Clinical Diagnosis

Optic atrophy type 1 (OPA1 or Kjer type optic atrophy) is diagnosed in individuals with the following:

• Bilateral vision loss that is usually symmetric
• Optic nerve pallor, the cardinal sign, usually bilateral and symmetric; temporal in about 50% of individuals and global in about 50% [Votruba et al 2003], particularly in older individuals and those with more severe involvement. In moderate cases, the optic atrophy may not be visible. Profound papillary excavation is reported in 21% of eyes with OPA1 [Alward 2003].
• Visual field defect that is typically centrocecal, central, or paracentral; it is often large in individuals with severe disease. The peripheral field is usually normal, but inversion of red and blue isopters may occur.
  
  Note: The isopters are lines joining points of equal sensitivity on a visual field chart. The red isopter represents the largest/brightest stimulus; the blue isopter represents the smallest/dimmest stimulus. Persons with OPA1 have scotomas (areas of impaired visual acuity) in the central visual fields and sparing of the peripheral visual fields.
• Color vision defect, often described as acquired blue-yellow loss (tritanopia)
• Childhood onset
• Family history consistent with autosomal dominant inheritance

The systematic molecular genetic testing of OPA1 in persons with autosomal dominant optic atrophy (ADOA) has revealed a wide range of clinical manifestations. Up to 10% of persons with an OPA1 mutation have additional extra-ophthalmologic abnormalities, most commonly sensorineural hearing loss, ataxia, and myopathy (see Clinical Description).

Electrophysiology

• Visual evoked potentials (VEPs) are typically absent or delayed, indicating a conduction defect in the optic nerve.
• Pattern electroretinogram (PERG) shows an abnormal N95:P50 ratio, with reduction in the amplitude of the N95 waveform [Holder et al 1998]. Since the N95 component of the PERG is thought to be specific for the retinal ganglion cell, this finding supports a ganglion cell origin for the optic atrophy.
  
  Note: The PERG originates from the inner retinal layers, enabling an assessment of ganglion cell function, and is increasingly used in the assessment of anterior visual pathway dysfunction. The normal PERG consists of a prominent positive peak at 50 ms (P50), and a slow, broad trough with a minimum at 95 ms (N95). The positive P50 component is invariably affected in retinal and macular dysfunction, whereas the negative N95 component is principally affected in optic nerve disease. Furthermore, the ratio between N95 and P50 has been shown to be an effective measure of retinal ganglion cell function.

Molecular Genetic Testing

Gene. OPA1 is the only gene known to be associated with optic atrophy type 1 [Alexander et al 2000, Delettre et al 2000].

Other loci. Because the detection rate for mutations in OPA1 is less than 100%, it is possible that families in which a mutation is not detected are not linked to the OPA1 locus; however, no evidence supports this possibility.

Clinical testing

• Sequence analysis/mutation scanning of all exons and flanking intron junctions from genomic DNA of OPA1 is available clinically.
• Sequence analysis of cDNA. RT-PCR amplification performed on OPA1 mRNA extracted from blood creates cDNA that can be sequenced to characterize splice-site mutations and abnormally spliced forms.
• Deletion/duplication analysis. OPA1 deletions involving multiple and single exons, and even the entire gene, have been reported. See Table A.
• Targeted mutation analysis for the Danish founder mutation is available clinically.

Table 1. Summary of Molecular Genetic Testing Used in Optic Atrophy Type 1

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Gene Symbol	Test Method	Mutations Detected	Mutation Detection Frequency by Test Method 1, 2		Test Availability
			Familial	Simplex 3
OPA1	Sequence analysis / mutation scanning 4	Sequence variants 5	8/9 6 10/14 7 17/19 8	4/8 6	Clinical
	Targeted mutation analysis	Danish founder mutation c.2826delT	Unknown	Unknown
	Deletion/duplication analysis 9	Exonic or whole-gene deletions	Unknown	Unknown

Test Availability refers to availability in the GeneTests Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. The theoretical possibilities of locus heterogeneity or presence of a large gene deletion not detected by sequence analysis may account for a detection rate less than 100% (see Interpretation of test results).

3. Simplex = a single occurrence in a family

4. Sequence analysis and mutation scanning of the entire gene can have similar detection frequencies; however, detection rates for mutation scanning may vary considerably between laboratories based on specific protocol used.

5. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions, missense, nonsense, and splice site mutations.

6. Nakamura et al [2006] found OPA1 mutations in 8/9 familial cases and 4/8 simplex cases. Of note, on examination of family members of two apparently simplex cases, Nakamura et al [2006] found OPA1 mutations in relatives with a normal or only mildly abnormal phenotype, supporting the notions of variable expressivity and reduced penetrance.

7. Puomila et al [2005]

8. Delettre et al [2001]

9. Testing that identifies deletions/duplications not readily detectable by sequence analysis of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted array GH (gene/segment-specific) may be used. A full array GH analysis that detects deletions/duplications across the genome may also include this gene/segment. See array GH.

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

To confirm/establish the diagnosis in a proband

• An individual suspected of having optic atrophy type 1 should have molecular genetic testing of OPA1.
• If no mutation is identified, molecular genetic testing of OPA3 for autosomal dominant optic atrophy type 3 (OPA3) and for the common mitochondrial DNA (mtDNA) point mutations responsible for Leber hereditary optic neuropathy (LHON) should be performed. See Differential Diagnosis.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

Normal allelic sequence variants in OPA1 may be associated with normal tension glaucoma (NTG), which could be considered a genetically determined optic neuropathy with similarities to both Leber hereditary optic neuropathy (LHON) and OPA1 [Yu-Wai-Man et al 2010].

Natural History

Variable expressivity of optic atrophy type 1 (OPA1) is observed both between and within families.

Vision loss. OPA1 usually presents as insidious decrease in visual acuity between ages four and six years; in mild cases visual acuity may remain normal until early adult life. Visual acuity usually declines slowly with age. Although rare, rapid decline in visual acuity has been reported in adults [Kjer et al 1996].

The visual impairment is usually moderate (6/10 to 2/10), but ranges from severe (legal blindness with acuity <1/20) to mild or even insignificant, and consequently can be underestimated.

The vision loss is occasionally asymmetric.

Typical ADOA is associated with a progressive and irreversible loss of vision. However, Cornille et al [2008] reported a 23-year-old man who developed unexplained isolated, progressive, painless bilateral optic neuropathy as a result of central scotomas (visual acuity 20/200 in the right eye and 20/100 in the left eye) three months after the first signs of visual loss. Six months later he had spontaneous and durable partial recovery of visual acuity (20/30 in the right eye and 20/25 in the left eye). The patient harbored a heterozygous mutation in exon 5b (c.740G>A), which was the first mutation to be described in one of the three alternative OPA1 exons, leading to an amino acid change in the N-terminal coiled coil domain (p.Arg247His) from isoform 8.

Extra-ophthalmogic findings. Up to 10% of persons with an OPA1 mutation have additional extra-ophthalmologic abnormalities, most commonly sensorineural hearing loss, ataxia, and myopathy, suggesting that mutation of OPA1 may be responsible for a continuum of phenotypes ranging from mild disorders affecting only the retinal ganglion cells to a severe and multisystemic disease.

Sensorineural hearing loss that ranges from severe and congenital to subclinical (requiring specific testing for detection) has been reported along with optic atrophy in a few families or individuals with the p.Arg445His mutation in OPA1 [Amati-Bonneau et al 2003, Amati-Bonneau et al 2005]. Amati-Bonneau et al [2005] concluded that the hearing loss resulted from auditory neuropathy. In an individual with the p.Arg445His mutation, auditory brain stem responses (ABRs) were absent and both ears had normal evoked otoacoustic emissions. Because evoked otoacoustic emissions reflect the functional state of presynaptic elements (the outer hair cells), and the ABRs reflect the integrity of the auditory pathway from the auditory nerve to the inferior colliculus, the presence of evoked otoacoustic emissions and the lack of ABRs support the diagnosis of auditory neuropathy.

Both intra- and interfamilial variation in the presence of hearing loss with optic atrophy have been observed. Furthermore, the p.Arg445His mutation was associated with optic atrophy without hearing loss in a 21-year-old Japanese individual; no other family member was clinically affected or had the OPA1 mutation [Shimizu et al 2003].

• Treft et al [1984] and Meire et al [1985] reported two unrelated families with autosomal dominant optic atrophy, hearing loss, ptosis, and ophthalmoplegia. Subsequent studies revealed the p.Arg445His mutation in OPA1 in both families [Payne et al 2004].
• Li et al [2005] identified the p.Arg445His mutation in a family with optic atrophy and hearing loss, without ptosis or ocular motility abnormalities. These family members are also myopic, but it is not clear if myopia is part of the phenotype.

Ataxia and myopathy. Some individuals developed proximal myopathy (35%), a combination of cerebellar and sensory ataxia in adulthood (29%), and axonal sensory and/or motor neuropathy (29%). These features became manifest from the third decade of life onwards.

Muscle biopsy revealed features diagnostic of mitochondrial myopathy. In these individuals approximately 10% of all fibers were deficient in histochemical COX activity and several fibers showing evidence of subsarcolemmal accumulation of abnormal mitochondria.

Pathology. The cardinal sign of OPA1 is optic atrophy that appears as bilateral and generally symmetric temporal pallor of the optic disc, implying the loss of central retinal ganglion cells.

Histopathology. Histopathology shows a normal outer retina and loss of retinal ganglion cells, primarily in the macula and in the papillo-macular bundle of the optic nerve.

Genotype-Phenotype Correlations

No correlation has been observed between the degree of visual impairment and the location or type of mutation [Puomila et al 2005].

Complete deletion of the OPA1 gene results in typical dominant optic atrophy without predictable severity or other deficits [Marchbank et al 2002]. However, it seems that in-frame deletions involve loss of visual acuity (1/10 on average) that is statistically slightly more severe than that resulting from truncating mutations or missense substitutions (2/10 on average) [Ait Ali et al, unpublished].

Penetrance

The estimated penetrance of 98% in OPA1 has been revised in the light of molecular genetic studies. Penetrance varies from family to family and mutation to mutation. It has been reported as high as 100% (c.1065+1G>T mutation resulting in exon 12 skipping) [Thiselton et al 2002] and as low as 43% (c.2708_2711delTTAG mutation in exon 27) [Toomes et al 2001]. In these two studies the clinical diagnosis was made on the basis of reduced visual acuity, abnormal color discrimination, fundus examination showing temporal pallor of the optic disc, and electrophysiology studies [Toomes et al 2001, Thiselton et al 2002].

Anticipation

Anticipation is not observed.

Prevalence

OPA1 is believed to be the most common of the hereditary optic neuropathies.

The estimated prevalence of OPA1 is 1:50,000 in most populations, or as high as 1:10,000 in Denmark. The relatively high frequency of OPA1 in Denmark may be attributable to a founder effect [Thiselton et al 2002].

Evaluations Following Initial Diagnosis

In order to establish the extent of disease in an individual with optic atrophy type 1 (OPA1), the following evaluations are recommended:

• Assessment of visual acuity, color vision, and visual fields
• Assessment of extraocular muscles (the patient is asked to follow the ophthalmoscope with his/her eyes without moving the head)
• Hearing evaluation: auditory brain stem responses (ABRs), auditory evoked potentials (AEPs), and evoked otoacoustic emissions
• Oral glucose tolerance test

Treatment of Manifestations

No treatment is of proven efficacy for OPA1.

Treatment of decreased visual acuity is symptomatic (e.g., low-vision aids).

For treatment of sensorineural hearing loss, see Deafness and Hereditary Hearing Loss Overview.

For treatment of ataxia, see Ataxia Overview.

Surveillance

Appropriate surveillance includes:

• Annual ophthalmologic examination
• Annual hearing evaluation

Agents/Circumstances to Avoid

Individuals with an OPA1 mutation are advised:

• Not to smoke
• To moderate their alcohol intake
• To use sunglasses to limit UV exposure (Note: While limiting UV exposure is a good practice, no evidence for its effectiveness exists.)

Testing of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

Mode of Inheritance

Optic atrophy type 1 (OPA1) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• Most individuals diagnosed with OPA1 have an affected parent.
• A proband with OPA1 may have the disorder as the result of a new gene mutation. Two instances of de novo mutations have been reported [Baris et al 2003].
• In a report of molecular genetic testing in 980 persons for suspected hereditary optic neuropathies, about half of the individuals identified to have an OPA1 mutation were simplex cases (i.e., a single occurrence in a family) [Ferré et al 2009].
• Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include: (1) ophthalmologic evaluation including an assessment of visual acuity, color vision, and visual fields, (2) audiologic examinations consisting of auditory brain stem responses (ABRs), auditory evoked potentials (AEP) recordings, and study of evoked otoacoustic emissions, and (3) molecular genetic testing of OPA1 if the disease-causing mutation has been identified in the proband.

Sibs of a proband

• The risk to the sibs of the proband depends on the genetic status of the proband's parents.
• If a parent of the proband is affected, the risk to the sibs is 50%.
• When the parents are found on the basis of visual acuity study, color vision evaluation, fundus examination, VEP, and PERG to be clinically unaffected, the risk to the sibs of a proband appears to be low.
• If a disease-causing mutation cannot be detected in the DNA of either parent, two possible explanations are germline mosaicism in a parent or a de novo mutation in the proband. Although no instances of germline mosaicism have been reported, it remains a possibility.

Offspring of a proband. Each child of an individual with OPA1 is at a 50% risk of inheriting the mutation.

Other family members of a proband. The risk to other family members depends on the status of the proband's parents. If a parent is affected or has a disease-causing mutation, his or her family members are at risk.

Related Genetic Counseling Issues

Considerations in families with an apparent de novo mutation. When neither parent of a proband with OPA1 has the disease-causing mutation or clinical evidence of the disorder based on visual acuity study, color vision evaluation, fundus examination, VEP, and PERG, it is likely that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See for a list of laboratories offering DNA banking.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation. The disease-causing allele of an affected family member must be identified before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Requests for prenatal testing for conditions such as OPA1 that do not affect intellect or life span are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, careful discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutation has been identified. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Molecular Genetic Pathogenesis

Because OPA1 expression is ubiquitous, and it was recently proposed that neither the pattern nor the abundance of OPA1 mRNA and dynamin-like 120-kd protein variants are specific to retinal ganglion cell (RGC) [Kamei et al 2005], a plausible hypothesis as to why these neurons may be more vulnerable to OPA1 inactivation could be a particular susceptibility to mitochondrial membrane disorders inducing mitochondrial dysfunction or mislocalization. While the former point is in agreement with reports that describe altered mitochondrial ATP synthesis and respiration in OPA1-inactivated cells [Lodi et al 2004, Amati-Bonneau et al 2005, Chen et al 2005], the latter may relate to the particular distribution of the mitochondria in retinal ganglion cells. These show an accumulation of mitochondria in the cell bodies and in the intraretinal unmyelinated axons, where they accumulate in the varicosities, and a relative paucity of mitochondria in the myelinated parts of axons [Andrews et al 1999, Bristow et al 2002, Wang et al 2003]. Furthermore, the effect of mitochondrial dynamics on the correct intracellular distribution of the mitochondria and its influence on neuronal plasticity and function was recently highlighted by inactivation of DRP1 in live hippocampal neurons [Li et al 2004]. A link between axonal transport of mitochondria [Hollenbeck & Saxton 2005] and mitochondrial dynamics was also enlightened by a recent study showing that Drosophila mutants lacking the ortholog of human DRP1 protein failed to populate the distal axon with mitochondria, affecting the mobilization of the synaptic vesicle reserve pool [Hollenbeck 2005]. Moreover, mutations in the pro-fusion protein encoded by the gene MFN2, which causes a peripheral neuropathy (see CMT2A) [Zuchner et al 2006], significantly impaired the transport of mitochondria in axons in neurons expressing disease-mutated forms of MFN2 [Baloh et al 2007]. These data suggest that proper localization of mitochondria is critical for axonal and synaptic function.

Normal allelic variants. The OPA1 gene consists of 31 exons spanning more than 114 kb of genomic DNA. Eight isoforms have been described as a result of alternative splicing of exons 4, 4b, and 5b [Delettre et al 2001].

Pathologic allelic variants. There is a wide spectrum of mutations, with over 213 reported to date (see eOPA1, an online database for OPA1 mutations). The OPA1 mutations are spread throughout the gene coding sequence, but most are localized in GTPase domain (exons 8-16) and in the 3' end of the coding region (exons 27-28), whereas few mutations are found in exons 1 to 7. To date no mutations have been found in exons 4 and 4b, which are alternatively spliced. See Table A. However, a heterozygous mutation in exon 5b (c.740G>A) has been described in one affected individual [Cornille et al 2008].

An Alu-element insertion located in intron 7 of OPA1 has been described to cause an in-frame deletion of exon 8 in a family with ADOA [Gallus et al 2010].

Normal gene product. Dynamin-like 120-kd protein (OPA1), encoded by the OPA1 gene, is a mitochondrial dynamin-related GTP protein of 960 amino acids. This is the first dynamin-related protein found to be involved in human disease. The dynamin-like 120-kd protein comprises a highly basic amino-terminal that provides mitochondrial targeting sequence (MTS), a dynamin-GTPase domain, and a C-terminus of unknown function; the C-terminus differs from that of other dynamin family members in lacking a proline-rich region, a dynamin GTPase effector domain, and a pleckstrin homology domain; the C-terminus may therefore determine the specific functions of the dynamin-like 120-kd protein.

OPA1 appears to exert its function in mitochondrial biogenesis and stabilization of mitochondrial membrane integrity. Downregulation of OPA1 leads to fragmentation of the mitochondrial network and dissipation of the mitochondrial membrane potential with cytochrome c release and caspase-dependent apoptosis [Olichon et al 2003]. Mitochondrial DNA (mtDNA) deletions have recently been identified in families with autosomal dominant optic atrophy who have complex multisystem involvement in addition to the optic neuropathy [Amati-Bonneau et al 2008; Ferraris et al 2008; Hudson et al 2008] suggesting a role of OPA1 in mtDNA maintenance.

Abnormal gene product. The functional consequences of mutations in OPA1 are unknown. Since almost 50% of mutations predict protein truncation, dominant inheritance of the disease may result from haploinsufficiency of dynamin-like 120-kd protein. However, missense mutations can also cause disease by a dominant-negative mechanism.

Interestingly, evidence for a dominant-negative mechanism has been reported in all the multi-systemic forms of the disease (ADOAD and “ADOA plus”). These disease forms have missense mutations affecting the GTPase domain [Amati-Bonneau et al 2008]. In addition, one person with ADOA, who was a compound heterozygote for two OPA1 missense mutations located in exon 8, was found to be severely affected by the disease [Pesch et al 2001], whereas her heterozygous parents and siblings were less severely affected, suggesting a semi-dominant mode of inheritance in this family.

Literature Cited

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Suggested Reading

1. Carelli V, Ross-Cisneros FN, Sadun AA. Mitochondrial dysfunction as a cause of optic neuropathies. Prog Retin Eye Res. 2004;23:53–89. [PubMed: 14766317]
2. Chinnery PF, Griffiths PG. Optic mitochondriopathies. Neurology. 2005;64:940–1. [PubMed: 15781804]
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4. Howell N. LHON and other optic nerve atrophies: the mitochondrial connection. Dev Ophthalmol. 2003;37:94–108. [PubMed: 12876832]
5. Newman NJ. Hereditary optic neuropathies: from the mitochondria to the optic nerve. Am J Ophthalmol. 2005;140:517–23. [PubMed: 16083845]
6. Newman NJ, Biousse V. Hereditary optic neuropathies. Eye. 2004;18:1144–60. [PubMed: 15534600]
7. Votruba M. Molecular genetic basis of primary inherited optic neuropathies. Eye. 2004;18:1126–32. [PubMed: 15534598]

Author Notes

Web site: Institut des Neurosciences de Montpellier

Revision History

• 20 July 2010 (me) Comprehensive update posted live
• 24 March 2009 (cd) Revision: targeted mutation analysis for Danish founder mutation available clinically
• 7 August 2008 (cd) Revision: deletion/duplication analysis available clinically
• 13 July 2007 (me) Review posted to live Web site
• 23 October 2006 (cdc) Original submission