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  • Childhood onset mitochondrial myopathy and lactic acidosis caused by a stop mutation in the mitochondrial cytochrome c oxidase III gene

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Childhood onset mitochondrial myopathy and lactic acidosis caused by a stop mutation in the mitochondrial cytochrome c oxidase III gene
  1. R Horváth1,
  2. C Scharfe2,
  3. M Hoeltzenbein3,
  4. B H Do2,
  5. C Schröder4,
  6. R Warzok5,
  7. S Vogelgesang5,
  8. H Lochmüller6,
  9. J Müller-Höcker7,
  10. K D Gerbitz1,
  11. P J Oefner2,
  12. M Jaksch1
  1. 1Metabolic Disease Centre Munich-Schwabing, Institutes of Clinical Chemistry, Molecular Diagnostics and Mitochondrial Genetics, Academic Hospital Schwabing, Munich, Germany
  2. 2Stanford University, Genome Technology Center, Palo Alto, CA, USA
  3. 3Institute of Human Genetics, Ernst-Moritz-Arndt University of Greifswald, Greifswald, Germany
  4. 4Department of Paediatrics, Ernst-Moritz-Arndt University of Greifswald, Greifswald, Germany
  5. 5Institute of Pathology, Ernst-Moritz-Arndt University of Greifswald, Greifswald, Germany
  6. 6Friedrich-Baur-Institut, Department of Neurology, Ludwig-Maximilians-University, Munich, Germany
  7. 7Institute of Pathology, LMU Munich, Germany
  1. Correspondence to:
 Dr M Jaksch, Metabolic Disease Centre Munich-Schwabing, Institutes of Clinical Chemistry, Molecular Diagnostics and Mitochondrial Genetics, Academic Hospital Schwabing, Kölner Platz 1, 80804 München, Germany;
 Michaela.Jaksch{at}lrz.uni-muenchen.de

https://doi.org/10.1136/jmg.39.11.812

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    More than 100 mitochondrial (mt) DNA mutations have been described in association with different complex neurological disorders and with respiratory chain (RC) deficiency in the past decade.1 Aside from more frequently reported mt tRNA mutations and deletions, a growing list of pathogenic mutations affecting structural genes of mtDNA encoded respiratory chain subunits, mainly cytochrome b and cytochrome c oxidase subunit genes, has now been reported in association with various mitochondrial disorders as well2 and most of these mutations are thought to be of sporadic origin.

    Cytochrome c oxidase (COX or complex IV), the terminal enzyme of the RC, catalyses the reduction of molecular oxygen by reduced cytochrome c. The complex is composed of 13 subunits. Three highly conserved mtDNA encoded subunits (COX I-III) form the catalytic core of the enzyme and the remaining 10 nuclear subunits are thought to modify or stabilise the complex. While the core forming subunits COX I and COX II contain the prosthetic groups and are known to play the most essential role in proton pumping and electron transfer, the function of COX III remains largely unknown. It is of interest that pathogenic mutations in mtDNA encoded subunits I-III have been identified whereas no mutations in the 10 nuclear genes are known so far. In contrast, numerous mutations in nuclear genes involved in the assembly of COX (SURF1, SCO2, SCO1, COX10) have been described.3 As with most mtDNA mutations, the clinical presentation of patients harbouring mutations in mt encoded COX subunit genes is highly variable, ranging from late childhood onset myopathy4–8 to severe childhood onset multisystem disorders,9–14 and this might be explained by the variable distribution and abundance of mutant mtDNA in different tissues and by different expression thresholds.3 All mt COX subunit gene mutations reported to date …

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