Quantification of Specific Urinary Oligosaccharide Biomarkers for Diagnosis and Treatment Monitoring of Alpha‐Mannosidosis

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Abstract
Alpha‐mannosidosis (AM, OMIM# 248500), an ultra‐rare lysosomal storage disorder (LSD), is caused by insufficient activity of alpha‐mannosidase, an enzyme involved in degradation of N‐glycan oligosaccharides. Hence, specific oligosaccharides accumulate in tissues, resulting in a progressive multi‐organ disease. Therapeutic options exist but treatment outcome depends on early diagnosis. Thus, multiple methods have been developed for analysis of these oligosaccharides in urine that are qualitative or semi‐quantitative, limiting their use for treatment monitoring. A rapid quantitative method without derivatization was developed for AM biomarkers GlcNAc(Man) 2 , GlcNAc(Man) 3 , and GlcNAc(Man) 4 in spot urine samples using ultra‐performance liquid chromatography coupled to tandem‐mass spectrometry. Urine samples of 208 controls, 20 AM patients, and 26 patients with other LSDs were analyzed. Method validation proved high recoveries (88%–108%) and precisions (standard deviation < 8%), low limits of quantification (0.12 μg GlcNAc(Man) 2 /mL), and high sample stability. We observed a clear separation between controls and AM patients (0.0–9.0 vs 39.4–99.3 μmol GlcNAc(Man) 2 /mmol creatinine, p < 0.0001). Furthermore, GlcNAc(Man) 2 concentration showed significant differences between untreated patients and those treated with enzyme replacement therapy (ERT; n = 13, p = 0.0006) or hematopoietic stem cell transplantation (HSCT; n = 3, p = 0.0143), and between both treatments ( p = 0.0143). Thus, the developed method is well‐suited for selective screening for AM and offers a simple way to monitor treatment efficacy.
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  • Chiesi Farmaceutici

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