The levels of urinary glycosaminoglycans of patients with attenuated and severe type of mucopolysaccharidosis II determined by liquid chromatography-tandem mass spectrometry

Abstract

Glycosaminoglycans (GAGs) play important roles on the regulation of extracellular signaling, neuronal development, and cartilage maintenance. The extracellular concentration of total GAGs has been used as an established measure for the diagnosis of mucopolysaccharidoses (MPSs). Heparan sulfate (HS), Dermatan sulfate (DS) and chondroitin sulfate are known to be elevated in the GAGs under pathological conditions associated with MPS. Furthermore, the selective accumulation of disease-specific one of, or a combination of, them has also been used for the estimation of subtypes of MPS. A previously developed method [Auray-Blais C et al. Molecular Genetics and Metabolism 102 (2011) 49–56.] measures the concentration of GAGs using liquid chromatography with tandem mass spectrometry (LC-MS/MS) with higher precision. To ask whether the selective accumulation of HS and DS in the urine of MPS II patients discriminate the attenuated and severe type of MPS II, we examined the concentrations of HS and DS by this methodology. Compared to the healthy controls, we found a marked elevation of HS and DS in all of the MPS II-affected patients. Among patients who received ERT with confirmed elevation of antibody titer, the concentrations of HS in the urine of patients with attenuated type were lower than those with severe type of MPS II. In these patients, the concentrations of DS by LC-MS/MS and of total GAG by DMB failed to depend on the accumulation of antibody. These results suggest that the LC-MS/MS method employed in this study might discriminate the subtypes of MPS II in different clinical background.

The relationships between urinary glycosaminoglycan levels and phenotypes of mucopolysaccharidoses

“…The LC‐MS/MS method can also be used to differentiate the subtypes of MPS II, and the concentration of HS is the main factor used to distinguish the mild form of MPS II from the severe form. Mashima et al ( reported that among patients who received ERT with confirmed elevation of antibody titers, the concentration of HS in the urine of patients with the severe form was higher than that in those with the mild form of MPS II. Consistently, the concentrations of HS detected in the samples of our patients with the severe form of MPS II were more than 60 times higher than those of the patients with the mild form (446.6 vs. 7.3 μg/ml).…”

“…The "Skeletal" group is caused by KS and includes patients with MPS IV presenting with joint laxity, genu valgum, odontoid hypoplasia, extreme short stature, and skeletal dysplasia (Hendriksz et al, 2015). The amounts of the affected GAG-derived disaccharides in the different types of MPS have been reported to be associated with the clinical manifestations, severity, and onset of MPS disorders (Auray-Blais et al, 2016;Mashima, Sakai, Tanaka, Kosuga, & Okuyama, 2016;Tomatsu et al, 2014).…”

“…2-D EP is the most commonly used method to help determine specific MPS diseases; however, it is time-consuming and the interpretation is ambiguous and subjective, making the diagnosis unreliable. To overcome the limitations of these first-line MPS screening methods, the liquid chromatography/tandem mass spectrometry (LC-MS/MS) method has been used to determine MPS subgroups, and it has been demonstrated to be a valuable and important method (Auray-Blais et al, 2016, 2011Chuang et al, 2014;Mashima et al, 2016).…”

Relationships among Height, Weight, Body Mass Index, and Age in Taiwanese Children with Different Types of Mucopolysaccharidoses

“…The "skeletal" group is caused by KS and includes MPS IVA, with manifestations of joint laxity, odontoid hypoplasia, genu valgum, extreme short stature, and skeletal dysplasia. The amounts of the affected GAG-derived disaccharides have been associated with the clinical presentations, onset, and severity of MPS disorders [25][26][27][28]. Settembre et al [29] reported that GAG accumulation in lysosomes disrupts autophagy, which is important for chondrocyte metabolism during endochondral ossification, leading to chondrocyte viability and thus the development of skeletal abnormalities.…”

Intravenous Enzyme Replacement Therapy in Mucopolysaccharidoses: Clinical Effectiveness and Limitations

“…In more than one study, ADA-positive patients are associated to higher uGAGs levels and in some cases to poorer outcome [18,19,32,36,133,196,214,215]. No impact was seen for vestronidase [21].…”