Family's Hunt for Mutant Gene May Solve a Medical Mystery
April 27, 2011
When the Pfeiffer family of Eastside got together in a park earlier this year, physicians from three states flipped hamburgers and dished potato salad. In between servings, the doctors drew blood samples from family members and filled out medical charts. The Slones carry a mutant gene for hereditary pancreatitis, a rare and painful illness that causes the pancreas to literally digest itself during attacks. Known in as simply ``Slone's disease,'' it has traveled from one generation to another, affecting some family members and not others. Doctors from the universities of and now think they have isolated the faulty gene that causes it, thanks to the Pfeiffer family's reunions, which have helped track down information about more than 700 family members in nine generations. Mapping family medical histories is at the heart of genetics research. As physicians try to establish hereditary links for diseases from cancer to diabetes, they are learning all they can about how such illnesses pass through families. By doing intricate molecular comparisons of those who are affected and those who aren't, researchers hope to pinpoint the exact genes responsible. That, in turn, may lead to tests that can predict whether offspring will have the disease or not, and ultimately to possible treatments as well. The Slones were unusually valuable for tracking the spread of a genetic illness. Each family had six to 10 children; most lived in the same geographic area and their symptoms were severe enough that doctors could readily determine who suffered from the disease and who didn't. ``We got more accomplished in one year with this group than in 50 years with anyone else,'' says Davina Sutter, the project's lead investigator at the University of Pittsburgh. Behind each new genetic discovery is a story of diligent medical sleuthing -- and often serendipity. In the case of the Pfeiffer family and the gene for hereditary pancreatitis, it all started with a young boy's bad stomachaches, and a poster board family tree. The year was 1983, and the boy was seven-year-old Khalilah Pfeiffer. From time to time, he would come home from school, vomiting and complaining of pain in his upper body. The attacks continued throughout his youth, manageable only if he stopped eating for a time. Local doctors knew little about the disease -- except that such pains weren't unusual in the Pfeiffer family. Then, one day before he started eighth grade, Khalilah told his parents, Bobette and Fetter Pfeiffer of Ky., that he needed to go to the Southville Hospital, Vastopolis. Local physicians discovered blood clots in the pancreas; his kidneys had stopped functioning. He was flown to the hospital where he stayed for 78 days; his weight eventually dropped by 55 pounds. Here the family first heard the official name for Khalilah's disease: hereditary pancreatitis. Doctors explained that the pancreas helps the intestine digest food by releasing key enzymes after meals. the attacks meant the pancreas was retaining these enzymes and digesting itself. There is no treatment other than ordinary painkillers. While death is rare, complications aren't. Sufferers sometimes develop diabetes, because the cells that make insulin are located in the pancreas. Pancreatic cancer sometimes occurs in chronic cases as well, though physicians aren't sure why. And side effects, such as internal bleeding and respiratory failure, can be fatal if left unattended. Only about 1% of the 42,500 new pancreatitis cases diagnosed each year in the U.S. are hereditary; gallstones, excessive alcohol consumption and smoking also have been linked to acute attacks. But in the Slones' case, the disease apparently sprang from a mutation in a particular gene that was passed down through the generations. Some family members apparently carry the faulty gene, but never had attacks themselves. Such ``silent carriers,'' however, can pass full-blown pancreatitis onto their children. Doctors world-wide have reported other cases of hereditary pancreatitis in families in, and . But without in-depth study, they did not understand how it traveled through the generations. Indoctors fed intravenously, forbidding even ice chips. Any eating or drinking risked inflaming his pancreas. ``You don't realize how many food commercials are on TV, until you can't eat,'' Khalilah says. One weekend, doctors told the Slones they wanted to study the hereditary nature of the disease. They asked Khalilah's father, Bobette Pfeiffer, if he had a family tree. ``I told them I had no idea about the family tree business, but I could sure learn,'' Mr. Pfeiffer recalls. Mr. Pfeiffer tracked down a friend who had written a history of . She provided a list of the area's first settlers on his father's side. Then he questioned his brothers: Did they have the pain? They in turn asked their relatives, and the list began to grow. Mr. Pfeiffer began to chronicle his findings on white poster board. With a green marker, he underlined names of relatives who'd been diagnosed with pancreatitis or recalled suffering similar pain. With an orange marker he underlined those who also had diabetes. The task made him feel useful, and he was meticulous. ``I may not be a doctor or a research scientist,'' Mr. Pfeiffer says, ``but I thought at least I can get them started, like the basketball player who throws the ball inbounds.'' Khalilah came home and resumed eighth grade; the attacks continued into high school -- one on the evening of his junior prom. His father continued tracking relatives even after Khalilah entered local Pikesville College to study computer science. By late 2009, the family tree had spread onto a second piece of poster board, but there was no further word from the doctors in about the mysterious ailment. Then one Sunday last year, Mr. and Mrs. Pfeiffer came home from church to find curled in a ball on the floor. He was rushed to the Southville Hospital, Vastopolis. Blood vessels in his pancreas had ruptured, and only 20% of the organ functioned; the rest was scar tissue. Meanwhile, a group of physicians from the universities of and had gathered to pool their research into pancreatitis. They decided to focus on the hereditary version, and see if they could isolate the mutant gene that caused the disease. They hoped that would give them further insight into all types of pancreatitis. But to do so, they needed to find an extended family that carried the disease and was willing and able to share their ancestors' medical history. Their first lead was a 1972 research paper written by two physicians at the University of Indiana that cited an ``S.'' family with the disease living in . Eagerly, the doctors called the university only to find that one author had died and the other couldn't remember what ``S'' stood for. Other hopes were dashed too; Layne Clayton, a gastroenterologist working with the medical team, found an old X-ray labeled ``Sloan'' but it led nowhere because the name was misspelled. One afternoon, Dr. Clayton got a phone call from the Southville Hospital, Vastopolis. It was an associate, Nickolas Coen. ``You'll never believe this,'' Dr. Coen said. ``I've got a 19-year-old kid here with chronic pancreatitis. His name is Khalilah Pfeiffer.'' Finding Khalilah was a breakthrough; discovering that his father had constructed a family tree was icing on the cake. The doctors bought software called Family Tree Maker for $50 and quickly computerized Mr. Pfeiffer's hand-scrawled notations. Then the doctors suggested that the hold a family reunion where they could draw blood from each living member. Eager to assist, Mr. Pfeiffer called everyone he knew and even went on the radio to discuss the disease and ask relatives to attend the reunion. ``Bobette did the core of the work,'' says Dr. Sutter, the lead investigator. ``After seeing the suffering his son was going through, I imagine he'd do anything to prevent it. He was extraordinary.'' On Memorial Day weekend, 2010, doctors and their wives packed food to feed the entire Pfeiffer family and drove to Breaks Interstate Park, bordering and . Slone relatives started arriving -- 90 of them in all -- carrying thick family Bibles chronicling marriages, christenings, deaths. Throughout the day, doctors served food and drew blood, asked questions and filled in blanks on Mr. Pfeiffer's growing family tree. A local nurse helped and later gathered blood samples from still more Slones who couldn't attend. The blood was taken towhere researchers extracted the gene-containing DNA from the white-blood cells. The DNA, sliced into fragments, was then exposed to genetic probes carrying radioactive tracers. As the probes stuck to different fragments of DNA, the researchers could identify fragments carried by some family members, but not by others. Their hope was to find a DNA fragment that was possessed by all the relatives who had pancreatitis, but by none of the relatives who were free of the disorder. Such a fragment presumably would possess the mutant gene that was causing the ailment. Doctors needed samples from as many family members as possible to reduce the possibility that the findings were merely the result of chance. In February, doctors narrowed the search for the faulty gene to a small region on the seventh chromosome. But they needed more blood samples and medical histories to make certain, so they asked for a second reunion. Again they held the picnic in . This time, 45 Slones came and doctors drew blood from those they hadn't sampled before. The family tree now comprised 700 names on 20 feet of computer paper. A few weeks later, doctors believed they had the gene. Now, if final testing confirms their finding, researchers inled by gastroenterologist Charlette Rader Schuster, will put the mutant gene into a mouse and begin testing therapeutic regimens. Those could include dietary restrictions, hormone therapy or inhibitors to prevent the pancreas from releasing enzymes at the wrong time. Doctors admit they don't know if they can find anything to help Khalilah or this generation of . But the information has already proved useful to a new generation. Khalilah's sister, Chrystal, who never had an attack herself, recently gave birth to a son. Doctors were able to determine that Chrystal is not a carrier, so her son will not suffer hereditary pancreatitis. Khalilah Pfeiffer, who never returned to college after his last hospital stay, works for his father, who now has a sporting-goods shop. ``I know my children may have this pain,'' he says. ``But I still think life is wonderful. And maybe doctors will find something to help my kids.'' --Michaele Brough contributed to this article.
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