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

Brenda Luna, Sanjiv Bhatia, Changwon Yoo, Quentin Felty, David I. Sandberg, Michael Duchowny, Ziad Khatib, Ian Miller, John Ragheb, Jayakar Prasanna, Deodutta Roy

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)752-766
Number of pages15
JournalJournal of Molecular Neuroscience
Volume54
Issue number4
DOIs
StatePublished - Nov 26 2014

Keywords

  • Copy number
  • mtDNA damages
  • mtDNA variants
  • Pediatric epilepsy

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience

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