Globotriaosylceramide is correlated with oxidative stress and inflammation in Fabry patients treated with enzyme replacement therapy

Abstract

Fabry disease is an X-linked inborn error of glycosphingolipid catabolism due to deficient activity of α-galactosidase A that leads to accumulation of the enzyme substrates, mainly globotriaosylceramide (Gb3), in body fluids and lysosomes of many cell types. Some pathophysiology hypotheses are intimately linked to reactive species production and inflammation, but until this moment there is no in vivo study about it. Hence, the aim of this study was to investigate oxidative stress parameters, pro-inflammatory cytokines and Gb3 levels in Fabry patients under treatment with enzyme replacement therapy (ERT) and finally to establish a possible relation between them. We analyzed urine and blood samples of patients under ERT (n=14) and healthy age-matched controls (n=14). Patients presented decreased levels of antioxidant defenses, assessed by reduced glutathione (GSH), glutathione peroxidase (GPx) activity and increased superoxide dismutase/catalase (SOD/CAT) ratio in erythrocytes. Concerning to the damage to biomolecules (lipids and proteins), we found that plasma levels of malondialdehyde (MDA) and protein carbonyl groups and di-tyrosine (di-Tyr) in urine were increased in patients. The pro-inflammatory cytokines IL-6 and TNF-α were also increased in patients. Urinary Gb3 levels were positively correlated with the plasma levels of IL-6, carbonyl groups and MDA. IL-6 levels were directly correlated with di-Tyr and inversely correlated with GPx activity. This data suggest that pro-inflammatory and pro-oxidant states occur, are correlated and seem to be induced by Gb3 in Fabry patients.

Α-Glucosidase Deficiency Promotes Increasing Protein Oxidative Damage in Pompe Disease Patients

“…Regarding the non-enzymatic antioxidant defenses (SH), no significant differences are shown between the groups studied in this paper (Figure 1), as previously found by Bianccini and colaborators in Fabry Disease [32]. When investigating the parameters of oxidative stress, pro-inflammatory cytokines and levels of globotriaosylceramide (Gb3) in patients with Fabry disease undergoing enzyme replacement therapy (ERT), the results suggest the pro-inflammatory and pro oxidants states that occur are correlated and appear to be induced by Gb3 in Fabry patients.…”

“…The results obtained in this study with markers of antioxidant defense CAT and SOD1 (Figure 2) showed no difference between groups, differing from other studies that show statistical differences between the control group and patients groups of Gaucher disease [32] and Mucopolysaccharidosis type IVA [33]. In addition to the enzymatic activity of SOD1 and CAT, we also evaluated the relationship between them, in which no changes were observed (p=0.42) in this parameter on both groups of the study (Figure 2).…”

The Kidney in Fabry Disease

“…Patients presented decreased levels of antioxidant defenses, reduced glutathione, reduced glutathione peroxidase activity, increased superoxide dismutase-catalase ratio in erythrocytes, and interleukin 6 and tumor necrosis factor a increments. 34 However, other studies show a decrease in tumor necrosis factor a.…”

“…35 An example to this phenomenon could be the reported different levels of tumor necrosis factor a in patients with Fabry disease, 34,35 although it could also be due to the stage of the disease under consideration. 9 …”

Age at First Cardiac Symptoms in Fabry Disease: Association with a Chinese Hotspot Fabry Mutation (IVS4+919G>A), Classical Fabry Mutations, and Sex in a Taiwanese Population from the Fabry Outcome Survey (FOS)

“…Indeed, there is some evidence to suggest that increased levels of urinary and plasma Gb 3 are not correlated with clinical Fabry symptoms (Vedder et al 2007). Perhaps there are other contributing pathogenic factors, such as degree of the inflammatory reaction (Biancini et al 2012;De Francesco et al 2013), the vulnerability of cardiomyocytes (modified by some cardiomyopathic genes or other unknown genes) (Desnick and Doheny 2014), or cell non-autonomous phenomena.…”