Researchers at the University of Leeds have found that a rare disease first discovered in 2020 – VEXAS syndrome – is more common than first thought.
Late last year, Beck et al. described VEXAS syndrome, a new late-onset treatment refractory inflammatory syndrome with associated haematological abnormalities. It specifically develops in men over 50, causing them to become very sick and fatigued and in some cases, is fatal. Moreover, VEXAS syndrome causes unexplained fevers, painful skin rashes and reduces the number of red and white blood cells. VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) is caused by acquired somatic mutations at Methionine 41 (p.Met41) of UBA1 on chromosome X. This is the major E1 enzyme responsible for initiating ubiquitylation.
Mutations are typically not present at birth and instead develop during the patient’s life. The paper found that mutations were predominantly in myeloid lineages. Functional analyses also identified loss of the cytoplasmic isoform UBA1b and subsequent gain of a new isoform, UBA1c, as the underlying disease mechanisms. The researchers identified no additional variants.
In a new study, published in Blood, researchers examined DNA samples to establish the prevalence of the genetic mutations identified when the disease was first discovered. They specifically found 10 patients (all men over 40 years of age matching the VEXAS clinical phenotype) with somatic mutations in UBA1. Of these patients, 8 had altered p.Met41 and two had novel variants. The first novel variant, c.167C>T; p.Ser56Phe, was present in myeloid and not lymphoid lineages. This led to preferential loss of the catalytic activity of cytoplasmic UBA1. The researchers identified an additional novel variant, c.118-1G>C, at the splice acceptor site of exon 3 leading to altered splicing in vitro.
This study confirms somatic p.Met41 substitutions in UBA1 as a major cause of VEXAS syndrome and identifies two new disease causing mutations. It also emphasises that sequencing in the UBA1 gene can help identify those patients who have VEXAS syndrome and get them the best treatment available.
Dr Sinisa Savic, Consultant Immunologist at Leeds Teaching Hospitals NHS Trust, stated:
“I have been looking after a number of patients with what we now know is VEXAS syndrome for several years. Their care has been complicated by the fact that we did not have a diagnosis which made choosing their treatment and advising them about the prognosis very difficult.
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.”
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