Skip to main content

Advertisement

SpringerLink
Log in

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

  • Published:
Journal of Molecular Neuroscience Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  • Andres M, Andre VM, Nguyen S, Salamon N, Cepeda C, Levine MS, Leite JP, Neder L, Vinters HV, Mathern GW (2005) Human cortical dysplasia and epilepsy: an ontogenetic hypothesis based on volumetric MRI and NeuN neuronal density and size measurements. Cereb Cortex 15:194–210

    Article  PubMed  Google Scholar 

  • Ayala-Torres S, Chen Y, Svoboda T, Rosenblatt J, Van Houten B (2000) Analysis of gene-specific DNA damage and repair using quantitative polymerase chain reaction. Methods 22:135–147

    Article  CAS  PubMed  Google Scholar 

  • Bai RK, Leal SM, Covarrubias D, Liu A, Wong LJ (2007) Mitochondrial genetic background modifies breast cancer risk. Cancer Res 67:4687–4694

    Article  CAS  PubMed  Google Scholar 

  • Bai R, Wong L, Leal SM (2008) Mitochondrial DNA variant interactions modify breast cancer risk. J Hum Genet 53:924–928

    Article  PubMed Central  PubMed  Google Scholar 

  • Barkovich AJ, Kuzniecky RI, Jackson GD, Guerrini R, Dobyns WB (2005) A developmental and genetic classification for malformations of cortical development. Neurology 65:1873–1887

    Article  CAS  PubMed  Google Scholar 

  • Baron M, Kudin A, Kunz W (2007) Mitochondrial dysfunction in neurodegenerative disorders. Biochem Soc Trans 35:1228–1231

    Article  CAS  PubMed  Google Scholar 

  • Bindoff LA, Engelsen BA (2012) Mitochondrial diseases and epilepsy. Epilepsia 53(suppl 4):92–97

    Article  CAS  PubMed  Google Scholar 

  • Brinckmann A, Weiss C, Wilbert F, von Moers A, Zwirner A, Stoltenburg-Didinger G, Wilichowski E, Schuelke M (2010) Regionalized pathology correlates with augmentations of mtDNA copy numbers in patients with myoclonic epilepsy with ragged-red fibers (MERRF-Syndrome). PLoS ONE 5:e13513

    Article  PubMed Central  PubMed  Google Scholar 

  • Canafoglia L, Franceschetti S, Antozzi C, Carrara F, Farina L, Granata T, Lamantea E, Savoiardo M, Uziel G, Villani F, Zeviani M, Avanzini G (2001) Epileptic phenotypes associated with mitochondrial disorders. J Neurol 56:1340–1346

    Article  CAS  Google Scholar 

  • Cardaioli E, Dotti MT, Hayek G, Zappella M, Federico A (1999) Studies on mitochondrial pathogenesis of Rett syndrome: ultrastructural data from skin and muscle biopsies and mutational analysis at mtDNA nucleotides 10463 and 2835. J Submicrosc Cytol Pathol 31:301–304

    CAS  PubMed  Google Scholar 

  • Chen C, Wu Y, Cheng M, Liu JL, Lee YM, Lee PW, Soong BW, Chiu DT (2007) Increased oxidative damage and mitochondrial abnormalities in the peripheral blood of Huntington’s disease patients. Biochem Biophys Res Commun 359:335–340

    Article  CAS  PubMed  Google Scholar 

  • Chinnery PF, Hudson G (2013) Mitochondrial genetics. Br Med Bull 106:135–159

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • DiMauro S (2001) Lessons from mitochondrial DNA mutations. Semin Cell Dev Biol 9:397–405

    Article  Google Scholar 

  • El Sabbagh S, Lebre A-S, Bahi-Buisson N, Delonlay P, Soufflet C, Boddaert N, Rio M, Rçtig A, Dulac O, Munnich A, Desguerre I (2010) Epileptic phenotypes in children with respiratory chain disorders. Epilepsia 51:1225–1235

    Article  PubMed  Google Scholar 

  • Felty Q, Roy D (2005) Estrogen, mitochondria, and growth of cancer and non-cancer cells. J Carcinog 4:e1

    Article  Google Scholar 

  • Filiano JJ, Goldenthal MJ, Rhodes H, Marín-García J (2002) Mitochondrial dysfunction in patients with hypotonia, epilepsy, autism, and developmental delay: HEADD syndrome. J Child Neurol 17:435–439

    Article  Google Scholar 

  • Fukuda M, Yamauchi H, Yamamoto H, Aminakab M, Murakamia H, Kamiyamaa N, Miyamotoa Y, Koitabashia Y (2008) The evaluation of oxidative DNA damage in children with brain damage using 8-hydroxyguanosine levels. Brain Dev 30:131–136

    Article  PubMed  Google Scholar 

  • Geman S, Geman D (1984) Stochastic relaxation, Gibbs distributions and the Bayesian restoration of images. IEEE Trans Pattern Anal Mach Intell 6:721–742

    Article  CAS  PubMed  Google Scholar 

  • Grazina M, Pratas J, Silva F, Oliveira S, Santana I, Oliveira C (2006) Genetic basis of Alzheimer’s dementia: role of mtDNA mutations. Genes Brain Behav 5(Suppl 2):92–107

    Article  CAS  PubMed  Google Scholar 

  • Hader WJ, Mackay M, Otsubo H, Chitoku S, Weiss S, Becker L, Snead OC 3rd, Rutka JT (2004) Cortical dysplastic lesions in children with intractable epilepsy: role of complete resection. J Neurosurg 100:110–117

    PubMed  Google Scholar 

  • Hanna M, Nelson P, Rahman S, Lane RJM, Land L, Heales S, Cooper MJ, Schapira AHV, Morgan-Hughes JA, Wood NW (1998) Cytochrome c oxidase deficiency associated with the first stop-codon point mutation in human mtDNA. Am J Genet 63:29–36

    Article  CAS  Google Scholar 

  • Howell N, Oostra R, Bolhuis P, Spruijt L, Clarke LA, Mackey DA, Preston G, Herrnstadt C (2003) Sequence analysis of the mitochondrial genomes from Dutch pedigrees with Leber Hereditary Optic Neuropathy. Am J Genet 72:1460–1469

    Article  CAS  Google Scholar 

  • Hsieh RH, Li J-Y, Pang C-Y, Wei Y-H (2001) A novel mutation in the mitochondrial 16S rRNA gene in a patient with MELAS syndrome, diabetes mellitus, hyperthyroidism and cardiomyopathy. J Biomed Sci 8:328–335

    Article  CAS  PubMed  Google Scholar 

  • Hua Y, Crino PB (2003) Single cell lineage analysis in human focal cortical dysplasia. Cereb Cortex 13:693–699

    Article  PubMed  Google Scholar 

  • MITOMAP: A Human Mitochondrial Genome Database (2009) http://www.mitomap.org/MITOMAP.

  • Jizong Z, Zhou F, Hongmin B (2011) Surgical treatment of intractable epilepsy associated with focal cortical dysplasia. In Humberto Foyaca-Sibat (Ed.) Novel treatment of epilepsy, ISBN: 978-953-307-667-6: http://www.intechopen.com/books/novel-treatment-of-epilepsy/surgicaltreatment-of-intractable-epilepsy-associated-with-focal-cortical-dysplasia

  • Kunkle BW, Yoo C, Roy D (2013) Reverse engineering of modified genes by Bayesian Network analysis defines molecular determinants critical to the development of glioblastoma. PLoS ONE 8(5):e64140

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Lee H, Wei Y (2005) Mitochondrial biogenesis and mitochondrial DNA maintenance of mammalian cells under oxidative stress. Int J Biochem Cell Biol 37:822–834

    Article  CAS  PubMed  Google Scholar 

  • Lee H, Yin P, Lu C, Chi CW, Wei YH (2000) Increase of mitochondria and mitochondrial DNA in response to oxidative stress in human cells. Biochem J 348:425–432

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Lee J, Park K, Im J, Kim MY, Lee DC (2010) Mitochondrial DNA copy number in peripheral blood associated with cognitive function in apparently healthy elderly women. Clin Chim Acta 411:592–596

    Article  CAS  PubMed  Google Scholar 

  • Lehtonen MS, Moilanen JS, Majamaa K (2003) Increased variation in mtDNA in patients with familial sensorineural hearing impairment. Hum Genet 113:220–227

    Article  CAS  PubMed  Google Scholar 

  • Lenroot R, Giedd J (2006) Brain development in children and adolescents: insights from anatomical magnetic resonance imaging. Neurosci Biobehav Rev 30:718–729

    Article  PubMed  Google Scholar 

  • Liang MH, Wong LJ (1998) Yield of mtDNA mutation analysis in 2,000 patients. Am J Med Genet 77:395–400

    Article  CAS  PubMed  Google Scholar 

  • Lin C, Wang L, Tsai C, Wei YH (2008) Low copy number and low oxidative damage of mitochondrial DNA are associated with tumor progression in lung cancer tissues after neoadjuvant chemotherapy. Interact Cardiovasc Thorac Surg 7:954–958

    Article  PubMed  Google Scholar 

  • Liu C, Cheng W, Lee C, Ma YS, Lin CY, Huang CC, Wei YH (2006) Alterations in the copy number of mitochondrial DNA in leukocytes of patients with mitochondrial encephalomyopathies. Acta Neurol Scand 113:334–341

    CAS  PubMed  Google Scholar 

  • Lopez J, Gonzalez M, Lorigados L, Morales L, Riverón G, Bauzá JY (2007) Oxidative stress in surgically treated patients with refractory epilepsy. Clin Biochem 40:292–298

    Article  CAS  PubMed  Google Scholar 

  • Luna B, Bhatia B, Ragheb B, Miller I, Jayakar P, Felty Q, Roy D (2011) Malformations of cortical development and epilepsy in children. Encycl Environ Health Gene Environ Interact 2:595–602

    Article  Google Scholar 

  • Malakhova L, Bezlepkin V, Antipova V, Ushakova T, Fomenko L, Sirota N, Gaziev AI (2005) The increase in mitochondrial DNA copy number in the tissue of γ-irradiated mice. Cell Mol Biol Lett 10:721–732

    CAS  PubMed  Google Scholar 

  • Okoh V, Deoraj A, Roy D (2011) Estrogen-induced ROS mediated redox signaling contributes in the development of breast cancer. Biochem Biophys Acta 1815:115–133

    CAS  PubMed  Google Scholar 

  • Patil C, Ahire Y, Pathade P, Pathade VV, Mali PR (2011) Free radical epilepsy and anti-oxidant: an overview. Int Res J Pharm 2:64–71

    CAS  Google Scholar 

  • Pieczenik S, Neustadt J (2007) Mitochondrial dysfunction and molecular pathways of disease. Exp Mol Pathol 83:84–92

    Article  CAS  PubMed  Google Scholar 

  • Rickert CH (2006) Cortical dysplasia: neuropathological aspects. Childs Nerv Syst 22:821–826

    Article  PubMed  Google Scholar 

  • Roy D, Felty Q, Narayan S, Jayakar P (2007) Signature of mitochondria of steroidal hormones-dependent normal and cancer cells: potential molecular targets for cancer therapy. Front Biosci 12:154–173

    Article  CAS  PubMed  Google Scholar 

  • Santorelli FM, Tanji K, Shanske S, DiMauro S (1997) Heterogeneous clinical presentation of the mtDNA NARP/T8993G mutation. Neurology 49:270–273

    Article  CAS  PubMed  Google Scholar 

  • Schwartzkroin PA, Walsh CA (2000) Cortical malformations and epilepsy. Ment Retard Dev Diagn 6:268–280

    Article  CAS  Google Scholar 

  • Shah NS, Mitchell WG, Boles RG (2002) Mitochondrial disorders: a potential under-recognized etiology of infantile spasms. J Child Neurol 17:369–372

    Article  PubMed  Google Scholar 

  • Shen J, Platek M, Mahasneh A, Ambrosone CB, Zhao H (2010) Mitochondrial copy number and risk of breast cancer: a pilot study. Mitochondrion 10:62–68

    Article  CAS  PubMed  Google Scholar 

  • Shoffner JM, Brown MD, Torroni A, Lott MT, Cabell MF, Mirra SS, Beal MF, Yang CC, Gearing M, Salvo R, Watts RL, Juncos JL, Hansen LA, Crain BJ, Fayad M, Reckord CL, Wallace DC (1993) Mitochondrial DNA variants observed in Alzheimer disease and Parkinson disease patients. Genomics 17:171–184

    Article  CAS  PubMed  Google Scholar 

  • Su S, Jou S, Cheng W, Lin T, Li J, Huang C, Lee Y, Soong B, Liu C (2010) Mitochondrial DNA damage in spinal and bulbar muscular atrophy patients and carriers. Clin Chim Acta 411:626–630

    Article  CAS  PubMed  Google Scholar 

  • Szuhai KS, van den Ouweland JM, Dirks RW, Lemaître M, Truffert J, Janssen G, Tanke H, Holme E, Maassen J, Raap A (2001) Simultaneous A8344G heteroplasmy and mitochondrial DNA copy number quantification in myoclonus epilepsy and ragged-red fibers (MERRF) syndrome by multiplex molecular beacon based real-time fluorescence PCR. Nucleic Acids Res 29:e13

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Thomas RD, Roy D (2001) Modifications in mitochondrial DNA by stilbene estrogen and hepatocarcinogenicity. Oncol Rep 8:1035–1038

    CAS  PubMed  Google Scholar 

  • Uusimaa J, Gowda V, McShane A, Smith C, Evans J, Shrier A, Narasimhan M, O'Rourke A, Rajabally Y, Hedderly T, Cowan F, Fratter C, Poulton J (2013) Prospective study of POLG mutations presenting in children with intractable epilepsy: prevalence and clinical features. Epilepsia 54:1002–1011

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Waldbaum S, Patel M (2010a) Mitochondrial dysfunction and oxidative stress: a contributing link to acquired epilepsy. J Bioenerg Biomembr 42:449–455

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Waldbaum S, Patel M (2010b) Mitochondria, oxidative stress, and temporal lobe epilepsy. Epilepsy Res 88:23–45

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Wong M (2007) Mechanisms of epileptogenesis in tuberous sclerosis complex and related malformations of cortical development with abnormal glioneuronal proliferation. Epilepsia 48:617–630

    Article  Google Scholar 

  • Wong M (2009) Animal models of focal cortical dysplasia and tuberous sclerosis complex: recent progress towards clinical applications. Epilepsia 50(Suppl):34–44

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Yoo C, Thorsson V, Cooper GF (2002) Discovery of causal relationships in a gene-regulation pathway from a mixture of experimental and observational DNA microarray data. Pac Symp Biocomput 7:498–509

Download references

Author information

Authors and Affiliations

  1. Department of Environmental and Occupational Health, Florida International University, 11200 SW 8th Street, Miami, FL, 33199, USA

    Brenda Luna, Quentin Felty & Deodutta Roy

  2. Neuroscience Program, Miami Children’s Hospital Brain Institute, Miami, FL, 33155, USA

    Sanjiv Bhatia, Michael Duchowny, Ziad Khatib, Ian Miller, John Ragheb & Jayakar Prasanna

  3. Department of Biostatistics, Florida International University, Miami, FL, 33199, USA

    Changwon Yoo

  4. Department of Pediatric Surgery, University of Texas Health Science Center at Houston, Houston, TX, 77030, USA

    David I. Sandberg

  5. Department of Neurosurgery, University of Texas Health Science Center at Houston, Houston, TX, 77030, USA

    David I. Sandberg

Authors
  1. Brenda Luna
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sanjiv Bhatia
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Changwon Yoo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Quentin Felty
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. David I. Sandberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Michael Duchowny
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ziad Khatib
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ian Miller
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. John Ragheb
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Jayakar Prasanna
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Deodutta Roy
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Deodutta Roy.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Luna, B., Bhatia, S., Yoo, C. et al. 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. J Mol Neurosci 54, 752–766 (2014). https://doi.org/10.1007/s12031-014-0364-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12031-014-0364-x

Keywords

Search

Navigation