Genetic Diagnosis Of Vexas Syndrome: A New Rare And Deadly Autoinflammatory Disorder In Adults
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Abstract
VEXAS (Vacuoles, E1 enzyme, X linked, autoinflammatory, somatic syndrome) syndrome is a rare autoimmune condition that can be fatal in adult persons. VEXAS syndrome is classified as an autoinflammatory disease. This syndrome typically affects older adults, primarily males, with signs and symptoms of the condition developing in a person's fifties, sixties, or seventies. About 1 in every 13,591 adults may have the condition. Mutations affecting methionine-41 (p. Met41) in UBA1 of blood cells, the major E1 enzyme that initiates ubiquitylation is responsible for VEXAS. The peripheral-blood exome sequence data was analysed, independent of clinical phenotype and inheritance pattern to identify deleterious mutations in ubiquitin-related genes. Sanger sequencing, immunoblotting, immunohistochemical testing, flow cytometry, and transcriptome and cytokine profiling were performed. CRISPR-Cas9-edited zebrafish were used as an in vivo model to assess the gene function. In such patient, treatment-refractory inflammatory syndrome develops in late adulthood, with fevers, cytopenias, characteristics vacuoles in myeloid and erythroid precursor cells, dysplastic bone marrow, neutrophilic cutaneous and pulmonary inflammation, chondritis, and vasculitis. Patients can also have a shortage of blood cells called platelets. Treatments include corticosteroids, immunosuppressants and sometimes a bone marrow transplant. In the future, VEXAS syndrome along with other related autoinflammatory conditions, and maybe other hemato-inflammatory diseases, in adulthood may change our perception of the already supposedly known rheumatic or systemic autoimmune diseases, and genetic diagnosis may become a routine clinical practice for physicians in experienced referral centres.
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