The Belgian family had puzzled doctors for more than a decade. Beginning when they were children, some members were prone to bouts of fever that could last for months. Their muscles and joints ached, their blood vessels were inflamed, and their skin erupted with sores that ranged from severe acne to abscesses and ulcers. One patient’s heart was so badly damaged that he needed a transplant at the age of 20.
Now, researchers have figured out why the family members became ill, revealing that they suffer from a previously undiscovered genetic disease that unleashes a protein that normally helps protect us from microbes. Armed with the findings, doctors might be able to recognize other people with similar symptoms who have gone undiagnosed and offer treatment. In addition, the researchers say, the results might provide insight into more common diseases such as inflammatory bowel disease, where inflammation is out of control.
“The paper beautifully works out the biochemistry” of how the mutation that causes the new disease alters a key immune protein, says geneticist Daniel Kastner of the National Human Genome Research Institute in Bethesda, Maryland, who wasn’t connected to the research.
Scientists have already identified several rare but painful diseases in which the immune system triggers inappropriate inflammation in various parts of the body. These conditions differ from autoimmune diseases like rheumatoid arthritis and type I diabetes because a different branch of the immune system, which includes the body’s first responders to foreign invaders, malfunctions. Some of the Belgian family’s symptoms resembled the symptoms of one of these so-called autoinflammatory diseases, familial Mediterranean fever (FMF), but they were much worse. In FMF, for instance, fever lasts for a few days, not months.
FMF results from mutations in the gene for pyrin, a protein inside many immune cells that detects infections by certain microbes. One attempt to track down the genetic flaw in the Belgian sufferers suggested that they could carry a defect in the same gene, but researchers dismissed the possibility because their symptoms were so different from those in people with FMF, says immunologist Seth Masters of the Walter and Eliza Hall Institute of Medical Research in Parkville, Australia, a co-author on the new paper. “It really didn’t look like the same disease.”
Yet when Masters and colleagues sequenced the DNA of the Belgian family, they found a mutation in the gene for pyrin. It’s in a different location than in most people with FMF, the team reports today in Science Translational Medicine. After searching disease databases and hearing from other doctors who had patients with the similar symptoms, the researchers identified three other families in Lebanon, France, and the United Kingdom that had the same mutation. They’ve named the resulting disease pyrin-associated autoinflammation with neutrophilic dermatosis (PAAND).
Although the same gene is mutated in people with FMF, the type and severity of the symptoms confirm that PAAND is a unique disease, Kastner says. “It’s not FMF. Period.” It’s rare for different mutations in the same gene to cause distinct diseases, but PAAND and FMF are not the only examples, says medical geneticist Wayne Grody of the University of California, Los Angeles (UCLA), who wasn’t connected to the study. He notes, for instance, that mutations in the CFTR gene can trigger the potentially lethal disease cystic fibrosis or a milder illness that results in male infertility.
Masters and colleagues further determined how the mutation in PAAND patients causes pyrin to go awry. When pyrin senses toxins released by some kinds of bacteria, it spurs formation of a structure called the inflammasome that in turn triggers inflammation. To prevent pyrin from switching on prematurely, cells typically shield it with another protein until they are in trouble. But the scientists found that this shield falls off the version of pyrin that the Belgian family produced, resulting in an overactive molecule. “In effect you take away the brake,” says co-author Adrian Liston, an immunologist at the University of Leuven in Belgium.
What makes the paper stand out, says Grody, is the team’s thorough investigation. “They really have a mechanism—we don’t have anything like that to explain FMF,” he says. The work also points to a potential treatment, a drug that blocks an inflammation-promoting molecule that was abundant in the patients. When the researchers treated one member of the Belgian family with the drug, “all the signs of disease disappeared within a couple of weeks,” Liston says. “It was really quite remarkable.” The scientists now plan to launch a clinical trial of the drug in more PAAND patients. Masters and Liston say that the results could also help researchers better understand the role of inflammation in non–auto-inflammatory illnesses, including Alzheimer’s disease and inflammatory bowel disease.
The study might provide more immediate benefits for some people as well. FMF is relatively common for an autoinflammatory disease, but even in the Mediterranean region only about one in 200 to one in 1000 people suffer from it. Although PAAND isn’t likely to be prevalent, researchers think that more patients are waiting for a diagnosis. Large numbers of people with the disease could live in populous countries such as India and China, Masters says. Grody and his colleagues at the FMF clinic at UCLA will be on the lookout for new cases. “I’m certain there are other families out there,” he says.