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Title: Metabolic analysis of neural tube defects
Author: Burren, Katie Ann
ISNI:       0000 0004 2674 3160
Awarding Body: University of London
Current Institution: University College London (University of London)
Date of Award: 2007
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Neural tube defects (NTDs), such as exencephaly and spina bifida, occur when the neural tube fails to close properly during embryonic development. Folic acid supplementation has been shown to effectively reduce the occurrence of NTDs and low folate is a known risk factor for human NTDs. However despite extensive research, the mechanism explaining how the folate status affects the incidence of NTDs remains unknown. One effect of sub-optimal folate could be suppression of the methylation cycle, which is interlinked with the folate cycle. To explore this hypothesis, a method has been developed to quantitatively measure the substrate, S-Adenosylmethionine (SAM), and the product, S-Adenosylhomocysteine (SAH), of methylation reactions in neurulation-stage mouse embryos by Liquid Chromatography Tandem Mass Spectrometry (LC-MS/MS). To investigate the link between methylation perturbation and neural tube defects, the abundance of SAM and SAH has been quantified in a series of experimental models and human NTD cell lines. Using a folate-deficient diet, this study also investigates folate deficiency using mouse models (splotch and curly tail) for NTDs. Results illustrate that folate deficiency, in both mouse models, caused an increase in the incidence of neural tube defects and, embryos were growth retarded. To examine the effect the folate deficient diet was having on endogenous folate metabolism, embryonic folate levels were analysed, in addition to maternal folate. Furthermore, using the established Ic-ms/ms method, the effect of folate deficiency on the abundance of SAM and SAH was determined. Increasing evidence suggests that myo-inositol may prove effective in preventing NTDs, in conjunction with folic acid. Thus, a double-blind, randomised clinical trial has been designed to investigate this and, in order to monitor patient compliance an LC-MS/MS method has been developed to quantify myo-inositol in urine.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available