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Mutations in the tricarboxylic acid cycle enzyme, aconitase 2, cause either isolated or syndromic optic neuropathy with encephalopathy and cerebellar atrophy
  1. Metodi Dimitrov Metodiev1,
  2. Sylvie Gerber1,
  3. Laurence Hubert1,
  4. Agnès Delahodde2,
  5. Dominique Chretien1,
  6. Xavier Gérard1,
  7. Patrizia Amati-Bonneau4,
  8. Marie-Christine Giacomotto5,
  9. Nathalie Boddaert3,
  10. Anna Kaminska3,
  11. Isabelle Desguerre3,
  12. Jeanne Amiel3,
  13. Marlène Rio3,
  14. Josseline Kaplan1,
  15. Arnold Munnich1,3,
  16. Agnès Rötig1,
  17. Jean Michel Rozet1,
  18. Claude Besmond1
  1. 1UMR1163, Université Paris Descartes, Sorbonne Paris Cité, Institut IMAGINE, Paris, France
  2. 2Institut de Génétique et Microbiologie UMR 8621, Université Paris-Sud, Orsay, France
  3. 3Departments of Pediatrics, Radiology and Genetics, Hôpital Necker-Enfants Malades, Paris, France
  4. 4Département de Biochimie et Génétique, CHU d'Angers, Angers, France
  5. 5Service d'Ophtalmologie, Polyclinique du Maine, Laval, France
  1. Correspondence to Dr Agnès Rötig, Institut IMAGINE, 24 Bd du Montparnasse, Paris 75015, France; agnes.rotig{at}


Background Inherited optic neuropathy has been ascribed to mutations in mitochondrial fusion/fission dynamics genes, nuclear and mitochondrial DNA-encoded respiratory enzyme genes or nuclear genes of poorly known mitochondrial function. However, the disease causing gene remains unknown in many families.

Methods We used exome sequencing in order to identify the gene responsible for isolated or syndromic optic atrophy in five patients from three independent families.

Results We found homozygous or compound heterozygous missense and frameshift mutations in the gene encoding mitochondrial aconitase (ACO2), a tricarboxylic acid cycle enzyme, catalysing interconversion of citrate into isocitrate. Unlike wild type ACO2, all mutant ACO2 proteins failed to complement the respiratory growth of a yeast aco1-deletion strain. Retrospective studies using patient-derived cultured skin fibroblasts revealed various degrees of deficiency in ACO2 activity, but also in ACO1 cytosolic activity.

Conclusions Our study shows that autosomal recessive ACO2 mutations can cause either isolated or syndromic optic neuropathy. This observation identifies ACO2 as the second gene responsible for non-syndromic autosomal recessive optic neuropathies and provides evidence for a genetic overlap between isolated and syndromic forms, giving further support to the view that optic atrophy is a hallmark of defective mitochondrial energy supply.

  • Ophthalmology
  • Genetics
  • Genome-wide
  • Metabolic disorders
  • Neurology

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