Margaret, the middle Bowlin sister, was the first to exhibit symptoms. As a toddler, she began having seizures. The eldest, Bettina, then experienced a brief and mysterious bout of weakness in her right hand. She had a two-week migraine as an adult in 1986 that was so severe that she couldn’t hold food in her mouth or money in her right hand. Susan, the youngest, felt fine, but her parents still took her for an exam when she was 19 in 1989. A brain scan revealed abnormal clusters of blood vessels, which were also found in her sisters’ brains. These brain malformations can be silent. They can, however, leak or, worse, burst suddenly, causing the seizures, migraines, and stroke-like symptoms that Bettina and Margaret experienced. If the bleeding in the brain becomes severe enough, it can be fatal.
Doctors couldn’t tell the Bowlins exactly what was wrong at the time, only that it ran in the family. Jerry Bowlin, the girls’ father, had the same malformations in his brain (though he had no symptoms), and he knew an uncle who had epilepsy. To better understand his daughters’ illnesses, he began creating a family tree. Jerry polled his family and later reconnected with long-lost cousins via Facebook, and he kept hearing stories of seizures and stroke-like illnesses. Even as the family tree grew, the exact cause of these malformations remained a mystery.
Bettina began having seizures multiple times per day in 2004. Her face would go numb, and she would be unable to speak. A scan revealed a malformation in her brain and one in her spinal cord that required immediate removal in two surgeries. Susan began to feel a tingling in her cheek around the same time. Over the course of a day, her speech became increasingly slurred. She was illiterate. She couldn’t even hold a pencil in her hand. She was rushed to the hospital, where doctors discovered a massive bleed in her brain caused by one of her malformations. “At one time, we had one daughter in ICU in New Orleans, and one daughter in ICU in Biloxi,” their mother, Charlene Bowlin, told me. Susan has permanent numbness on her right side, and Bettina still has nerve pain and can’t feel hot or cold on her right side.
During this trying time, the family discovered a silver lining. Bettina learned that she could donate tissue from her second surgery to a lab that studies the genetics of unusual blood vessels in the brain, known formally as cerebral cavernous malformations, or CCMs, through the Angioma Alliance, a patient advocacy group. Her tissue donation resulted in a significant breakthrough in understanding her family’s brain malformations, the cause of which was eventually traced back to the 1760s.
Bettina’s tissue was sent to the lab of Douglas Marchuk, a Duke geneticist who has studied CCM mutations that run in families, including one in Ashkenazi Jews and another in Hispanics in New Mexico who can be traced back to descendants of 16th-century Spanish colonists. These mutations typically occur in one of three genes known as CCM1, CCM2, and CCM3. Any of them can cause the walls of certain blood vessels to become abnormally weak. These weakened blood vessels in the brain can develop into mulberry-shaped malformations filled with blood. CCMs are uncommon, but they do occur in people who have no family history of them; patients with an inherited CCM mutation, on the other hand, can have multiple malformations at the same time. Even if a single CCM remains silent, having so many increases the likelihood of at least one leaking or bursting. And they usually begin when people are between the ages of 20 and 50.
The malformation of the Bowlin family can be explained by a mutation, albeit a recently discovered one. Their mutation is a deletion in the gene CCM2, and it is dominant, which means it does not skip generations and has a 50% chance of being passed on. Marchuk’s lab discovered it not only in Bettina’s donated tissue, but also in seven other unrelated patients at the same time in 2007.