Analysis of Mucopolysaccharidosis Type VI through Integrative Functional Metabolomics

Abstract

Metabolic phenotyping is poised as a powerful and promising tool for biomarker discovery in inherited metabolic diseases. However, few studies applied this approach to mcopolysaccharidoses (MPS). Thus, this innovative functional approach may unveil comprehensive impairments in MPS biology. This study explores mcopolysaccharidosis VI (MPS VI) or Maroteaux–Lamy syndrome (OMIM #253200) which is an autosomal recessive lysosomal storage disease caused by the deficiency of arylsulfatase B enzyme. Urine samples were collected from 16 MPS VI patients and 66 healthy control individuals. Untargeted metabolomics analysis was applied using ultra-high-performance liquid chromatography combined with ion mobility and high-resolution mass spectrometry. Furthermore, dermatan sulfate, amino acids, carnitine, and acylcarnitine profiles were quantified using liquid chromatography coupled to tandem mass spectrometry. Univariate analysis and multivariate data modeling were used for integrative analysis and discriminant metabolites selection. Pathway analysis was done to unveil impaired metabolism. The study revealed significant differential biochemical patterns using multivariate data modeling. Pathway analysis revealed that several major amino acid pathways were dysregulated in MPS VI. Integrative analysis of targeted and untargeted metabolomics data with in silico results yielded arginine-proline, histidine, and glutathione metabolism being the most affected. This study is one of the first metabolic phenotyping studies of MPS VI. The findings might shed light on molecular understanding of MPS pathophysiology to develop further MPS studies to enhance diagnosis and treatments of this rare condition.

Targeted Metabolomic Analysis of a Mucopolysaccharidosis IIIB Mouse Model Reveals an Imbalance of Branched-Chain Amino Acid and Fatty Acid Metabolism

“…These results are consistent with a previous metabolite analysis of the liver of MPS I mice showing decreased levels of lipids, simple carbohydrates, and nucleotides, whereas most amino acids, amino acid derivatives, dipeptides, and urea resulted in being increased, suggesting an increase in protein catabolism [36]. Although some results have been reported in previous global metabolomic profiling of MPS IIIB mice and patients, where a reduction of all key amino acids was observed in the serum of affected subjects as compared to controls, probably due to either differences in the methodological strategies or metabolic differences in the tested tissues [29,37], our findings are definitely in agreement with previous metabolic phenotyping performed on the urine of MPS III (A-D) and MPS VI patients [31,32].…”

“…Serum global metabolomic profiling revealed disturbances in the amino acid, peptide, carbohydrate, lipid, nucleotide, vitamin, cofactor, and xenobiotic metabolism in MPS IIIA and IIIB patients [29]. Furthermore, targeted and untargeted metabolomic analyses of urine samples from MPS I-, MPS III-, and MPS VI-affected patients showed impairment in the arginine, proline, histidine, and glutathione metabolism [30][31][32]. Here, we applied a targeted metabolomic approach to identify impaired amino acid and fatty acid metabolic pathways or other metabolic phenotypes in the liver and heart of the NAGLU −/− mouse model of the MPS IIIB disease.…”

The rapidly evolving view of lysosomal storage diseases

“…Mass spectrometry has become the most widely used platform for inborn metabolic diseases because of its ability to analyze a wide range of molecules in different body fluids, with optimal dynamic range and great sensitivity (Costanzo et al , 2017). Metabolome analyses have been performed in some LSDs, such as some mucopolysaccharidoses (Fu et al , 2017; Tebani et al , 2019), Fabry disease (Boutin & Auray‐Blais, 2015), Pompe disease (Sato et al , 2017), Niemann‐Pick disease type C (Fan et al , 2013; Maekawa et al , 2015; Probert et al , 2017), neuronal ceroid lipofuscinoses (Sindelar et al , 2018), or in some sphingolipidoses (Polo et al , 2019).…”

Disruption of morphogenic and growth pathways in lysosomal storage diseases

“…The deregulation of the Hh pathway may occur in LSDs and has been described in different mucopolysaccharidoses (MPS), a group of disorders whose common hallmark is an impairment on the degradation of glycosaminoglycans (GAGs). Proteoglycan-attached GAGs function as co-receptors located adjacent to the primary cilia under normal conditions, promoting Hedgehog (Hh) binding and signaling (Kingma et al, 2016;Tebani et al, 2019;Witt et al, 2013).…”