specific laboratories that have been approved to perform these tests. Because not all of the genes have been identified, genetic testing can not rule out a familial mutation. However, if a mutation is identified, it becomes very easy and economical to test other family members.
Whether to have genetic testing is a very personal decision. Please make sure that you have a knowledgeable genetic counselor or physician to help guide you.
Many researchers working on cavernous malformations are focused on genetic issues. It seems to hold the most promise for future understanding and eventual cure. The current focus is on identifying the precise functions of the proteins created by the genes. Please follow the 2008 Research Studies link to see a PDF document with a summary of research published in 2008. Also, please see our newsletter for ongoing information about genetic discoveries in this area.
To find general information on genetics, visit GeneTests or the Genetics Home Reference.
Bergametti F, Denier C, Labauge P, Arnoult M, Boetto S, Clanet M, Coubes P, Echenne B, Ibrahim R, Irthum B, Jacquet G, Lonjon M, Moreau JJ, Neau JP, Parker F, Tremoulet M, Tournier-Lasserve E; Societe Francaise de Neurochirurgie.
Mutations within the programmed cell death 10 gene cause cerebral cavernous malformations. Am J Hum Genet. 2005 Jan;76(1):42-51.
Craig HD, Gunel M, Cepeda O, Johnson EW, Ptacek L, Steinberg GK, Ogilvy CS, Berg MJ, Crawford SC, Scott RM, Steichen-Gersdorf E, Sabroe R, Kennedy CTC, Mettler G, Beis M. J, Fryer A, Awad IA, LiftonRP, Multilocus linkage identifies two new loci for a Mendelian form of stroke, cerebral cavernous malformation, at 7p15-13 and 3q25.2-27. Hum. Molec. Genet. 7: 1851-1858, 1998.
Hsu F, Rigamonti D, and Huhn S. Epidemiology of cavernous malformations. In: Awad I and Barrow D., eds. Cavernous Malformations. Park Ridge, Ill.: American Association of Neurological Surgeons; 1993:13-23.
Liquori CL, Berg MJ, Siegel AM, Huang E, Zawistowski JS, Stoffer T, Verlaan D, Balogun F, Hughes L, Leedom TP, Plummer NW, Cannella M, Maglione V, Squitieri F, Johnson EW, Rouleau GA, Ptacek L, Marchuk DA.
Mutations in a gene encoding a novel protein containing a phosphotyrosine-binding domain cause type 2 cerebral cavernous malformations. Am J Hum Genet. 73(6):1459-64, Dec 2003.
Zawistowski JS, Stalheim L, Uhlik MT, Abell AN, Ancrile BB, Johnson GL, Marchuk DA. CCM1 and CCM2 protein interactions in cell signaling: implications for cerebral cavernous malformations pathogenesis.
Hum Mol Genet. 2005 Jul 21; [Epub ahead of print].