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ACO2 gene

Overview

Gene (OMIM No.)
Function of gene/protein
  • Protein: Mitochondrial aconitase
  • Functions as a catalytic enzyme in the Krebs cycle
Clinical phenotype
(OMIM phenotype no.)
  • Optic atrophy 9, OPA9 (#616289)
  • Infantile cerebellar retinal degeneration, ICRD (#614559)
Inheritance
  • Autosomal recessive
Signs for OPA9
  • Reduced VA from early childhood
  • Isolated, non-progressive optic atrophy
  • No extraocular features
Signs for ICRD
  • Age of onset: 2-6 months
  • Predominantly neurological and eye movement abnormalities at onset
  • Visual tracking and pursuit may be normal as a newborn with progressive deterioration
  • Strabismus
  • Nystagmus
  • Retinal dystrophy
  • Bilateral optic atrophy
Visual functionOPA9
  • VA 6/60 in 3rd decade of life
  • Paracentral scotoma
  • Red-green dyschromatopsia
ICRD
  • Poor visual function from early childhood
Systemic featuresICRD
  • Truncal hypotonia, ataxia
  • Athetosis
  • Seizures
  • Microcephaly
  • Psychomotor retardation
  • Progressive sensorineural hearing loss (less common)
  • High arched foot (less common)
Key investigations
  • VEP: may be normal/reduced in early infancy
  • ERG: Severely reduced/extinguished in early childhood
  • OCT: reduction in retinal nerve fibre layers
  • FAF: salt and pepper appearance
  • Neurologic assessment (EEG, MRI brain usually normal within the first months of life but global atrophy gradually develops affecting the cerebellum predominantly)
Molecular diagnosisNext generation sequencing
  • Targeted gene panels (retinal)
  • Whole exome sequencing
  • Whole genome sequencing
ManagementOcular
  • Supportive ocular management
Systemic
  • Multidisciplinary approach including neurology input
Therapies under research
  • None at present
Further information

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Additional information

One case of optic atrophy with spastic paraplegia has been reported in a patient with compound heterozygous ACO2 mutation.[4]

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References

  1.  Spiegel R, Pines O, Ta-Shma A, et al. Infantile cerebellar-retinal degeneration associated with a mutation in mitochondrial aconitase, ACO2. Am J Hum Genet. 2012;90(3):518-523.
  2.  Metodiev MD, Gerber S, Hubert L, et al. 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;51(12):834-838.
  3.  Sharkia R, Wierenga KJ, Kessel A, et al. Clinical, radiological, and genetic characteristics of 16 patients with ACO2 gene defects: Delineation of an emerging neurometabolic syndrome. J Inherit Metab Dis. 2019;42(2):264-275.
  4.  Marelli C, Hamel C, Quiles M, et al. ACO2 mutations: A novel phenotype associating severe optic atrophy and spastic paraplegia. Neurol Genet. 2018;4(2):e225.

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Updated on November 30, 2020
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