Metabolic and genetic imbalance of the homocysteine-methionine cycle in trisomy 21

The homocysteine-methionine cycle is involved in critical human cellular functions such as proliferation and epigenetic regulation. S-adenosyl-methionine (SAM) and S-adenosylhomocysteine (SAH) are synthetized in this metabolic cycle and their levels are finely regulated to ensure proper functioning of key enzymes controlling cellular growth and differentiation. SAM and SAH levels were found altered in plasma of subjects with trisomy 21 (T21) but how this metabolic dysregulation influences the clinical manifestation of T21 phenotype has not been previously described. SAM and SAH quantification was performed in urine samples of 58 subjects with T21 and 48 controls (N) through liquid chromatography with tandem mass spectrometry. SAH resulted slightly more excreted in urine of subjects with T21 (T21/N mean ratio=1.16, pvalue=0.021), while no difference was found in SAM levels. Metabolite urine levels were compared with those previously observed in plasma in which higher amounts of SAM and SAH were found. In addition, we examined if an association between the levels of SAM and SAH in T21 and the expression levels of genes involved in their production/utilization exists using the transcriptome map of blood samples of T21 and N subjects. The analysis showed overexpression of 44 methyltransferase genes responsible for the conversion of SAM to SAH, of 2 genes involved in SAH utilization (AHCYL1, AHCYL2), and of 1 gene involved in SAM utilization (AMD1). These data support the hypothesis that T21 genetic imbalance is responsible of SAM and SAH excess which may be involved in the T21 phenotypic features. New & Noteworthy S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) are critical metabolites for fundamental cellular functions such as proliferation and epigenetic regulation. For the first time, their levels were quantified in the urine of subjects with trisomy 21 (T21) and compared with euploid controls (N). These dosages were compared with their plasma levels and the expression of genes involved in SAM and SAH production/utilization were further investigated in the differential blood transcriptome map of T21 vs. N samples.