Abstract
Mucopolysaccharidosis (MPS) is caused by the deficiency of a specific hydrolytic enzyme that catalyzes the step-wise degradation of glycosaminoglycans (GAGs). In this study, we propose an empirical method to calculate levels of GAG-derived disaccharides based on the quantity (peak areas) of chondroitin sulfate (CS) with the aim of making a diagnosis of MPS more accurate and reducing the occurrence of false positive and false negative results. In this study, levels of urinary GAG-derived disaccharides were measured in 67 patients with different types of MPS and 165 controls without MPS using a tandem mass spectrometry assay. Two different methods of reporting GAG-derived disaccharides were assessed; normalization to urinary CS (in μg/mL), and normalization to μg/mg creatinine. CS-normalization yielded more consistent values than creatinine-normalization. In particular, levels of urinary dermatan sulfate (DS), heparan sulfate (HS), and keratan sulfate (KS) significantly varied because of changes in urine creatinine levels, which were proportional to age but inversely proportional to DS, HS, and KS measurements. Using CS-normalization revealed the actual status of DS, HS, and KS without the influence of factors such as age, urine creatinine, and other physiological conditions. It could discriminate between the patients with MPS and controls without MPS, and also to evaluate changes in GAG levels pre- and post-enzyme replacement therapy.
Highlights
Mucopolysaccharidoses (MPSs) are a group of lysosomal storage disorders (LSDs) caused by deficiency in one specific enzyme that catalyzes the stepwise degradation of glycosaminoglycans (GAGs)
Urine creatinine levels were directly proportional to age, but inversely proportional to the quantities of GAG-derived disaccharides when creatinine-normalization was used for the calculations (Fig. 1a,1b)
Using creatinine-normalization, some dermatan sulfate (DS) and heparan sulfate (HS) values may have been underestimated in some cases (6/25) which may have resulted in false negative interpretations (Supplementary Table 2)
Summary
Mucopolysaccharidoses (MPSs) are a group of lysosomal storage disorders (LSDs) caused by deficiency in one specific enzyme that catalyzes the stepwise degradation of glycosaminoglycans (GAGs). The LC-MS/MS assay can provide very valuable and precise information with regards to changes in the quantities of individual GAG-derived disaccharides to assist in making an initial diagnosis of MPS and in monitoring outcomes to assess the pharmacodynamic (PD) effect on GAG levels by ERT. Most MPS reference laboratories express levels of GAG-derived disaccharides in μg/mg creatinine, even though this can increase the difficulty and uncertainty in making a diagnosis, and when evaluating the efficacy of ERT. The rationale of this research was to propose normalizing the units of the urinary levels of three GAG-derived disaccharides (DS, HS and KS) with respect to CS (area of the CS peak) as μg/mL instead of μg/mg creatinine, with the aim of making a diagnosis of MPS more accurate and reducing the occurrence of false positive and false negative results
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