Dr. Douglas Marchuk, professor of genetics at Duke, has spent years studying the genetics of cardiovascular disease. According to a recent article in the Atlantic, his research at the University of Michigan’s Medical Center for the Bowlin family led him to brain disorders with origins dating back to the 1600s.
Three girls in the Bowlin family were experiencing mysterious symptoms. The first daughter to show symptoms was Margaret, the middle daughter, who had seizures when she was a toddler.
Bettina is the oldest daughter. Bettina began having unexplained, but temporary, problems with her right hand. In her later years, she had severe migraines that lasted two weeks.
Although the youngest child, Susan, did not show any similar symptoms, in 1989 her parents decided to take her to be examined. Susan’s brain scan detected a group of abnormal blood vessels. Further examination of her sisters found similar clusters in their brains.
The malformations may either show no symptoms, or they can burst and cause migraines, stroke-like symptoms, or seizures. Severe bleeding may occur and can be fatal.
The Bowlin’s doctors were unable to provide a diagnosis. They were only able to tell the family that they believe the unknown disorder was inherited.
Upon examination, Jerry Bowlin, their father, learned he had the malformations though he had no symptoms. He told the doctors that he had an uncle who had epilepsy.
That recollection prompted Jerry to contact various family members. He made contact with some cousins on Facebook.
Jerry heard many stories about seizures and episodes resembling strokes but never learned the possible cause of the malformations.
Bettina started to have seizures again in 2004, but this time they occurred several times each day. During those seizures, she had no feeling in her face and was unable to speak.
Scans showed malformations in her spinal cord and brain that were eventually removed by surgery.
During this period Susan began to report twitching in her face which worsened to a point that she had trouble speaking, holding light objects, or reading. Her parents rushed her to the emergency room, and the doctors discovered a massive brain bleed. It appeared that one of the malformations burst.
After they had recovered, Susan was left with permanent numbness to the right side of her face, and Bettina continues to experience nerve pain. She is also unable to feel either cold or hot objects on the right side.
On the other hand, Jerry is eighty-two and recently had an MRI that showed malformations. Yet he has never had symptoms.
An Opportunity to Help Others
Bettina learned, through the Angioma Alliance, an advocacy group, that she would be able to donate a portion of tissue from her brain surgery to Dr. Marcuk’s lab. The tissue would be used for their studies of abnormal blood vessels located in the brain called cerebral cavernous malformations (CCM), which is a type of angioma.
Dr. Marchuk studies CCM mutations as they occur in families such as Ashkenazi Jews and Hispanics in New Mexico, and has traced their origins to Spanish colonists of the 16th century.
Bettina’s tissue donation produced a breakthrough. It helped the doctors understand the brain malformations that have occurred in her family since the 1760s.
The mutations occur in genes named CCM1, CCM2, and CCM3. They can weaken blood vessel walls in the brain that have grown into abnormal shapes. At times they may burst. Although rare, they usually occur in adults between twenty and fifty years old.
In the case of the Bowlin family, their malformation has been newly discovered as a deletion of the CCM2 gene. Deletion is defined as being a mutation that involves the loss of genetic material. CCM2 is a dominant mutation that affects each generation with a fifty percent risk of passing to the next generation.
More Prevalent Than Expected
In 2007, Marchuk’s lab not only found evidence in the tissue Bettina donated, but the lab also found the mutation in seven unrelated patients. Dr. Marchuk said they could not connect the eight families to any common heritage.
The Angioma Alliance also began testing people suspected of having CCM mutations. They located families throughout the U.S., mostly in the Midwest and the South. They found that about 25% of participants that were tested had CCM2 deletion. Dr. Marchuk’s researchers believe that these families were probably related.
The families involved in the testing were able to trace their mutation to a couple named Matthew Rushing and Sarah Mae Harrell born circa 1760. The Bowlin daughters were linked to this couple through their DNA.
Looking Forward
Just before her brain surgery, Bettina prayed that it would have some purpose attached to it. Bettina said that Dr. Marchuk’s research resulting from the tissue she donated fulfilled her wishes. Not only has genetic testing enabled patients to learn if they are at risk, but there are clinical trials investigating multiple medications to control the disorder.
