Systemic metabolic remodeling in mucopolysaccharidosis revealed by untargeted urinary metabolomics

Abstract

Abstract Background Mucopolysaccharidoses (MPS) are lysosomal storage disorders characterized by glycosaminoglycan (GAG) accumulation and progressive multi-organ dysfunction. However, the systemic metabolic consequences of lysosomal dysfunction remain incompletely defined. Methods Untargeted urinary metabolomics was performed using LC–MS in 27 patients with MPS and 26 age-matched healthy controls. Multivariate analyses, including principal component analysis (PCA) and partial least squares–discriminant analysis (PLS-DA), were applied to characterize metabolic differences. Differential metabolites were identified using variable importance in projection (VIP) > 1, |log₂ fold change (log₂FC)| ≥ 0.58, and false discovery rate (FDR)-adjusted P < 0.05. Receiver operating characteristic (ROC) analysis was conducted to evaluate discriminative performance. Results A total of 32 differential metabolites were identified, with the majority showing decreased abundance in MPS. These metabolites were primarily involved in microbial–host co-metabolism, lipid and mitochondrial energy metabolism, nucleotide turnover, and amino sugar metabolism. Several metabolites demonstrated good to excellent discriminative performance, with area under the curve (AUC) values ranging from 0.722 to 0.909, including guanine, phenylacetaldehyde, pyrocatechol, and trimethylamine N-oxide. Integrated pathway analysis indicated coordinated metabolic network remodeling associated with lysosomal dysfunction. Conclusions Urinary metabolomics reveals a distinct metabolic signature in MPS characterized by multi-pathway metabolic remodeling beyond primary substrate accumulation. These findings provide insight into the systemic metabolic consequences of lysosomal dysfunction and support the potential of metabolomics for disease characterization in lysosomal storage disorders.