Abstract
The pathogenesis of human spontaneous abortion involves a complex interaction of several genetic and environmental factors. The firm association between increased homocysteine concentration and neural tube defects (NTD) has led to the hypothesis that high concentrations of homocysteine might be embryotoxic and lead to decreased fetal viability. There are several genetic polymorphisms that are associated with defects in folate- and vitamin B12-dependent homocysteine metabolism. The methylenetetrahydrofolate reductase (MTHFR) 677C>T and 1298A>C polymorphisms cause elevated homocysteine concentration and are associated with an increased risk of NTD. Additionally, low concentration of vitamin B12 (cobalamin) or transcobalamin that delivers vitamin B12 to the cells of the body leads to hyperhomocysteinemia and is associated with NTD. This effect involves the transcobalamin (TC) 776C>G polymorphism. Importantly, the biochemical consequences of these polymorphisms can be modified by folate and vitamin B12 supplementation. In this review, I focus on recent studies on the role of hyperhomocysteinemia-associated polymorphisms in the pathogenesis of human spontaneous abortion and discuss the possibility that periconceptional supplementation with folate and vitamin B12 might lower the incidence of miscarriage in women planning a pregnancy.
Highlights
Accumulating evidence suggest that the sulfur-containing amino acid homocysteine plays a role in various developmental disorders [1]
Two main factors affect homocysteine concentration in humans: diet and polymorphisms in genes that encode enzymes or transport proteins involved in folateand vitamin B12-dependent homocysteine metabolism, the so called one-carbon metabolism, which is a complex series of metabolic pathways crucial for DNA synthesis and repair and a wide range of methylation reactions (Fig. 1)
The enzyme catalyzes the conversion of 5,10-methylenetetrahydrofolate into 5-methyltetrahydrofolate, the predominating circulating form of folate. 5methyltetrahydrofolate participates in the vitamin B12dependent remethylation of homocysteine to methionine that is converted to S-adenosylmethionine that serves as a methyl group donor in the methylation of DNA, proteins
Summary
Recurrent spontaneous abortion Maternal genotypes Foka et al [58] Holmes et al [59] Kumar et al [56] Kutteh et al [60] Lissak et al [55] Murphy et al [61] Nelen et al [53] Pihusch et al [62] Wramsby et al [63]. The prevalence of the mutated TC 776G allele was significantly increased in aborted embryos while the frequency of wild-type TC 776C homozygotes was much lower among spontaneously aborted embryos than controls (9.1% and 32.2%, respectively; p < 0.001) [70] These data are consistent with the view that the 776C allele may have beneficial influences during embryogenesis, conceivably through its positive effect on vitamin B12 intracellular bioavailability, which among other things results in reduced homocysteine concentration. Since the MTHFR and TC polymorphisms are very common, and since the data indicate that the fetal genotype is as important as the maternal genotype, a general recommendation of periconceptional supplementation with folate and vitamin B12 may be considered It should, be remembered that certain populations already have adequate intake of folate and vitamin B12 even for carriers of variant alleles. The data reviewed in this article warrant additional investigations exploring the potential beneficial effects of periconceptional supplementation with both folate and vitamin B12 in the prevention of spontaneous abortion
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