An elevation in plasma homocysteine is a sensitive but nonspecific biomarker for an imbalance in the integrated pathways of one-carbon metabolism (1, 2). Chronic nutritional deficiencies in folate, choline, methionine, vitamin B 6 , and/or vitamin B 12 can perturb the complex regulatory network that maintains normal one-carbon metabolism and homocysteine homeostasis (3-7). Genetic polymorphisms in these pathways can act synergistically with nutritional deficiencies to accelerate the metabolic pathology associated with chronic disease states (8). Although several hypotheses have been proposed to explain the association between hyperhomocysteinemia and the thrombotic/atherosclerotic process occurring with occlusive cardiovascular disease, as yet none has been definitive (9 -12). Similarly, increases in plasma homocysteine concentrations have been associated with increased risk of certain birth defects (13-16), but the underlying mechanism remains elusive. A major unanswered question is whether direct cellular toxicity of homocysteine is causally involved in pathogenesis or whether homocysteinemia is simply a passive and indirect indicator of a more complex mechanism.Homocysteine is derived solely from methionine metabolism and is significantly recycled to conserve sufficient methionine for protein and S-adenosylmethionine synthesis. The interactive and interdependent pathways of the methionine/homocysteine cycle are diagrammed in Fig. 1 to emphasize the indirect effects of pathway perturbations on cellular methyltransferase reactions. The metabolic generation of homocysteine from methionine is initiated by the ATP-dependent transfer of adenosine to methionine via methionine adenosyltransferase. The product, S-adenosylmethionine (SAM), 1 is a priority for onecarbon metabolism because it is the methyl donor for most cellular methyltransferase reactions. In addition to DNA methylation, SAM-dependent methyltransferase activity is essential for hundreds of other cellular methylation reactions including synthesis of creatine in the liver, membrane phosphatidylcholine synthesis, central nervous system neurotransmittor synthesis, methylation/detoxification, and RNA and protein methylation (17). After transfer of the methyl group, SAM is converted to S-adenosylhomocysteine (SAH) within the active site of the methyltransferase enzyme. Because most methyltransferases bind SAH with higher affinity than SAM, they are subject to potent product inhibition by SAH (18). Thus, the efficiency of methyltransferase reactions is absolutely dependent on efficient product removal of SAH. This is effectively accomplished by SAH hydrolase (SAHH), an enzyme that appears to act in close proximity to the methyltransferases, at least in the nucleus (19). The crystal structure of SAHH has been recently reported, and interestingly, the polypeptide folding pattern at the catalytic domain of SAHH is almost identical to that reported for the DNA methyltransferases and suggests that SAH molecules can travel easily between the catalytic pockets of th...

The results of this initial study indicate that folate metabolism is abnormal in mothers of children with Down syndrome and that this may be explained, in part, by a mutation in the MTHFR gene.