Alpha-Mannosidosis: Quantitative Oligosaccharide Biomarker Analysis in Dried Blood Spots for Diagnosis, Newborn Screening, and Treatment Monitoring
Year: 2026
Type: preprint
Abstract: Background Alpha-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. Methods A rapid and fully quantitative method for the specific AM oligosaccharide biomarker Man 2 GlcNAc 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. Results A distinct separation in biomarker concentrations was observed between unaffected individuals and untreated AM patients (0.1 – 0.8 vs 3.2 – 11.3 µmol Man 2 GlcNAc/L, p <0.0001). Furthermore, Man 2 GlcNAc 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 µmol Man 2 GlcNAc/L, p =0.0001). Conclusion We present a simple and rapid method for quantitative analysis of the specific AM oligosaccharide biomarker Man 2 GlcNAc, 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, Man 2 GlcNAc 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.
Source: medRxiv
Authors: Dominik Badekow, Michelle Jeschik, Benjamin Dreyer, Katharina Hoff, Anja Friederike Köhn, Mona Lindschau, Anna Baghdasaryan, Anibh Martin Das, Simone Harmeling, Xinying Hong, Pavel Ješina, Vassiliki Konstantopoulou, Francyne Kubaski, Alexander Laemmle, Florian Lagler, Thomas Lücke, Martin Magner, Lara Maleen Marten, Neslihan Önenli Mungan, Anke Schumann, Lina Verena Sevenich, Ronen Spiegel, Marcus Stange, Ali Tunç Tuncel, Sema Kalkan Uçar, Nicole Muschol, René Santer, Simona Murko
Institutions: University Medical Center Hamburg-Eppendorf, Medical University of Graz, Medizinische Hochschule Hannover, University Hospital Münster, Children's Hospital of Philadelphia, University of Pennsylvania, Charles University, General University Hospital in Prague, Medical University of Vienna, Greenwood Genetic Center, University of Bern, University Hospital of Bern, Paracelsus Medical University, University Hospitals of the Ruhr-University of Bochum, Ruhr University Bochum, Universitätsmedizin Göttingen, Cukurova University, University of Freiburg, Charité – Universitätsmedizin Berlin, Technion – Israel Institute of Technology, Emek Medical Center, University Hospital in Halle, Heidelberg University, Ege University, Helmholtz Munich, Institut für Humangenetik
Language: English
Subfield: Genetics (clinical)
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7214047058