Abstract
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 = 9), MPS II (n = 13), MPS III (n = 23), MPS VI (n = 7), beta-galactosidase deficiency (n = 7), mucolipidosis (ML) type II, II/III and III (n = 51), alpha-mannosidosis (n = 11), fucosidosis (n = 4), sialidosis (n = 5), Pompe disease (n = 3), aspartylglucosaminuria (n = 4), and galactosialidosis (n = 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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Acknowledgements
We would like to thank Yana Bierezovskaya, Nicole Miller (BioMarin), David Millington, and Hayogue Zhang (Duke University) for assistance in the development of this method. Drs. Roger Stevenson and Charles Schwartz provided thoughtful reviews of early versions of this manuscript.
This work was partially supported by the Greenwood Genetic Center Foundation and South Carolina Department of Disabilities and Special Needs. It was also supported in part by the Lysosomal Disease Network. The Lysosomal Disease Network (U54NS065768) is a part of the National Institutes of Health (NIH) Rare Diseases Clinical Research Network (RDCRN), supported through collaboration between the NIH Office of Rare Diseases Research (ORDR) at the National Center for Advancing Translational Science (NCATS), the National Institute of Neurological Disorders and Stroke (NINDS), and National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Conflict of Interest
The authors received funding from BioMarin Pharmaceuticals to support development of the urinary KS assay.
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Communicated by: Jörn Oliver Sass
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Fig. 4
Urine keratan sulfate levels in unaffected individuals is age-dependent. Urine KS was measured in 105 unaffected controls (20 days – 63 years of age) (PNG 10 kb)
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Synopsis
Urine keratan sulfate elevations are not specific to MPS IVA and may be found in other LSDs.
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Conflict of Interest
Tim Wood, Laura Pollard, and Katarzyna Ellsworth received support from BioMarin Pharmaceuticals to develop/validate the urine KS assay. Additionally they received speaker honoraria from BioMarin Pharmaceuticals. Sara Cathey declares no conflicts of interest.
Informed Consent
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000 (5). Informed consent was obtained from all patients for being included as part of the Longitudinal Studies of the Glycoproteinoses (NCT01891422). The remaining samples were sent to the clinical biochemical laboratory at the Greenwood Genetic Center for clinical testing. These samples were de-identified prior to use.
Animal Rights
This article does not contain any studies with animal subjects performed by the any of the authors.
Details of the Contributions of Individual Authors
Katarzyna Ellsworth performed the laboratory work for this study as well as the review of data. She was involved in the writing of the manuscript and preparation of figures.
Laura Pollard was involved in data analysis, manuscript editing, and the preparation of figures.
Tim Wood was involved in data analysis, manuscript editing, and the preparation of figures.
Sara Cathey was involved in data analysis, manuscript editing, and the preparation of figures. Dr. Cathey also provided clinical information about specific patients.
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Ellsworth, K.A., Pollard, L.M., Cathey, S., Wood, T. (2016). 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. In: Morava, E., Baumgartner, M., Patterson, M., Rahman, S., Zschocke, J., Peters, V. (eds) JIMD Reports, Volume 34. JIMD Reports, vol 34. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2016_1
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DOI: https://doi.org/10.1007/8904_2016_1
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