Plasma metabolome and cognitive skills in Down syndrome

Abstract

Trisomy 21 (Down syndrome, DS) is the main human genetic cause of intellectual disability (ID). Lejeune hypothesized that DS could be considered a metabolic disease, and we found that subjects with DS have a specific plasma and urinary metabolomic profile. In this work we confirmed the alteration of mitochondrial metabolism in DS and also investigated if metabolite levels are related to cognitive aspects of DS. We analyzed the metabolomic profiles of plasma samples from 129 subjects with DS and 46 healthy control (CTRL) subjects by 1H Nuclear Magnetic Resonance (NMR). Multivariate analysis of the NMR metabolomic profiles showed a clear discrimination (up to 94% accuracy) between the two groups. The univariate analysis revealed a significant alteration in 7 metabolites out of 28 assigned unambiguously. Correlations among the metabolite levels in DS and CTRL groups were separately investigated and statistically significant relationships appeared. On the contrary, statistically significant correlations among the NMR-detectable part of DS plasma metabolome and the different intelligence quotient ranges obtained by Griffiths-III or WPPSI-III tests were not found. Even if metabolic imbalance provides a clear discrimination between DS and CTRL groups, it appears that the investigated metabolomic profiles cannot be associated with the degree of ID.

One-carbon pathway and cognitive skills in children with Down syndrome

“…In 50 of 77 subjects evaluated by Griffiths-III and WPPSI-III tests (see Methods section), several other metabolites were already analyzed with 1 H-Nuclear Magnetic Resonance (H-NMR) in Antonaros et al 31 , but none of them showed a correlation with IQ scores. These data suggest that metabolites analyzed in the present work could have a crucial role in cognitive function.…”

Meta-analysis of metabolites involved in bioenergetic pathways reveals a pseudohypoxic state in Down syndrome

“…Caracausi et al ( 2018 ) and Antonaros et al ( 2020 ) reported raw data values. M, SD, and N were calculated for each compound both in DS and in control groups, as well as in plasma and in urine samples while the fasting condition was not considered.…”

“…” section). The fundamental role of metabolic and bioenergetic alterations in DS have been suspected for over 70 years and has periodically re-emerged as a working hypothesis (Simon et al 1954 ; Anon 1954 ; Breg 1977 ; Shapiro 1983 ; Blass et al 1988 ; Lejeune 1990 ; Chango et al 2002 ; Coppedè 2009 ; Izzo et al 2018 ; Vacca et al 2019 ; Antonaros et al 2020 ). Jerome LeJeune, the French physician-scientist, who discovered the chromosome abnormality in humans that causes DS, constructed a “Lejeune Machine” (Lejeune 1990 ), to illustrate the biochemical and metabolic alterations associated with this condition.…”

Effects of Probiotics Administration on Human Metabolic Phenotype

“…One of the main findings of metabolomics is that systemic biofluids like blood, urine and saliva, contain a strong individual metabolic signature, called metabolic phenotype or metabotype, which is stable over time, allowing us to monitor individual status and response to different stimuli [ 22 , 23 , 24 , 25 , 26 , 27 ], as well as to fingerprint several different diseases [ 28 , 29 , 30 , 31 , 32 , 33 ]. The metabotype is a multifactorial entity; in fact, besides being a snapshot of the subject’s genotype and metabolism, it is also influenced by many other factors, like gut microbiota, diet, lifestyle, drugs, etc.…”