In approximately 80% of cases, cavernous malformation (CM) is not hereditary.  This means that if a person is diagnosed with CM, they did not have it passed to them from a parent, nor will CM be passed to their children.  In these cases, this is referred to as sporadic cavernous malformation. Sporadic cavernous malformation is the most common form of CM disease.

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Sporadic cavernous malformation typically presents as one lesion. However, there are some exceptions to this. Research suggests that patients with a developmental venous anomaly (DVA) in their brain may develop more than one CM in the area around the DVA.  

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Another exception is for a patient that has been treated with radiation therapy/treatment to the head or neck.  They may develop radiation induced cavernous malformation (RICM) which may result in multiple lesions.  These cases are sporadic CM and are not hereditary.

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In rare cases, an individual may have a DVA and many CMs throughout their brain and/or spine.  In these cases, it is recommended that patients work closely with their specialists to ascertain if this is a genetic form of cavernous malformation.

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How Did I Get a Sporadic Lesion?

​Evidence has demonstrated that sporadic CMs develop in a similar manner as that of familial (hereditary) CMs. Researchers have found that there are genetic mutations of the CM genes but that these mutations only occur in the blood vessels of a sporadic CM lesion.  These mutations are randomly acquired within blood vessels, causing a CM to form-they are not hereditary.  As noted above, it is also suggested that a developmental venous anomaly (DVA), which is also a vascular malformation, tends to be a setting for the formation of sporadic CMs in the brain in some instances.

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Familial Cavernous Malformation

Familial cavernous malformation is caused by a single gene mutation in one of three different genes, commonly known as CCM1, CCM2 or CCM3.  For those with familial CM, it is typical to have multiple lesions and/or a family history, with a propensity to develop lesions over time.

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Familial cavernous malformation is a hereditary disease that follows an autosomal-dominant pattern of inheritance.  This means that if you have been diagnosed with one of the familial types of CM, one of your parents has it.  Additionally, each child of a person diagnosed with one of the familial types, has a 50% chance of inheriting the disease.

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CCM1, CCM2, & CCM3

At this time, three genes have been identified as a cause of the familial form of cavernous malformation.

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In 1999, the gene CCM1 (Cavernous Malformation 1) was identified. CCM1 is responsible for creating the CCM1 protein, also called KRIT1, or Krev interaction-trapped 1 protein.

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Later, in 2003, CCM2 was identified. CCM2 controls the production of a protein named malcavernin.

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The third gene, CCM3 was identified in 2005. CCM3 is responsible for creating a protein called Programmed Cell Death 10 or PDCD10.

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Research has uncovered that while these three gene products (proteins) each have their own unique properties, they work together as part of a signaling complex, communicating and interacting with each other. The function of these genes is related to important processes, such as maintaining signaling networks responsible for the tight junctions between neighbouring blood vessel cells.

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However, 5-15% of familial cases cannot be explained by the three known CCM genes, suggesting the existence of additional CCM loci.

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Overall, both sporadic and familial cavernous malformation can develop at any age and are equally present in males and females.  CM can affect people across all ethnic backgrounds for both sporadic and familial forms of the disease.  Not all individuals that have sporadic or familial cavernous malformation have symptoms.  Research has shown that in approximately 40-50% of cases, patients do not have symptoms.

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Identified Founder Mutations

New Mexico, USA is the geographical location with the highest known number of individuals affected by cavernous malformation.  This is due to a specific genetic mutation in the gene, CCM1 which has been named the Common Hispanic Mutation.  This is known as a founder mutation as it arose hundreds of years ago and has been passed through at least 14 generations of Americans that descend from the original Spanish settlers of the Southwest United States.  This 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.  It is important to note that individuals who are Hispanic or Latinx does not make them more likely to have cavernous malformation.

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Researchers have also identified two additional founder mutations, arising from specific gene mutations in CCM2.  One of the founder mutations identified runs in the Ashkenazi Jewish population and another, traces its ancestry to an originating family born in the southern United States in the 1700’s or earlier.  The genealogy is still being developed for all founder mutations.