Mutations in the tricarboxylic acid cycle enzyme, aconitase 2, cause either isolated or syndromic optic neuropathy with encephalopathy and cerebellar atrophy

J Med Genet. 2014 Dec;51(12):834-8. doi: 10.1136/jmedgenet-2014-102532. Epub 2014 Oct 28.


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.

Keywords: Genetics; Genome-wide; Metabolic disorders; Neurology; Ophthalmology.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aconitate Hydratase / genetics*
  • Aconitate Hydratase / metabolism
  • Adult
  • Brain / pathology
  • Child, Preschool
  • Citric Acid Cycle
  • Enzyme Activation
  • Exome
  • Fatal Outcome
  • Female
  • Gene Expression
  • Genes, Recessive
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Magnetic Resonance Imaging
  • Male
  • Mutation*
  • Ophthalmoscopes
  • Optic Atrophy / diagnosis
  • Optic Atrophy / genetics
  • Optic Nerve Diseases / diagnosis
  • Optic Nerve Diseases / genetics*
  • Optic Nerve Diseases / metabolism
  • Patient Outcome Assessment
  • Siblings


  • ACO2 protein, human
  • Aconitate Hydratase