THE BASICS

For yourself…

Familial cavernous malformation is caused by mutations in one of three genes: CCM1, CCM2, or CCM3. These mutations, typically inherited from one’s mother or father, can be detected in a blood or saliva sample that is subjected to sequencing and/or deletion testing.

While all forms of cavernous malformation cause brain lesions that look identical, they can vary greatly among different individuals. Studies have also shown trends in each of the mutation classes. For example, individuals with mutations in the CCM3 gene tend to have an earlier age of onset (often in childhood), higher rates of hemorrhage, and a propensity to develop certain types of brain tumors and other co-morbidities.

As we continue to learn more about all forms of cavernous malformation, undergoing genetic testing can help to provide your doctors with useful information to guide you in your treatment regimen.

For your family…

Your genetic testing can also benefit your family. Familial cavernous malformation is passed from parent to child with each child having a 50% chance of inheritance from an affected parent. Similarly, you had a 50/50 chance of inheriting the mutation from one of your parents.

By identifying your genetic mutation, your children and extended family members can undergo targeted genetic testing to see whether or not they also carry your family’s specific disease-causing mutation. Targeted genetic testing of a previously identified mutation is a quick and cost-effective way to diagnose family members. Genetic screening of family members can provide them with a definitive diagnosis or with relief if they don’t have a mutation. It can also help avoid unnecessary and costly MRIs for family members who have not inherited the disease-causing mutation.

We are beginning to identify lifestyle changes that may reduce the rate of new lesion development and disease risk. Adopting a CCM-healthy lifestyle early may make a lifetime difference.

For the Alliance to Cure Cavernous Malformation Community…

We have finally begun clinical research as well as clinical trials of treatments for cavernous malformation. Successful clinical research and clinical trials require participation and rapid recruitment from the patient community. In order to be prepared for such research, we need to have a well-defined group of patient volunteers who are willing to participate.

To keep up to date with the latest research volunteer opportunities, please register with the Alliance to Cure Cavernous Malformation International Cavernous Malformation Patient Registry. This online registry is a communication tool that links the patient and research communities. Once you create an account, a portal allows you to upload your genetic testing results so we can identify and contact those individuals who are eligible for any upcoming study. (Alliance to Cure Cavernous Malformation will never share any of your personal information without your permission.)

By joining the International Cavernous Malformation Patient Registry and sharing your genetic testing results, you are helping us to define the cavernous malformation patient community and helping researchers design feasibility studies for quickly recruiting participants. Recruitment problems are among the most difficult and cost-prohibitive problems of many clinical trials.

WHAT IF YOU HAVE A SINGLE LESION AND NO FAMILY HISTORY?

Genetic testing is not recommended for sporadic CCM (single lesions without a family history). This is because sporadic CCM is not caused by inherited mutations; testing your blood would not identify a mutation. Please see Do I Have Sporadic CCM? to learn about the use of MRI with SWI sequencing to confirm sporadic CCM.

At a cellular level, sporadic CCM lesions look identical to those of any inherited form. Therefore, similar processes are causing all forms of this illness. A treatment that works for familial CCM should also work for sporadic CCM. While genetic testing is not recommended for individuals with sporadic CCM, we still need you to join our registry so that we can keep you up to date with new announcements for clinical studies.

TESTING ASYMPTOMATIC CHILDREN

Deciding whether to test asymptomatic children is personal. No matter what choice a family makes, a person known to have multiple lesions would need to be tested first, as the “index patient.” Knowing the index patient’s exact mutation allows for specific testing of family members to determine if they are affected.

Benefits

Once the family mutation is known, there are a number of reasons to test asymptomatic kids:

1. Relief. You will find out if your child does not have a mutation, which will let you stop worrying about their disease status. Each child of a parent with a mutation has only a 50% chance of inheriting the mutation.
2. Prevention. We are beginning to identify lifestyle changes that may reduce the rate of new lesion development and disease risk. Adopting a CCM-healthy lifestyle early may make a lifetime difference.
3. Proper medical care. If a child who does have a mutation has ambiguous symptoms, doctors and insurance companies will be more driven to follow up with neurological testing, including imaging. Children have died because they were not tested despite a known family mutation. They presented to the ER and were sent home with a diagnosis of migraine or treated for flu instead of a brain hemorrhage. Insurance companies have denied coverage for CT scans in undiagnosed children when the only symptom is a headache. Additionally, seizure disorders can be picked up sooner, before they cause developmental damage. ADHD can be understood in its context instead of being treated with stimulants.
4. Precautions. You can take precautions for kids who have a mutation and you can eliminate the need to take precautions for kids who test negative. For example, it can be a burden to restrict preservatives in the diet, but a preservative-free diet may have a significant positive impact on lifetime disease. If parents don’t know whether their child has the illness, they should be treating them as if they do, just in case. This means all children of a parent with multiple cavernous malformations, regardless of their mutation status, should be restricted from preservatives if they haven’t had genetic testing. That’s an unnecessary restriction on kids who don’t have a mutation but don’t know it.
5. Confirmation. An MRI isn’t enough. A negative MRI in a child doesn’t mean the child doesn’t have a mutation. It simply means the child has no lesions at that moment or very small lesions that are undetectable. In people with a hereditary form of the illness, more cavernous malformations develop over time. A child, particularly those with a CCM1 or CCM2 mutation, may not develop their first lesion until later in childhood. Only a genetic test can determine if a child doesn’t have the illness or simply hasn’t developed a lesion yet.
6. Estate planning. You may want to consider changes to your will. Some parents choose to establish trusts for children with positive genetic results to protect the child’s ability to receive benefits should the child become disabled at some point in their life. This is something to discuss with an estate planning attorney.
7. Life insurance. You may want to consider a change to your life insurance. Having a cavernous malformation diagnosis may make it difficult to obtain life insurance. Some parents include a small child rider on their personal life insurance policy. This can be converted into a whole life insurance policy when the child becomes an adult.

Risks

However, there is also a negative side to testing asymptomatic children:

1. Adjustment. There is no denying that a positive genetic result changes childhood and family life. At a minimum, it adds MRIs, visits to a neurologist, and anxiety to both the life of the child and the parents. It can mean seeking out a therapist, at least temporarily, to help with the emotional adjustment. There may also be issues between siblings if some test positive for a mutation while others do not.
2. Pre-empting choice. You take away the child’s choice of knowing if they have a mutation. Doctors often advise parents to wait on testing for diseases that have no treatment until an individual reaches an age of consent so they can make their own choice about whether or not they want to know. With our new knowledge about the impact of lifestyle choices on the disease, this argument has become less relevant for familial cavernous malformation. Also, since there can be childhood-onset, surgical intervention is sometimes critical; and, symptoms like seizure and headache do have treatments.
3. Financial implications. In the US, a positive genetic result can have a financial impact depending on your insurance coverage. As long as the Affordable Care Act is in place, your health insurance rates will not be affected, but adding an MRI and a specialist visit every year can be a strain because of co-insurance and co-pays. If genetic testing itself isn’t covered by insurance, the cost of testing each child will be approximately $250. (This is the price to test a family member where the index patient’s mutation is known. Testing of the index patient can cost more depending on the family background and whether the familial disease is caused by a large deletion versus a mutation).
4. Life insurance. In the US, children won’t have difficulty obtaining medical insurance and they can’t be discriminated against in employment as a result of a positive genetic test since the Genetic Information Nondiscrimination Act (GINA) was enacted. However, they may have difficulty buying life insurance if they start as adults. Children can be added to a parent’s life insurance policy even with a positive genetic test. When they are adults, the children will be able to separate to their own policy and add more coverage as needed.

There are some conditions where testing should be strongly considered. If a parent’s testing finds a mutation on the CCM3 gene, testing of kids is necessary. At least 50% of people with a CCM3 mutation will have their first hemorrhage as children, lesions will bleed often, and such children will be at risk for a number of other disorders as part of what we’re coming to understand is a CCM3 syndrome. Diet change early may mitigate some of the impacts. Second, once we have drug treatments, it could be considered negligent to withhold something that could prevent a brain or spinal hemorrhage. Not all kids will get medication; just the ones who test positive for a mutation. So, in a few years, it’s likely all kids of parents with the hereditary form of the illness will be tested as part of the standard of care.

If you do decide to go ahead with genetic testing for your children, you’ll find information for you and your doctor in the Genetic Testing Labs section.

—- Amy Akers, Ph.D., Alliance to Cure Cavernous Malformation Chief Scientific Officer
—- Connie Lee, Psy.D., President, Alliance to Cure Cavernous Malformation

Last update 3.26.23