Welcome to Study of the Week from Patient Worthy. In this segment, we select a study we posted about from the previous week that we think is of particular interest or importance and go more in-depth. In this story we will talk about the details of the study and explain why it’s important, who will be impacted, and more.
If you read our short form research stories and find yourself wanting to learn more, you’ve come to the right place.
This week’s study is…
Novel somatic mutations in UBA1 as a cause of VEXAS syndrome
We previously published about this research in a story titled “VEXAS Syndrome May Be More Common Than Initially Believed,” which can be found here. The study was originally published in the research journal Blood. You can view the abstract of the study here.
The team of researchers in this study were affiliated with the University of Leeds.
VEXAS syndrome is a newly discovered illness that was first described less than a year ago in October 2020. As with all recently recognized diseases and syndromes, very little is known about it and scientists are learning more about VEXAS syndrome every day. Researchers have been hard at work trying to understand the cause of the disease, and a recent study has linked the illness to mutations impacting a gene called UBA1.
More specifically, the mutations identified were somatic mutations at methionine 41 (Met41) on the UBA1. In this study, the researchers were seeking to find out how prevalent these mutations were in a cohort of patients that presented with clinical symptoms of the syndrome. In the process of searching for the known mutations, the scientists found two new mutations in the cohort that also appeared to correlate with VEXAS syndrome.
The researchers utilized a cohort of 18 patients that fit the clinical profile of the illness. From this group, they were able to find mutations in 10 patients. However, while eight of them had the previously known somatic mutation, two patients were found to have different ones. These mutations were considered novel variants and were called c.167C>T; p.Ser56Phe and c.118-1G>C. The patient with the p.Ser56Phe variant had a bone marrow profile that was distinct from the others, suggesting a differing, but overlapping, disease mechanism.
The findings helped confirm the importance of the Met41 mutation as a cause of VEXAS syndrome while also identifying two previously unseen mutations that also can cause the illness. With two new mutations discovered so early on, it’s pretty likely that the medical world doesn’t really have a good grasp on how many VEXAS syndrome patients are really out there.
About VEXAS Syndrome
VEXAS Syndrome is a recently discovered autoinflammatory illness first described in 2020. VEXAS stands for Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic. So far the disease has been linked to mutations affecting the UBA1 gene. As this is an X-linked disease, only males are affected by it, and the symptoms of the disease only appear in adulthood, particularly in those over 50 years old. The discovery of the disease has been considered an important link that may connect several other adult-onset autoinflammatory syndromes that initially didn’t appear related to one another. Symptoms include fevers, vasculitis, painful skin rashes, vacuoles in myeloid cells, dysplastic bone marrow, blood clots, lung abnormalities, and swelling of the cartilage found in the ears and nose. The disease can be severe and potentially fatal. Treatments are still be evaluated, but future options may include gene therapy or bone marrow transplant. To learn more about VEXAS syndrome, click here.
Why Does it Matter?
When a new disease is discovered for the first time, research can sometimes move very quickly. In this case, the findings from this study indicate that the overall impact of VEXAS syndrome could actually be a lot more substantial than the medical community originally thought:
“Having established the cause of VEXAS we now have a real opportunity to transform the care of these patients. We know there are still many patients who have a VEXAS-like condition, but in whom we do not know the cause. We plan to continue our research in the hope of discovering other genetic causes of these disorders.” – Dr. Sinisa Savic
With the discovery of new mutations that can cause the illness, the scientists believe that it is likely that the size of the patient population living with this disease could be far larger than was originally understood. These findings highlight the continued urgency of further research into VEXAS syndrome so that the full range of causes and disease variants can be discovered and formally described.
Ultimately, disease caused by somatic mutations (mutations that develop during life, as opposed to those that occur during fetal development or are passed from parents) may be more important than scientists originally believed.