Differences In The Metabolomic Profile On Down Syndrome

BACKGROUND: Trisomy 21 is a mutation of the 21st chromosome, also known as Down syndrome (DS), characterized by intellectual disability but also endocrinological and metabolic co-morbidities like obesity. Additionally, motor coordination, balance, and functional problems may reduce participation in physical activities in individuals with DS. Metabolomics is a powerful technique for identifying, quantifying, and characterizing molecules with lower molecular weight known as metabolites that may offer insight into the metabolic health of individuals with DS and the degree to which their profiles differ from those of individuals without DS. PURPOSE: To examine if there are differences in metabolomic profiles between individuals with and without DS. METHODS: 27 individuals with DS (10 women; 17 men; age 24 ± 4 years) and 16 without DS (6 women; 10 men; age 24 ± 4 years) were subjected to venopulsion, and blood samples were centrifuged at 3000 rpm for 15 minutes to obtain blood serum. Subsequently, the blood samples were filtered in 3kda filters in 10000 rgf for 30 minutes, to obtain 200ul of filtered blood serum. The filters were washed 5 times with 500ul of milli-q water. Then, the filtered serum was analyzed by nuclear magnetic resonance. 62 metabolites were acquired. Data were checked for normality, homoscedasticity, and sphericity with the Komolgorov-Smirnov, Levene and Mauchly test, and to meet assumptions, the data were transformed with Box and Cox transformations and z-score standardizations. The data were analyzed with a partial least squares discriminant analysis (PLS-DA) model and the metabolite with Vip Score >1 in both components was retained for pathway enrichment analysis. The Kruskal-Wallis test with Dunn’s post hoc test and Eta square (η²) was utilized to compare the main metabolites between groups. RESULTS: The PLS-DA analysis (accuracy = 0.93; R2X = 0.19; R2Y = 1) retained 11 metabolites which meet the criteria. From these metabolites, 8 were retained after the enrichment pathway analysis. These metabolites were: 1,3-diaminopropane, ascorbate, asparagine, glutamate, glutamine, lysine, methionine and phenylalanine. The most enrichment pathways were ammonia recycling, aspartate metabolism, carnitine synthesis, phenylalanine and tyrosine metabolism, urea cycle, lysine degradation, amino sugar metabolism, beta-alanine metabolism, nicotinate and nicotinamide metabolism, biotin metabolism. The Kruskal-Wallis test showed that all metabolites were significantly higher (p < 0.05) in individuals with DS, with a moderate effect size (η² > 0.068), except for glutamate with a large effect size (η² = 2.971). The main differences in the metabolic profile of individuals with DS were the metabolism and transportation of lipids, the degradation and the metabolism of amino acids, and the excretion and transportation of metabolic residues. CONCLUSIONS: Individuals with DS show higher plasmatic concentration of  metabolites associated with synapse formation and function in neural transmission than individuals without DS, such as glutamate and phenylalanine which are  typically associated with intellectual disability.