Alpha-Mannosidosis: Quantitative Oligosaccharide Biomarker Analysis in Dried Blood Spots for Diagnosis, Newborn Screening, and Treatment Monitoring
- 1University Children's Hospital, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Abstract
BackgroundAlpha-mannosidosis (AM) is a debilitating lysosomal storage disorder (LSD) caused by insufficient activity of alpha-mannosidase, an enzyme responsible for cleavage of alpha-linked mannose residues from N-glycan-type oligosaccharides during their degradation. As a result, specific oligosaccharides accumulate in tissues and are also detectable in body fluids. AM is a progressive multi-organ disease for which hematopoietic stem cell transplantation (HSCT) and enzyme replacement therapy (ERT) are therapeutic options, however, treatment results depend considerably on early diagnosis. Therefore, inclusion of AM into newborn screening panels would significantly contribute to improving therapeutic outcome.
MethodsA rapid and fully quantitative method for the specific AM oligosaccharide biomarker Man2GlcNAc in dried blood spots (DBS) using ultra-performance liquid chromatography coupled to tandem-mass spectrometry was developed. DBS from 420 controls, 27 AM patients (including five newborn screening samples), and 35 patients with other LSDs were analyzed.
ResultsA distinct separation in biomarker concentrations was observed between unaffected individuals and untreated AM patients (0.1 - 0.8 vs 3.2 - 11.3 {micro}mol Man2GlcNAc/L, p<0.0001). Furthermore, Man2GlcNAc concentrations significantly differed between untreated patients and those on ERT (n = 17, p<0.0001) or after HSCT (n = 15, p<0.0001), and between both treatment groups (p<0.0001). Moreover, we demonstrated that this method is appropriate for monitoring treatment efficacy by analysis of samples from individual patients before and after initiation of therapy. We retrospectively analyzed residual samples of dried blood spots (DBS) from routine newborn screening that had been stored from patients with later-confirmed AM, which resulted in clear separation from the concentrations observed in a newborn screening control cohort (7.7 - 11.3 vs 0.1 - 0.8 {micro}mol Man2GlcNAc/L, p=0.0001).
ConclusionWe present a simple and rapid method for quantitative analysis of the specific AM oligosaccharide biomarker Man2GlcNAc, which is remarkably stable compared to enzymatic assays. Thus, the method is useful for selective screening in suspected cases as well as for monitoring the response to different forms of treatment. Furthermore, Man2GlcNAc has the potential to serve as a useful biomarker for newborn screening offering the prospect of earlier treatment initiation, improved therapeutic outcome and higher quality of life for AM patients.
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BibTeX
@misc{badekow2026alphamannosidosis,
title = {{Alpha-Mannosidosis: Quantitative Oligosaccharide Biomarker Analysis in Dried Blood Spots for Diagnosis, Newborn Screening, and Treatment Monitoring}},
author = {D. Badekow and M. Jeschik and B. Dreyer and K. Hoff and A. F. Köhn and M. Lindschau and A. Baghdasaryan and A. M. Das and S. Harmeling and X. Hong and P. Jesina and V. Konstantopoulou and F. Kubaski and A. Laemmle and F. Lagler and T. Lücke and M. Magner and L. M. Marten and N. Önenli Mungan and A. Schumann and L. V. Sevenich and R. Spiegel and M. Stange and A. T. Tuncel and S. K. Ucar and N. Muschol and R. Santer and S. Murko},
howpublished = {medRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.16.26362975},
url = {https://www.medrxiv.org/content/10.64898/2026.09.16.26362975v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Alpha-Mannosidosis: Quantitative Oligosaccharide Biomarker Analysis in Dried Blood Spots for Diagnosis, Newborn Screening, and Treatment Monitoring
AU - D. Badekow
AU - M. Jeschik
AU - B. Dreyer
AU - K. Hoff
AU - A. F. Köhn
AU - M. Lindschau
AU - A. Baghdasaryan
AU - A. M. Das
AU - S. Harmeling
AU - X. Hong
AU - P. Jesina
AU - V. Konstantopoulou
AU - F. Kubaski
AU - A. Laemmle
AU - F. Lagler
AU - T. Lücke
AU - M. Magner
AU - L. M. Marten
AU - N. Önenli Mungan
AU - A. Schumann
AU - L. V. Sevenich
AU - R. Spiegel
AU - M. Stange
AU - A. T. Tuncel
AU - S. K. Ucar
AU - N. Muschol
AU - R. Santer
AU - S. Murko
PY - 2026
DA - 2026/09/16
PB - medRxiv
DO - 10.64898/2026.09.16.26362975
UR - https://www.medrxiv.org/content/10.64898/2026.09.16.26362975v1
AB - BackgroundAlpha-mannosidosis (AM) is a debilitating lysosomal storage disorder (LSD) caused by insufficient activity of alpha-mannosidase, an enzyme responsible for cleavage of alpha-linked mannose residues from N-glycan-type oligosaccharides during their degradation. As a result, specific oligosaccharides accumulate in tissues and are also detectable in body fluids. AM is a progressive multi-organ disease for which hematopoietic stem cell transplantation (HSCT) and enzyme replacement therapy (ERT) are therapeutic options, however, treatment results depend considerably on early diagnosis. Therefore, inclusion of AM into newborn screening panels would significantly contribute to improving therapeutic outcome. MethodsA rapid and fully quantitative method for the specific AM oligosaccharide biomarker Man2GlcNAc in dried blood spots (DBS) using ultra-performance liquid chromatography coupled to tandem-mass spectrometry was developed. DBS from 420 controls, 27 AM patients (including five newborn screening samples), and 35 patients with other LSDs were analyzed. ResultsA distinct separation in biomarker concentrations was observed between unaffected individuals and untreated AM patients (0.1 - 0.8 vs 3.2 - 11.3 {micro}mol Man2GlcNAc/L, p<0.0001). Furthermore, Man2GlcNAc concentrations significantly differed between untreated patients and those on ERT (n = 17, p<0.0001) or after HSCT (n = 15, p<0.0001), and between both treatment groups (p<0.0001). Moreover, we demonstrated that this method is appropriate for monitoring treatment efficacy by analysis of samples from individual patients before and after initiation of therapy. We retrospectively analyzed residual samples of dried blood spots (DBS) from routine newborn screening that had been stored from patients with later-confirmed AM, which resulted in clear separation from the concentrations observed in a newborn screening control cohort (7.7 - 11.3 vs 0.1 - 0.8 {micro}mol Man2GlcNAc/L, p=0.0001). ConclusionWe present a simple and rapid method for quantitative analysis of the specific AM oligosaccharide biomarker Man2GlcNAc, which is remarkably stable compared to enzymatic assays. Thus, the method is useful for selective screening in suspected cases as well as for monitoring the response to different forms of treatment. Furthermore, Man2GlcNAc has the potential to serve as a useful biomarker for newborn screening offering the prospect of earlier treatment initiation, improved therapeutic outcome and higher quality of life for AM patients.
ER -