THE IMPORTANCE OF FOLIC ACID METABOLISM IN THE DEVELOPMENT OF NEURAL TUBE DEFECTS

Neural tube defects (NTDs) are congenital malformations resulting from failure of the neural tube closure in early embriogenesis. Depending on the geografical region and the population, the rate of NTDs is 0.5-2.0 per 1000 live births worldwide. The etiology of isolated NTDs is multi factorial and involves multiple genes and environmental factors. It was suggested that risk of NTDs development depends on mutations and polymorphisms of genes connected with the regulation of neurulation. The polymorphisms of genes encoding enzymes that are related with the metabolic cycle of folates may influence the incidence of NTDs. Several studies point out that single nucleotide polymorphisms in the gene encoding methylenetetrahydrofolate reductase (MTHFR), especially in locations 677, may increase the risk (threat) of NTD development. Epidemiological studies helped the researchers to identify the environmental risk factors contributing to etiology of NTDs. The risk of NTDs may be increased by the influence of factors such as low folate level, the antagonists of folic acid, antiepileptic drugs, mycotoxins, pesticides, smoking tobacco, alcohol, obesity, diabetes and others. One of the important factors is supplementary maternal peri-conceptional intake of folic acid, which has been demonstrated to reduce the occurrence of human NTD by as much as 70% The mechanism of the protective effect of folic acid and its metabolites on the NTDs development is not fully understood. It is suggested, that one of the possible cause leading to NTDs in newborns is the existence of antibodies against folate receptors, which are present predominantly in mothers to NTD-affected infants. There is growing evidence indicating that NTDs may result in changes of epigenetic regulation during intrauterine development. Epigenetic regulation of genes expression is strongly influenced by environmental factors. Folate metabolism - a main process regulating the supply of methyl groups, affects the disturbances epigenetic mechanism. Thus, insufficient folate supply correlates with increased susceptibility to NTDs development. There are still many studies under way aiming to determine the reasons behind NTDs as well as to develop methods for their prevention. The aim of the article is to review various aspects of the genetic and environmental risk of NTDs, with a particular view to the role of folates and epigenetic interactions.