Objective Down syndrome (DS) is caused by trisomy 21. The cystathionine-beta synthase (CBS) and the reduced-folate carrier (RFC1) genes map on chromosome 21 and are critical regulators of the homocysteine/folate metabolism. To investigate whether the homocysteine/folate pathway is disrupted in DS, we analysed the CBS844ins68, the RFC1A80G, the methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C, the methionine synthase reductase (MTRR) A66G and the methionine synthase (MTR) A2756G polymorphisms as well as plasma homocysteine, methionine, folates, B12 and B6 vitamins.

Methods Genotype analysis was performed by restriction fragment-length polymorphism. Genotype and allele frequencies were evaluated in 134 DS subjects and 93 controls, and the odds ratio was used as a measure of association between polymorphisms and DS. Biochemical data were analysed by t test. The relation between homocysteine/folate levels and genotypes was also evaluated.

Results No association was found between the analysed polymorphisms and the risk of DS. A negative interaction was found between RFC80G homozygotes and: MTP 2756AA and AA/AG; MTRR 66AG/AA and AG/GG; MTHFR 1298AA/AC and AA; MTHFR 677CC/CT; CBSins−. Homocysteine and methionine levels were lower in DS subjects (p = 0.004 and p = 0.011, respectively), whereas folates, B12 and B6 levels were not different. Low homocysteine levels were associated with the following genotypes: MTHFR 677CT (p = 0.012); MTHFR 1298AA (p = 0.006); MTRR 66AG (p = 0.008); MTRR 66GG (p = 0.001); MTR 2756AA (p = 0.006); CBSins−/− (p = 0.022). Among DS subjects, low folate levels were associated with the MTR 2756GG genotype.

Conclusions Homocysteine/folate metabolism is impaired in DS with a reduction of homocysteine and methionine, partly depending on the genotype. This metabolic imbalance may affect cellular methylation reactions.