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Objective: Somatic mutations in UBA1 have recently been causally linked to a severe adult‐onset inflammatory condition referred to as VEXAS (vacuoles, E1 enzyme, X‐linked, autoinflammatory, somatic) syndrome. Ubiquitin‐activating enzyme E1 (UBA‐1) is of fundamental importance to the modulation of ubiquitin homeostasis and to the majority of downstream ubiquitylation‐dependent cellular processes. Direct sequencing analysis of exon 3 containing the prevalent variants p.Met41Leu, p.Met41Val, and/or p.Met41Thr is usually used to confirm the disease‐associated mutations. Methods: We studied the clinical, biochemical, and molecular genetic characteristics of a 59‐year‐old man with a 2‐year history of arthritis, fever, night sweats, nonspecific skin rash, lymphadenopathy, and myelodysplastic syndrome with multilineage dysplasia. Results: The mutational analysis revealed a previously undescribed sequence variant c.1430G>C in exon 14 (p.Gly477Ala) in the gene UBA1. In vitro enzymatic analyses showed that p.Gly477Ala led to both decreased E1 ubiquitin thioester formation and E2 enzyme charging. Conclusion: We report a case of a patient of European ancestry with clinical manifestations of VEXAS syndrome associated with a newly identified dysfunctional UBA‐1 enzyme variant. Due to the patient's insufficient response to various immunosuppressive treatments, allogeneic hematopoietic stem cell transplantation was performed, which resulted in significant improvement of clinical and laboratory manifestations of the disease. [ABSTRACT FROM AUTHOR]

The article offers information about the VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome and disease taxonomy in rheumatology. It mentions that VEXAS syndrome, discovered through the use of a genotype-first approach, whereby a large genetic database was analyzed for commonalities among patients, with minimal consideration of clinical phenotype.

Objective: To identify patients with VEXAS syndrome (vacuoles, E1 enzyme, X‐linked, autoinflammatory, somatic syndrome) from a single‐center cohort of Italian patients with vasculitis, using a clinically oriented phenotype‐first approach. Methods: We retrospectively reviewed the clinical records of 147 consecutive male patients followed up in our vasculitis clinic from 2013 to date. All patients with a diagnosis of vasculitis and treatment‐resistant manifestations of inflammation, persistently elevated inflammation markers, and hematologic abnormalities were identified. Bone marrow aspirates were examined for the presence of vacuoles. Sequencing of ubiquitin‐activating enzyme E1 (UBA‐1) was performed using genomic DNA from peripheral blood leukocytes or bone marrow tissue. Results: Seven patients with vasculitis and concomitant features of VEXAS syndrome were identified. A final diagnosis of VEXAS syndrome was made in 3 of the 5 patients who underwent sequencing of UBA‐1 (diagnosis was made postmortem for 1 patient). In all 3 patients, examination of the bone marrow aspirate revealed vacuoles characteristic of VEXAS syndrome, and all 3 patients met the definitive World Health Organization criteria for myelodysplastic syndrome. Cytogenetic analysis showed normal karyotypes in all 3 patients. Conclusion: To our knowledge, this is the first report of VEXAS syndrome associated with antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis. Our data emphasize the need to consider VEXAS syndrome when evaluating patients with various forms of systemic vasculitis. The novel association between VEXAS syndrome and ANCA‐associated vasculitis reported herein warrants further investigation. [ABSTRACT FROM AUTHOR]

The article describes a novel phenotype of the described vacuoles, E1 enzyme, X-linked, inflammatory somatic (VEXAS) syndrome. Topics discussed include evaluation for noted leucopenia, finding on subsequent high muscle magnetic resonance imaging (MRI), and myositis as a prominent presenting feature of the syndrome.