Homocysteine metabolism in children with Down syndrome: In vitro modulation

The gene for cystathionine beta -synthase (CBS) is located on chromosome 21 and is overexpressed in children with Down syndrome (DS), or trisomy 21. T he dual purpose of the present study was to evaluate the impact of overexpr ession of the CBS gene on homocysteine metabolism in children with DS and t o determine whether the supplementation of trisomy 21 lymphoblasts in vitro with selected nutrients would shift the genetically induced metabolic imba lance. Plasma samples were obtained from 42 children with karyotypically co nfirmed full trisomy 21 and from 36 normal siblings (mean age 7.4 years). M etabolites involved in homocysteine metabolism were measured and compared t o those of normal siblings used as controls. Lymphocyte DNA methylation sta tus was determined as a functional endpoint. The results indicated that pla sma levels of homocysteine, methionine, S-adenosylhomocysteine, and S-adeno sylmethionine were all significantly decreased in children with DS and that their lymphocyte DNA was hypermethylated relative to that in normal siblin gs. Plasma levels of cystathionine and cysteine were significantly increase d, consistent with an increase in CBS activity. Plasma glutathione levels w ere significantly reduced in the children with DS and may reflect an increa se in oxidative stress due to the overexpression of the superoxide dismutas e 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 increase d activity of CBS in children with DS significantly alters homocysteine met abolism such that the folate-dependent resynthesis of methionine is comprom ised. The decreased availability of homocysteine promotes the well-establis hed "folate trap," creating a functional folate deficiency that may contrib ute to the metabolic pathology of this complex genetic disorder.