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Optic Atrophy Type 1

Synonym: Kjer Type Optic Atrophy

, PhD, , MD, and , PhD.

Author Information
, PhD
Inserm U 583
INM Hôpital Saint Eloi
Montpellier, France
, MD
Inserm U 583
INM Hôpital Saint Eloi
Montpellier, France
, PhD
Inserm U 583
INM Hôpital Saint Eloi
Montpellier, France

Initial Posting: ; Last Update: July 20, 2010.


Clinical characteristics.

Optic atrophy type 1 (OPA1, or Kjer type optic atrophy) is characterized by bilateral and symmetric optic nerve pallor associated with insidious decrease in visual acuity usually between ages four and six years, visual field defects, and color vision defects. Visual impairment is usually moderate (6/10 to 2/10), but ranges from mild or even insignificant to severe (legal blindness with acuity <1/20). The visual field defect is typically centrocecal, central, or paracentral; it is often large in those with severe disease. The color vision defect is often described as acquired blue-yellow loss (tritanopia). Spontaneous recovery of vision has not been reported. Other findings can include auditory neuropathy resulting in sensorineural hearing loss that ranges from severe and congenital to subclinical (i.e., identified by specific audiologic testing only).


The diagnosis of OPA1 is based on a combination of clinical findings, electrophysiologic studies, family history, and molecular genetic testing. Visual evoked potentials (VEPs) are typically absent or delayed; pattern electroretinogram (PERG) shows an abnormal N95:P50 ratio. Tritanopia is the classic feature of color vision defect, but more diffuse nonspecific dyschromatopsia is not uncommon. Ophthalmoscopic examination discloses temporal or diffuse pallor of the optic discs, sometimes associated with optic disc excavation. The neuroretinal rim shows some pallor in most cases, sometimes associated with a temporal pigmentary grey crescent. OPA1 is the only gene known to be associated with OPA1.


Treatment of manifestations: Low-vision aids for decreased visual acuity.

Surveillance: Annual ophthalmologic and hearing evaluations.

Agents/circumstances to avoid: Smoking, excessive alcohol intake.

Genetic counseling.

OPA1 is inherited in an autosomal dominant manner. Most individuals diagnosed with OPA1 have an affected parent; however, de novo mutations have been reported. Each child of an individual with OPA1 has a 50% chance of inheriting the mutation. Prenatal diagnosis for pregnancies at increased risk is possible if the disease-causing mutation has been identified in an affected family member but genetic counseling remains complicated by the incomplete penetrance and the markedly variable inter- and intra-familial expressivity of the disease.


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 Characteristics).


  • 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
  • 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. Genes and Databases.
  • Targeted mutation analysis for the Danish founder mutation

Table 1.

Summary of Molecular Genetic Testing Used in Optic Atrophy Type 1

Gene 1Test MethodMutations Detected 2Mutation Detection Frequency by Test Method 3, 4
FamilialSimplex 5
OPA1Sequence analysis / mutation scanning 6Sequence variants 78/9 8
10/14 9
17/19 10
4/8 8
Targeted mutation analysisDanish founder mutation
analysis 11
Exonic or whole-gene deletionsUnknown Unknown

See Table A. Genes and Databases for chromosome locus and protein name.


See Molecular Genetics for information on allelic variants.


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


The theoretic 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).


Simplex = a single occurrence in a family


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.


Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions, missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.


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.


Puomila et al [2005]


Delettre et al [2001]


Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

Testing Strategy

To confirm/establish the diagnosis in a proband

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

Clinical Characteristics

Clinical Description

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].

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 OPA1 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].


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 is not observed.


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].

Differential Diagnosis

OPA3. OPA3 consists of three exons and encodes for an inner mitochondrial membrane protein. The function of this protein is not well known. Two disorders are associated with OPA3 mutations:

  • Costeff optic atrophy syndrome. Truncating mutations are responsible for 3-methylglutaconic aciduria type 3, also called Costeff optic atrophy syndrome, a neuroophthalmologic syndrome consisting of early-onset bilateral optic atrophy and later-onset spasticity, extrapyramidal dysfunction, and cognitive deficit. Urinary excretion of 3-methylglutaconic acid and of 3-methglutaric acid is increased. Inheritance is autosomal recessive.
  • Autosomal optic atrophy and cataract (ADOAC, OPA3). Reynier et al [2004] have identified two causative mutations in OPA3 (p.Gly93Ser and p.Gln105Glu) that change one of the amino acids. Inheritance is autosomal dominant.

Leber hereditary optic neuropathy (LHON) is the major differential diagnosis for optic atrophy type 1 (OPA1). LHON typically presents in young adults as painless subacute bilateral visual failure. Males are more commonly affected than females. Women tend to develop the disorder slightly later in life and may be more severely affected. The acute phase begins with blurring of central vision and color desaturation that affect both eyes simultaneously in up to 50% of cases. After the initial symptoms, both eyes are usually affected within six months. The central visual acuity deteriorates to the level of counting fingers in up to 80% of cases. Following the nadir, acuity may improve. Individuals then proceed into the atrophic phase and are usually legally blind for the rest of their lives with a permanent large centrocecal scotoma. Minor neurologic abnormalities (such as a postural tremor or the loss of ankle reflexes) are said to be common in individuals with LHON. Some individuals with LHON, usually women, also have a multiple sclerosis (MS)-like illness.

LHON is inherited by mitochondrial inheritance. In one large study, 95% of individuals with LHON were found to have one of three point mutations of mtDNA: m.11778G>A, m.14484T>C, m.3460G>A.

Autosomal dominant optic atrophy (ADOA). Two other loci associated with autosomal dominant optic atrophy have been identified:

The phenotype of the three families with OPA4 or OPA5 is comparable to the phenotype seen in OPA1: optic nerve pallor, decreased visual acuity, color vision defects, impaired VEP, and normal ERG. No extraocular findings were described in these families.

Another OPA locus for ADOA was mapped to 16q21-q22 in one Italian family with extraophthalmologic features extending to the auditory system [Carelli et al 2007].The gene in which mutation is causative is unknown.

Deafness-dystonia-optic neuronopathy syndrome (DDON). Males with DDON have prelingual or postlingual sensorineural hearing impairment, slowly progressive dystonia or ataxia in the teens, slowly progressive decreased visual acuity from optic atrophy beginning about age 20 years, and dementia beginning at about age 40 years. Psychiatric symptoms such as personality change and paranoia may appear in childhood and progress. The hearing impairment phenotype is a progressive auditory neuropathy, while the neurologic, visual, and neuropsychiatric signs vary in degree of severity and rate of progression. Females may have mild hearing impairment and focal dystonia.

Inheritance is X-linked. The DDON syndrome occurs as either a single-gene disorder resulting from mutation in TIMM8A or a contiguous gene deletion syndrome at Xq22, which also includes X-linked agammaglobulinemia caused by disruption of BTK, located telomeric to TIMM8A.

WFS1. Mutations in WFS1 are generally associated with optic atrophy (OPA) as part of the autosomal recessive Wolfram syndrome phenotype (DIDMOAD [diabetes insipidus, diabetes mellitus, optic atrophy, deafness]) or with autosomal dominant progressive low-frequency sensorineural hearing loss (LFSNHL) without ophthalmologic abnormalities [Cryns et al 2003]. However, Eiberg et al [2006] identified a WFS1 mutation associated with autosomal dominant optic atrophy, hearing loss, and impaired glucose regulation in one family, supporting the notion that mutations in WFS1 as well as in OPA1 may lead to optic atrophy combined with hearing impairment (see WFS1-Related Disorders).

MFN2. Charcot-Marie-Tooth (CMT) neuropathy type 2A2 (see CMT2A) with visual impairment resulting from optic atrophy has been designated as hereditary motor and sensory neuropathy type VI (HMSN VI) [Voo et al 2003]. Zuchner et al [2006] described six families with HMSN VI with a subacute onset of optic atrophy and subsequent slow recovery of visual acuity in 60% of affected individuals. In each pedigree a unique mutation in MFN2, encoding mitofusin 2, was identified. Inheritance is autosomal dominant.

Other optic neuropathies. The acquired blue-yellow loss (tritanopia) helps differentiate OPA1 from other optic neuropathies in which the axis of confusion is red-green:

  • OPA2. A gene for X-linked optic atrophy (OPA2) has been mapped to chromosome Xp11.4-p11.21; to date no gene has been identified.
  • OPA6. The first locus for isolated autosomal recessive optic atrophy (ROA1) has been mapped to chromosome 8q. Dyschromatopsia for red-green confusion occurs in OPA6.
  • OPA7. Hanein et al [2009] identified an autosomal recessive juvenile-onset optic atrophy in a large multiplex consanguineous Algerian family and subsequently in three other Maghreb families. This form of optic atrophy is caused by mutation in TMEM126A (chromosome 11q14.1-q21) that encodes a mitochondrial protein found in higher eukaryotes that has four transmembrane domains and a central domain conserved with the related protein encoded by TMEM126B.

Acquired optic neuropathy can be caused by the following:

  • Nutritional deficiencies of protein, or of the B vitamins and folate, associated with starvation, malabsorption, or alcoholism
  • Toxic exposures. The most common is "tobacco-alcohol amblyopia," thought to be caused by exposure to cyanide from tobacco smoking, and by low levels of vitamin B12 caused by poor nutrition and poor absorption associated with drinking alcohol. Other possible toxins include ethambutol, methyl alcohol, ethylene glycol, cyanide, lead, and carbon monoxide.
  • Certain medications


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.


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.)

Evaluation of Relatives at Risk

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

Therapies Under Investigation

Search 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.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

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

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.

Prenatal Testing

If the disease-causing mutation has been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation).

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 which (like OPA1) 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, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation has been identified.


GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Foundation Fighting Blindness
    11435 Cronhill Drive
    Owings Mills MD 21117-2220
    Phone: 800-683-5555 (toll-free); 800-683-5551 (toll-free TDD); 410-568-0150
  • National Eye Institute
    31 Center Drive
    MSC 2510
    Bethesda MD 20892-2510
    Phone: 301-496-5248
  • National Federation of the Blind (NFB)
    200 East Wells Street
    (at Jernigan Place)
    Baltimore MD 21230
    Phone: 410-659-9314
    Fax: 410-685-5653
  • eyeGENE® - National Ophthalmic Disease Genotyping Network Registry
    Phone: 301-435-3032

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Optic Atrophy Type 1: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B.

OMIM Entries for Optic Atrophy Type 1 (View All in OMIM)

605290OPA1 GENE; OPA1

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 MFN2, which cause 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. OPA1 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].

Pathogenic 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].

Table 2.

Selected OPA1 Pathogenic Allelic Variants

DNA Nucleotide Change
(Alias 1)
Protein Amino Acid ChangeReference Sequences
isoform 8
isoform 1
c.1334G>A p.Arg445His

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​ See Quick Reference for an explanation of nomenclature.

1. Variant designation that does not conform to current naming conventions

Normal gene product. Dynamin-like 120-kd protein (OPA1), encoded by OPA1, 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

  1. Alexander C, Votruba M, Pesch UE, Thiselton DL, Mayer S, Moore A, Rodriguez M, Kellner U, Leo-Kottler B, Auburger G, Bhattacharya SS, Wissinger B. OPA1, encoding a dynamin-related GTPase, is mutated in autosomal dominant optic atrophy linked to chromosome 3q28. Nat Genet. 2000;26:211–5. [PubMed: 11017080]
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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]
  3. Delettre C, Lenaers G, Pelloquin L, Belenguer P, Hamel CP. OPA1 (Kjer type) dominant optic atrophy: a novel mitochondrial disease. Mol Genet Metab. 2002;75:97–107. [PubMed: 11855928]
  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]

Chapter Notes

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
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