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Utilization of the microsomal epoxide hydolase gene for the detection of high risk epileptic pregnancies
Abstract
Most women with epilepsy have normal, healthy babies despite fetal exposure to anti-epileptic drugs (AEDs). Congenital malformations are seen in 2-3% of all pregnancy outcomes, and this rate increases 2-3 times for epileptic women. Results from numerous animal studies have implicated AEDs as having a significant teratogenic potential. Microsomal epoxide hydrolase (mEH) is an important enzyme in the metabolism of AEDS, and metabolites of these drugs have been associated with birth defects. Further studies, both animal and human, suggest that susceptibility to fetal anti-epileptic drug effects (FADE) may be linked to variation in the mEH gene. Low levels of mEH activity are associated with an increased risk for FADE and can be used to identify families at risk for FADE outcome. A genetic model for mEH activity has been proposed that suggests a two-allele, single locus pattern of transmission underlying differing fetal susceptibility for FADE. In this model, three phenotypes are assigned to different activity levels (low, intermediate, and high), which respectively correspond to homozygous recessive, heterozygous, and homozygous dominant genotypes. Recently a polymorphism in exon 3 of the mEH gene has been seen to reduce mEH activity in vitro. In this current study, AED literature pertaining to FADE was reviewed, and mEH activity data was analyzed for 30 AED exposed samples where pregnancy outcome was known. All 15 children diagnosed with FADE had mEH activities of less than 40% of a control standard, and 14 of the children who failed to exhibit FADE had mEH activity levels greater than 40%. mEH enzyme activities were also determined for eight families undergoing maternal AED therapy. A pattern of transmission was observed that corresponded to the two-aliele model. Finally, mEH exon 3 DNA was sequenced from 17 individuals to determine if the exon 3 polymorphism which lowered mEH activity in vitro was associated with FADE affected individuals or their families. This particular polymorphism was found in five samples. Additionally, five other polymorphisms were identified, two were silent mutations, two would alter the amino acid sequence of mEH, and one was for a stop codon.
Description
Due to the character of the original source materials and the nature of batch digitization, quality control issues may be present in this document. Please report any quality issues you encounter to digital@library.tamu.edu, referencing the URI of the item.Includes bibliographical references: p. 81-98.
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Citation
Bielec, Barbara Young (1997). Utilization of the microsomal epoxide hydolase gene for the detection of high risk epileptic pregnancies. Master's thesis, Texas A&M University. Available electronically from https : / /hdl .handle .net /1969 .1 /ETD -TAMU -1997 -THESIS -B54.
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