Despite that mutations in
mitochondrial DNA (
mtDNA) have been associated with
major epilepsy syndromes, the role of
mtDNA instability and
mitochondrial dysfunction in epileptogenesis has not been comprehensively examined. In the present study, we investigated the role of
mtDNA copy number, oxidative damage, and
mtDNA variants as independent or combined risk factors for the development of intractable childhood
epilepsy. We analyzed
mtDNA copy number and oxidative damage by quantitative polymerase chain reaction (PCR), and
mtDNA variants by dot blot in brain tissue specimens collected from 21 pediatric
intractable epilepsy patients and 11 non-epileptic patients. Bayesian network and mechanistic hierarchical structure Markov chain Monte Carlo (MCMC) modeling were used to analyze the relationship between these variables. The combined effects of oxidative
mtDNA damages and
mtDNA copy number produced more significant correlation with
epilepsy than that of
mtDNA copy number alone with
epilepsy.
Epilepsy patients showed significant correlations with
mtDNA single nucleotide polymorphisms (SNPs)--A1555G, G3196A, T3197C, G9952A, A10006G, A10398G,
cortical dysplasia status, oxidative
mtDNA damage and relative
mtDNA copy number. Comparison of 12 mechanistic structure models suggested that female children who have the wild type allele 10398A and variant allele 9952A, and high
mtDNA copy number and oxidative stress have increased probability of developing
intractable epilepsy. Estimation of nuclear genes controlling mitochondrial biogenesis,
cortical dysplasia, and the effect of the environment using MCMC method showed that these latent variables had a very significant contribution in the development of
intractable epilepsy. These data suggest that mitochondrial genetics play a significant role in the pathogenesis of
epilepsy in children, and findings of this study may guide the prospects for targeting mitochondria for therapeutic treatment of childhood
intractable epilepsy.