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Sunday, April 14, 2024

A Little-Known Inflammatory Disease Is Hiding in Plain Sight

Sometime in the early 1800s, a young woman who lived in a village along the shore of Lake Maracaibo in Venezuela gave birth to several children and, in doing so, indelibly entered the records of human genetics. Unbeknownst to her, she harbored a stretch of excess DNA on her fourth chromosome, which she passed down to many of her children. By the time they reached late middle age, many of her descendents would develop jerky, uncontrollable movements, dementia, and depression: the hallmarks of Huntington’s disease.

In 1993, almost 200 years after the woman lived, scientists managed to pinpoint the single gene responsible for the disease by sampling DNA from hundreds of members of the Venezuelan family. These days, though, no one is discovering new diseases by looking for symptoms that run in families—those low-hanging fruit have all been picked. The ever-expanding field of medical genetics now looks quite different: Researchers strive to tether conditions as different as depression and diabetes to scores of different genes, and doctors decide how to treat cancers based on the combinations of genetic mutations they carry. Science has left behind the era of the lone wolf mutations.

Or so it seemed until, in 2020, researchers showed that a single mutation in a gene called UBA1 could cause a previously unknown inflammatory disease, which they named Vexas (an abbreviation of some of its key characteristics: vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic). Scientifically speaking, the disease was big news—the first Vexas study was published in the The New England Journal of Medicine, the most prestigious medical journal in the United States—but that wasn’t necessarily enough to make clinicians care. “Most people think, ‘Oh, this is another disease from the NIH that I’ll never see in my life,’” says Peter Grayson, an investigator at the US National Institutes of Health and one of the discoverers of Vexas. 

But late last month, a study published in the Journal of the American Medical Association revealed that Vexas might not be all that rare after all. Sifting through a genetic database, researchers found 11 people with the condition, equating to a rate of about 1 in 4,000 in men over 50. That’s just a preliminary estimate of Vexas’ prevalence—the data all came from a rural Pennsylvania health care system, so it will be important to replicate the results in more diverse populations—but it’s still a far more dramatic result than the researchers anticipated. If the estimate is correct, Vexas is more common than ALS, the disease that successfully captured the world’s attention when the Ice Bucket Challenge went viral in 2014. 

For decades, Vexas has hidden in plain sight. It shares symptoms with many other diseases—frequent fevers, widespread inflammation, intense fatigue—so patients were siloed off into different diagnostic categories, isolated from the many others who had the same mutation. That’s because in rheumatology—the medical field that specializes in inflammation and the immune system—the underlying cause of most conditions remains a mystery, so diseases are often defined by appearances alone. The end result is that Vexas patients will have previously been classified as having conditions like vasculitis, psoriasis, and even leukemia—if they got any diagnosis at all.

But sometimes, peeling away the layers of symptoms and laboratory tests to look at the genetics beneath can bear fruit. “Vexas shows us that we can create entirely different taxonomies of disease,” Grayson says. “It really does radically transform how we may think about adult onset inflammation diseases.”

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Vexas would have been discovered a long time ago if it were a garden variety genetic disease, caused by an inherited genetic mutation. For instance, the single gene responsible for familial Mediterranean fever, also an inflammatory disease, was identified in 1997 by screening the DNA of families that carried the disease. But Vexas can’t run in families. Like cancer, Vexas is caused by what scientists call a “somatic mutation,” a gene mutation that develops in someone’s body after they are born.

Because somatic mutations appear later in life, they affect only a fraction of a person’s cells, which makes them difficult to find. Conventional genetic analyses will miss them entirely: If a particular mutation only shows up in some of a person’s DNA, it may get labeled as a mistake. To find somatic mutations, scientists must look very, very carefully.

But looking that closely at the entire genome is untenable: There would be far too much data to sift through. So when David Beck, an assistant professor of medicine at New York University, decided to go looking for disease-causing somatic mutations, he knew he needed to focus. He ended up targeting a cellular process known as ubiquitylation, in which proteins are marked with another protein called ubiquitin, often to be destroyed or shuttled elsewhere in the cell. It’s a fundamental cellular process with wide-ranging consequences, and previous research has shown that ubiquitylation issues can cause inflammatory disease.

Still, ubiquitylation is complex: Beck identified 841 different genes that are involved. But that focus was narrow enough. After searching through a database of over 2,500 people with undiagnosed diseases, both inflammatory and otherwise, he found three men who shared a somatic mutation at the same spot in the same gene: UBA1, which helps initiate the ubiquitylation process. These men all had problems with their blood—too few platelets, unusually large red blood cells—and immune system issues like cartilage and lung inflammation.

But because Vexas shares these symptoms with a number of other disorders, no one would have suspected these men all had the same disease without Beck’s genetic sleuthing—there are just too many people out there with unexplained inflammatory conditions for researchers to identify such subtle symptom patterns. They were just three men among the masses of people chafing under ill-fitting diagnoses.

For years, David Adams was one of those people, too. An affable man in his seventies, he’s spent almost an entire decade in and out of the hospital with pneumonia, severe inflammation, and pain so bad “it almost feels like your body is trying to push out through your pores.” He might never have discovered what was happening to him had it not been for his tenacious primary care physician, Risa Huber, who sent him to rheumatologists, hematologists, and, eventually, the NIH, where he was diagnosed with Vexas. 

Treatment-wise, that diagnosis hasn’t meant much to Adams so far. As of now, the only cure for Vexas is a bone marrow transplant, a procedure that carries substantial risks. Adams was supposed to get a transplant last year, but doctors discovered that his right coronary artery was almost entirely blocked. He received a stent, and he hopes to get a transplant sometime soon, but for now he remains dependent on the steroids he has had to use since he got sick. 

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And yet, knowing he has Vexas has changed his life. “I went for a long time feeling very alone,” he says. “That was probably the worst emotional part.” Despite an extremely supportive wife and medical team, Adams felt it was impossible for anyone around him to truly understand his fatigue and pain—especially without a confirmed diagnosis to explain it. Vexas offered him proof that his suffering was real.

One of his doctors at the NIH, Marcela Ferrada, understands precisely how Adams felt. She both lives with and studies relapsing polychondritis, an inflammatory disease that primarily affects cartilage in places like the nose and ears. Like many such diseases, relapsing polychondritis can only be diagnosed on the basis of symptoms—there’s no laboratory test. That lack of clarity can be tricky for patients. “If someone’s not telling you, ‘You have this,’ you’re always going to be questioning what is happening to you,” Ferrada says.

But now, for some patients, relapsing polychondritis does have a straightforward cause: Vexas. Ferrada fondly remembers calls she has made to patients to deliver the news that they have a UBA1 mutation—sometimes, she says, they are so excited to have a genetic diagnosis that they scream into the phone. 

Ferrada’s hope is that, as her research continues, more and more patients will get to experience that same relief. She thinks the odds are good that other people with relapsing polychondritis—herself, perhaps, included—carry somatic mutations that are yet to be discovered. After all, she and her colleagues have already discovered a couple of new Vexas mutations at different spots in the UBA1 gene. And, she notes, many inflammatory diseases tend to appear late in life, and somatic mutations accrue as people age. 

Grayson agrees that there are many other somatic mutation diseases waiting to be discovered, though he is skeptical that any new disease they find will be quite as widespread as Vexas. Then again, he admits, he never expected Vexas would affect so many people. Until more disease-causing mutations are discovered, it’s impossible to estimate how many people might be affected. 

The good news is that the task of uncovering genetic diseases is only getting easier as gene sequencing becomes ever cheaper and more efficient. And the discovery of Vexas is a signal to the scientific community that searching for common genetic mutations among people with a wide variety of different symptoms is a fruitful strategy. “We found one, and we’ll keep working hard to find the other ones,” Ferrada says. “It’s only going to be a matter of time.”

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