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Cytochrome c oxidase deficit is associated with the seizure onset zone in young patients with focal cortical dysplasia Type II

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Abstract

It has been postulated that mitochondrial dysfunction may be an important factor in epileptogenesis of intractable epilepsy. The current study tests the hypothesis that mitochondrial Complex IV (CIV) or cytochrome c oxidase dysfunction is associated with the seizure onset zone (SOZ) in patients with focal cortical dysplasia (FCD). Subjects were selected based on: age <19y; epilepsy surgery between May, 2010 and October, 2011; pathological diagnosis of isolated focal cortical dysplasia Type I (FCDI) or Type II (FCDII); and sufficient residual cortical tissue to conduct analysis of electron transport chain complex (ETC) activity in SOZ and adjacent cortical regions. In this retrospective study, patients were identified who had sufficient unfixed, frozen brain tissue for biochemical analysis in tissue homogenates. Specimens were subtyped using ILAE classification for FCD, and excluded if diagnosed with FCD Type III or dual pathology. Analysis of ETC activity in resected tissues was conducted independently and without knowledge of the identity, diagnosis, or clinical status of individual subjects. Seventeen patients met the inclusion criteria, including 6 FCDI and 11 FCDII. Comparison of adjacent cortical resections showed decreased CIV activity in the SOZ of the FCDII group (P = 0.003), but no significant CIV difference in adjacent tissues of the FCDI group. Because of the importance of CIV as the terminal and rate-limiting complex in the mitochondrial electron transport chain, these authors conclude that 1) a deficit of CIV is associated with the SOZ of patients with FCDII; 2) CIV deficiency may contribute to the spectrum of FCD neuropathology; and 3) further investigation of CIV in FCD may lead to the discovery of new targets for neuroprotective therapies for patients with intractable epilepsy.

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Abbreviations

CIII:

decylubiquinol-cytochrome c oxidoreductase

CIV:

cytochrome c oxidase

CS:

citrate synthase

ICEEG:

intracranial electrocorticography

ETC:

electron transport chain

FCD:

focal cortical dysplasia

FDG-PET:

2-[18 F]fluoro-2-deoxy-D-glucose positron emission tomography

MRI:

magnetic resonance imaging

NCP:

non-collagen protein

SOZ:

seizure onset zone

SSZ:

secondary spread zone

SDH:

succinate dehydrogenase

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Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. For this type of study formal consent is not required.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Division of Pathology and Laboratory Medicine, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Ave., Cincinnati, OH, 45229, USA

    Lili Miles

  2. Division of Neurology, Department of Pediatrics, Cincinnati Children’s Hospital Medical, Cincinnati, OH, USA

    Hansel M. Greiner & Michael V. Miles

  3. Division of Pediatric Neurosurgery, Department of Surgery, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

    Francesco T. Mangano

  4. Divisions of Neurology and Biostatistics & Epidemiology, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

    Paul S. Horn

  5. Department of Radiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

    James L. Leach

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  1. Lili Miles
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  2. Hansel M. Greiner
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  3. Francesco T. Mangano
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  4. Paul S. Horn
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  5. James L. Leach
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  6. Michael V. Miles
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Correspondence to Lili Miles.

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Miles, L., Greiner, H.M., Mangano, F.T. et al. Cytochrome c oxidase deficit is associated with the seizure onset zone in young patients with focal cortical dysplasia Type II. Metab Brain Dis 30, 1151–1160 (2015). https://doi.org/10.1007/s11011-015-9680-2

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  • DOI: https://doi.org/10.1007/s11011-015-9680-2

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