Inflammation, Oxidative Stress, and Endothelial Dysfunction in the Pathogenesis of Vascular Damage: Unraveling Novel Cardiovascular Risk Factors in Fabry Disease

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(15), P. 8273 - 8273

Published: July 29, 2024

Anderson-Fabry disease (AFD), a genetic disorder caused by mutations in the α-galactosidase-A

Language: Английский

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Cardiac involvement in Fabry disease: Implications of retinal vessel analysis in detecting early microvascular alterations despite ERT

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 15, 2025

Abstract Background Cardiac complications driven by microvascular changes are one of the primary reasons for mortality in patients with Fabry disease (FD). While enzyme replacement therapy (ERT) can effectively clear globotriaosylceramide (Gb3) deposits endothelium, it remains controversial whether ERT fully resolves dysfunction, particularly advanced cases. Methods We conducted a cross-sectional observational study 63 FD patients, whom 60 had quality retinal vessel analysis (RVA) data and were age- gender-matched to healthy control group (HC, n=60, matched out 204). Associations severity, echocardiographic laboratory parameters, explored. Results exhibited significantly reduced venular flicker-induced dilation (vFID, 3.5% ± 1.6% vs. 4.6% 2.4%; p = 0.006), narrower central arteriolar equivalents (CRAE, 165.2 µm [153.5 - 183.2] 183.2 [174.7 191.4], < 0.001), lower arteriolar-venular ratio (AVR, 0.82 [0.74 0.87] 0.86 [0.82 0.91]; 0.001) compared HC, independent cardiovascular risk factors. Despite ERT, health incompletely recovered severely affected patients. Narrower arterioles closely associated parameters markers cardiac involvement. Additionally, CRAE demonstrated accuracy comparable LysoGb3 levels identifying GLA variants potential phenotype. elevated chronic inflammation endothelial dysfunction markers, including Rantes, MCP1, CXCL10, ICAM-1, VCAM-1, VEGF. In variants, higher inflammatory impaired microcirculation. Conclusion Our findings demonstrate that RVA detect alterations FD, offering non-invasive approach assessing severity monitoring health. The persistence despite may reflect need earlier interventions. Longitudinal studies warranted further explore predictive value Fabry-related outcomes. Registration https://clinicaltrials.gov/study/NCT06758648 ; Unique identifier: NCT06758648 . Novelty Significance What Is Known? (FD) is an X-linked lysosomal storage disorder characterized accumulation (Gb3), leading complications. Enzyme pharmacological chaperone (PCT) available treatments, but their ability reverse uncertain. Retinal tool previously used monitor systemic diseases. New Information Does This Article Contribute? abnormalities, narrowing dilation, detectable even receiving ERT. strongly offers non-invasive, cost-effective method assess could serve as valuable stratification FD. Summary rare genetic significant due progressive Gb3. Although cornerstone management, we abnormalities persist treatment, disease. By employing RVA, highlights close association between narrowing, involvement severity. These underscore health, involvment results suggest interventions adjunctive therapies targeting be necessary improve outcomes play pivotal role routine care providing insights into vascular optimizing Fabry-specific therapies.

Language: Английский

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Fabry Disease and Inflammation: Potential Role of p65 iso5, an Isoform of the NF-κB Complex

Cells, Journal Year: 2025, Volume and Issue: 14(3), P. 230 - 230

Published: Feb. 6, 2025

Fabry disease (FD) is an X-linked lysosomal storage disease, caused by mutations in the GLA gene on X chromosome, resulting a deficiency of enzyme α-GAL. This leads to progressive accumulation Gb3 cells, causing multi-systemic effects. FD has been classified as subgroup autoinflammatory diseases. NF-κB family ubiquitous and inducible transcription factors that play critical roles inflammation, which p65/p50 heterodimer most abundant. The glucocorticoid receptor (GR) represents physiological antagonists inflammation process. A novel spliced variant p65, named p65 iso5, can bind dexamethasone, enhancing GR activity, found. study investigates potential role iso5 subjects with FD. We evaluated peripheral blood mononuclear cells (PBMCs), from over 100 patients, mRNA level, protein expression. results showed significantly lower expression levels compared controls. These findings, along ability dexamethasone regulation response opposite way strongly suggest involvement inflammatory

Language: Английский

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Sex Differences in Circulating Inflammatory, Immune, and Tissue Growth Markers Associated with Fabry Disease-Related Cardiomyopathy

Cells, Journal Year: 2025, Volume and Issue: 14(5), P. 322 - 322

Published: Feb. 20, 2025

Fabry disease (FD) is a lysosomal disorder due to alpha-galactosidase-A enzyme deficiency, accumulation of globotriaosylceramide (Gb3) and globotriaosylsphingosine (lyso-Gb3) which lead proinflammatory effects. Males develop progressive hypertrophic cardiomyopathy (HCM) followed by fibrosis; females nonconcentric hypertrophy and/or early fibrosis. The inflammatory response Gb3/lyso-Gb-3 one the suggested pathogenic mechanisms in FD when secretion transforming growth factors with infiltration lymphocytes macrophages into tissue promotes cardiofibrosis. This study aims evaluate inflammation-driving cytokines cardio-hypertrophic remodeling biomarkers contributing sex-specific HCM progression. Biomarkers were studied 20 healthy subjects 45 patients. IL-2, IL-10, TNF-α, IFN-γ elevated all patients, while IL-1α, MCP-1, TNFR2 showed differences. increased associated NF-kB pathway males HCM, revealing correlation between IFN-γ, VEGF, GM-CSF, IL-2. In female impaired TNFα/TNFR2/TGFβ cluster correlations IL-1α was observed. activation indicates significant inflammation during males. signaling may explain fibrosis cardiomyopathy. Sex-specific responses influence severity progression HCM.

Language: Английский

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Impact of ER stress and the unfolded protein response on Fabry disease

EBioMedicine, Journal Year: 2025, Volume and Issue: 115, P. 105733 - 105733

Published: April 28, 2025

Language: Английский

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Use of Quantum Dots as Nanotheranostic Agents: Emerging Applications in Rare Genetic Diseases

Small, Journal Year: 2025, Volume and Issue: 21(9)

Published: Jan. 19, 2025

Abstract Rare genetic diseases (RGDs) affect a small percentage of the global population but collectively have substantial impact due to their diverse manifestations. Although precise reasons behind these remain unclear, roughly 80% cases are genetically linked. Recent efforts focus on understanding pathology and developing new diagnostic therapeutic approaches for RGDs. However, there persists gap between fundamental research clinical approaches, where advancements in nanotechnology offer promising improvements. In this context, nanosized light‐emitting quantum dots (QDs), ranging from 2–10 nm, materials applications. Their size‐tunable light emission, high yield, photostability allow tracking cargo. Additionally, QDs can be functionalized with agents, antibodies, or peptides target specific cellular pathways, enhancing treatment efficacy while minimizing side effects. By combining capabilities single platform, thus versatile powerful approach tackle rare disorders. Despite several reviews various applications QDs, utilization domain RGDs is not well documented. This review highlight QDs’ potential diagnosing treating certain addresses challenges limiting application.

Language: Английский

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Septal Myectomy in Patients with Hypertrophic Cardiomyopathy and Non-classical Anderson-Fabry Disease.

Published: July 15, 2024

Anderson-Fabry disease (AFD) results from decreased enzyme activity of lyzosmal and intralyzosomal storage its nonhydrolyzed. Cadiovascular complications, mainly in s form HCM contribute substantially for AFD-patient’s mortality. Here we report three new cases obstructive (HOCM) due to unclassical presentation AFD isolated cardiac involvement. In all the diagnosis was made postoperative by routine genetic morphological testing. Together with previously published this illustrates potential safely beneficial effect septal surgical myectomy patients AFD-HOCM, as well underlines need more thorough screening clinical signs AFD-associated cardiomyopathy GLA variants among HOCM.

Language: Английский

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Complement System and Adhesion Molecule Skirmishes in Fabry Disease: Insights into Pathogenesis and Disease Mechanisms

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(22), P. 12252 - 12252

Published: Nov. 14, 2024

Fabry disease is a rare X-linked lysosomal storage disorder caused by mutations in the galactosidase alpha (

Language: Английский

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Septal Myectomy in Patients with Hypertrophic Cardiomyopathy and Nonclassical Anderson–Fabry Disease

Journal of Cardiovascular Development and Disease, Journal Year: 2024, Volume and Issue: 11(9), P. 293 - 293

Published: Sept. 20, 2024

Anderson–Fabry disease (AFD) results from decreased enzyme activity of lysosomal enzymes and intralysosomal storage nonhydrolyzed forms. Cardiovascular complications, mainly in the form HCM, contribute substantially to AFD patient mortality. Here, we report three new cases obstructive HCM (HOCM) nonclassical presentations isolated cardiac involvement. In all cases, diagnosis was made postoperatively by routine genetic morphological testing. Together with previously published this illustrates potential safety beneficial effect septal surgical myectomy patients AFD-HOCM, as well underlines need for more thorough screening clinical signs AFD-associated cardiomyopathy GLA variants among HOCM.

Language: Английский

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Fabry nephropathy: focus on podocyte damage and therapeutic target

Journal of Translational Genetics and Genomics, Journal Year: 2024, Volume and Issue: 8(4), P. 302 - 11

Published: Sept. 30, 2024

Fabry disease, a rare X-linked lysosomal storage disorder, is marked by deficiency in the activity of enzyme α-galactosidase A. This results accumulation globotriaosylceramide (Gb3) within various tissues and organs, which leads to life-threatening complications poor prognosis. Clinical manifestations are multisystemic, heterogeneous, progressive. Early diagnosis treatment great importance. nephropathy lesions characterized cell vacuolization glomeruli, tubules, interstitium, arteries ultrastructural myelin bodies. Kidney injury can occur structures, with podocytes being first be impacted due their low regeneration extensive exposure Gb3. The Gb3 causes podocytes, essential components glomerular cells, responsible for maintaining integrity filtration barrier. Enzyme replacement therapy, dynamic monitoring podocyte injury, research on repair mechanism will contribute overall kidney damage disease improve renal

Language: Английский

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