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The gene for cystathionine beta-synthase (CBS) is located on chromosome 21 and is overexpressed in children with Down syndrome (DS), or trisomy 21. The dual purpose of the present study was to evaluate the impact of overexpression of the CBS gene on homocysteine metabolism in children with DS and to determine whether the supplementation of trisomy 21 lymphoblasts in vitro with selected nutrients would shift the genetically induced metabolic imbalance. Plasma samples were obtained from 42 children with karyotypically confirmed full trisomy 21 and from 36 normal siblings (mean age 7.4 years). Metabolites involved in homocysteine metabolism were measured and compared to those of normal siblings used as controls. Lymphocyte DNA methylation status was determined as a functional endpoint. The results indicated that plasma levels of homocysteine, methionine, S-adenosylhomocysteine, and S-adenosylmethionine were all significantly decreased in children with DS and that their lymphocyte DNA was hypermethylated relative to that in normal siblings. Plasma levels of cystathionine and cysteine were significantly increased, consistent with an increase in CBS activity. Plasma glutathione levels were significantly reduced in the children with DS and may reflect an increase in oxidative stress due to the overexpression of the superoxide dismutase gene, also located on chromosome 21. The addition of methionine, folinic acid, methyl-B(12), thymidine, or dimethylglycine to the cultured trisomy 21 lymphoblastoid cells improved the metabolic profile in vitro. The increased activity of CBS in children with DS significantly alters homocysteine metabolism such that the folate-dependent resynthesis of methionine is compromised. The decreased availability of homocysteine promotes the well-established "folate trap," creating a functional folate deficiency that may contribute to the metabolic pathology of this complex genetic disorder.

Fetal life is characterized by a tremendous plasticity and ability to respond to various environmental and lifestyle factors, including maternal nutrition. Identification of the role of dietary factors that can modulate and reshape the cellular epigenome during development, including methyl group donors (e.g., folate, choline) and bioactive compounds (e.g., polyphenols) is of great importance; however, there is insufficient knowledge of a particular effect of each type of modulator and/or their combination on fetal life. To enhance the quality and safety of food products for proper fetal health and disease prevention in later life, a better understanding of the underlying mechanisms of dietary epigenetic modulators during the critical prenatal period is necessary. This review focuses on the influence of maternal dietary components on DNA methylation, histone modification, and microRNAs, and summarizes current knowledge of the effect and importance of dietary components on epigenetic mechanisms that control the proper expression of genetic information. Evidence reveals that some components in the maternal diet can directly or indirectly affect epigenetic mechanisms. Understanding the underlying mechanisms of how early-life nutritional environment affects the epigenome during development is of great importance for the successful prevention of adult chronic diseases through optimal maternal nutrition.

We have studied the effect of common mutations (677C ! T and 1298A ! C) of the methylenetetrahydrofolate reductase (MTHFR) gene in sixty-six healthy French subjects, aged 27±47 years. Serum folate, vitamin B 12 , and plasma total homocysteine were measured as well as the speci®c activity of MTHFR in lymphocytes. The frequency of subjects homozygous for the 677TT genotype was 18 %, and that of those homozygous for the 1298CC genotype was 12×5 %. The frequency of individuals heterozygous for both mutations was 23×5 %. The 1298A ! C mutation was associated with decreased MTHFR speci®c activity in subjects with both 677CC and 677CT genotypes. This activity was 60 % for the 677CC/1298AC genotype and 52 % for the 677CC/ 1298CC genotype when compared with the MTHFR speci®c activity of the 677CC/1298AA genotype. Heterozygotes for both mutations (677CT/1298AC genotype) had 36 % of the reference speci®c activity. Although homocysteine levels in 677TT and 1298CC genotype subjects were higher than for other genotypes, no signi®cant differences were observed among different genotypes. This may be due to high serum folate level in our samples, and suggests that folate therapy may be useful to prevent hyperhomocysteinaemia in homozygous mutant subjects.