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Dominant optic atrophy: for professionals


Overview

Prevalence
  • 1:25,000 in the UK
Inheritance
  • Autosomal dominant (most common)
  • Autosomal recessive (small number of OPA1-related cases)
Genes involved (OMIM No.)
Symptoms
  • Usually present in the first two decades of life
  • Bilateral progressive painless loss of vision
  • No spontaneous visual recovery
Signs
  • Reduced visual acuity
  • Severe dyschromatopsia
  • Central/centrocaecal scotoma
  • Temporal optic nerve pallor due to preferential degeneration of the papillomacular retinal ganglion cell bundle
  • Blue-dot cerulean cataracts have been described in OPA3-related DOA
Systemic features
  • About 20% of DOA cases have extraocular involvement
  • Sensorineural deafness (most common)
  • Progressive external ophthalmoplegia
  • Proximal myopathy
  • Ataxia
  • Peripheral neuropathy
  • Spastic paraplegia (rare)
  • Multiple sclerosis-like illness (rare)
Key investigations
  • Orthoptic assessment and refraction
  • Colour vision testing
  • Formal visual field testing (if possible)
  • Optic nerve head photographs
  • OCT of optic nerve head
  • Electrophysiology
  • MRI brain
  • Audiology Systemic assessment with pediatricians, neurologists, and other relevant specialists if indicated
Molecular diagnosisNext generation sequencing
  • Targeted gene panels (optic atrophy panel)
  • Whole exome sequencing
  • Whole genome sequencing
Management
  • Supportive management
  • Optimisation of early childhood development by referring patients to practitioners familiar with developmental surveillance and intervention for children with visual impairment
  • Multidisciplinary approach if systemic features are present
Therapies under research
  • Idebenone for OPA1-associated DOA

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Clinical phenotype

Dominant optic atrophy (DOA) is the most common inherited optic neuropathy with an estimated prevalence of 1:25,000 in the UK.[1] It is genetically heterogeneous, resulting in variable clinical phenotype and severity, even among family members.[2]

Typically, patients present within the first two decades of life with bilateral progressive, painless visual loss without spontaneous recovery and central or centrocaecal scotoma.[3] Visual acuity (VA) can range from “normal” to no perception of light, although the visual loss is usually moderate with an average VA of 6/36-6/60.[2] Early-onset blue-dot cerulean cataracts have been reported in patients with OPA3 mutation.[4] Fundoscopy usually shows temporal optic nerve head pallor as a result of preferential degeneration of the retinal ganglion cells (RGCs) of the papillomacular bundle.[5,6]

Extraocular features

Most cases of DOA are non-syndromic. However, approximately 20% of patients present with systemic features (DOA+) and are generally associated with more severe visual impairment.[7] Sensorineural deafness is the most common systemic association and occurs in roughly 2/3 of patients with systemic involvement, and typically occur after the onset of visual loss in the second to third decade of life. Identifying hearing loss is crucial as hearing aids and cochlear implants can be of benefit.[8]

Other reported systemic association include:

  • Progressive external ophthalmoplegia
  • Peripheral neuropathy
  • Ataxia
  • Proximal myopathy
  • Multiple sclerosis-like illness (rare)[7]
  • Spastic paraplegia (rare)[7]

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Genetics

DOA is a genetically heterogeneous condition where the most common causative gene associated is the OPA1 gene, accounting for up to 75% of cases.[9] OPA1 encodes a dynamin-related GTPase expressed in the mitochondrial inner membrane. It is involved in maintaining mitochondrial network stability, oxidative phosphorylation and mitochondrial cell death pathways.[10] Heterozygous (autosomal dominant) OPA1 mutations are associated with both isolated and syndromic DOA. On the other hand, compound heterozygous OPA1 variants result in a more severe syndromic DOA phenotype known as Behr syndrome.[7,11,12] It is characterised by early onset progressive optic neuropathy, ataxia, spasticity and peripheral neuropathy. It is postulated that the co-occurrence of a missense variant, particularly in the GTPase domain, with another truncating mutation result in a more potent deleterious impact, potentially via a dominant negative mechanism.[13]

It is also important to emphasise that eponymous terms such as Behr syndrome should be viewed as historical descriptions instead of being used as clinical diagnoses. With major advances in genetic sequencing in recent times, it is now clear that most eponymous syndromes are genetically heterogenous.

Other genes or chromosomal loci associated with DOA/DOA+ are:

Gene/Locus
(OMIM no.)
Phenotype (OMIM no.)Remarks
OPA2 (#311050)Optic atrophy 2, X-linked (#311050)Optic atrophy with developmental delay and peripheral neuropathy
OPA3 (#606580)Optic atrophy 3 with cataract (#165300)Autosomal dominant optic atrophy with early onset cataract
OPA6 (#258500)Optic atrophy 6 (#258500)Autosomal recessive
OPA8 (#616648)Optic atrophy 8 (#616648)Autosomal dominant

Further information about each gene can be found on OMIM and Medline Plus.

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Key investigations

Ocular

1) Orthoptic assessment and refraction

This is to document baseline visual function and assess if vision can be optimised with correction of refractive error (if present).

2) Colour vision testing

Patients usually have severe dyschromatopsia.

3) Perimetry

A formal visual field test should be performed if the child is able to cooperate to document any central/centrocaecal scotoma. In the initial stages, 24-2 perimetry can assess for any central field but Goldmann visual field is usually required in more advanced cases where the scotoma extends beyond the central 20 degrees.

4) Optic nerve head imaging

A colour photograph of the optic disc should be obtained for future comparisons. Optical coherence tomography of the optic disc and macula should also be undertaken. Measurements of the peripapillary retinal nerve fibre layer (RNFL) thickness, peripapillary and macular RGC thickness should be included. There is usually a global thinning of the peripapillary RNFL, although the nasal quadrant is often relatively spared.

5) Electrophysiology

A reduced N95:P50 ratio on pattern electroretinogram (ERG) in the presence of a normal pattern visual evoked potential (VEP) usually indicates RGC dysfunction in early cases of inherited optic neuropathies.

Systemic

A systemic assessment either by a paediatrician (in children) or a neurologist (in adults) should be undertaken to exclude compressive, inflammatory, toxic, nutritional or metabolic causes for optic neuropathy. All patients with optic neuropathies will need MRI brain imaging to exclude a compressive lesion or an inflammatory cause, which may be amenable to treatment in the acute setting. Audiological testing is recommended given the association of hearing loss with DOA and inherited optic neuropathies in general.

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Diagnosis

DOA can be diagnosed clinically along with a suggestive family history, but given the genetic heterogeneity of inherited optic neuropathies and intra-familial clinical variability, genetic testing should be undertaken to confirm the diagnosis. In addition, having a molecular diagnosis can also help facilitate genetic counselling, provide accurate advice on prognosis and future family planning, direct further clinical management and aid in clinical trial participation.

This can be achieved through a variety of next generation sequencing (NGS) methods:

  • Targeted gene panels (optic atrophy panel)
  • Whole exome sequencing
  • Whole genome sequencing

Related links

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Management

Ocular

1) Supportive management

The management of DOA is mainly supportive, which include:

  • Correcting any associated refractive errors
  • Referral to low vision services
  • Encourage a healthy diet consisting of fresh fruit and green leafy vegetables
  • Smoking cessation
  • Avoid heavy consumption of alcohol
  • Encourage the use of assistive technology that may improve quality of life

2) Idebenone (Raxone)

Idebenone is an antioxidant approved for the treatment of Leber Hereditary Optic Neuropathy (LHON) in the UK and the European Union (EU). This is mainly based on the result of a randomised controlled trial[14] which showed increased rate of visual recovery, especially when given during the early stages of the condition and for a prolonged period of time.[15,16] The International Consensus Statement recommends idebenone (900mg/day) in LHON patients within twelve months of disease onset.[17]

There are similar features between OPA1-associated DOA and LHON, namely both are caused by mitochondrial dysfunction (albeit through different mechanisms), the propensity to affect the RGCs of the papillomacular bundle initially and chronic production of reactive oxygen species.[3,6] As a result, off-label usage of idebenone was investigated as a potential therapeutic option in a small pilot study initially.[18] A further retrospective cohort study demonstrated that idebenone treatment for at least 7 months was associated with VA stabilisation or recovery in OPA1-related DOA.[19] Dosages ranged from 135mg/day to 675mg/day but most patients in that study were on 540mg/day. While the results are promising, a well-designed placebo-controlled randomised controlled trial is required to confirm this finding.

Optimisation of development

In cases of DOA+, patients should be jointly managed with a paediatrician and/or neurologist in a multidisciplinary setting. Hearing loss can be addressed with either cochlear implant or hearing aids. Children with inherited optic neuropathies are affected by severe visual impairment, and possibly hearing loss. As vision and hearing are equally important in normal childhood development and education, children affected by inherited optic neuropathies should be referred to developmental paediatricians and advisory teaching services for children/adolescents with hearing loss and visual impairment (e.g. sensory support services within local authority). This will enable provisions to be made within the educational and home settings so that the child can reach his/her developmental potential and develop skills to achieve independence.

Dual sensory clinics are now being established in some centres to improve the clinical experience of children with hearing and sight impairment. Patients are able to access a multidisciplinary clinic in one visit, hence reducing the stress and burden associated with numerous, separate medical appointments. Such specialist clinics will promote faster and more accurate diagnosis through extensive genetic testing and detection of visual symptoms at an earlier stage.

Family management and counselling

DOA is mostly inherited in an autosomal dominant manner. Less commonly, OPA1-related DOA can also be inherited in an autosomal recessive pattern. An X-linked inheritance pattern is associated with the OPA2 chromosomal loci.[20,21]

Patients and families require genetic counselling and can seek advice for family planning including prenatal testing and preimplantation genetic diagnosis.

Emotional and social support

Eye Clinic Liaison Officers (ECLOs) act as an initial point of contact for newly diagnosed patients and their parents in clinic. They provide emotional and practical support to help patients and parents deal with the diagnosis and maintain independence. They work closely with the local council’s sensory support team and are able to advise on the broad range of services provided, such as visual rehabilitation, home assessment, work and access to qualified teachers for children with visual impairment (QTVI) among other services.

Related links

Referral to a specialist centre

In the UK, patients should be referred to their local genomic ophthalmology (if available) or clinical genetics services to receive a more comprehensive genetic management of their conditions (genetic testing and genetic counselling) and having the opportunity to participate in clinical research.

In addition, a referral to a dual sensory clinic (if available) such as the one in Great Ormond Street Hospital for Children in London can be very helpful in optimising patient management where both visual and audio-vestibular issues can be addressed simultaneously.

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Current research in DOA

As inherited optic neuropathies are genetically and phenotypically heterogeneous, the increasing availability of next generation sequencing technology in routine clinical practice should lead to more patients receiving a molecular diagnosis and managed appropriately at an earlier stage, therefore improving quality of life and gaining access to research and clinical trials.[22] Furthermore, it will also expand our understanding of how mutations in specific genes contribute to RGC loss and ultimately, optic nerve degeneration and visual loss by using cell-based or animal models. In terms of potential therapies, idebenone may be a viable option for DOA but larger randomised controlled studies are required to verify the positive findings observed in a recently concluded retrospective cohort study.[19]

Related links

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Further information and support

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References

  1.  Yu-Wai-Man P, Chinnery PF. Dominant optic atrophy: novel OPA1 mutations and revised prevalence estimates. Ophthalmology. Aug 2013;120(8):1712-1712.e1
  2.  Yu-Wai-Man P, Griffiths PG, Burke A, et al. The prevalence and natural history of dominant optic atrophy due to OPA1 mutations. Ophthalmology. Aug 2010;117(8):1538-46, 1546.e1
  3.  Yu-Wai-Man P, Griffiths PG, Chinnery PF. Mitochondrial optic neuropathies – disease mechanisms and therapeutic strategies. Prog Retin Eye Res. Mar 2011;30(2):81-114
  4.  Reynier P, Amati-Bonneau P, Verny C, et al. OPA3 gene mutations responsible for autosomal dominant optic atrophy and cataract. J Med Genet. Sep 2004;41(9):e110
  5.  Yu-Wai-Man P, Votruba M, Moore AT, Chinnery PF. Treatment strategies for inherited optic neuropathies: past, present and future. Eye (Lond). May 2014;28(5):521-37
  6.  Carelli V, Ross-Cisneros FN, Sadun AA. Mitochondrial dysfunction as a cause of optic neuropathies. Prog Retin Eye Res. Jan 2004;23(1):53-89
  7.  Yu-Wai-Man P, Griffiths PG, Gorman GS, et al. Multi-system neurological disease is common in patients with OPA1 mutations. Brain. Mar 2010;133(Pt 3):771-86
  8.  Santarelli R, Rossi R, Scimemi P, et al. OPA1-related auditory neuropathy: site of lesion and outcome of cochlear implantation. Brain. Mar 2015;138(Pt 3):563-76
  9.  Lenaers G, Hamel C, Delettre C, et al. Dominant optic atrophy. Orphanet J Rare Dis. Jul 9 2012;7:46
  10.  Lenaers G, Reynier P, Elachouri G, et al. OPA1 functions in mitochondria and dysfunctions in optic nerve. Int J Biochem Cell Biol. Oct 2009;41(10):1866-74
  11.  Bonneau D, Colin E, Oca F, et al. Early-onset Behr syndrome due to compound heterozygous mutations in OPA1. Brain. Oct 2014;137(Pt 10):e301
  12.  Schaaf CP, Blazo M, Lewis RA, et al. Early-onset severe neuromuscular phenotype associated with compound heterozygosity for OPA1 mutations. Mol Genet Metab. Aug 2011;103(4):383-7
  13.  Yu-Wai-Man P, Chinnery PF. Reply: Early-onset Behr syndrome due to compound heterozygous mutations in OPA1. Brain : a journal of neurology. 2014;137(Pt 10):e302-e302
  14.  Klopstock T, Yu-Wai-Man P, Dimitriadis K, et al. A randomized placebo-controlled trial of idebenone in Leber’s hereditary optic neuropathy. Brain. Sep 2011;134(Pt 9):2677-86
  15.  Mashima Y, Kigasawa K, Wakakura M, Oguchi Y. Do idebenone and vitamin therapy shorten the time to achieve visual recovery in Leber hereditary optic neuropathy? J Neuroophthalmol. Sep 2000;20(3):166-70
  16.  Carelli V, La Morgia C, Valentino ML, et al. Idebenone treatment in Leber’s hereditary optic neuropathy. Brain. Sep 2011;134(Pt 9):e188
  17.  Carelli V, Carbonelli M, de Coo IF, et al. International Consensus Statement on the Clinical and Therapeutic Management of Leber Hereditary Optic Neuropathy. J Neuroophthalmol. Dec 2017;37(4):371-381
  18.  Barboni P, Valentino ML, La Morgia C, et al. Idebenone treatment in patients with OPA1-mutant dominant optic atrophy. Brain. Feb 2013;136(Pt 2):e231
  19.  Romagnoli M, La Morgia C, Carbonelli M, et al. Idebenone increases chance of stabilization/recovery of visual acuity in OPA1-dominant optic atrophy. Ann Clin Transl Neurol. Apr 2020;7(4):590-594
  20.  Katz BJ, Zhao Y, Warner JE, Tong Z, Yang Z, Zhang K. A family with X-linked optic atrophy linked to the OPA2 locus Xp11.4-Xp11.2. Am J Med Genet A. Oct 15 2006;140(20):2207-11
  21.  Assink JJ, Tijmes NT, ten Brink JB, et al. A gene for X-linked optic atrophy is closely linked to the Xp11.4-Xp11.2 region of the X chromosome. Am J Hum Genet. Oct 1997;61(4):934-9
  22.  Black GC, MacEwen C, Lotery AJ. The integration of genomics into clinical ophthalmic services in the UK. Eye. 2020/06/01 2020;34(6):993-996

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Updated on February 1, 2021

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