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Chondroitin sulfate disaccharide is a specific and sensitive biomarker for mucopolysaccharidosis type IVA.

ABSTRACT: Mucopolysaccharidosis type IVA (MPS IVA) is an inborn error of glycosaminoglycan (GAG) catabolism characterized by a deficiency of the lysosomal enzyme, N-acetylgalactosamine 6-sulphatase (GALNS). Consequently, partially degraded GAG, chondroitin 6-sulfate (CS) and keratan sulfate (KS), accumulate in the lysosomes of affected cells, primarily in cartilage resulting in skeletal disease. Excessive urinary excretion of these GAG is often used as the initial biochemical parameter to inform a laboratory diagnosis. Here we present the utility of a CS-disaccharide with a non-reducing 6-sulfated N-acetylgalactosamine residue (HNAc-UA (1S))-the enzyme's substrate-for the diagnosis and biochemical monitoring of MPS IVA patients. Following implementation of this method into the diagnostic laboratory, we identified one MPS IVA patient over 3?years of MPS urine screening, with no false positive results from 2050 urines tested. Uniquely, urinary concentrations of HNAc-UA (1S) are independent of age meaning that age-related reference ranges are not required. Urinary HNAc-UA (1S) was also able to identify two MPS IVA siblings who remained misdiagnosed with spondyloepiphyseal dysplasia for 5?years because of normal urinary GAG. HNAc-UA (1S) could also be used as a biomarker for monitoring response to enzyme replacement therapy (ERT) as there was a drop in urinary concentration following the administration of ERT in all 12 patients and concentrations correlated with urinary KS (R 2 = 0.92). In conclusion, HNAc-UA (1S) is a reliable, sensitive and specific biomarker for the diagnosis of MPS IVA and can be used to biochemically monitor the response to ERT.

SUBMITTER: Chin SJ

PROVIDER: S-EPMC7463049 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Chondroitin sulfate disaccharide is a specific and sensitive biomarker for mucopolysaccharidosis type IVA.

Chin Sharon J SJ Saville Jennifer T JT McDermott Belinda K BK Zankl Andreas A Fletcher Janice M JM Fuller Maria M

JIMD reports 20200630 1

Mucopolysaccharidosis type IVA (MPS IVA) is an inborn error of glycosaminoglycan (GAG) catabolism characterized by a deficiency of the lysosomal enzyme, <i>N</i>-acetylgalactosamine 6-sulphatase (GALNS). Consequently, partially degraded GAG, chondroitin 6-sulfate (CS) and keratan sulfate (KS), accumulate in the lysosomes of affected cells, primarily in cartilage resulting in skeletal disease. Excessive urinary excretion of these GAG is often used as the initial biochemical parameter to inform a ...[more]

PMID: 32905071

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Project description:Cardiovascular disease (CVD) in Mucopolysaccharidosis Type IVA (Morquio A), signified by valvular disease and cardiac hypertrophy, is the second leading cause of death and remains untouched by current therapies. Enzyme replacement therapy (ERT) is the gold-standard treatment for MPS disorders including Morquio A. Early administration of ERT improves outcomes of patients from childhood to adulthood while posing new challenges including prognosis of CVD and ERT's negligible effect on cardiovascular health. Thus, having accurate biomarkers for CVD could be critical. Here we show that cathepsin S (CTSS) and elastin (ELN) can be used as biomarkers of extracellular matrix remodeling in Morquio A disease. We found in a cohort of 54 treatment naïve Morquio A patients and 74 normal controls that CTSS shows promising attributes as a biomarker in young Morquio A children. On the other hand, ELN shows promising attributes as a biomarker in adolescent and adult Morquio A. Plasma/urine keratan sulfate (KS), and urinary glycosaminoglycan (GAG) levels were significantly higher in Morquio A patients (p < 0.001) which decreased with age of patients. CTSS levels did not correlate with patients' phenotypic severity but differed significantly between patients (median range 5.45-8.52 ng/mL) and normal controls (median range 9.61-15.9 ng/mL; p < 0.001). We also studied α -2-macroglobulin (A2M), C-reactive protein (CRP), and circulating vascular cell adhesion molecule-1 (sVCAM-1) in a subset of samples to understand the relation between ECM biomarkers and the severity of CVD in Morquio A patients. Our experiments revealed that CRP and sVCAM-1 levels were lower in Morquio A patients compared to normal controls. We also observed a strong inverse correlation between urine/plasma KS and CRP (p = 0.013 and p = 0.022, respectively) in Morquio A patients as well as a moderate correlation between sVCAM-1 and CTSS in Morquio A patients at all ages (p = 0.03). As the first study to date investigating CTSS and ELN levels in Morquio A patients and in the normal population, our results establish a starting point for more elaborate studies in larger populations to understand how CTSS and ELN levels correlate with Morquio A severity.

Dataset Information

Chondroitin sulfate disaccharide is a specific and sensitive biomarker for mucopolysaccharidosis type IVA.

Publications

Chondroitin sulfate disaccharide is a specific and sensitive biomarker for mucopolysaccharidosis type IVA.

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