VEXAS, Chediak–Higashi syndrome and Danon disease: myeloid cell endo-lysosomal pathway dysfunction as a common denominator?

Cellular & Molecular Biology Letters, Journal Year: 2025, Volume and Issue: 30(1)

Published: Jan. 26, 2025

Abstract Vacuolization of hematopoietic precursors cells is a common future several otherwise non-related clinical settings such as VEXAS, Chediak–Higashi syndrome and Danon disease. Although these disorders have priori nothing to do with one other from point view, all share abnormal vacuolization in different cell types including the erythroid/myeloid lineage that likely consequence moderate drastic dysfunctions ubiquitin proteasome system and/or endo-lysosomal pathway. Indeed, genes affected three diseases UBA1, LYST or LAMP2 are known be direct indirect regulators lysosome trafficking function modes autophagy. Furthermore, highly expressed more mature myeloid pointing out their important cells. deficiency for instance associated alterations architecture function. It thus well established disease patients harbor invalidating mutations exhibit giant lysosomes containing undigested materials characteristic defects fusion autophagosomes, feature also found VEXAS CHS. Other similarities regarding include granulocyte monocyte recurrent inflammatory climate. In present review we discuss possibility some manifestations diseases, notably ones consecutive dysfunction pathway myeloid/erythroid progenitors neutrophiles, monocytes macrophages. Finally, propose reacidification way reinducing functionalities autophagy potential approach better management diseases.

Language: Английский

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Emerging treatment approaches for VEXAS syndrome: a systematic review and meta-analysis

Annals of Hematology, Journal Year: 2025, Volume and Issue: unknown

Published: April 27, 2025

Abstract VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is a monogenic autoinflammatory disorder with significant morbidity and mortality. Numerous treatment options including azacitidine, JAK inhibitors, IL-6 anti-IL-1, anti-TNF agents have been proposed. However, no consensus on optimal algorithm has reached. This study aims to evaluate the efficacy safety of medical through meta-analysis existing data help establish clearer guidelines for managing VEXAS. The protocol was registered in PROSPERO (CRD42024590134). MEDLINE EMBASE were screened from inception until March 2025. We included patients who received or agents. primary outcome proportion complete responders. Partial response reported adverse events also evaluated. A total 16 studies 367 included. Concomitant myelodysplastic (MDS) 149 (40.6%) patients. Azacitidine resulted partial 67% [95% CI (0.56,0.77)] 73% (0.64,0.82)] cases, respectively. inhibitors produced 42% (0.33,0.52)] 79% (0.71,0.87)]. led 24% (0.15,0.32)] 72% (0.64,0.81)]. Adverse frequently observed. demonstrated MDS. may be viable options. Prospective clinical trials are needed further confirmation results.

Language: Английский

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VEXAS syndrome: A newly identified X-Linked hematoinflammatory disorder – A comprehensive overview of its genetic, molecular, inflammatory, and clinical landscape

Journal of Autoimmunity, Journal Year: 2025, Volume and Issue: 154, P. 103425 - 103425

Published: April 29, 2025

Language: Английский

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VEXAS Syndrome: A Comprehensive Review of Current Therapeutic Strategies and Emerging Treatments

Journal of Clinical Medicine, Journal Year: 2024, Volume and Issue: 13(22), P. 6970 - 6970

Published: Nov. 19, 2024

VEXAS syndrome is a recently identified autoinflammatory disorder resulting from somatic mutations in the UBA1 gene, leading to complex spectrum of severe inflammatory and hematologic manifestations. The absence established treatment guidelines variability clinical presentation make its management particularly challenging. Current therapeutic approaches are often based on limited evidence, their effectiveness remains inconsistent. This review seeks consolidate existing knowledge strategies for syndrome, offering critical evaluation efficacy addressing gaps current literature. As recognition grows, there an urgent need explore more targeted, effective treatments that can address both aspects disease. By providing comprehensive analysis landscape, this aims guide clinicians researchers toward developing effective, long-term life-threatening condition.

Language: Английский

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UBA1 dysfunction in VEXAS and cancer

Oncotarget, Journal Year: 2024, Volume and Issue: 15(1), P. 644 - 658

Published: Sept. 30, 2024

, an X-linked gene, encodes one of the only two ubiquitin E1 enzymes, playing a pivotal role in initiating most essential post-translational modifications. In late 2020, partial loss-of-function mutations

Language: Английский

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Methodology and clinical utility of longitudinal UBA1 tracking in VEXAS syndrome

British Journal of Haematology, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 13, 2024

Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) is a haemato-inflammatory syndrome genetically defined by mutations in the X-linked UBA1 gene, typically Val/Thr/Leu substitutions at Met41 hotspot. Clinical manifestations are heterogeneous and refractory to most haemato-rheumatological treatments. To date, no guidelines exist for management of VEXAS, scarce evidence on methodology clinical significance longitudinal clonal burden evaluation upon therapy. Here, we validated method quantify explored its applicability patients with VEXAS. Given different treatment interactions, droplet digital polymerase chain reaction (ddPCR) may allow informed therapeutic decisions implementation personalized strategies.

Language: Английский

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