A little-known inflammatory disease lurks in plain sight

Vexas would have been discovered a long time ago if it were a genetic disease in a garden variety caused by an inherited genetic mutation. For example, a 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 work for families. Like cancer, Vexas is caused by what scientists call a “somatic mutation,” a gene mutation that develops in someone’s body after birth.

Because somatic mutations appear later in life, they affect only a subset of human cells, making them difficult to detect. Conventional genetic analyzes miss them completely: if a particular mutation is found only in some part of a person’s DNA, it can be flagged as a mistake. To find somatic mutations, scientists have to look very, very carefully.

But looking at the whole genome so carefully is impossible: there will be too much data to sift through. So when David Beck, assistant professor of medicine at New York University, set out to look for disease-causing somatic mutations, he knew he needed to focus. He eventually targeted a cellular process known as ubiquitination, in which proteins are labeled with another protein called ubiquitin, which often must be destroyed or moved to another location in the cell. It is a fundamental cellular process with a wide range of implications. Previous research showed that ubiquitination problems can cause inflammatory diseases.

However, ubiquitination is complex: Beck has identified 841 different genes that are involved in it. But this focus was rather narrow. After searching a database of more than 2,500 people with undiagnosed diseases, both inflammatory and otherwise, he found three men who had a common somatic mutation at the same location in the same gene: UBA1, which helps initiate the ubiquitination process. All of these men had blood problems—too few platelets, unusually large red blood cells—and immune system problems, such as cartilage and lung inflammation.

But since Vexas has the same symptoms as a number of other disorders, no one would have suspected that all these men had the same disease without Beck’s genetic investigation – there are too many people with unexplained inflammatory conditions for researchers to identify such subtle symptom patterns. . . They were just three men in a mass of people who were annoyed by inappropriate diagnoses.

For many years, David Adams was one of those people too. An affable man in his seventies, he spent almost a full decade in and out of the hospital with pneumonia, severe inflammation, and pain so intense that “it almost feels like your body is trying to push out your pores.” He may never have known what was happening to him if not for the persistent attending physician, Rhys Huber, who sent him to rheumatologists, hematologists, and, eventually, the National Institutes of Health, where he was diagnosed with Vexas.

In terms of treatment, this diagnosis means little to Adams so far. For now, the only cure for Vexas is a bone marrow transplant, a procedure that carries significant risks. Adams was supposed to have a transplant last year, but doctors discovered that his right coronary artery was almost completely blocked. He’s got a stent and hopes to get a transplant soon, but for now he’s still dependent on steroids, which he’s had to take since he got sick.