title: Bayesian network and mechanistic hierarchical structure modeling of increased likelihood of developing intractable childhood epilepsy from the combined effect of mtDNA variants, oxidative damage, and copy number.
abstract: 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.
authors.affiliation: Department of Environmental and Occupational Health, Florida International University, 11200 SW 8th Street, Miami, FL, 33199, USA.
authors.forename: Brenda
authors.initials: B
authors.lastname: Luna
authors.forename: Sanjiv
authors.initials: S
authors.lastname: Bhatia
authors.forename: Changwon
authors.initials: C
authors.lastname: Yoo
authors.forename: Quentin
authors.initials: Q
authors.lastname: Felty
authors.forename: David I
authors.initials: DI
authors.lastname: Sandberg
authors.forename: Michael
authors.initials: M
authors.lastname: Duchowny
authors.forename: Ziad
authors.initials: Z
authors.lastname: Khatib
authors.forename: Ian
authors.initials: I
authors.lastname: Miller
authors.forename: John
authors.initials: J
authors.lastname: Ragheb
authors.forename: Jayakar
authors.initials: J
authors.lastname: Prasanna
authors.forename: Deodutta
authors.initials: D
authors.lastname: Roy
mesh_terms: D001499:Bayes Theorem; D016022:Case-Control Studies; D002648:Child; D056915:DNA Copy Number Variations; D004272:DNA, Mitochondrial / Q000235:genetics*; D004827:Epilepsy / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006801:Humans; D016013:Likelihood Functions; D008297:Male; D008957:Models, Genetic; D018384:Oxidative Stress; D020641:Polymorphism, Single Nucleotide; D012737:Sex Factors
chemical_list: D004272:DNA, Mitochondrial