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Case Report/Case Series
December 2013

COX10 Mutations Resulting in Complex Multisystem Mitochondrial Disease That Remains Stable Into Adulthood

Author Affiliations
  • 1Medical Research Council Centre for Neuromuscular Diseases, University College London Institute of Neurology and National Hospital for Neurology and Neurosurgery, London, England
  • 2Department of Clinical Neuroscience, University College London Institute of Neurology, London, England
  • 3Mitochondrial Research Group, Clinical and Molecular Genetics Unit, University College London Institute of Child Health, London, England
  • 4Centre de Génétique Moléculaire, UPR3404, Centre national de la recherche scientifique, Gif-sur-Yvette, France
  • 5Division of Mathematical Biology, National Institute for Medical Research, London, England
  • 6Dubowitz Neuromuscular Centre, University College London Institute of Child Health and Great Ormond Street Hospital for Children NHS Foundation Trust, London, England
  • 7Neurometabolic Unit, National Hospital for Neurology and Neurosurgery, London, England
  • 8Neurogenetics Unit, National Hospital for Neurology and Neurosurgery, London, England
  • 9The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, England
  • 10Department of Clinical Neurophysiology, University College London Institute of Neurology and National Hospital for Neurology and Neurosurgery, London, England
  • 11Department of Clinical Neurophysiology, Norfolk and Norwich University Hospital, Norwich, England
  • 12Division of Neuropathology, University College London Institute of Neurology, London, England
  • 13Department of Molecular Neuroscience, University College London Institute of Neurology, London, England
JAMA Neurol. 2013;70(12):1556-1561. doi:10.1001/jamaneurol.2013.3242
Abstract

Importance  Isolated cytochrome-c oxidase (COX) deficiency is one of the most frequent respiratory chain defects seen in human mitochondrial disease. Typically, patients present with severe neonatal multisystem disease and have an early fatal outcome. We describe an adult patient with isolated COX deficiency associated with a relatively mild clinical phenotype comprising myopathy; demyelinating neuropathy; premature ovarian failure; short stature; hearing loss; pigmentary maculopathy; and renal tubular dysfunction.

Observations  Whole-exome sequencing detected 1 known pathogenic and 1 novel COX10 mutation: c.1007A>T; p.Asp336Val, previously associated with fatal infantile COX deficiency, and c.1015C>T; p.Arg339Trp. Muscle COX holoenzyme and subassemblies were undetectable on immunoblots of blue-native gels, whereas denaturing gels and immunocytochemistry showed reduced core subunit MTCO1. Heme absorption spectra revealed low heme aa3 compatible with heme A:farnesyltransferase deficiency due to COX10 dysfunction. Both mutations demonstrated respiratory deficiency in yeast, confirming pathogenicity. A COX10 protein model was used to predict the structural consequences of the novel Arg339Trp and all previously reported substitutions.

Conclusions and Relevance  These findings establish that COX10 mutations cause adult mitochondrial disease. Nuclear modifiers, epigenetic phenomenon, and/or environmental factors may influence the disease phenotype caused by reduced COX activity and contribute to the variable clinical severity related to COX10 dysfunction.

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