A gene is the basic unit of heredity. Genes are made from DNA, and carry the information for creating the proteins which are the units that perform a particular job or function. When a gene mutates, it changes from its natural state to become nonfunctional, or it can gain a new function. Mutations that change the function of a gene product can cause illness.
Genetic mutations can be inherited from a parent, or, they can happen randomly over time as an individual grows and ages. When an individual inherits a mutation from his or her parent, that mutation is present in every cell in that person’s body. Randomly acquired (sporadic) mutations can occur in any cell type. This type of mutation is a result of an accident in the process of cell replication.
All genes are in pairs, with one copy inherited from each parent. Some illnesses require mutations of both copies of a gene. These are recessive diseases that typically skip generations in a family. An example of a commonly known recessive disease is cystic fibrosis. By comparison, autosomal dominant diseases are caused by the inheritance of just one copy of a mutated disease gene. Familial cavernous malformation is an example of an autosomal dominant disease. Autosomal dominant diseases do not skip generations.
Cavernous malformations (also known as cavernous angioma or cavernoma) can occur either sporadically, or they may run in families and be inherited due to a genetic mutation.
Sporadic Cavernous Malformation
A sporadic cavernous malformation is the most common form of the illness. Sporadic cases are defined as having no family history and no inherited mutation. Generally, affected individuals have only one lesion.
A solitary cavernous malformation may be present at birth or may form later. Children of individuals with a sporadic cavernous malformation 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 developmental venous anomaly (also known as a DVA, venous malformation, or venous angioma) or if they have undergone radiation treatments in the brain or spinal cord. Please see our page on Developmental Venous Anomalies for more information about the relationship between a DVA and the development of cavernous malformations.
As MRI technology has improved, there are also more cases in which small blood vessel leakage associated with aging or birth trauma 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 determine if you have the hereditary form.
Familial Cavernous Angioma
Familial cavernous malformations are caused by a single gene mutation in one of three different genes, CCM1, CCM2, or CCM3. In familial cavernous malformation, it is typical to develop multiple lesions and to have affected family members in consecutive generations.
Familial cavernous malformations are caused by a hereditary illness that follows an autosomal dominant pattern of inheritance. This means that only one parent must have the illness for it to be passed on to offspring. Each child of a parent with familial cavernous malformation has a 50% chance of inheriting the illness.
Familial cavernous malformations are caused by a genetic mutation found in every cell in your body, destroying the function of one copy of one of the CCM genes. Several studies suggest that lesion formation is seeded when a brain blood vessel cell acquires a second mutation in the other copy of that CCM gene, resulting in a complete loss of function in a brain blood vessel cell. This loss of function causes that cell to start growing and dividing uncontrollably (like a tumor) and starts the formation of a cavernous malformation lesion.
Genes and Sporadic Cavernous malformation
Even though mutations are not inherited in sporadic cavernous malformation, the cause of sporadic lesion development is quite similar to familial lesions. Researchers have found that there are genetic mutations of the CCM genes, but that these mutations occur only in the blood vessels of the sporadic CCM lesion. These mutations are not heritable; they are randomly acquired within brain blood vessels and cause a CCM lesion to form.
This data suggests that all forms of CCM lesions develop following a similar mechanism (a complete loss of function of one of the CCM genes within the brain blood vessel cells). Because of this biological similarity, there is optimism that the same therapeutic drug may treat all forms of CCM in the future.
The Three CCM Genes
Three genes have been identified as a cause of the familial form of cavernous malformation. Researchers discovered the CCM genes by studying families with the illness and looking for genetic mutations across the genome. Over time, three genes were identified and we now call them CCM1, CCM2, and CCM3.
The first gene was identified in 1999 and was named CCM1 (for cerebral cavernous malformation 1). Subsequently, CCM2 was identified in 2003, and CCM3 was found in 2005.
Genes are names for their functions. When each of these was discovered, no one knew what they did, only that mutation causes cavernous malformation. This is how they got their names, and since their discoveries, researchers have been working to determine the function of these genes, and why a mutation of any causes the onset of cavernous malformation.
CCM1 is responsible for creating the CCM1 protein, also called KRIT1, or Krev interaction-trapped 1 protein. The second gene is called CCM2 and controls the production of a protein named malcavernin. The third gene, CCM3, is responsible for creating a protein called Programmed Cell Death 10 or PDCD10. The name of the protein refers to this gene’s function in regulating cell survival.
Research has uncovered that these three gene products (proteins) each have their own unique properties, and also work together as part of a signaling complex, communicating and interacting with each other. The signaling complex is related to critical processes, such as maintaining the tight junctions between neighboring blood vessel cells, cell cycle regulation, and blood vessel development.
In general, cavernous malformations can develop at any age and are present in males and females in equal numbers. Importantly, all ethnic populations are susceptible to the development of a CCM and to familial forms of the illness.
The highest known density of individuals affected by cavernous malformation is in New Mexico, USA. The disproportionate number of affected individuals is because of a specific genetic mutation in the CCM1 gene, termed the Common Hispanic Mutation. This mutation is known as a founder mutation; it arose hundreds of years ago and has been passed through at least 14 generations of Americans descended from the original Spanish settlers of the Southwest. Being Hispanic or Latinx does not predispose individuals to cavernous malformation. Instead, the large population affected by the Common Hispanic Mutation is due to family relatedness and passing the mutation from generation to generation for several hundred years.
In recent years, researchers identified two additional CCM2 gene founder mutations. One of the founder mutations runs in the Ashkenazi Jewish population, and another, a large deletion in the CCM2 gene, traces its ancestry to an originating family born in the southern United States in the 1700s or earlier. The genealogy for all of the founder mutations is still a work in progress. Please visit Alliance to Cure Cavernous Malformation Historical Projects for more information on our genealogy projects.
CCM3 gene mutations cause a uniquely aggressive form of the illness that requires special consideration. Individuals with CCM3 gene mutations are more likely to be diagnosed as children, hemorrhage at an early age, develop high numbers of lesions, and may also experience scoliosis, cognitive disability, benign brain tumors, and/or skin lesions. Please visit CCM3 Syndrome for more information.
Clinical genetic testing is routinely available and recommended for individuals with family history and/or multiple cavernous malformation lesions that can’t be explained by the presence of a DVA or a history of radiation. It is important to have an MRI with an SWI sequence to determine whether there are, indeed, multiple lesions. Please see our page Do I Have Sporadic CCM? for more information on determining the appropriateness of genetic testing.
Tests must be ordered by a physician or genetic counselor and require a saliva or blood sample. See our Genetic Testing Labs page to find specific laboratories that have been approved to perform these tests. Because some kinds of mutations are not detected using commercial testing, 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.
If you do not have insurance coverage for testing, Alliance to Cure Cavernous Malformation offers a free genetic testing program. To request free testing, please begin by enrolling in our patient registry.
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.
Researchers around the world are using chemical, cell, and animal systems to study cavernous malformation. In 2018, our first clinical trials began recruitment and the pace of research is moving faster than ever before. Please see our newsletter and Facebook Pages for ongoing information about genetic discoveries in this area.
– By Amy Akers, PhD and Connie Lee, PsyD
CCM Genetics and You Webinar
To find general information on genetics, visit the Genetics Home Reference.
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