Oxidative profile exhibited by Mucopolysaccharidosis type IVA patients at diagnosis: Increased keratan urinary levels

Abstract

Morquio A disease (Mucopolysaccharidosis type IVA, MPS IVA) is one of the 11 mucopolysaccharidoses (MPSs), a heterogeneous group of inherited lysosomal storage disorders (LSDs) caused by deficiency in enzymes need to degrade glycosaminoglycans (GAGs). Morquio A is characterized by a decrease in N-acetylgalactosamine-6-sulfatase activity and subsequent accumulation of keratan sulfate and chondroitin 6-sulfate in cells and body fluids. As the pathophysiology of this LSD is not completely understood and considering the previous results of our group concerning oxidative stress in Morquio A patients receiving enzyme replacement therapy (ERT), the aim of this study was to investigate oxidative stress parameters in Morquio A patients at diagnosis. It was studied 15 untreated Morquio A patients, compared with healthy individuals. The affected individuals presented higher lipid peroxidation, assessed by urinary 15-F2t-isoprostane levels and no protein damage, determined by sulfhydryl groups in plasma and di-tyrosine levels in urine. Furthermore, Morquio A patients showed DNA oxidative damage in both pyrimidines and purines bases, being the DNA damage positively correlated with lipid peroxidation. In relation to antioxidant defenses, affected patients presented higher levels of reduced glutathione (GSH) and increased activity of glutathione peroxidase (GPx), while superoxide dismutase (SOD) and glutathione reductase (GR) activities were similar to controls. Our findings indicate that Morquio A patients present at diagnosis redox imbalance and oxidative damage to lipids and DNA, reinforcing the idea about the importance of antioxidant therapy as adjuvant to ERT, in this disorder.

Analysis of Mucopolysaccharidosis Type VI through Integrative Functional Metabolomics

“…Mitochondria dysfunction and the subsequent programed cell death disruptions may represent the most significant cellular deregulation underlying LSD pathogenesis. Indeed, oxidative damage contribution in the LSD pathophysiology in general and in MPSs in particular has recently been documented [34,40]. These data suggest metabolic remodeling and provide a functional snapshot profile of metabolite abundances.…”

Recommendations for the management of MPS IVA: systematic evidence- and consensus-based guidance

“…General anaesthesia carries substantial risk for patients with MPS95% Flexion/extension computerised tomography (CT) of the craniocervical junction may be considered in patients with MPS IVA if MRI is not available or if sedation is not possible92% The presence of specific radiological signs may indicate the need for surgical intervention to correct skeletal deformities; however, there is insufficient evidence to support preventative surgery based on radiological findings88%Endurance Choice of assessment depends on the patient’s physical and developmental ability97% Baseline assessment is the most important and ideally two values should be obtained as a minimum. Consistent protocols should be used when performing repeat measurements to minimise variability95% Annual endurance testing using the 6-min walk test (6MWT) is recommended, as per the American Thoracic Society guidelines [1, 45] Evidence Grade: C (level 4 study and extrapolation from level 1 study) [8, 46]87% In patients with limited ambulation who are unable to perform the 6MWT, endurance should be assessed via alternative methods such as an adapted timed 25-ft walk test (T25FW)76% Endurance testing is also recommended prior to initiation of ERT and annually thereafter as a measure of treatment efficacy and to provide early evidence of possible neurologic or skeletal issues87%Growth Assessment of growth should be performed at each clinic visit (ideally every 6 months) as part of a regular physical examination and should include: standing height (sitting height if the patient is unable to stand), length (supine position), weight, head circumference (≤3 years), Tanner pubertal stage (until maturity) [47]95% Height and weight should also be measured before initiation of ERT and at every clinic visit thereafter (ideally every 6 months) to evaluate the impact of treatment [47]95%Urinary keratan sulphate (KS)/urinary glycosaminoglycan (uGAG) levels Where available, tandem mass spectrometry may be used to assess levels of urinary keratan sulphate prior to starting elosulfase alfa and every 6 months thereafter to determine the pharmacodynamic effects of ERT [48] Evidence Grade: D (level 3/4 studies support the statement; [8, 49–54] however, one level 3 study [55] does not support use of urinary keratan sulphate for monitoring the therapeutic effect of ERT)94% Total uGAG levels are often elevated in neonates and infants with MPS IVA and may overlap with normal values in adults and some teenagers. However, if a specific keratan sulphate assay is not available, measurement of uGAG levels using standard dye-binding methods may be useful.…”

“…Evidence Grade: D (level 3/4 studies support the statement; [8, 49–54] however, one level 3 study [55] does not support use of urinary keratan sulphate for monitoring the therapeutic effect of ERT)…”

Characterization of New Proteomic Biomarker Candidates in Mucopolysaccharidosis Type IVA

“…Oxidative stress is caused by the accumulation of substrates in lysosomes. Therefore, the combination of anti-oxidants with ERT treatment can improve therapeutic efficacy [ 62 ]. We found that TRFL was upregulated in untreated MPS IVA patients compared with healthy controls, and that this effect was corrected after ERT.…”