Sandhoff disease (SD) results from mutations in the HEXB gene, subsequent 
deficiency of N-acetyl-β-hexosaminidase (Hex) and accumulation of GM2 
gangliosides. SD leads to progressive neurodegeneration and early death. 
However, there is a lack of established SD biomarkers, while the pathogenesis 
etiology remains to be elucidated. To identify potential biomarkers and unveil 
the pathogenic mechanisms, metabolomics analysis with reverse phase liquid 
chromatography (RPLC) was conducted. A total of 177, 112 and 119 metabolites 
were found to be significantly dysregulated in mouse liver, mouse brain and 
human hippocampus samples, respectively (p < .05, ID score > 0.5). Principal 
component analysis (PCA) analysis of the metabolites showed clear separation of 
metabolomics profiles between normal and diseased individuals. Among these 
metabolites, dipeptides, amino acids and derivatives were elevated, indicating a 
robust protein catabolism. Through pathway enrichment analysis, we also found 
alterations in metabolites associated with neurotransmission, lipid metabolism, 
oxidative stress and inflammation. In addition, N-acetylgalactosamine 
4-sulphate, key component of glycosaminoglycans (GAG) was significantly 
elevated, which was also confirmed by biochemical assays. Collectively, these 
results indicated major shifts of energy utilization and profound metabolic 
impairments, contributing to the pathogenesis mechanisms of SD. Global 
metabolomics profiling may provide an innovative tool for better understanding 
the disease mechanisms, and identifying potential diagnostic biomarkers for SD.