OPA1 gene

Overview

Gene (OMIM No.)
Function of gene/protein
  • Protein: mitochondrial dynamin like GTPase
  • Inner mitochondrial membrane protein regulating mitochondrial stability and energy output
  • Pathogenic mutations result in mitochondrial dysfunction and preferential degeneration of retinal ganglion cells (RGCs)
Clinical phenotype
(OMIM phenotype no.)
Inheritance
  • Autosomal dominant (majority) and autosomal recessive
  • Heterozygous OPA1 mutations are associated with isolated dominant optic atrophy (~75% of cases) or syndromic optic atrophy (dominant optic atrophy plus syndrome)
  • Compound heterozygous OPA1 mutations are associated with Behr syndrome
Ocular features
  • Variable phenotypic severity (even within families); usually more severe visual impairment in syndromic forms
  • Symptom onset usually in the first two decades of life
  • Bilateral progressive, painless visual loss without spontaneous recovery and central/centrocaecal scotoma
  • Dyschromatopsia
  • Temporal optic nerve head pallor (preferential degeneration of RGCs of the papillomacular bundle)
  • Chronic progressive external ophthalmoplegia has been reported in syndromic forms
Systemic features
  • Sensorineural hearing loss (most common)
  • Proximal myopathy
  • Peripheral neuropathy
  • Ataxia
  • Spasticity
  • Multiple sclerosis-like illness
  • Behr syndrome (ataxia, spasticity and peripheral neuropathy in addition to early onset progressive optic neuropathy)
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
  • 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
ManagementOcular
  • Supportive management
  • Smoking cessation
  • Avoid excessive alcohol consumption
Systemic
  • 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
Further information

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References

  1.  Yu-Wai-Man P, Chinnery PF. Dominant optic atrophy: novel OPA1 mutations and revised prevalence estimates Ophthalmology. 2013 Dec;120(12):2448
  2.  Yu-Wai-Man P, Griffiths PG, Gorman GS, et al. Multi-system neurological disease is common in patients with OPA1 mutations. Brain. 2010;133(Pt 3):771-786
  3.  Lenaers G, Hamel C, Delettre C, et al. Dominant optic atrophy. Orphanet J Rare Dis. 2012;7:46
  4.  Yu-Wai-Man P, Bailie M, Atawan A, Chinnery PF, Griffiths PG. Pattern of retinal ganglion cell loss in dominant optic atrophy due to OPA1 mutations. Eye (Lond). 2011;25(5):596-602
  5.  Barboni P, Savini G, Cascavilla ML, et al. Early macular retinal ganglion cell loss in dominant optic atrophy: genotype-phenotype correlation. Am J Ophthalmol. 2014;158(3):628-36.e3
  6.  Santarelli R, Rossi R, Scimemi P, et al. OPA1-related auditory neuropathy: site of lesion and outcome of cochlear implantation. Brain. 2015;138(Pt 3):563-576
  7.  Ferr√© M, Bonneau D, Milea D, et al. Molecular screening of 980 cases of suspected hereditary optic neuropathy with a report on 77 novel OPA1 mutations. Hum Mutat. 2009;30(7):E692-E705
  8.  Bonneau D, Colin E, Oca F, et al. Early-onset Behr syndrome due to compound heterozygous mutations in OPA1. Brain. 2014;137(Pt 10):e301
  9.  Schaaf CP, Blazo M, Lewis RA, et al. Early-onset severe neuromuscular phenotype associated with compound heterozygosity for OPA1 mutations. Mol Genet Metab. 2011;103(4):383-387
  10.  Yu-Wai-Man P, Votruba M, Moore AT, Chinnery PF. Treatment strategies for inherited optic neuropathies: past, present and future. Eye (Lond). 2014;28(5):521-537
  11.  Carelli V, Ross-Cisneros FN, Sadun AA. Mitochondrial dysfunction as a cause of optic neuropathies. Prog Retin Eye Res. 2004;23(1):53-89

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Updated on January 30, 2021

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