Validation of an LC–MS/MS Assay for Detecting Relevant Disaccharides from Keratan Sulfate as a Biomarker for Morquio A Syndrome

Martell, Lisa Argento; Cunico, Robert L.; Ohh, Jayoung; Fulkerson, Wendy; Furneaux, Richard H.; Foehr, Erik D

doi:10.4155/bio.11.172

Cited by 50 publications

(65 citation statements)

References 24 publications

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“…It was observed that urine KS levels decrease with age ( Supplementary Fig. 1), as has been previously observed by Martell et al (2011). This phenomenon was also observed for GAGs (de Jong et al 1989;Whitley et al 1989;Piraud et al 1993;Gray et al 2007;Wood et al 2012).…”

Section: Establishing Normal Reference Rangessupporting

confidence: 70%

“…Previous reports have documented the age-dependent decrease in keratan sulfate levels (de Jong et al 1989;Whitley et al 1989;Piraud et al 1993;Gray et al 2007;Martell et al 2011;Wood et al 2012). However, these studies had a limited number of samples for patients under the age of 3 years.…”

Section: Discussionmentioning

confidence: 92%

“…Urine keratan sulfate disaccharides Galb1-4GlcNAc(6S) (predominant species) and Gal(6S)b1-4GlcNAc(6S) were produced by keratanase II enzymatic digestion of keratan sulfate (KS) as described previously (Oguma et al 2001;Martell et al 2011). The internal standards (heavy-isotopelabeled Galb1-4GlcNAc(6S) 13 C 6 , and Gal(6S)b1-4GlcNAc (6S) 13 C 6 ), the reference standards (Galb1-4GlcNAc(6S) and Gal(6S)b1-4GlcNAc(6S)), KS (Bovine cornea, Na salt), and keratanase II (Bacillus sp.)…”

Section: Urine Keratan Sulfate Measurementsmentioning

confidence: 99%

“…However, a high false negative rate has been reported for these assays and false negative results are more common in mildly affected patients (Whitley et al 1989;Piraud et al 1993;Gray et al 2007). Oguma et al (2001) followed by Martell et al (2011) reported LC-MS/MS assays that measure two specific KS disaccharides after enzymatic digestion of the GAG polymer with keratanase II. These disaccharides, Gal-1-4GlcNAc(6S) (1S) and Gal(6S)-1-4GlcNAc(6S) (2S), were found to be increased in all of the MPS IVA patients suggesting this assay would be highly sensitive for the detection of patients with this condition.…”

Section: Introductionmentioning

confidence: 99%

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Measurement of Elevated Concentrations of Urine Keratan Sulfate by UPLC-MSMS in Lysosomal Storage Disorders (LSDs): Comparison of Urine Keratan Sulfate Levels in MPS IVA Versus Other LSDs

et al. 2016

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Keratan sulfate (KS) is commonly elevated in urine samples from patients with mucopolysaccharidosis type IVA (MPS IVA) and is considered pathognomonic for the condition. Recently, a new method has been described by Martell et al. to detect and measure urinary KS utilizing LC-MS/MS. As a part of the validation of this method in our laboratory, we studied the sensitivity and specificity of elevated urine KS levels using 25 samples from 15 MPS IVA patients, and 138 samples from 102 patients with other lysosomal storage disorders, including MPS I (n ¼ 9), MPS II (n ¼ 13), MPS III (n ¼ 23), MPS VI (n ¼ 7), betagalactosidase deficiency (n ¼ 7), mucolipidosis (ML) type II, II/III and III (n ¼ 51), alpha-mannosidosis (n ¼ 11), fucosidosis (n ¼ 4), sialidosis (n ¼ 5), Pompe disease (n ¼ 3), aspartylglucosaminuria (n ¼ 4), and galactosialidosis (n ¼ 1). As expected, urine KS values were significantly higher (fivefold average increase) than age-matched controls in all MPS IVA patients. Urine KS levels were also significantly elevated (threefold to fourfold increase) in patients with GM-1 gangliosidosis, MPS IVB, ML II and ML II/III, and fucosidosis. Urine KS was also elevated to a smaller degree (1.1-fold to 1.7-fold average increase) in patients with MPS I, MPS II, and ML III. These findings suggest that while the UPLC-MS/MS urine KS method is 100% sensitive for the detection of patients with MPS IVA, elevated urine KS is not specific for this condition. Therefore, caution is advised when interpreting urinary keratan sulfate results.

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Section: Establishing Normal Reference Rangessupporting

confidence: 70%

Section: Discussionmentioning

confidence: 92%

Section: Urine Keratan Sulfate Measurementsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Measurement of Elevated Concentrations of Urine Keratan Sulfate by UPLC-MSMS in Lysosomal Storage Disorders (LSDs): Comparison of Urine Keratan Sulfate Levels in MPS IVA Versus Other LSDs

et al. 2016

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“…Similar methods have been validated in another laboratory (Martell et al 2011). KS levels in blood and urine in patients with MPS IVA are associated with age and clinical severity (Tomatsu et al 2010c) and are decreased with enzyme replacement therapy (ERT) on mouse model and bone marrow transplantation (BMT) in a patient with MPS IVA Chinen et al 2014).…”

Section: Introductionmentioning

confidence: 99%

Di-sulfated Keratan Sulfate as a Novel Biomarker for Mucopolysaccharidosis II, IVA, and IVB

et al. 2014

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Keratan sulfate (KS) is a storage material in mucopolysaccharidosis IV (MPS IV). However, no detailed analysis has been reported on subclasses of KS: monosulfated KS and di-sulfated KS. We established a novel method to distinguish and quantify mono-and di-sulfated KS using liquid chromatography-tandem mass spectrometry and measured both KS levels in various specimens.Di-sulfated KS was dominant in shark cartilage and rat serum, while mono-sulfated KS was dominant in bovine cornea and human serum. Levels of both mono-and di-sulfated KS varied with age in the blood and urine from control subjects and patients with MPS II and IVA. The mean levels of both forms of KS in the plasma/serum from patients with MPS II, IVA, and IVB were elevated compared with that in age-matched controls. Di-sulfated KS provided more significant difference between MPS IVA and the age-matched controls than mono-sulfated KS. The ratio of di-sulfated KS to total KS in plasma/serum increased with age in control subjects and patients with MPS II but was age independent in MPS IVA patients. Consequently, this ratio can discriminate younger MPS IVA patients from controls. Levels of monoand di-sulfated KS in urine of MPS IVA and IVB patients were all higher than age-matched controls for all ages studied.In conclusion, the level of di-sulfated KS and its ratio to total KS can distinguish control subjects from patients with MPS II, IVA, and IVB, indicating that di-sulfated KS may be a novel biomarker for these disorders. Abbreviations

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Targeted Quantification of Carbohydrate Biomarkers Using LC–MS

Wei

Gao

2017

Targeted Biomarker Quantitation by LC–MS

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Validation of an LC–MS/MS Assay for Detecting Relevant Disaccharides from Keratan Sulfate as a Biomarker for Morquio A Syndrome

Abstract: Clinical sample analysis in 168 MPS IVA patients and 225 healthy controls demonstrates the clinical utility of this method.

Cited by 50 publications

References 24 publications

Measurement of Elevated Concentrations of Urine Keratan Sulfate by UPLC-MSMS in Lysosomal Storage Disorders (LSDs): Comparison of Urine Keratan Sulfate Levels in MPS IVA Versus Other LSDs

Measurement of Elevated Concentrations of Urine Keratan Sulfate by UPLC-MSMS in Lysosomal Storage Disorders (LSDs): Comparison of Urine Keratan Sulfate Levels in MPS IVA Versus Other LSDs

Di-sulfated Keratan Sulfate as a Novel Biomarker for Mucopolysaccharidosis II, IVA, and IVB

Targeted Quantification of Carbohydrate Biomarkers Using LC–MS

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