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Researchers propose that all cases of CCM are genetic -- meaning that they are caused by gene mutations, or changes. However, some people have hereditary or familial CCM meaning that they inherited the condition from a parent, while others have a sporadic, or non-hereditary form. This section will give a brief description of genetics in general, as well as the differences between sporadic and hereditary CCM.
Genes are the basic building blocks we inherit from our parents; they tell our bodies how to grow and develop, what color our eyes will be, and even how our blood vessels will form. We have 46 chromosomes in each cell of our body, receiving 23 chromosomes from our mother in her egg, and 23 chromosomes from our father in his sperm. Genes are located on these chromosomes, thus we have 2 copies of each gene (one from each parent). With some genetic diseases, both copies of a gene must be mutated to cause a person to have any effects, called autosomal recessive conditions. Others, like familial CCM, are autosomal dominant meaning that a person only needs to inherit one gene mutation from a parent to develop CCM.
Sporadic CCM
Individuals with sporadic CCM did not inherit the mutation from a parent. They typically have only one CCM and have no family members with CCMs. For sporadic CCM, the CCM developed from gene mutations that occurred after conception and are not present in all cells of their body. Therefore, the individual will most likely not have a greater chance of having a child with CCM than anyone in the general population (1 in 200), because the mutation is not located in the reproductive cells of the individual. Additionally, no genetic test could be performed on the blood of someone with sporadic CCM, because the gene mutation may not be located in the blood (see diagram below).
Familial CCM
With familial CCM, an individual inherits a gene mutation from a parent, in either the egg or sperm. Because all the cells in the body originate from the egg and sperm, every cell in the individual’s body will have the gene mutation. Therefore, there is a much greater likelihood of this person developing many CCMs. Additionally, a person with familial CCM has one gene mutation in his or her reproductive cells as well, thus has a 50% chance of passing that mutation to each child. Therefore, families with familial CCM typically have several affected individuals in more than one generation.
Surprising Evidence
Although it was once thought that the vast majority of cases of CCM were sporadic (not familial), recent evidence has shown that familial CCM may be more common than we originally thought. In fact, in one study, an MRI was given to first degree relatives (mothers, fathers, sisters, brothers) of an individual with supposed sporadic CCM, and 75% of families had another family member with a CCM that had not yet shown symptoms. Therefore, it may be recommended that first degree relatives have an MRI when one family member is diagnosed as having a CCM.
Genes and Research
Three different gene mutations have been linked to CCM. A family with familial CCM has one of these gene mutations. Only the gene for CCM1, called KRIT1, has been discovered at this point, and it is located on chromosome 7. This gene mutation is the one most commonly found in Hispanic families with familial CCM, due to a common ancestor. Researchers are now studying the function of the KRIT1 protein so as to better understand how it leads to the formation of cavernous malformations when mutated. At this time, clinical testing for CCM1 is available. .
The two genes for CCM2 and CCM3 have not yet been discovered but have been linked to chromosome 3 and 7, respectively. Researchers are attempting to pinpoint the exact location and gene function for these two forms of familial CCM as well. Research testing is available for families with familial CCM in order to look for these genes, but no diagnostic information is available from this testing. These studies usually involve no more than a blood sample and are free and confidential. Please see Research Studies for laboratory information on current research studies.
Scenarios
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1) John began to have seizures when he was 22 years old. He went to his family practice doctor, who referred him to a neuroradiologist for an MRI. After his test, the doctor told him he had a cerebral cavernous malformation. The doctor then asked him about his family history. John explained that he had no one in his family that had ever had a CCM, but his second cousin twice-removed had passed away of a stroke. No one else in his family had ever had a seizure or had any slurred speech or other neurological problems. Does John most likely have familial or sporadic CCM?
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2) Jack was a six-year old that complained of severe headaches for a month. His mother, who had headaches as a child as well and has been found to have several cerebral cavernous malformations in her brain and spinal column, took him to the pediatrician. The doctor referred him for an MRI, which found 3 CCMs in his brain. When asking about the family history, Jack’s mother explained that one of her two brothers just had an MRI that spotted a CCM, and her mother (Jack’s grandmother) has four CCMs, diagnosed by MRI. Jack’s great-grandfather died of a stroke, and his great-grandmother died of cancer. Does Jack most likely have familial or sporadic CCM?
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Answers:
1) Sporadic, no genetic testing is available at this time.
2) Familial, research testing is available for this family. |
Diagram of Sporadic CCM
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