Optic Atrophy Type 1

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Summary

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 4 and 6 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). 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).

Visual evoked potentials are typically absent or delayed; pattern electroretinogram 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 gray crescent.

Diagnosis.

The diagnosis of OPA1 is made based on a combination of clinical findings, electrophysiologic studies, and family history and/or by the identification of a heterozygous pathogenic variant in OPA1, the only gene known to be associated with OPA1, by molecular genetic testing.

Management.

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

Surveillance: Annual ophthalmologic evaluations (including measurement of visual acuity, visual fields, and optical coherence tomography) and hearing evaluations.

Agents/circumstances to avoid: Smoking, excessive alcohol intake, medications (antibiotics, antivirals) that interfere with mitochondrial metabolism.

Genetic counseling.

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

Diagnosis

Suggestive Findings

Optic atrophy type 1 (OPA1 or Kjer type optic atrophy) should be suspected in individuals with the following clinical, electrophysiologic, and family history findings:

Clinical findings

  • Childhood onset
  • Bilateral vision loss that is usually symmetric
  • Visual field defect that is typically centrocecal, central, or paracentral
  • Peripheral field that is usually normal, although 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)
  • Opthalmoscopic examination that demonstrates:
    • Optic nerve pallor (the cardinal sign) that is most often bilateral and symmetric, but may be temporal (50% of individuals) and global (50%) [Votruba et al 2003];
    • Profound papillary excavation (21% of eyes with OPA1) [Alward 2003];
    • Neuroretinal rim pallor in most cases, sometimes associated with a temporal pigmentary gray crescent.

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.

Family history consistent with autosomal dominant inheritance

Note: Absence of a family history of OPA1 does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of optic atrophy type 1 (OPA1) is established in a proband with the above clinical findings and/or a heterozygous pathogenic variant in OPA1 by molecular genetic testing (see Table 1).

Molecular testing approaches can include single-gene testing, use of a multigene panel, and genomic testing.

Single-gene testing

  • Targeted analysis for the c.2826delT pathogenic variant can be performed first in individuals of Danish ancestry.
  • In individuals who are not of Danish ancestry or if targeted analysis does not identify a pathogenic variant, sequence analysis of OPA1 is performed, followed by gene-targeted deletion/duplication analysis if no pathogenic variant is found.
  • If no pathogenic variant is identified, molecular genetic testing of OPA3 for autosomal dominant optic atrophy type 3 (OPA3) and for the common mitochondrial DNA (mtDNA) single-nucleotide pathogenic variants responsible for Leber hereditary optic neuropathy (LHON) should be considered (see Differential Diagnosis).

A multigene panel that includes OPA1 and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

More comprehensive genomic testing (when available) including exome sequencing, genome sequencing, and mitochondrial sequencing may be considered if serial single-gene testing (and/or use of a multigene panel) fails to confirm a diagnosis in an individual with features of optic atrophy type 1.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in Optic Atrophy Type 1

Gene 1MethodProportion of Probands with a Pathogenic Variant 2 Detectable by Method
FamilialSimplex 3
OPA1Sequence analysis 48/9 5
10/14 6
17/19 7		4/8 5
Gene-targeted deletion/duplication analysis 8Unknown 9Unknown
Targeted analysis for pathogenic variants 10UnknownUnknown
Unknown 11NA
1.

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

2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

Simplex = a single occurrence in a family

4.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5.

Nakamura et al [2006] found heterozygous OPA1 pathogenic variants 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 heterozygous OPA1 pathogenic variants in relatives with a normal or only mildly abnormal phenotype, supporting the notions of variable expressivity and reduced penetrance.

6.

Puomila et al [2005]

7.

Delettre et al [2001]

8.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

9.

A ~325-bp intronic insertion resulting in exon skipping has been reported [Gallus et al 2010]. See Molecular Genetics.

10.

Detects the Danish founder pathogenic c.2826delT variant. Note: Pathogenic variants included in a panel may vary by laboratory.

11.

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

Clinical Characteristics

Clinical Description

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.

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).

Typical OPA1 is associated with a progressive and irreversible loss of vision. However, Cornille et al [2008] reported a man age 23 years 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). He was the first affected individual described with a heterozygous pathogenic variant in one of the three alternative OPA1 exons (see Genotype-Phenotype Correlations).

Extra-ophthalmogic findings. Up to 10% of persons with a heterozgyous OPA1 pathogenic variant have additional extra-ophthalmologic abnormalities, most commonly sensorineural hearing loss, ataxia, and myopathy, suggesting that pathogenic variants in 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) is the most frequently extra-ocular feature observed. Such hearing loss appears to be due to auditory neuropathy [Amati-Bonneau et al 2005]. Seven pathogenic variants in OPA1 have been found to be associated with optic atrophy and hearing loss (see Genotype-Phenotype Correlations). Both intra- and interfamilial variation in the presence of hearing loss with optic atrophy has been observed.

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 showed 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 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 pathogenic variant [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 appears that pathogenic in-frame deletions involve loss of visual acuity (1/10 on average) that is statistically slightly more severe than that resulting from pathogenic truncating variants or pathogenic missense substitutions (2/10 on average) [Ait Ali et al, unpublished].

Optic atrophy and hearing loss. Seven different pathogenic variants in OPA1 have been reported in individuals with both optic atrophy and hearing loss: p.Arg445His, p.Gly401Asp, p.Leu243Ter, c.983A>G, p.Ile463_Phe464dup, p.Gln437Arg, and p.Ala357LeufsTer4 [Leruez et al 2013].

  • In an individual with the p.Arg445His pathogenic variant, auditory brain stem responses (ABRs) were absent and both ears had normal evoked otoacoustic emissions [Amati-Bonneau et al 2005]. 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.
  • 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 pathogenic variant in OPA1 in both families [Payne et al 2004].
  • Li et al [2005] identified the p.Arg445His pathogenic variant 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 whether myopia is part of the phenotype.
  • In contrast, the p.Arg445His pathogenic variant was associated with optic atrophy without hearing loss in a Japanese individual age 21 years; no other family member was clinically affected or had the OPA1 pathogenic variant [Shimizu et al 2003].

Alternate OPA1 transcripts. Cornille et al [2008] reported a young man with unexplained isolated, progressive, painless bilateral optic neuropathy as a result of central scotomas (see Clinical Description, Visual loss) who harbored a heterozygous pathogenic variant in exon 5b (c.740G>A). This was the first report of a pathogenic variant 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. This individual had spontaneous and durable partial recovery of visual acuity (20/30 in the right eye and 20/25 in the left eye) six months later.

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 pathogenic variant to pathogenic variant. It has been reported as high as 100% (variant c.1065+1G>T, resulting in exon 12 skipping) [Thiselton et al 2002] and as low as 43% (variant c.2708_2711delTTAG 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].

Nomenclature

Optic atrophy type 1 was formerly known as Kjer type optic atrophy.

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].

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 pathogenic variants in OPA3:

  • Costeff optic atrophy syndrome (3-methylglutaconic aciduria type 3). Pathogenic truncating variants are responsible for this 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) (OMIM 165300). Reynier et al [2004] have identified two pathogenic variants 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 25% 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 the majority of cases. After the acute phase, the optic discs become atrophic. Significant improvements in visual acuity are rare. Individuals then proceed into the atrophic phase and are usually legally blind for the rest of their lives with a permanent large centrocecal scotoma. Neurologic abnormalities such as postural tremor, peripheral neuropathy, nonspecific myopathy, and movement disorders have been reported to be more common in individuals with LHON than in controls. Some individuals with LHON, usually women, also have a multiple sclerosis (MS)-like illness.

LHON is transmitted by maternal inheritance. In one large study, 90% of individuals with LHON were found to have one of three pathogenic variants in 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:

  • OPA4 (OMIM 605293) was mapped to 8q12.2-q12.3 in a single large family by Kerrison et al [1999]; however, the locus has not been confirmed and the gene in which mutation is causative is unknown.
  • OPA5 (OMIM 610708) was mapped to 22q12.1-q13.1 by Barbet et al [2005] in two unrelated families.

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 autosomal dominant optic atrophy (OPA8) 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 in early childhood, 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 pathogenic variants 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. Biallelic pathogenic variants 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]). Heterozygous pathogenic variants in WFS1 cause autosomal dominant progressive low-frequency sensorineural hearing loss (LFSNHL) without ophthalmologic abnormalities [Cryns et al 2003]. However, Eiberg et al [2006] identified a WFS1 heterozygous pathogenic variant associated with autosomal dominant optic atrophy, hearing loss, and impaired glucose regulation in one family, supporting the notion that heterozygous pathogenic variants 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 2A with visual impairment resulting from optic atrophy has been designated as hereditary motor and sensory neuropathy type VI (HMSN VI) [Voo et al 2003]. Züchner 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 heterozygous pathogenic variant 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 (OMIM 311050). 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 (OMIM 258500). 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 (OMIM 612989). 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 biallelic pathogenic variants in TMEM126A, which 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

See Optic atrophy: OMIM Phenotypic Series to view genes associated with this phenotype in OMIM.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs 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 affected individual 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
  • Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

No treatment for OPA1 is of proven efficacy.

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

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

For treatment of ataxia, see Ataxia Overview.

Surveillance

Appropriate surveillance includes:

  • Annual ophthalmologic examination, including measurement of visual acuity and visual fields and optical coherence tomography (OCT);
  • Annual hearing evaluation.

Agents/Circumstances to Avoid

Individuals with an OPA1 pathogenic variant 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.
  • To avoid medications (antibiotics, antivirals) that interfere with mitochondrial metabolism.

Evaluation of Relatives at Risk

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

Therapies Under Investigation

A study using the antioxidant EPI-743 in individuals with autosomal dominant optic atrophy (ADOA), including persons with OPA1, is in preparation in Italy (Dr. Valerio Carelli, University of Bologna).

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe 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.