Prenatal Environmental Exposure and Neurodevelopmentally Important Gene Expression in Malformed Brain Tissue from Pediatric Intractable Epilepsy Patients

Authors

Brenda Luna, Florida International UniversityFollow

Document Type

Dissertation

Major/Program

Public Health

First Advisor's Name

Deodutta Roy

First Advisor's Committee Title

Committee Chair

Second Advisor's Name

Quentin Felty

Third Advisor's Name

Wei-Chiang Lin

Fourth Advisor's Name

Berrin Serdar

Keywords

pediatric epilepsy, brain tumor, MCD, mitochondrial dysfunction, oxidative damage, mtDNA

Date of Defense

7-13-2011

Abstract

The primary objective of this proposal was to determine whether mitochondrial oxidative stress and variation in a particular mtDNA lineage contribute to the risk of developing cortical dysplasia and are potential contributing factors in epileptogenesis in children. The occurrence of epilepsy in children is highly associated with malformations of cortical development (MCD). It appears that MCD might arise from developmental errors due to environmental exposures in combination with inherited variation in response to environmental exposures and mitochondrial function. Therefore, it is postulated that variation in a particular mtDNA lineage of children contributes to the effects of mitochondrial DNA damage on MCD phenotype. Quantitative PCR and dot blot were used to examine mitochondrial oxidative damage and single nucleotide polymorphism (SNP) in the mitochondrial genome in brain tissue from 48 pediatric intractable epilepsy patients from Miami Children’s Hospital and 11 control samples from NICHD Brain and Tissue Bank for Developmental Disorders.

Epilepsy patients showed higher mtDNA copy number compared to normal health subjects (controls). Oxidative mtDNA damage was lower in non-neoplastic but higher in neoplastic epilepsy patients compared to controls. There was a trend of lower mtDNA oxidative damage in the non-neoplastic (MCD) patients compared to controls, yet, the reverse was observed in neoplastic (MCD and Non-MCD) epilepsy patients. The presence of mtDNA SNP and haplogroups did not show any statistically significant relationships with epilepsy phenotypes. However, SNPs G9804A and G9952A were found in higher frequencies in epilepsy samples. Logistic regression analysis showed no relationship between mtDNA oxidative stress, mtDNA copy number, mitochondrial haplogroups and SNP variations with epilepsy in pediatric patients. The levels of mtDNA copy number and oxidative mtDNA damage and the SNPs G9952A and T10010C predicted neoplastic epilepsy, however, this was not significant due to a small sample size of pediatric subjects. Findings of this study indicate that an increase in mtDNA content may be compensatory mechanisms for defective mitochondria in intractable epilepsy and brain tumor. Further validation of these findings related to mitochondrial genotypes and mitochondrial dysfunction in pediatric epilepsy and MCD may lay the ground for the development of new therapies and prevention strategies during embryogenesis.

Identifier

FI11080204

Recommended Citation

Luna, Brenda, "Prenatal Environmental Exposure and Neurodevelopmentally Important Gene Expression in Malformed Brain Tissue from Pediatric Intractable Epilepsy Patients" (2011). FIU Electronic Theses and Dissertations. 445.
https://digitalcommons.fiu.edu/etd/445