VEXAS is an auto-inflammatory disease that starts in late adulthood. It is caused by a mutation in the UBA1 gene. The mutation affects the production of E1 enzyme which initiates ubiquitylation—that is, the enzyme that activates a regulatory protein called ubiquitin which can combine with other proteins and change the way they act, their location and other factors. Ubiquitin is also important for the regulation of the immune system.

The condition affects men who have the mutated UBA1 gene in some of the X-chromosomes in their body and the normal gene in the other X-chromosomes (mosaicism). The inflammatory disease that is reportedly fatal in four out of 10 patients produces symptoms like widespread inflammation, recurring fever and vacuoles (bubbles) myeloid and erythroid precursor cells.

Currently, the diagnosis is made based on a study of the genomic sequence—by looking for specific changes in the UBA1 gene. Before this discovery, patients with this condition were mistakenly diagnosed as having an inflammatory condition (examples include relapsing polychondritis, Sweet’s syndrome, polyarteritis nodosa, or giant-cell arteritis) or with a blood-related or hematologic condition such as myelodysplastic syndrome or multiple myeloma. (Read more: Bone marrow transplant)

Researchers at the National Human Genome Research Institute, US, discovered the disease after looking for the common genetic mutations across 800 genes in over 2,500 patients with inflammatory disease. They found 50 examples with the specific mutation responsible for VEXAS.

  1. Symptoms of VEXAS
  2. Causes of VEXAS
  3. Diagnosis and treatment of VEXAS
  4. Doctors for VEXAS inflammatory syndrome

VEXAS stands for vacuoles, E1 enzyme, X-linked, autoinflammatory and somatic syndrome.

  • Vacuoles are hollow, cavity-like structures that develop in the myeloid cells. Myeloid cells are blood cells that arise from progenitor cells (which become blood cells).
  • E1 enzyme refers to an enzyme made by the UBA1 gene that normally activates ubiquitin protein (ubiquitin-activating enzyme).
  • X-linked is a reference to the fact that the gene mutation occurs on the X chromosome in men who show “mosaicism”: a condition in which the genetic mutation is limited to some cells while the other cells have the normal gene.
  • Auto-inflammatory talks to the main symptom of the disease: systemic inflammation that doesn’t have an obvious cause.
  • Somatic syndrome here means the condition develops later in life rather than being present at birth.

The symptoms of VEXAS include:

  • Problems related to the blood, blood cells and blood cell production:
    • Blood clots in veins
    • Dysplastic bone marrow—problems with bone marrow that affect blood cell production
    • Cytopenias, or reduction in the number of mature blood cells
    • Unusual hollows or cavity-like structures or vacuoles in the myeloid cells and erythroid precursor cells
  • Fever that keeps coming back
  • Abnormalities in the lungs, including pulmonary inflammation
  • Problems linked to inflammation:
    • Inflammation that is resistant to many treatments (treatment-refractory), develops later in life and can be fatal
    • Neutrophilic cutaneous inflammation (skin lesions caused by the infiltration of neutrophils, a type of immune cells)
    • Chondritis, or inflammation in the cartilage
    • Vasculitis, or inflammation in the blood vessels

VEXAS is caused by a mutation in the UBA1 gene which results in problems with a regulatory protein called ubiquitin. Ubiquitin is present in almost all tissues of the human body. When ubiquitin combines with another substrate protein (ubiquitylation), it can change that protein’s location, activity, and even mark it for degradation (destruction). Ubiquitin also has a role in regulating the immune system. In this condition, the enzyme that activates ubiquitylation is affected.

Researchers at the US National Institutes of Health’s National Human Genome Research Institute looked at the genome sequences of 2,560 people who had an inflammatory disease but its cause was unknown. The scientists studied about 800 genes involved in ubiquitylation—which affects how proteins act within the cells and the immune system—in these people and found the specific change that causes VEXAS in three adult men. Later investigations showed 47 more people with this mutation.

There’s another nuance to what the scientists discovered about this rare genetic disease: Most men have only one X chromosome (as they have XY sex chromosomes). But the scientists found both normal X chromosomes and X chromosomes with the UBA1 gene mutation that causes VEXAS in the men who were positive for VEXAS. So the scientists looked for further explanation for how it affects these men. The answer was mosaicism or the occurrence of groups of cells with the mutations and others with the normal form of the gene in the same body.

The scientists confirmed this using DNA-sequencing methodologies.

Scientists believe that women may be protected against this disease because they have two copies of the X chromosome in each cell, which may have a protective effect in this case.

Currently, testing patients for this genetic mutation in the UBA1 gene is the way to diagnose the condition. Risk factors include being male and middle-aged—these factors could help with the diagnosis to a small extent.

Treatment options are yet to be developed. Scientists already know that many of these patients don’t respond to many treatments like steroids and chemotherapy.

Dr. Hemanth Kumar

Dr. Hemanth Kumar

Neurology
3 Years of Experience

Dr. Deepak Chandra Prakash

Dr. Deepak Chandra Prakash

Neurology
10 Years of Experience

Dr. Virender K Sheorain

Dr. Virender K Sheorain

Neurology
19 Years of Experience

Dr. Vipul Rastogi

Dr. Vipul Rastogi

Neurology
17 Years of Experience

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References

  1. Beck D.B., Ferrada M.A., Sikora K.A., Ombrello A.K., Collins J.C., Pei W., Balanda N., Ross D.L., Cardona D.O., Wu Z., Patel B., Manthiram K., et al. Somatic mutations in UBA1 and severe adult-onset autoinflammatory disease. The New England Journal of Medicine, 27 October 2020.
  2. National Institutes of Health. [Internet]. U.S. Scientists use clues in the human genome to discover new inflammatory syndrome, 27 October 2020.
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