Autosomal Dominant Optic Atrophy (ADOA)

Key Points at a Glance

Key Points of This Disease

• ADOA is the most common hereditary optic neuropathy, with an estimated prevalence of 1:12,000 to 1:50,000.
• More than 60% of cases are caused by OPA1 gene mutations (chromosome 3q28-q29), and over 500 pathogenic mutations have been identified.
• Onset often occurs in childhood to the 20s, but due to slow progression, awareness is often delayed.
• Typical findings include wedge-shaped temporal optic disc pallor and decreased sensitivity on blue-on-yellow perimetry.
• There is no established effective treatment; low vision care and genetic counseling are the mainstays of management.
• Penetrance ranges from 43% to 100% depending on the family, and some patients maintain good visual function until middle age.
• Gene therapy and antisense oligonucleotide (ASO) therapy are in preclinical research stages.

1. What is Autosomal Dominant Optic Atrophy?

Autosomal Dominant Optic Atrophy (ADOA) is a hereditary optic neuropathy characterized by bilateral progressive optic atrophy. OMIM number is 165500. It is the most common hereditary optic neuropathy, with an estimated prevalence of 1:12,000 to 1:50,000 ²⁾.

Hereditary optic neuropathies are broadly divided into ADOA, caused by nuclear gene mutations with Mendelian inheritance, and Leber hereditary optic neuropathy (LHON), caused by mitochondrial DNA mutations with maternal inheritance. Autosomal recessive optic atrophy includes Wolfram syndrome. Both ADOA and LHON share the common pathology of retinal ganglion cell (RGC) degeneration due to mitochondrial dysfunction, but their clinical features and genetic causes differ ⁶⁾.

Q How common is autosomal dominant optic atrophy?

A

The prevalence is estimated at 1:12,000 to 1:50,000, making it the most common hereditary optic neuropathy ²⁾. In the UK, the overall prevalence of hereditary optic neuropathies is reported to be about 1:25,000 ⁶⁾.

2. Main Symptoms and Clinical Findings

Fundus photograph of autosomal dominant optic atrophy

Murati Calderon RA, et al. Clinical and Genetic Findings in an Autosomal Dominant Optic Atrophy-Compatible Phenotype Harboring an OPA1 Variant: A Case Report. Cureus. 2025. Figure 1. PMCID: PMC12659938. License: CC BY.

Color fundus photographs of the right eye (A) and left eye (B) at initial visit, showing mild temporal optic disc pallor (red arrows) and enlarged optic cup in both eyes. This corresponds to the optic disc pallor discussed in section “2. Main Symptoms and Clinical Findings.”

Subjective Symptoms

Typical onset occurs in the first to second decades of life. Because progression is slow, many patients cannot pinpoint the exact time of onset.

• Vision loss: Bilateral, symmetric, with a slow and insidious course.
• Discovery: Often detected during school age as a developmental disorder of binocular vision. Symptoms are scarce, and it may be found incidentally during screening.
• Degree of vision: More than 80% of patients maintain vision of 20/200 (0.1) or better, but some cases have corrected visual acuity of 0.1 or worse.
• Penetrance: Ranges from 43% to 100% depending on the family ²⁾. Some cases maintain relatively good visual function (best-corrected visual acuity [BCVA] 0.6–1.0) until middle age ²⁾.
• No sex difference: There is no sex difference in onset.

Q Is it possible to have ADOA even with good vision?

A

Yes. In a report by Tachibana et al. (2025), a novel OPA1 mutation was identified in a patient who maintained best-corrected visual acuity of 0.8/0.6 at age 56 ²⁾. Penetrance ranges from 43% to 100%, and abnormalities may be detected only by OCT in asymptomatic carriers.

Clinical Findings

The three main findings involve the optic disc, color vision, and visual field.

• Optic disc: Typical finding is wedge-shaped temporal pallor centered on the temporal side. Diffuse atrophy may also be seen.
• Color vision abnormality: May present with acquired tritanopia.
• Visual field defects: Central scotoma, cecocentral scotoma, and paracentral scotoma are most common. Some cases have almost no abnormalities.
• Blue-on-yellow perimetry: More sensitive in detecting sensitivity loss than standard white-on-white automated perimetry ²⁾.
• Optical coherence tomography (OCT): Thinning of the inner retinal layers, mainly in the papillomacular bundle. Characteristic temporal thinning of the retinal nerve fiber layer (RNFL). Microcystic macular edema (MME) may be present.
• Electrophysiology: VEP shows reduced amplitude and prolonged latency. Pattern electroretinography (pERG) shows reduced N95 component.

ADOA can present as DOA plus phenotype with systemic abnormalities beyond optic atrophy. 20–30% of patients have complications such as hearing loss, peripheral neuropathy, myopathy, ataxia, and chronic progressive external ophthalmoplegia (CPEO) ³⁾.

Typical type (DOA)

Symptoms: Bilateral slowly progressive visual loss.

Optic disc findings: Temporal wedge pallor is a key finding.

Systemic symptoms: Optic atrophy only.

Visual acuity: Over 80% maintain 0.1 or better.

DOA plus

Frequency: Occurs in 20–30% of patients ³⁾.

Complications: Hearing loss, peripheral neuropathy, myopathy, ataxia, CPEO, etc.

Severe type: Biallelic OPA1 mutations cause Behr syndrome (early onset, severe visual impairment, ataxia, spasticity) ³⁾.

3. Causes and Risk Factors

Main causative gene

Over 60% of ADOA cases are caused by OPA1 gene mutations ⁶⁾. OPA1 is located on chromosome 3q28-q29, and more than 500 pathogenic mutations have been identified ⁶⁾. In Japan, c.2708_2711 delTTAG is known as a frequent mutation.

• Haploinsufficiency: Most OPA1 mutations cause premature termination of translation, leading to reduced OPA1 protein levels ⁶⁾.
• Incomplete penetrance: complicates diagnosis, prognosis prediction, and genetic counseling⁶⁾.
• De novo mutations: occur at a high rate, so diagnosis cannot be ruled out even without a family history¹⁾.

Other causative genes besides OPA1

In OPA1-negative cases, other genetic mutations should be investigated. The main causative genes are listed below.

Gene	Associated disease	Notes
OPA1	ADOA (typical type, DOA plus)	Over 60% of all cases6)
AFG3L2	Optic atrophy type 12 (OAT12), SCA28	Approximately 3% of hereditary optic neuropathies1)
OPA3	Dominant optic atrophy with cataract and hearing loss (Costeff syndrome)	OMIM #258501
WFS1	Wolfram syndrome-like	OMIM #222370, #614296
DNM1L	Optic atrophy type 5 (OPA5)	Mitochondrial fission regulation

Brodsky et al. (2023) identified optic atrophy type 12 due to the AFG3L2 gene c.1064C>T (p.Thr355Met) mutation in a father and daughter of East African (Somali) descent ¹⁾. In a cohort study of 2186 cases, AFG3L2 was among the top 10 causative genes for hereditary optic neuropathy, accounting for 14 of 451 cases (3%).

Genetic counseling

Because of autosomal dominant inheritance, the probability of passing the mutation from an affected parent to a child is 50%. However, due to incomplete penetrance, individuals who inherit the mutation may not develop the disease. Even without a family history, de novo mutations can cause the disease. Consultation with a specialist is recommended.

Q Are there causative genes other than OPA1?

A

Yes. Several genes have been identified, including AFG3L2, OPA3, WFS1, and DNM1L (OPA5). In particular, AFG3L2 accounts for about 3% of hereditary optic neuropathies ¹⁾, and when OPA1 is negative, comprehensive search by exome/genome sequencing is important.

4. Diagnosis and testing methods

Clinical diagnosis

Suspect this disease when bilateral unexplained visual developmental impairment is discovered during school age. A family history of similar symptoms is an important clue, but due to incomplete penetrance, there may be no family history.

Main tests

• Farnsworth-Munsell 100 hue test: Shows a tritanopia axis.
• Blue-on-yellow automated perimetry: More sensitive in detecting sensitivity loss than standard white-on-white perimetry²⁾.
• OCT: Assesses RNFL thinning predominantly in the temporal and inferior quadrants. Even asymptomatic carriers may show abnormalities on OCT alone.

In a 56-year-old male case reported by Tachibana et al. (2025), HFA 24-2 white-on-white perimetry was normal, but blue-on-yellow perimetry detected sensitivity loss²⁾. OCT showed temporal RNFL thinning, and CFF was reduced to 30/31 Hz (normal >39 Hz).

• OPA1 genetic testing: Required for definitive diagnosis. Outsourced testing is not yet widely available and requires referral to a core facility.
• Exome/genome sequencing: In OPA1-negative cases, searching for other genes including AFG3L2 is important. Reanalysis may yield a new diagnosis¹⁾.
• Electrophysiological tests: Show VEP (reduced amplitude, prolonged latency), pERG (reduced N95), and reduced CFF.
• OCTA: Useful for evaluating neurovascular changes in the macula and peripapillary region.

Differential Diagnosis

Disease	Onset Pattern	Inheritance	Key Differentiating Features
LHON	Acute to subacute	Maternal inheritance	Predominantly affects young males, severe
ADOA	Slow, insidious	Autosomal dominant	Childhood, bilateral symmetric
Glaucoma	Slow	Multifactorial	Elevated intraocular pressure, enlarged optic cup
Compressive optic neuropathy	Slow to subacute	Non-hereditary	MRI shows chiasmal lesion

Other differential diagnoses: toxic optic neuropathy (e.g., ethambutol), nutritional deficiency optic neuropathy, occult macular dystrophy, cone dystrophy, functional amblyopia, psychogenic visual disturbance.

5. Standard Treatment

There is no established effective treatment. Low vision care and patient counseling are the mainstays of treatment.

Low Vision Care and Regular Monitoring

• Regular monitoring: Recommended annually. Assess visual acuity, visual field, color vision, extraocular muscles, and hearing.
• Refractive correction: Optimal correction of refractive errors and management of eyeglass compliance.
• Visual rehabilitation: Utilize assistive devices such as magnifiers and text-to-speech ³⁾.

Supplemental Supplements

The following have been proposed to reduce oxidative stress, but none are established as standard treatment.

• Idebenone: A synthetic analog of coenzyme Q10 (CoQ10). It bypasses complex I of the electron transport chain to improve mitochondrial respiration ⁶⁾. Reports suggest it may stabilize or improve vision in patients with OPA1 mutation ADOA ⁴⁾⁵⁾.
• CoQ10, vitamin B12, C, lutein: Proposed as antioxidant supplements.

Genetic Counseling

It is important to explain autosomal dominant inheritance and provide information on the risk of severe disease (Behr syndrome) due to biallelic mutations ³⁾.

Prognosis

Vision loss generally progresses slowly and follows a milder course compared to LHON. Over 80% of patients maintain corrected visual acuity of 0.1 or better, but some cases decline to 0.1 or worse. Because onset is gradual, patients may not notice it, and it is sometimes discovered incidentally during checkups. Since there is no established treatment, long-term management with regular monitoring and low vision care is important.

Precautions in Treatment

Since there is no established effective treatment, caution is needed regarding therapies with unknown rationale that claim to be standard treatment. Although supplements such as idebenone have shown potential for stabilizing vision in some reports ⁴⁾⁵⁾, evidence confirming efficacy is insufficient. Treatment decisions should be made in consultation with a specialist.

Q Is there an effective treatment for ADOA?

A

Currently, there is no established effective treatment. Low vision care is the mainstay of treatment. Idebenone has been reported to show potential for stabilizing or improving vision⁴⁾⁵⁾, but it is not established as a standard treatment. For investigational treatment approaches, see “Latest Research and Future Prospects” section.

6. Pathophysiology and Detailed Mechanisms

Function of OPA1 Protein

OPA1 is a dynamin-related GTPase located in the mitochondrial inner membrane. It is synthesized in the nucleus and transported to mitochondria, where it performs the following functions⁶⁾.

• Inner membrane fusion: Maintenance of mitochondrial network
• Maintenance of cristae structure: Stabilization of respiratory chain complexes
• Assembly of electron transport complexes: Efficiency of oxidative phosphorylation
• Regulation of Ca²⁺ homeostasis
• Suppression of apoptosis

Pathogenesis

The main pathological mechanism is haploinsufficiency. Most OPA1 mutations cause premature termination of translation, leading to insufficient OPA1 protein levels⁶⁾.

Decreased OPA1 protein → increased mitochondrial fragmentation and enhanced recycling³⁾ → mitochondrial metabolic dysfunction and impaired oxidative phosphorylation → elevated reactive oxygen species (ROS) → apoptosis of RGCs.

RGCs in the papillomacular bundle are primarily affected, manifesting as temporal optic atrophy.

Function of AFG3L2

AFG3L2 encodes a subunit of the mitochondrial matrix AAA metalloprotease (m-AAA)¹⁾. It forms a complex with SPG7 (paraplegin) and performs ATP-dependent processing, maturation, and quality control of mitochondrial proteins. Mutations cause RGC degeneration similar to OPA1¹⁾.

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7. Latest Research and Future Prospects (Research Stage Reports)

For Patients: Please Read Carefully

The following content is currently at the research stage or in clinical trials, and is not standard treatment available at general hospitals. It is reference information for experts regarding future medical developments.

ASO Therapy

Target: NMD (nonsense-mediated decay)-inducing exon of OPA1 pre-mRNA.

Mechanism: Inhibits the inclusion of the exon that induces NMD, enhancing wild-type OPA1 translation through a mutation-independent approach ⁶⁾.

Current Status: Confirmed increased OPA1 protein production and improved mitochondrial bioenergetics in three ADOA patient-derived cell lines ⁶⁾. Requires regular repeated administration via intravitreal injection, with risks of endophthalmitis and chronic uveitis as challenges.

Gene Therapy

Mouse Model: OPA1 gene therapy prevented RGC loss in a DOA mouse model ⁷⁾.

Isoform Optimization: Optimized OPA1 isoforms 1 and 7 show therapeutic effects in mitochondrial dysfunction models ⁸⁾.

Current Status: Preclinical stage.

Gene Editing

CRISPR-Cas9: Correction of the OPA1 c.1334G>A: p.R445H mutation in iPSCs restored mitochondrial homeostasis ⁹⁾.

Trans-splicing: An approach to correct pathogenic mutations at the mRNA level is also under investigation ⁶⁾.

Stem cells: Preclinical studies are investigating optic nerve regeneration using iPSC-derived RGCs⁶⁾.

Iterative reanalysis of exome sequencing is also an important diagnostic advance. With the expansion of genetic knowledge, new diagnoses may be obtained from data that were previously negative¹⁾.

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8. References

1. Brodsky MC, Olson RJ, Asumda FZ, et al. Identification of AFG3L2 dominant optic atrophy following reanalysis of clinical exome sequencing. Am J Ophthalmol Case Rep. 2023;30:101825.
2. Tachibana M, Hayashi T, Igawa Y, et al. Case of autosomal dominant optic atrophy with relatively good visual function. BMC Ophthalmol. 2025;25:443.
3. Al Othman B, Ong JE, Dumitrescu AV. Biallelic Optic Atrophy 1 (OPA1) Related Disorder—Case Report and Literature Review. Genes. 2022;13:1005.
4. Barboni P, Valentino ML, La Morgia C, et al. Idebenone treatment in patients with OPA1-mutant dominant optic atrophy. Brain. 2013;136:e231.
5. 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. 2020;7:590-4.
6. Wong DCS, Makam R, Yu-Wai-Man P. Advanced therapies for inherited optic neuropathies. Eye. 2026;40:177-84.
7. Sarzi E, Seveno M, Piro-Mégy C, et al. OPA1 gene therapy prevents retinal ganglion cell loss in a Dominant Optic Atrophy mouse model. Sci Rep. 2018;8:2468.
8. Maloney DM, Chadderton N, Millington-Ward S, et al. Optimized OPA1 isoforms 1 and 7 provide therapeutic benefit in models of mitochondrial dysfunction. Front Neurosci. 2020;14:571479.
9. Sladen PE, Perdigão PRL, Salsbury G, et al. CRISPR-Cas9 correction of OPA1 c.1334G>A: p.R445H restores mitochondrial homeostasis in dominant optic atrophy patient-derived iPSCs. Mol Ther Nucleic Acids. 2021;26:432-43.