A Multiplex Assay for the Diagnosis of Mucopolysaccharidoses and Mucolipidoses

Langereis, Eveline J.; Wagemans, Tom; Kulik, Wim; Lefeber, Dirk; Lenthe, Henk van; Oussoren, Esmée; Ploeg, Ans T. van der; Ruijter, George J. G.; Wevers, Ron A.; Wijburg, Frits A.; Vlies, Naomi van

doi:10.1371/journal.pone.0138622

Cited by 36 publications

(33 citation statements)

References 24 publications

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“…Enzyme activity assay is the "gold standard" for diagnosing MPSs, but quantitative and qualitative analysis of urinary (or blood) GAGs is used as a primary screening test for most types of MPSs [8]. Levels of different GAGs increase depending on the type of MPSs; however, they can also be elevated in mucolipidoses (MLs).…”

Section: Introductionmentioning

confidence: 99%

Elevated LysoGb3 Concentration in the Neuronopathic Forms of Mucopolysaccharidoses

et al. 2020

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Mucopolysaccharidoses (MPSs) are a group of lysosomal storage disorders associated with impaired glycosaminoglycans (GAGs) catabolism. In MPS I, II, III, and VII, heparan sulfate (HS) cannot be degraded because of the lack of sufficient activity of the respective enzymes, and its accumulation in the brain causes neurological symptoms. Globotriaosylsphingosine (LysoGb3), the deacylated form of globotriaosylceramide (Gb3), is described as a highly sensitive biomarker for another lysosomal storage disease-Fabry disease. The connection between MPSs and LysoGb3 has not yet been established. This study included 36-MPS I, 15-MPS II, 25-MPS III, 26-MPS IV, and 14-MPS VI patients who were diagnosed by biochemical and molecular methods and a control group of 250 males and 250 females. The concentration of lysosphingolipids (LysoSLs) was measured in dried blood spots by high pressure liquid chromatography-tandem mass spectrometry. We have demonstrated that LysoGb3 concentration was significantly elevated (p < 0.0001) in untreated MPS I (3.07 + 1.55 ng/mL), MPS II (5.24 + 2.13 ng/mL), and MPS III (6.82 + 3.69 ng/mL) patients, compared to the control group (0.87 + 0.55 ng/mL). LysoGb3 level was normal in MPS VI and MPS IVA (1.26 + 0.39 and 0.99 + 0.38 ng/mL, respectively). Activity of α-galactosidase A (α-Gal A), an enzyme deficient in Fabry disease, was not, however, inhibited by heparan sulfate in vitro, indicating that an increase of LysoGb3 level in MPS I, MPS II, and MPS III is an indirect effect of stored MPSs rather than a direct result of impairment of degradation of this compound by HS. Our findings indicate some association of elevated LysoGb3 concentration with the neuronopathic forms of MPSs. The pathological mechanism of which is still to be studied.

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Section: Introductionmentioning

confidence: 99%

Elevated LysoGb3 Concentration in the Neuronopathic Forms of Mucopolysaccharidoses

et al. 2020

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“…Two main branches of GAG detection methods by MS/MS have been developed: detection of digested disaccharides (direct or labeled with aniline) [45–50] and chemically depolymerized GAGs by methanolysis and/or butanolysis [51–56]. Such MS/MS methods have been used to measure specific GAGs in blood and urine of MPS and ML patients [51, 54, 55, 57–65]. MS/MS provides a sensitive, specific, and reproducible GAG analysis and allows measurement of several GAGs simultaneously, indicating its potential for use in mass screening, prognosis, and monitoring therapeutic effect in patients with MPS and ML.…”

Section: Introductionmentioning

confidence: 99%

Glycosaminoglycan levels in dried blood spots of patients with mucopolysaccharidoses and mucolipidoses

Kubaski

Suzuki

Orii

et al. 2017

Molecular Genetics and Metabolism

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Mucopolysaccharidoses (MPSs) and mucolipidoses (ML) are groups of lysosomal storage disorders in which lysosomal hydrolases are deficient leading to accumulation of undegraded glycosaminoglycans (GAGs), throughout the body, subsequently resulting in progressive damage to multiple tissues and organs. Assays using tandem mass spectrometry (MS/MS) have been established to measure GAGs in serum or plasma from MPS and ML patients, but few studies were performed to determine whether these assays are sufficiently robust to measure GAG levels in dried blood spots (DBS) of patients with MPS and ML. Material and methods In this study, we evaluated GAG levels in DBS samples from 124 MPS and ML patients (MPS I = 16; MPS II = 21; MPS III = 40; MPS IV = 32; MPS VI =10; MPS VII = 1; ML= 4), and compared them with 115 age-matched controls. Disaccharides were produced from polymer GAGs by digestion with chondroitinase B, heparitinase, and keratanase II. Subsequently, dermatan sulfate (DS), heparan sulfate (HS-0S, HS-NS), and keratan sulfate (mono-sulfated KS, di-sulfated KS, and ratio of di-sulfated KS in total KS) were measured by MS/MS. Results Untreated patients with MPS I, II, VI, and ML had higher levels of DS compared to control samples. Untreated patients with MPS I, II, III, VI, and ML had higher levels of HS-0S; and untreated patients with MPS II, III and VI and ML had higher levels of HS-NS. Levels of KS were age dependent, so although levels of both mono-sulfated KS and di-sulfated KS were generally higher in patients, particularly for MPS II and MPS IV, age group numbers were not sufficient to determine significance of such changes. However, the ratio of di-sulfated KS in total KS was significantly higher in all MPS patients younger than 5 years old, compared to age-matched controls. MPS I and VI patients treated with HSCT had normal levels of DS, and MPS I, VI, and VII treated with ERT or HSCT had normal levels of HS-0S and HS-NS, indicating that both treatments are effective in decreasing blood GAG levels. Conclusion Measurement of GAG levels in DBS is useful for diagnosis and potentially for monitoring the therapeutic efficacy in MPS.

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“…There is a potential demand for the discrimination of the disease subtype of MPS II through a non-invasive manner. It is generally accepted that the urinary GAGs decreases over the age [17] . This, at least in part, is affected by the concentration of creatinine, because it increases over age due to the increasing mass of muscle [14] .…”

Section: Resultsmentioning

confidence: 99%

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

Mashima

Sakai

Tanaka

et al. 2016

Molecular Genetics and Metabolism Reports

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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.

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A Multiplex Assay for the Diagnosis of Mucopolysaccharidoses and Mucolipidoses

Cited by 36 publications

References 24 publications

Elevated LysoGb3 Concentration in the Neuronopathic Forms of Mucopolysaccharidoses

Elevated LysoGb3 Concentration in the Neuronopathic Forms of Mucopolysaccharidoses

Glycosaminoglycan levels in dried blood spots of patients with mucopolysaccharidoses and mucolipidoses

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

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