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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 &lt, 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 &gt, Golgi apparatus &gt, mitochondria &gt, 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.