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optic atrophy 12 (OPA12) - Clinical Profile, Genes & Research | Kisho | Kisho

Rare Disease

optic atrophy 12

MONDO:0033549

Also known as:OPA12

Overview

GeneticsAutosomal dominant · AFG3L2 (chr 18)

Clinical Presentation

Built from Human Phenotype Ontology (HPO) phenotype annotations and GeneReviews clinical descriptions. Features represent findings documented across known cases — not an exhaustive list of possible symptoms.

Features include always present findings: Peripheral axonal neuropathy, Gait ataxia, CSF oligoclonal immunoglobulin G bands, and Low muscle tone (hypotonia) and others; and very common findings: Reduced visual acuity and Color vision defect. 40 total HPO annotations.

Organ System	Phenotype Count	Example Features
Brain and nerves	14	Peripheral axonal neuropathy, Mild intellectual disability, Dystonia

Genetic Landscape

Assembled from HGNC gene records, ClinGen gene-disease validity evidence, and ClinVar pathogenic variant data. Validity classifications reflect the strength of published evidence linking each gene to this disease.

AFG3L2 encodes AFG3 like matrix AAA peptidase subunit 2 (797 aa). Catalytic component of the m-AAA protease, a protease that plays a key role in proteostasis of inner mitochondrial membrane proteins, and which is essential for axonal and neuron development. Highest expression in Muscle Skeletal (82.4 TPM) and Cells EBV-transformed lymphocytes (75.1 TPM).

Optic atrophy 12 is caused by mutations in the AFG3L2 gene on chromosome 18.

The AFG3L2 protein participates in Substrate of AFG3L2 (mitochondrial matrix), Substrate of AFG3L2 (mitochondrial inner membrane), and Substrate of YME1L1 (mitochondrial inner membrane) pathways.

AFG3L2 is classified as a druggable target (Enzyme, Neutral Zinc Metallopeptidase, and Protease categories) with score 0.0.

Diagnosis

Drawn from GeneReviews diagnostic guidelines, newborn screening panel status (RUSP), and ClinGen gene-disease validity classifications. Reflects current clinical evidence and consensus where available.

GeneReviews

Diagnostic Criteria

No consensus clinical diagnostic criteria for AFG3L2-related neurologic disorders have been published.

Suggestive Findings

The diagnosis of an AFG3L2-related neurologic disorder should be considered in probands with the following clinical and imaging findings and family history.

Clinical findings

Source: GeneReviews — "AFG3L2-Related Neurologic Disorders"

Treatment

Compiled from FDA-approved drug records, orphan drug designations, and FDA Adverse Event Reporting System (FAERS) safety data. GeneReviews management guidance is included where available.

No approved treatments are currently available for optic atrophy 12. The disease remains an area of unmet medical need.

GeneReviews

Management Guidelines

No clinical practice guidelines for AFG3L2-related neurologic disorders have been published. In the absence of published guidelines, the following recommendations are based on the authors' personal experience managing individuals with this disorder.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with an AFG3L2-related neurologic disorder, the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Prognosis

Based on GeneReviews surveillance recommendations, HPO phenotype frequency and severity annotations, and published prevalence estimates from Orphanet and OMIM.

GeneReviews

Surveillance Guidelines

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in are recommended.

Table 5.

AFG3L2-Related Neurologic Disorders: Recommended Surveillance

System/Concern | Evaluation | Frequency

Neurologic

| • Neurologic assessment for progression of ataxia, UMN or LMN signs, dystonia parkinsonism, autonomic dysfunction

Data assembled from 6 of 12 sources · Last updated Sep 18, 2026, 2:36 PM UTC

MONDOHPOClinicalTrials.govFDAPubMedHGNCClinVarClinGenGeneReviewsOrphanetOMIMRUSP

Medical References

External Resources

OMIM

Online Mendelian Inheritance in Man

OMIM:618977

GARD

Genetic and Rare Diseases Info Center

GARD:16399

Questions for Your Care Team

→Should I pursue genetic testing for AFG3L2, and what would the results mean for my family?
→Are there specialists or centers of excellence for this condition in my area?
→Is there a patient registry I should consider joining?

← Back to All Diseases

GeneReviews

Differential Diagnosis

Spinocerebellar ataxia type 28 (SCA28). The ataxic gait of individuals with SCA28 is indistinguishable from that seen in other adult-onset inherited or acquired ataxias. When the family history suggests autosomal dominant inheritance, all other autosomal dominant cerebellar ataxias should be considered (see Hereditary Ataxia Overview). Spastic ataxia type 5 (SPAX5). The differential diagnosis of SPAX5 should include other spastic ataxias and complex ataxias. AFG3L2-related autosomal recessive spinocerebellar ataxia (AFG3L2-SCAR) presents with a clinical phenotype that closely resembles SCA28; therefore, the differential diagnosis is similar to that of SCA28. Optic atrophy type 12 (OPA12). Optic atrophy observed in individuals with OPA12 is clinically indistinguishable from that seen in other forms of optic atrophy. See for selected genes of interest in the differential diagnosis of AFG3L2-related neurologic disorders. Table 2. Genes of Interest in the Differential Diagnosis of AFG3L2-Related Neurologic Disorders

Phenotype	MOI	Gene(s)	Disorder	Features of This Disorder / Comment
Spinocerebellar ataxia(See Hereditary Ataxia Overview.)	AD	ATN1	DRPLA	Polyglutamine expansions; Typically present before age 40 years; More rapidly progressive than SCA28 AFG3L2-SCAR; Assoc w/brain stem involvement on MRI AD
FGF14	GAA-FGF14-related ataxia (SCA27B)	Adult-onset ataxia; Typically begins w/episodic ataxia assoc w/downbeat nystagmus AR	—	—
APTX	Ataxia w/oculomotor apraxia type 1 (AOA1) (OMIM 208920)	AOA1 AOA2 are childhood-onset disorders characterized by marked peripheral involvement, incl severe polyneuropathy.; They are typically more rapidly progressive than SCA28 AFG3L2-SCAR. AR	SETX	Ataxia w/oculomotor apraxia type 2 (AOA2) AR
Chronic cough can precede neurologic symptoms by several decades. Spastic ataxia (SPAX)(OMIM PS108600)	AR	—	—	—
CHP1	SPAX9	Spastic ataxia that may present w/childhood onset AR	COQ4	SPAX10 AR

Source: GeneReviews — "AFG3L2-Related Neurologic Disorders"

Kisho

optic atrophy 12

Overview

Clinical Presentation

Genetic Landscape

Diagnosis

Diagnostic Criteria

Suggestive Findings

Treatment

Management Guidelines

Evaluations Following Initial Diagnosis

Prognosis

Surveillance Guidelines

Neurologic

Medical References

External Resources

OMIM

GARD

Questions for Your Care Team

Questions for Your Care Team

Clinical Guidance

Spinocerebellar Ataxia Type 28 (SCA28)

Explore clinical features

Clinical Guidance

Penetrance

Differential Diagnosis

Cerebellar extracerebellar

Clinical Guidance

Therapies Under Investigation

Clinical Trials

Dysarthria

Dysphagia

Weight/ Nutritional status

Family/Community

optic atrophy 12

Overview

Clinical Presentation

Genetic Landscape

Diagnosis

Diagnostic Criteria

Suggestive Findings

Treatment

Management Guidelines

Evaluations Following Initial Diagnosis

Prognosis

Surveillance Guidelines

Neurologic

Medical References

External Resources

OMIM

GARD

Related Diseases

Questions for Your Care Team

Questions for Your Care Team

Clinical Guidance

Spinocerebellar Ataxia Type 28 (SCA28)

Explore clinical features

Clinical Guidance

Penetrance

Differential Diagnosis

Cerebellar extracerebellar

Clinical Guidance

Therapies Under Investigation

Clinical Trials

Dysarthria

Dysphagia

Weight/ Nutritional status

Family/Community