Biomarkers of Glycosaminoglycans (GAG) accumulation in patients with mucopolysaccharidosis type VI-LeukoGAG, Corneal Opacification (COM) and Carotid Intima Media Thickening (CIMT)

Young Bae Sohn; Raymond Wang; Jane Ashworth; Pierre Broqua; Mireille Tallandier; Jean-Louis Abitbol; Erin Jozwiak; Laura Pollard; Timothy C Wood; Tariq Aslam; Paul R Harmatz

doi:10.1016/j.ymgmr.2023.101041

Biomarkers of Glycosaminoglycans (GAG) accumulation in patients with mucopolysaccharidosis type VI-LeukoGAG, Corneal Opacification (COM) and Carotid Intima Media Thickening (CIMT)

Mol Genet Metab Rep. 2023 Dec 28:38:101041. doi: 10.1016/j.ymgmr.2023.101041. eCollection 2024 Mar.

Authors

Affiliations

¹ Department of Medical Genetics, Ajou University Hospital, Ajou University School of Medicine, Suwon, Republic of Korea.
² Children's Hospital of Orange County, Orange, CA, USA.
³ Manchester Royal Eye Hospital, Manchester, UK.
⁴ Inventiva S.A., Daix, France.
⁵ UCSF Benioff Children's Hospital Oakland, Oakland, CA, USA.
⁶ Greenwood Genetic Center, Greenwood, SC, USA.
⁷ Section of Genetics and Metabolism, University of Colorado/Children's Hospital of Colorado, Aurora, CO, USA.
⁸ Manchester University NHS, Manchester, UK.

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.