OPA3 gene

Overview

Gene (OMIM No.)
Function of gene/protein
  • Protein: outer mitochondrial membrane lipid metabolism regulator
  • Expressed in mitochondria but exact role uncertain at present
  • May play a role in regulating mitochondrial morphology and fission
Clinical phenotype
(OMIM phenotype no.)
  • Optic atrophy 3 with cataract (#165300)
  • 3-methylglutaconic aciduria, type III (#258501)
Inheritance
  • Autosomal dominant: Optic atrophy 3 with cataract
  • The p.Gln105Glu mutation is the most common OPA3 variant associated with dominant disease
  • Autosomal recessive: 3-methylglutaconic aciduria, type III/Costeff syndrome (most patients are of Iraqi Jewish descent)
Ocular features
  • Progressive bilateral optic atrophy and vision loss without spontaneous recovery
  • Dyschromatopsia
  • Nystagmus may present from birth
  • Retinal ganglion cells (RGCs) of the papillomacular bundle primarily affected
  • Severity of visual impairment is highly variable among patients, even among family members (some may be asymptomatic though this is rare)
  • Usually associated with early-onset/congenital cataracts but may not be present in all cases
Systemic features
  • Costeff syndrome is characterised by early-onset bilateral optic atrophy, later-onset movement disorder (spasticity, ataxia and extrapyramidal dysfunction) and increased urinary excretion of 3-methylglutaconic acid
  • Visual symptoms usually manifest in the first decade of life
  • Developmental delays may be present
  • Seizures and electrical status epilepticus during slow wave sleep have been reported in some patients
  • Neurological symptoms may be present in heterozygous cases such as sensorineural hearing loss (most common), movement disorders (spasticity and extrapyramidal dysfunction), peripheral neuropathy and gastrointestinal dysmotility
Key investigations
  • Orthoptic assessment and refraction
  • Colour vision testing
  • Perimetry: central/centrocaecal scotoma
  • Optic nerve head photograph
  • OCT of the optic disc: Global thinning of the peripapillary retinal nerve fibre layer (nasal aspect is often relatively spared)
  • Electrophysiology
  • MRI brain
  • Audiology
  • Urine organic acid analysis to detect increased excretion of 3-methylglutaconate and 3-methylglutaric acids (level of increment is variable and some may have levels that overlap with normal controls)
  • Systemic assessment with a pediatricians, neurologists and other relevant specialists to exclude other causes of optic neuropathies
Molecular diagnosisNext generation sequencing
  • Targeted gene panels (optic atrophy)
  • Whole exome sequencing
  • Whole genome sequencing
ManagementOcularSystemic
  • Multidisciplinary approach coordinated by paediatrician and/or neurologist
  • Hearing aids/cochlear implants helpful in those with sensorineural hearing loss
  • Involvement of physiotherapists and occupational therapists to address motor disability
  • Early involvement of practitioners familiar with developmental surveillance and intervention for children with visual impairment
Therapies under research
  • None at present
Further information

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Additional information

Biallelic OPA3 variants are associated with Costeff syndrome, where the c.143-1G>C variant is found in all patients of Iraqi-Jewish origin, but intra- and interfamilial variability in phenotypic severity exist.[5]

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References

  1.  Reynier P, Amati-Bonneau P, Verny C, et al. OPA3 gene mutations responsible for autosomal dominant optic atrophy and cataract. J Med Genet. 2004;41(9):e110
  2.  Sergouniotis PI, Perveen R, Thiselton DL, et al. Clinical and molecular genetic findings in autosomal dominant OPA3-related optic neuropathy. Neurogenetics. 2015;16(1):69-75
  3.  Grau T, Burbulla LF, Engl G, et al. A novel heterozygous OPA3 mutation located in the mitochondrial target sequence results in altered steady-state levels and fragmented mitochondrial network. J Med Genet. 2013;50(12):848-858
  4.  Horga A, Bugiardini E, Manole A, et al. Autosomal dominant optic atrophy and cataract “plus” phenotype including axonal neuropathy. Neurol Genet. 2019;5(2):e322
  5.  Anikster Y, Kleta R, Shaag A, Gahl WA, Elpeleg O. Type III 3-methylglutaconic aciduria (optic atrophy plus syndrome, or Costeff optic atrophy syndrome): identification of the OPA3 gene and its founder mutation in Iraqi Jews. Am J Hum Genet. 2001;69(6):1218-1224
  6.  Ho G, Walter JH, Christodoulou J. Costeff optic atrophy syndrome: new clinical case and novel molecular findings. J Inherit Metab Dis. 2008;31 Suppl 2:S419-S423
  7.  Anikster Y. Costeff Syndrome. In: Adam MP, Ardinger HH, Pagon RA, et al., eds. GeneReviews®. Seattle (WA): University of Washington, Seattle; July 28, 2006
  8.  Kleta R, Skovby F, Christensen E, Rosenberg T, Gahl WA, Anikster Y. 3-Methylglutaconic aciduria type III in a non-Iraqi-Jewish kindred: clinical and molecular findings. Mol Genet Metab. 2002;76(3):201-206
  9.  Gaier ED, Sahai I, Wiggs JL, McGeeney B, Hoffman J, Peeler CE. Novel homozygous OPA3 mutation in an Afghani family with 3-methylglutaconic aciduria type III and optic atrophy. Ophthalmic Genet. 2019;40(6):570-573
  10.  Carmi N, Lev D, Leshinsky-Silver E, et al. Atypical presentation of Costeff syndrome-severe psychomotor involvement and electrical status epilepticus during slow wave sleep. Eur J Paediatr Neurol. 2015;19(6):733-736

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Updated on January 30, 2021
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