Biomarkers of Glycosaminoglycans (GAG) accumulation in patients with mucopolysaccharidosis type VI-LeukoGAG, Corneal Opacification (COM) and Carotid Intima Media Thickening (CIMT) - PubMed (original) (raw)
Biomarkers of Glycosaminoglycans (GAG) accumulation in patients with mucopolysaccharidosis type VI-LeukoGAG, Corneal Opacification (COM) and Carotid Intima Media Thickening (CIMT)
Young Bae Sohn et al. Mol Genet Metab Rep. 2023.
Abstract
Mucopolysaccharidosis type VI (MPS VI) is an autosomal recessive lysosomal storage disorder characterized by deficient activity of arylsulfatase B enzyme (ASB) resulting in cellular accumulation of dermatan sulfate (DS) and chondroitin sulfate (CS) that leads to cell injury. Urinary glycosaminoglycans (GAG) are often used as a biomarker in MPS diseases for diagnosis and to monitor treatment efficacy. This study evaluated leukocyte GAGs (leukoGAG) and skin GAGs as alternate biomarkers representing intracellular GAG changes in patients with MPS VI and treated with enzyme replacement therapy (ERT). In addition, we evaluated corneal opacification measurements (COM) and carotid intima media thickness (CIMT) as indicators of GAG accumulation and tissue injury. The study was performed in a serial two-step design in a single center. A quantitative method to measure leukoGAG levels in leukocytes was developed in Study 1 to compare the GAG levels between MPS VI patients and a control group and to assess correlations between leukoGAG and urineGAG. Study 2 validated the leukoGAG measurement, assessed the effect of ERT infusion on leukoGAG and ASB activity in leukocytes, identified correlations between leukoGAG and other biomarkers, and assessed differences in GAG accumulation between MPS VI patients and control subjects. In Study 1, leukoCS and leukoDS levels were significantly higher in the MPS VI group than the control group (leukoCS: 37.9 ± 10.2 and 2.9 ± 1.5 μg/μg protein, respectively, p = 0.005; leukoDS: 0.26 ± 0.2 and 0.0 ± 0.0 μg/μg protein, respectively, p = 0.028) with positive correlations between leukoCS and urine CS and leukoDS and urineDS. In Study 2, leukoCS (32.0 ± 11.8 vs 6.9 ± 3.1 μg/mg protein, p = 0.005) and leukoDS (0.4 ± 0.1 and 0.2 ± 0.1 μg/mg protein, p = 0.020) were significantly higher compared with control subjects. Thus, these results highlight the potential of leukoGAG as a new biomarker representing intracellular GAG accumulation in MPS VI patients and may be valuable for patient management.
Keywords: Carotid intima media thickness; Corneal opacification measurements; Leukocyte GAG; Mucopolysaccharidosis type VI; Skin GAG.
© 2023 The Authors.
Conflict of interest statement
PH has received consulting fees/other remuneration from Aeglea, 10.13039/100006396Alexion Pharmaceuticals, ArmaGen, Audentes, AVROBIO, 10.13039/100008484BioMarin Pharmaceutical, Capsida Biotherapeutics, Chiesi, Denali Therapeutics, Edigene, Enzyvant, 10.13039/501100002426Fondazione Telethon, Grace Science, Inventiva Pharma, JCR Pharmaceuticals, Orphazyme, Paradigm Biopharma, 10.13039/100013223PTC Therapeutics, Novel Pharma, Orchard Therapeutics, Rallybio, REGENXBIO, Renoviron, Sangamo Therapeutics, Saliogene, 10.13039/100013995Sanofi Genzyme, Takeda, and 10.13039/100013220Ultragenyx Pharmaceutical; and has received research support from 10.13039/100006396Alexion Pharmaceuticals, Adrenas, ArmaGen, Amicus, Ascendis, ASPA, Azafaros, 10.13039/100008484BioMarin Pharmaceutical, Calcilytics, Denali, Enzyvant, Homology, Inventiva Pharma, JCR, Orphazyme, Prevail, QED, RegenXbio, Sangamo Therapeutics, 10.13039/501100012112Swedish Orphan Biovitrum, Takeda, and 10.13039/100013220Ultragenyx Pharmaceutical.
Figures
Fig. 1
Levels of CS, DS, and HS in leukocytes. In MPS VI patients, CS and DS leukoGAG were significantly higher compared with control subjects (32.0 ± 11.8 and 6.9 ± 3.1 μg/mg protein, p = 0.005) and (0.4 ± 0.1 and 0.2 ± 0.1 μg/mg protein, p = 0.020), respectively, compared with control subjects. HS in leukocytes was similar in both groups (2.6 ± 1.0 and 2.8 ± 1.0 μg/mg protein, respectively). CS: chondroitin sulfate, DS: dermatan sulfate, ERT: enzyme replacement therapy, GAG: glycosaminoglycan, HS: heparan sulfate, leukoGAG: GAG contained in leukocytes, MPS VI: mucopolysaccharidosis type VI.
Fig. 2
Evolution of mean CS, DS, and HS leukoGAG, and leukoASB over 48 h after ERT infusion in MPS VI patients. The y-axis is divided in two portions (from 0 to the threshold of 4 and from the threshold of 24 to 150) in order to represent all values in the graph. Two black lines identify the two thresholds. ASB: arylsulfatase B enzyme, CS: chondroitin sulfate, DS: dermatan sulfate, ERT: enzyme replacement therapy, GAG: glycosaminoglycan, HS: heparan sulfate, leukoASB: ASB activity in leukocytes, leukoGAG: GAG in leukocytes, MPS VI: mucopolysaccharidosis type VI.
Fig. 3
Carotid intima media thickness in each group. CIMT was significantly higher in MPS VI patients compared with control subjects (0.592 ± 0.087 mm and 0.425 ± 0.072 mm, respectively, p = 0.0192, Wilcoxon test). CIMT: carotid intima media thickness, ERT: enzyme replacement therapy, MPS VI: mucopolysaccharidosis type VI.
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