Abstract

Background

Adult-onset inflammatory syndromes often manifest with overlapping clinical features. Variants in ubiquitin-related genes, previously implicated in autoinflammatory disease, may define new disorders.

Methods

We analyzed peripheral-blood exome sequence data 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 gene function.

Results

We identified 25 men with somatic mutations affecting methionine-41 (p.Met41) in UBA1, the major E1 enzyme that initiates ubiquitylation. (The gene UBA1 lies on the X chromosome.) In such patients, an often fatal, treatment-refractory inflammatory syndrome develops in late adulthood, with fevers, cytopenias, characteristic vacuoles in myeloid and erythroid precursor cells, dysplastic bone marrow, neutrophilic cutaneous and pulmonary inflammation, chondritis, and vasculitis. Most of these 25 patients met clinical criteria for an inflammatory syndrome (relapsing polychondritis, Sweet’s syndrome, polyarteritis nodosa, or giant-cell arteritis) or a hematologic condition (myelodysplastic syndrome or multiple myeloma) or both. Mutations were found in more than half the hematopoietic stem cells, including peripheral-blood myeloid cells but not lymphocytes or fibroblasts. Mutations affecting p.Met41 resulted in loss of the canonical cytoplasmic isoform of UBA1 and in expression of a novel, catalytically impaired isoform initiated at p.Met67. Mutant peripheral-blood cells showed decreased ubiquitylation and activated innate immune pathways. Knockout of the cytoplasmic UBA1 isoform homologue in zebrafish caused systemic inflammation.

Conclusions

Using a genotype-driven approach, we identified a disorder that connects seemingly unrelated adult-onset inflammatory syndromes. We named this disorder the VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome. (Funded by the NIH Intramural Research Programs and the EU Horizon 2020 Research and Innovation Program.)

Descripción de un caso | 08 ABR 20

Describimos a un paciente con Covid-19 y coagulopatía clínicamente significativa, anticuerpos antifosfolípidos e infartos múltiples

Autor/a: Yan Zhang, M.D., Meng Xiao, M.Sc. Shulan Zhang, M.D. Peng Xia, M.D. Wei Cao, et al. Wei Jiang, M.D. Fuente: NEJM DOI: 10.1056/NEJMc2007575 Coagulopathy and Antiphospholipid Antibodies in Patients with Covid-19

Nota del New England Journal of Medicine: Para comunicar rápidamente información sobre el esfuerzo clínico global contra Covid-19, el Journal ha iniciado una serie de informes de casos que ofrecen puntos de enseñanza importantes o hallazgos novedosos. Los informes de casos deben verse como observaciones más que como recomendaciones para evaluación o tratamiento. En aras de la puntualidad, estos informes son evaluados por editores internos, con la revisión por pares reservada para los puntos clave según sea necesario.
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Describimos a un paciente con Covid-19 y coagulopatía clínicamente significativa, anticuerpos antifosfolípidos e infartos múltiples.

Fue uno de los tres pacientes con estos hallazgos en una unidad de cuidados intensivos designada para pacientes con Covid-19. Esta unidad, que fue administrada por un equipo multidisciplinario del Hospital de la Facultad de Medicina de la Unión de Pekín en la sucursal chino-francesa de la Ciudad Nueva de Tongji Hospital en Wuhan, China, se creó de manera urgente para aceptar a los pacientes más críticos durante el brote de COVID-19.