Folate metabolism and neural tube defects: a review

Abstract

iThe importance o f folate in norm al fetal developm ent and wellbeing has been recognized only during the past three decades and knowledge concerned is still far from complete. In m an, folate acts as a substrate in the transfer of one-carbon moieties and thereby, plays an essential role in the synthesis o f several am ino acids such as m ethionine and nucleic acids. Consequently, folate require ments are related to the am ount of tissue growth. Epidemiological, clinical and teratological research showed that this B-vitamin is particularly involved in the prevention and pathogenesis o f neural tube defects. Therefore, in this review the metabolism o f folate has been outlined. Furtherm ore, the characteristics of the various genically determ ined folate 'deficiencies5 as well as a possible biochemical explanation o f the relationship between folate and neural tube defects are being discussed. Finally, the new recommen dations launched in N ovem ber 1993 by the D utch H ealth Council as well as the Food and N utrition Council with regard to folate supplementation in the prevention o f neural tube defects are presented.

Embryology of myelomeningocele and anencephaly

“…Ingestion of higher doses of folate may overcome this relative deficiency by restoring more normal homocysteine and methionine levels. 51,57,58 Numerous observations support this view. For example, elevated maternal homocysteine levels have been identified in women carrying a fetus that harbors an NTD, both in serum 40 and in amnionic fluid.…”

“…11 Although the exact mechanism is not known, valproic acid appears to disrupt folate metabolic pathways, perhaps by interfering with the conversion of tetrahydrofolate to 5-formyltetrahydrofolate. 57 Maternal folate administration reduces the incidence of valproic acid-associated NTDs in some, but not all, studies, and mouse strains that are susceptible to valproate acid-induced NTDs have significantly lower levels of 5,10-methylenetetrahydrofolate following valproic acid administration compared with resistant strains. In addition, a number of developmental regulatory genes (such as transcription factors and cell cycle checkpoint genes) may be altered in these susceptible strains.…”

“…In particular, the role of folate in methionine and homocysteine metabolism has generated considerable interest recently. 5,6,27,40,47,57,59,63,67 The metabolism of homocysteine follows one of two pathways. One involves a transsulphuration to cystathionine, catalyzed by the enzyme cystathionine synthase; cystothianine is subsequently converted to cysteine.…”

“…For example, elevated maternal homocysteine levels have been identified in women carrying a fetus that harbors an NTD, both in serum 40 and in amnionic fluid. 57 Disordered methionine metabolism has been demonstrated in nonpregnant women who previously had given birth to a child with an NTD.57,58 Methionine supplementation can reduce the risk of NTDs in rats and possibly in humans. 65 Finally, polymorphisms involving the 5,10-methylenetetrahydrofolate reductase gene have been demonstrated in one study in 18% of individuals with NTDs, and in 13% of parents of children with NTDs, compared with 6% in controls.…”

“…For example, elevated maternal homocysteine levels have been identified in women carrying a fetus that harbors an NTD, both in serum 40 and in amnionic fluid. 57 Disordered methionine metabolism has been demonstrated in nonpregnant women who previously had given birth to a child with an NTD. 57,58 Methionine supplementation can reduce the risk of NTDs in rats and possibly in humans.…”