Oxidative stress and inflammation in mucopolysaccharidosis type IVA patients treated with enzyme replacement therapy

Abstract

Mucopolysaccharidosis type IVA (MPS IVA) is an inborn error of glycosaminoglycan (GAG) catabolism due to the deficient activity of N-acetylgalactosamine-6-sulfate sulfatase that leads to accumulation of the keratan sulfate and chondroitin 6-sulfate in body fluids and in lysosomes. The pathophysiology of this lysosomal storage disorder is not completely understood. The aim of this study was to investigate oxidative stress parameters, pro-inflammatory cytokine and GAG levels in MPS IVA patients. We analyzed urine and blood samples from patients under ERT (n=17) and healthy age-matched controls (n=10-15). Patients presented a reduction of antioxidant defense levels, assessed by a decrease in glutathione content and by an increase in superoxide dismutase activity in erythrocytes. Concerning lipid and protein damage, it was verified increased urine isoprostanes and di-tyrosine levels and decreased plasma sulfhydryl groups in MPS IVA patients compared to controls. MPS IVA patients showed higher DNA damage than control group and this damage had an oxidative origin in both pyrimidine and purine bases. Interleukin 6 was increased in patients and presented an inverse correlation with GSH levels, showing a possible link between inflammation and oxidative stress in MPS IVA disease. The data presented suggest that pro-inflammatory and pro-oxidant states occur in MPS IVA patients even under ERT. Taking these results into account, supplementation of antioxidants in combination with ERT can be a tentative therapeutic approach with the purpose of improving the patient's quality of life. To the best of our knowledge, this is the first study relating MPS IVA patients with oxidative stress.

Systems biology study of mucopolysaccharidosis using a human metabolic reconstruction network

“…All models showed a similar behavior excepting MPS VII. In addition, other studies have unlinked the inflammation as a cause of oxidative stress in the MPS IIIB neurodegeneration [67] and it is in discussion the mechanisms that trigger the excessive production of free radicals and the saturation of the defense systems against these molecules [66]. The present results suggest that there may be a metabolic contribution to this oxidative stress.…”

“…They attributed these changes to the metabolic activation of autophagy as a consequence of lysosome dysfunction. Recently, it was described the finding of oxidative stress in MPS IVA patients due to the accumulation of toxic substrates [66]. The MPS models predicted a hypothetical mechanism that contributing to the oxidative stress.…”

Α-Glucosidase Deficiency Promotes Increasing Protein Oxidative Damage in Pompe Disease 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).…”

Possible diagnostic markers for Mucopolysaccharidoses; Cathepsin-D, Galectin-3 and Chitotriosidase

“…However, they found only one of two patients with MPS IVA had significantly high chitotriosidase activity. Donida et al showed increased plasma IL-6 levels of MPS IVA patients compared to controls and they suggested the presence of a proinflammatory state which was supported by our findings (17) . MPS IVA diagnosis is mostly delayed and has some challenges due to the variable severity of the clinical presentations, high rate of false negative results in urine GAG testing, the presence of other diseases (multiple sulfatase deficiency; MSD) and mucolipidosis II or III (ML I/III) together with the deficiency of GALNS [galactosamine (Nacetyl)-6-sulfatase] activity (18) .…”