Abstract
Biomarkers currently available for the diagnosis, prognosis, and therapeutic monitoring of GM1 gangliosidosis type 2 (GM1T2) disease are mainly limited to those discovered in targeted proteomic-based studies. In order to identify and establish new, predominantly low-molecular-mass biomarkers for this disorder, we employed an untargeted, multi-analyte approach involving high-resolution 1H NMR analysis coupled to a range of multivariate analysis and computational intelligence technique (CIT) strategies to explore biomolecular distinctions between blood plasma samples collected from GM1T2 and healthy control (HC) participants (n = 10 and 28, respectively). The relationship of these differences to metabolic mechanisms underlying the pathogenesis of GM1T2 disorder was also investigated. 1H NMR-linked metabolomics analyses revealed significant GM1T2-mediated dysregulations in ≥13 blood plasma metabolites (corrected p < 0.04), and these included significant upregulations in 7 amino acids, and downregulations in lipoprotein-associated triacylglycerols and alanine. Indeed, results acquired demonstrated a profound distinctiveness between the GM1T2 and HC profiles. Additionally, employment of a genome-scale network model of human metabolism provided evidence that perturbations to propanoate, ethanol, amino-sugar, aspartate, seleno-amino acid, glutathione and alanine metabolism, fatty acid biosynthesis, and most especially branched-chain amino acid degradation (p = 10−12−10−5) were the most important topologically-highlighted dysregulated pathways contributing towards GM1T2 disease pathology. Quantitative metabolite set enrichment analysis revealed that pathological locations associated with these dysfunctions were in the order fibroblasts > Golgi apparatus > mitochondria > spleen ≈ skeletal muscle ≈ muscle in general. In conclusion, results acquired demonstrated marked metabolic imbalances and alterations to energy demand, which are consistent with GM1T2 disease pathogenesis mechanisms.
Highlights
Gangliosidoses represent lysosomal storage disorders (LSDs) arising from the adverse accumulation of GM1 or GM2 gangliosides; GM1 gangliosidosis (MIM# 230500) has both central nervous system (CNS) and systemic findings, whilst GM2 disorders are essentially limited to the former
The 700 MHz CPMG 1H nuclear magnetic resonance (NMR) spectra of these the human blood plasma samples collected contained many prominent, sharp signals assignable to wide range of lowmolecular-mass biomolecules; Figure 1 shows the expanded 0.75–4.40 and 5.00–8.70 regions of typical spectra acquired on GM1T2 and healthy control (HC) participants
These 1H NMR profiles contained relatively broad resonances arising from a series of lipoprotein-associated TAGs, with 1H NMR-distinguishable very low, low, and highdensity-lipoproteins; the acetamido (-NHCOCH3) functions of N-acetylneuraminate and N-acetylglucosamine residues present in the molecularly-mobile carbohydrate side-chains of selected ‘acute-phase’ glycoproteins; and those arising from both aliphatic and aromatic amino acid protein residues
Summary
Gangliosidoses represent lysosomal storage disorders (LSDs) arising from the adverse accumulation of GM1 or GM2 gangliosides; GM1 gangliosidosis (MIM# 230500) has both central nervous system (CNS) and systemic findings, whilst GM2 disorders (including Tay-Sachs and Sandhoff diseases) are essentially limited to the former. Both diseases have autosomal recessive inheritance modes, and are characterized by a series of sequential clinical presentations, which range from a severe infantile form to a milder, chronic adult one. The incidence of GM1 gangliosidosis has been estimated to be 1 in 100,000–2000,000 live births [5], this pan-ethnic condition has an enhanced prevalence in Roma, Brazilian, Maltese, and Cypriot populations [1,6]
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