Neural tube defects between folate metabolism and genetics
Neural tube defects (NTDs) are a group of birth defects in which an opening in the spinal cord The diagnosis can usually be made on antenatal ultrasound scanning, but if not will undoubtedly be made immediately The association seen between reduced neural tube defects and folic acid supplementation is due to a. Spina bifida and anencephaly, the most common neural tube defects, affect approximately 4, pregnancies in the US annually. Folic acid supplementation . Neural tube defects are abnormalities that occur in the development of the spinal cord and brain of some babies. About 2 thirds of neural tube defects can be prevented through increasing folate (folic acid) This first scan may be able to detect problems with your baby's spine that Dietitians Association of Australia ( 2).
In order to investigate potential abnormalities in folate metabolism in the embryo itself, we derived primary fibroblastic cell lines from foetuses affected by NTDs and subjected them to the dU suppression test, a sensitive metabolic test of folate metabolism. Significantly, a subset of NTD cases exhibited low scores in this test, indicative of abnormalities in folate cycling that may be causally linked to the defect.
Neural tube defect
Susceptibility to NTDs may be increased by suppression of the methylation cycle, which is interlinked with the folate cycle. However, reduced efficacy in the dU suppression test was not associated with altered abundance of the methylation cycle intermediates, s-adenosylmethionine and s-adenosylhomocysteine, suggesting that a methylation cycle defect is unlikely to be responsible for the observed abnormality of folate metabolism.
Genotyping of samples for known polymorphisms in genes encoding folate-associated enzymes did not reveal any correlation between specific genotypes and the observed abnormalities in folate metabolism. These data suggest that as yet unrecognized genetic variants result in embryonic abnormalities of folate cycling that may be causally related to NTDs. Population and family studies indicate a genetic component in human NTDs, while more than genetic mutations are known to cause NTDs in mice Copp et al.
Among these factors, maternal nutritional status is a key determinant of pregnancy outcome and attention has focused on folic acid, a vitamin whose biological derivatives are integral to the interlinked folate and methionine cycles Scott, ; Blom et al.Folic Acid in Minimizing the Risk of Spina bifida
Clinical trials demonstrate that supplementation with folic acid prior to and during early pregnancy reduces the risk of NTDs in the developing foetus Wald et al. Conversely, reduced folate levels or elevated homocysteine levels an inverse indicator of folate status in maternal serum or plasma are risk factors for NTDs Kirke et al.
Despite compelling evidence for an involvement of folate metabolism, neither the protective mechanism nor the relationship between maternal folate status and susceptibility to NTDs are well defined. One possibility is that folic acid acts to overcome insufficient maternal folate levels. However, in most cases, mothers of affected foetuses have either normal folate status or are, at most, mildly folate-deficient, arguing against maternal folate deficiency as a major causative factor Mills et al.
Alternatively, it is postulated that supplemental folic acid may act to overcome an underlying defect in folate metabolism that results from a genetic mutation in mother or foetus.
For this reason proteins that mediate, or are functionally associated with, folate metabolism have provided candidates for genetic analysis in human NTDs Boyles et al. Attention has particularly focused on polymorphisms in the gene encoding 5,methylenetetrahydrofolate reductase MTHFRwith the CT polymorphism conferring increased risk of NTDs in some, but not all, populations Van der Put et al.
Therefore, the extent to which the genetic component of NTDs involves folate-related genes is currently unclear. As an alternative approach to screening for genetic mutations we decided to directly test the possibility that abnormalities in folate metabolism may be associated with increased risk of NTDs, by analysis of fibroblastic cell lines generated from foetuses affected by NTDs.
As a means of investigating the integrity of the folate cycle we utilized the deoxyuridine dU suppression test Killman, ; Fleming and Copp,which depends on the ability of deoxyuridine monophosphate dUMP to suppress the incorporation of thymidine into DNA.
Neural tube defect - Wikipedia
Deoxythymidine monophosphate dTMPthe precursor of pyrimidines, can be generated from dUMP de novo synthesis catalysed by thymidylate synthase or by phosphorylation of thymidine the salvage pathway effected by thymidylate kinase Fig.
Exogenous dUMP stimulates the de novo pathway and thereby suppresses incorporation of thymidine into genomic DNA, provided that the key intermediate 5,methylenetetrahydrofolate is available as part of normal folate metabolism Fig.
Therefore, the ability of dUMP to suppress thymidine incorporation into DNA provides a sensitive metabolic indicator of the integrity of the folate cycle.
A Addition of dU stimulates de novo synthesis of dTMP and suppresses incorporation of thymidine via the salvage pathway. B—C Effect of dU and exogenous inhibitors on thymidine incorporation in a human primary fibroblast cell line derived from a normal control pregnancy. Women who take medicines to control epilepsy, seizures or psychiatric disorders should talk to their doctor before taking folate because it can interfere with how their medications work.
For more information see folate and pregnancy. Diagnosis Neural tube defects may be diagnosed during the ultrasound scan that is carried out around week 12 of the pregnancy or, more likely, during the anomaly scan that is carried out at around weeks 19 to Ultrasound scans An ultrasound scan is a safe procedure that uses sound waves to create an image of the inside of your body.
Most hospitals will offer women at least 2 ultrasound scans during their pregnancy.
Neural tube defects between folate metabolism and genetics
Anomaly scan The anomaly scan is an ultrasound scan that is carried out around weeks 19 to 20 of your pregnancy. This scan aims to identify any physical problems with your baby.
It is usually during this scan that spina bifida is diagnosed. Coping with the results If tests confirm that your baby has spina bifida, the implications will be fully discussed with you. You will need to consider your options carefully. Your options are to: They will be able to provide you with important information and advice.
Your options for ending your pregnancy will depend on how many weeks pregnant you are when you make the decision. If you decide to end your pregnancy, you may wish to talk to a counsellor afterwards. Your doctor or midwife will be able to arrange this for you.