Abstract
This work investigates the role of metabolite levels in the intellectual impairment of subjects with Down syndrome (DS). Homocysteine, folate, vitamin B12, uric acid (UA), creatinine levels and MTHFR C677T genotype were analyzed in 147 subjects with DS. For 77 subjects, metabolite levels were correlated with cognitive tests. Griffiths-III test was administered to 28 subjects (3.08–6.16 years) and WPPSI-III test was administered to 49 subjects (7.08–16.08 years). Significant correlations were found among some metabolite levels and between homocysteine levels and MTHFR C677T genotype. Moreover, homocysteine, UA and creatinine levels resulted increased with age. We did not find any correlation between metabolites and cognitive test score in the younger group. Homocysteine showed statistically significant correlation with WPPSI-III subtest scores when its level is ≥ 7.35 µmol/L, remaining correlated in higher thresholds only for non-verbal area scores. Vitamin B12 showed correlations with all WPPSI-III subtest scores when its level is < 442 pg/mL. The relevance of the present findings is the detection of a specific metabolite threshold related with a better or worse cognitive score, suggesting that vitamin B12 and homocysteine may have a role in cognitive development in children with DS.
Highlights
This work investigates the role of metabolite levels in the intellectual impairment of subjects with Down syndrome (DS)
The information regarding age, sex, fasting state, the levels of Hcy, folate, vitamin B12, uric acid (UA), creatinine, methylenetetrahydrofolate reductase (MTHFR) C677T genotype and cognitive tests are listed in Supplementary Dataset S1
Cognitive test results were available for 77 DS children out of 147 subjects enrolled in the context of our clinical experimental study
Summary
This work investigates the role of metabolite levels in the intellectual impairment of subjects with Down syndrome (DS). Homocysteine, folate, vitamin B12, uric acid (UA), creatinine levels and MTHFR C677T genotype were analyzed in 147 subjects with DS. The relevance of the present findings is the detection of a specific metabolite threshold related with a better or worse cognitive score, suggesting that vitamin B12 and homocysteine may have a role in cognitive development in children with DS. CBS might have a role in dysregulated DNA methylation levels in subjects with DS, causing decreased Hcy availability and consequentially methionine (Met) s ynthesis[9]. Another critical enzyme for the regulation of Hcy concentration is 5,10-methylenetetrahydrofolate reductase (MTHFR) since it catalyzes the conversion of 5,10-methylenetetrahydrofolate (THF) to 5-methyl-THF. Subjects with DS resulted to have a lower tolerance to the antifolate drug methotrexate (MTX) and their blood levels of vitamin B12 and folate have been reported to be lower than healthy c ontrols[13]
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