Optic Atrophy 14 (MIEF1/MID51-related): Comprehensive Disease-Characteristics Report

Executive summary and evidence limits

Optic atrophy 14 (OPA14) is an ultra-rare, apparently autosomal-dominant mitochondrial-dynamics disorder caused by heterozygous variants in MIEF1, encoding the outer-mitochondrial-membrane protein MID51. Its defining phenotype is isolated, late-onset, progressive bilateral optic neuropathy, unusual among inherited optic neuropathies because peripheral visual-field loss precedes or exceeds central loss. The entire disease-defining clinical evidence retrieved traces to two women reported in 2021; consequently, frequencies calculated below describe that two-person series, not reliable population estimates. Open Targets recognizes the MIEF1–OPA14 association but likewise grounds its four evidence records in the same publication, PMID 33632269. (OpenTargets Search: optic atrophy 14-MIEF1, charif2021dominantmutationsin pages 1-3)

The most important verified findings and evidence gaps are summarized here:

Table: This table summarizes the verified evidence base for MIEF1/MID51-related optic atrophy, separating patient-level findings from broader mechanistic and epidemiologic evidence. It is useful for quickly identifying what is established, what is extrapolated, and what remains unknown.

1. Disease information

Definition

OPA14 is a nonsyndromic inherited optic neuropathy involving retinal ganglion-cell (RGC) degeneration, retinal nerve-fiber-layer (RNFL) loss, optic-disc pallor, visual-field constriction, and progressive visual impairment. The defining authors described it as an “unusual form of late-onset progressive optic neuropathy characterized by the initial loss of peripheral visual fields.” This contrasts with the central-to-peripheral field progression typical of most inherited optic neuropathies. (charif2021dominantmutationsin pages 1-3, charif2021dominantmutationsin pages 3-4)

Identifiers and synonyms

• MONDO: MONDO:0957824, optic atrophy 14.
• Causal target: MIEF1, Ensembl ENSG00000100335, approved name mitochondrial elongation factor 1.
• Protein/synonyms: MID51, MiD51, mitochondrial dynamics protein 51; MIEF1-related optic neuropathy; dominant MIEF1-related optic atrophy.
• Primary publication: Charif et al., Molecular Neurodegeneration, published February 2021; PMID 33632269; DOI and URL: https://doi.org/10.1186/s13024-021-00431-w. (charif2021dominantmutationsin pages 1-3, OpenTargets Search: optic atrophy 14-MIEF1)
• ClinVar condition records: RCV003387453 and RCV003387454, reported through Open Targets with release date 28 October 2023. (OpenTargets Search: optic atrophy 14-MIEF1)
• OMIM: the retrieved primary article gives MIEF1-related disease context but does not supply an OPA14 OMIM number; therefore none should be assigned from this evidence set.
• Orphanet, ICD-10, ICD-11 and MeSH: no disease-specific entries were verified. Broader codes for optic atrophy/hereditary optic neuropathy may be used clinically, but are not specific to OPA14.

The evidence consists of an aggregated disease-level ontology record linked to a primary, patient-level research cohort—not EHR-derived population data. Open Targets aggregates literature, Genomics England and EVA/ClinVar evidence, but all four association items cited the same human paper. (OpenTargets Search: optic atrophy 14-MIEF1)

2. Etiology, risk, protective and environmental factors

Causal factor

The established cause is a germline heterozygous MIEF1 missense variant that perturbs MID51-dependent mitochondrial-network dynamics. Both reported variants were confirmed by Sanger sequencing. A monoallelic autosomal, non-imprinted model is recorded by Open Targets and is biologically consistent with the authors’ designation of dominant disease. However, familial segregation was not reported, so transmission versus de novo occurrence remains unresolved. (charif2021dominantmutationsin pages 3-4, OpenTargets Search: optic atrophy 14-MIEF1)

Genetic risk factors

Two disease-associated variants are known from the defining report:

1. NM_019008.5:c.718T>A; p.(Tyr240Asn), p.Y240N, exon 6. It was absent from the databases queried in 2021 and affects the MID51 DRP1-binding region.
2. NM_019008.5:c.436C>T; p.(Arg146Trp), p.R146W, exon 5; dbSNP rs778124994; reported gnomAD allele frequency 1.99 × 10⁻⁵. Arg146 is conserved with MID49, although no specific function was assigned to that region. (charif2021dominantmutationsin pages 3-4)

Both were predicted damaging by SIFT and PolyPhen and disease-causing by MutationTaster. These predictions are supporting—not independently decisive—evidence. Functional assays substantially strengthen causality, but the tiny case count and absent segregation require caution in asserting penetrance or a broad genotype–phenotype relationship. (charif2021dominantmutationsin pages 3-4)

No susceptibility loci, modifier genes, protective alleles, founder variants, anticipation, germline mosaicism, or carrier-frequency estimates have been established. Because this is dominant disease, “carrier” is not clinically equivalent to an unaffected recessive carrier; variant-positive relatives may instead have age-dependent or presently unquantified risk.

Non-genetic factors and gene–environment interaction

No validated toxin, infection, dietary, smoking, alcohol, occupational, sex, or lifestyle risk factor is known. Patient 2 noticed loss one month after cesarean delivery, but a temporal association in one person does not establish pregnancy or surgery as a trigger. Patient 1 had seronegative rheumatoid polyarthritis treated with leflunomide; patient 2 had hypothyroidism, hypercholesterolemia and iron deficiency. Neither pattern was interpreted as causal. (charif2021dominantmutationsin pages 4-6)

No protective environmental factor or demonstrated gene–environment interaction exists. General avoidance of tobacco, excessive alcohol and known mitochondrial/optic-nerve toxins is biologically prudent in mitochondrial optic neuropathy, but this is extrapolation, not OPA14-specific evidence.

3. Phenotypes

Because only two patients are documented, “2/2” means the published series, not an estimated disease frequency.

• Late-adult visual loss (symptom): 2/2 women noticed visual dysfunction in adulthood; the clinical assessments occurred at ages 55 and 47. Onset was chronic/insidious in Patient 1 before an acute worsening and apparently sudden/painless in Patient 2. Suggested HPO: Adult onset (HP:0003581), Visual impairment (HP:0000505).
• Painless bilateral optic neuropathy/atrophy (sign): 2/2 had pale, moderately excavated optic discs and normal retina apart from Patient 2’s macular microcysts. Suggested HPO: Optic atrophy (HP:0000648), Bilateral optic atrophy where supported by the current HPO release. (charif2021dominantmutationsin pages 3-4, charif2021dominantmutationsin pages 4-6)
• Peripheral visual-field loss (functional sign): 2/2; Patient 2 had severely narrowed isopters and a bilateral superior altitudinal defect. Peripheral-to-central evolution is the phenotype’s most discriminating feature. Suggested HPO: Constricted visual fields (HP:0001133) and Visual field defect (HP:0001123). (charif2021dominantmutationsin pages 3-4, charif2021dominantmutationsin pages 4-6)
• Reduced visual acuity (symptom/sign): progressive and severe but variable between eyes. Suggested HPO: Decreased visual acuity (HP:0007663).
• RNFL loss (imaging sign): documented by OCT in Patient 2, with collapse in all quadrants of both eyes. Suggested HPO: Retinal nerve fiber layer thinning, subject to current HPO term verification. (charif2021dominantmutationsin pages 4-6)
• Abnormal VEP (electrophysiological abnormality): strongly affected bilaterally in 2/2. Suggested HPO: Abnormal visual evoked potentials (HP:0030453).
• Normal photoreceptor function: Patient 1’s scotopic and photopic ERGs were normal, supporting optic-nerve rather than generalized retinal disease. (charif2021dominantmutationsin pages 4-6)
• Macular microcysts: present in Patient 2 only (1/2); likely secondary to severe optic neuropathy rather than defining macular dystrophy. Suggested HPO: Cystoid macular edema (HP:0011505) only if the clinical morphology satisfies that term.
• Extraocular neurological/systemic disease: no additional neurological or neuromuscular syndrome was observed in either patient. Peripheral neuropathy was absent in Patient 1; Patient 2 had no diabetes, epilepsy or neuromuscular disorder, and normal brain MRI and ENT examination. (charif2021dominantmutationsin pages 3-4, charif2021dominantmutationsin pages 4-6)

Patient-level course

Patient 1: Maghreb-origin woman, age 55. A faint right-eye problem was noticed in 2002 with best visual acuity (BVA) 10/20. In 2015 she developed acute painless loss, mainly peripheral in both eyes and central in the right: right 1/20, left 18/20. VEPs were strongly abnormal; ERGs and retina were normal. (charif2021dominantmutationsin pages 4-6)

Patient 2: Egyptian-born woman, age 47, without youthful visual complaints. One month after an uneventful cesarean delivery in 2002, painless loss began in the right eye (3/20), then left (10/20). Acuity progressed to 2/20 and 8/20 in 2012, and hand-motion and 4/20 in 2015. OCT showed bilateral RNFL collapse; IOP was 9/10 mmHg, VEPs were severely affected, and MRI was normal. (charif2021dominantmutationsin pages 4-6)

Quality of life

No EQ-5D, SF-36, PROMIS or disease-specific quality-of-life instrument was reported. Nevertheless, hand-motion vision in one eye, marked field constriction and bilateral acuity loss imply substantial limitations in mobility, driving, reading and occupational independence. Those functional consequences are clinically plausible but were not quantitatively assessed.

4. Genetic and molecular information

Gene: MIEF1; transcript used in the report NM_019008.5; protein MID51. The retrieved evidence does not provide a verified HGNC numeric identifier, so it is not inferred here. (charif2021dominantmutationsin pages 3-4)

Variant class: both are germline heterozygous missense substitutions. No frameshift, nonsense, splice, structural, somatic or chromosomal cause of OPA14 has been demonstrated. SNP-array testing in both patients found no chromosomal abnormality, copy-number variant or large homozygous interval. (charif2021dominantmutationsin pages 4-6)

Functional consequence: the data support an altered-function mechanism rather than simple mistargeting or failure to oligomerize. Both proteins reached mitochondria and formed monomers, dimers, tetramers and rare high-molecular-weight species similarly to wild type, but failed to produce the wild-type increase in mitochondrial fusion and disrupted network dynamics. p.Y240N directly affects the DRP1-interacting loop at residues 238–242. Whether the human disease mechanism is dominant-negative, partial loss of regulatory function, or another gain-of-abnormal-function effect remains unproven. (charif2021dominantmutationsin pages 3-4, charif2021dominantmutationsin pages 6-8)

No modifier-gene, methylation, histone, chromatin, repeat-expansion or disease-specific epigenetic evidence is available.

5. Environmental information

No environmental toxin, ionizing radiation, pollution, occupational exposure, lifestyle behavior or infectious agent has been causally implicated. Lyme and Treponema serology were normal in Patient 1; anti-NMO and anti-MOG tests were negative in Patient 2. These findings helped exclude acquired inflammatory/infectious mimics rather than identify causal exposures. (charif2021dominantmutationsin pages 4-6)

6. Mechanism and pathophysiology

Disease-specific causal chain

1. Upstream trigger: heterozygous p.Y240N or p.R146W MID51 substitution.
2. Protein-level defect: preserved outer-mitochondrial-membrane targeting and self-oligomerization, but impaired regulation of mitochondrial fusion/fission dynamics.
3. Organelle-level consequence: reduced mitochondrial fusion events relative to wild-type MID51 and disrupted network remodeling in live-cell mito-PAGFP assays.
4. Cell vulnerability: RGCs and their long axons have unusually high ATP requirements and substantial unmyelinated intra-retinal segments; current expert reviews therefore regard mitochondrial energetic/dynamic failure and oxidative stress as central vulnerabilities.
5. Tissue injury: RGC/axon degeneration produces RNFL collapse, optic-disc pallor, abnormal VEPs, peripheral field loss and eventually severe acuity loss. (charif2021dominantmutationsin pages 1-3, charif2021dominantmutationsin pages 3-4, charif2021dominantmutationsin pages 4-6, d’esposito2024insightsonthe pages 2-4)

MID51 biology

MID51 is an integral outer-mitochondrial-membrane DRP1 adaptor. Its N-terminal transmembrane region anchors it, while a cytosolic nucleotidyltransferase-like domain binds ADP. General mechanistic studies indicate that ADP-bound MID51 stimulates DRP1 GTPase activity and oligomerization, connecting metabolic state to fission. Expression context matters: endogenous MID51 can organize productive DRP1 fission complexes, whereas overexpression can sequester inactive DRP1 and produce apparent mitochondrial elongation/fusion. This context dependence cautions against reducing OPA14 to simply “too much” or “too little” fission. (atkins2016theroleof pages 1-2, atkins2016theroleof pages 8-9, simpson2023posttranslationalcontrolof pages 52-57)

Suggested ontology annotations include:

• GO biological process: mitochondrial fission; mitochondrial fusion; regulation of mitochondrial organization; mitochondrial morphogenesis; mitophagy; cellular response to oxidative stress; neuron apoptotic process.
• GO cellular component: mitochondrion; mitochondrial outer membrane; mitochondrial fission site; mitochondria-associated ER membrane.
• GO molecular function: DRP1 binding/protein binding; adenyl ribonucleotide binding.
• Cell Ontology: retinal ganglion cell (CL:0000740) as the primary vulnerable cell; HeLa cell is the experimental system, not a disease-relevant retinal cell.

There is no direct OPA14 evidence for immune-mediated pathology, respiratory-chain enzyme deficiency, altered metabolites/lipids, apoptosis measurements, mitophagy flux, mtDNA instability, transcriptomic signatures or RGC-specific bioenergetics. Those remain plausible downstream research areas rather than established annotations.

Molecular profiling and advanced technologies

No disease-specific RNA-seq, single-cell sequencing, spatial transcriptomics, proteomics, metabolomics, lipidomics, methylomics, CRISPR screen, patient-derived iPSC, retinal organoid or multi-omics study was identified. The only functional system was transient expression of tagged wild-type or mutant MID51 in HeLa cells, assessed by confocal microscopy, immunoprecipitation and mito-PAGFP fusion assays. (charif2021dominantmutationsin pages 3-4, charif2021dominantmutationsin pages 6-8)

7. Anatomical structures affected

• Primary organ/system: eye and visual nervous system.
• Primary cells/tissue: RGCs and their axons; retinal nerve-fiber layer; optic-nerve head and optic nerve.
• Laterality: bilateral in both reported patients, with asymmetric severity in Patient 1 and more symmetric progression in Patient 2.
• Retina: structurally normal overall; Patient 2 had macular microcysts, while Patient 1 had normal photopic/scotopic ERGs.
• Brain and other organs: no demonstrated primary involvement; Patient 2’s brain MRI was normal. (charif2021dominantmutationsin pages 3-4, charif2021dominantmutationsin pages 4-6)

Suggested anatomy terms: UBERON:0000966 retina, UBERON:0001785 retinal nerve fiber layer, UBERON:0000962 optic nerve, and mitochondrial outer membrane as the relevant GO cellular compartment. Exact identifiers should be release-validated before database import.

8. Temporal development

OPA14 appears to be a chronic, lifelong, progressive disorder with late-adult clinical recognition. A latent peripheral-field defect may precede perceived acuity loss by years. The reported course combines insidious early dysfunction with sudden painless subjective worsening, followed by continued progression over 10–13 years. Patient 1 preserved good left-eye acuity despite severe right-eye disease; Patient 2 progressed bilaterally to profound impairment. No remission, episodic recovery or treatment-induced improvement was documented. (charif2021dominantmutationsin pages 3-4, charif2021dominantmutationsin pages 4-6)

No formal staging system or progression-rate model exists. A practical observational scheme would be: early peripheral-field constriction; intermediate bilateral field/acuity involvement with disc pallor; advanced severe RNFL loss and profound visual impairment. This is a proposed clinical abstraction, not a validated scale.

9. Inheritance and population

Inheritance is classified as autosomal dominant/monoallelic, but the evidence is based on heterozygosity and functional studies rather than reported multigenerational segregation. Penetrance, age dependence, expressivity across families, de novo rate, parental mosaicism, anticipation and reproductive fitness are unknown. (OpenTargets Search: optic atrophy 14-MIEF1)

The original study found MIEF1 variants in 2/200 (1.0%) French molecularly unresolved inherited-optic-neuropathy referrals. This is a selected-cohort diagnostic fraction, not prevalence. (charif2021dominantmutationsin pages 3-4)

A 2023 analysis of 2,186 hereditary-optic-neuropathy probands reported an overall molecular diagnosis in 30%; the autosomal subgroup had 451 diagnoses among 1,680 referrals, and ten major genes accounted for 96% of those diagnoses. MIEF1 appeared in only two individuals among the rare-gene findings, confirming that it is a minor diagnostic contributor. Reported “1.08%” refers to the relevant diagnosed subgroup, not the general population. (rocatcher2023thetop10 pages 2-3, rocatcher2023thetop10 pages 1-1)

Population prevalence, annual incidence, geographic distribution, ancestry-specific enrichment and sex ratio cannot be estimated. Both known patients were women—one of Maghreb origin and one born in Egypt—but n=2 cannot support a female predisposition or North African founder effect.

10. Diagnostics

Clinical evaluation

The phenotype should prompt neuro-ophthalmic assessment comprising best-corrected acuity, color vision, pupils, slit-lamp examination, IOP, dilated funduscopy, automated and/or kinetic perimetry, optic-disc/RNFL and macular OCT, and VEP. ERG is useful when retinal dystrophy is a concern. Color-vision data were not reported in the defining cases. MRI of brain/orbits with contrast and inflammatory/infectious testing should be guided by presentation, particularly for acute or asymmetric loss.

Findings supporting OPA14 are bilateral pale/excavated discs with normal IOP, marked peripheral or superior-altitudinal field loss, progressive RNFL thinning and severely abnormal VEP despite an otherwise normal retina. (charif2021dominantmutationsin pages 3-4, charif2021dominantmutationsin pages 4-6)

Molecular testing

1. Exclude common mitochondrial and nuclear optic-neuropathy causes using a comprehensive hereditary optic-neuropathy panel that includes MIEF1, OPA1, OPA3, WFS1, ACO2, SPG7, MFN2, AFG3L2, RTN4IP1, TMEM126A, NR2F1, FDXR, DNM1L, MFF, and relevant mtDNA variants.
2. Confirm candidate MIEF1 variants by an orthogonal method and perform parental/relative testing for segregation and penetrance assessment.
3. If panel testing is negative, WES/WGS can identify newly recognized genes, intronic variants, mtDNA changes and structural variants, subject to assay validation.
4. CMA is reasonable when syndromic features or developmental abnormalities suggest a copy-number disorder; it was negative in both OPA14 cases. Karyotyping/FISH, repeat-expansion testing and liquid biopsy are not routine OPA14 tests. (charif2021dominantmutationsin pages 4-6, charif2021dominantmutationsin pages 6-8, rocatcher2023thetop10 pages 2-3)

The original 22-gene panel achieved >100× coverage for 95% of targeted bases, with Sanger fill-in of poorly covered regions. Modern broader panels or exome/genome sequencing are preferable because the 2023 cohort demonstrated extensive locus heterogeneity. (charif2021dominantmutationsin pages 4-6, rocatcher2023thetop10 pages 1-1)

Differential diagnosis

Important alternatives include OPA1-dominant optic atrophy, LHON, WFS1/ACO2/MFN2/SPG7/AFG3L2-related neuropathies, glaucoma, toxic/nutritional optic neuropathy, compressive lesions, ischemic optic neuropathy, neuromyelitis-optica-spectrum disorder, MOG-associated disease and infectious optic neuropathy. Peripheral-to-central field progression, normal IOP, absent disc edema and a pathogenic functional MIEF1 variant favor OPA14, but no consensus diagnostic criteria exist. (charif2021dominantmutationsin pages 3-4, charif2021dominantmutationsin pages 4-6)

Screening

There is no newborn or population screening. Once a credible pathogenic familial variant is established, targeted cascade testing with pre-test counseling and baseline/serial ophthalmic assessment is appropriate. Testing asymptomatic minors requires individualized consideration because onset appears adult and no preventive therapy is proven.

11. Outcome and prognosis

The documented outcome is progressive, irreversible visual morbidity. Over approximately 13 years, Patient 2 reached hand-motion vision in the right eye and 4/20 in the left; Patient 1 reached 1/20 in the right while retaining 18/20 in the left. Thus, severe bilateral disability is possible, but asymmetry and retained useful vision can occur. (charif2021dominantmutationsin pages 3-4, charif2021dominantmutationsin pages 4-6)

No survival, mortality, life-expectancy, recovery-rate or validated prognostic-biomarker data exist. Neither patient had a life-limiting neurological syndrome, so available evidence supports vision-dominant morbidity rather than reduced survival. Prognostic inference from variant, onset age, OCT thickness or initial visual field is currently impossible.

12. Treatment and current implementation

No pharmacological, surgical, gene, cell, RNA or immune therapy is approved or clinically validated specifically for OPA14. No MIEF1-specific interventional trial or treatment-response series was identified. The 2021 report describes clinical progression, not a therapeutic intervention. (charif2021dominantmutationsin pages 3-4, charif2021dominantmutationsin pages 4-6)

Current real-world management is therefore supportive:

• periodic neuro-ophthalmic follow-up with acuity, fields and OCT;
• low-vision rehabilitation, optical/electronic aids, orientation-and-mobility training and occupational accommodations;
• management of reversible coincident deficiencies and avoidance of recognized optic-nerve toxins;
• genetic counseling and cascade testing;
• psychological and social support for progressive visual disability.

Suggested NCIT-level intervention concepts include Genetic Counseling, Genetic Testing, Ophthalmologic Examination, Optical Coherence Tomography, Visual Field Test, Low Vision Rehabilitation, and Assistive Device; identifiers should be checked against the target NCIT release.

Recent 2023–2024 reviews discuss idebenone, coenzyme Q10, cysteamine/NAD⁺ strategies, AAV gene therapy, CRISPR and RNA therapies for other optic neuropathies. Idebenone is approved in Europe for LHON—not MIEF1 disease—and none should be prescribed as OPA14-directed therapy without evidence or a protocol. Experts emphasize integrating genotype and phenotype while recognizing that mitochondrial-dynamics therapeutics remain investigational. (d’esposito2024insightsonthe pages 11-12, d’esposito2024insightsonthe pages 1-2, d’esposito2024insightsonthe pages 12-14)

13. Prevention

Primary prevention by lifestyle change, immunization or prophylactic medication is unavailable because OPA14 is genetic. Reproductive options after identification of a well-supported familial variant include genetic counseling, prenatal diagnosis and preimplantation genetic testing; these require discussion of uncertain penetrance and the limited variant evidence.

Secondary prevention consists of cascade testing and surveillance to detect presymptomatic field/RNFL changes, although no study proves that early detection alters progression. Tertiary prevention centers on low-vision care, fall-risk reduction, workplace adaptation and avoiding additional acquired optic-nerve injury. Vaccination and infectious-disease public-health measures have no disease-specific role.

14. Other species and natural disease

No naturally occurring MIEF1-related optic atrophy was identified in companion animals, livestock or wildlife, and there is no zoonotic or cross-species transmission. MIEF1/MID51 biology is evolutionarily conserved among vertebrates, but conservation alone is not evidence of a homologous veterinary disorder. NCBI Taxon identifiers relevant to future comparative work include Homo sapiens: 9606 and Mus musculus: 10090; ortholog gene IDs should be verified directly in the current NCBI Gene release before import.

15. Model organisms and research models

The disease-defining model was transfected HeLa cells, not an organismal or retinal model. Tagged p.Y240N and p.R146W proteins were tested for mitochondrial localization, oligomerization and fusion/network behavior by live-cell confocal microscopy and mito-PAGFP. This model provides strong evidence for variant-dependent organelle dysfunction but cannot reproduce RGC identity, optic-nerve architecture, age-dependent penetrance, visual-field loss or long-term neurodegeneration. (charif2021dominantmutationsin pages 3-4, charif2021dominantmutationsin pages 6-8)

No OPA14-specific knock-in/knockout mouse, rat, zebrafish, Drosophila, C. elegans, yeast, patient fibroblast, iPSC-RGC or retinal organoid model was identified. Priority models are heterozygous p.Y240N and p.R146W knock-in animals and patient-derived iPSC-RGCs, with endpoints including DRP1 recruitment, mitochondrial transport/fission/fusion, mitophagy, ATP/ROS, axonal survival, RNFL thickness and visual function.

Recent developments and expert interpretation

The principal post-discovery development is diagnostic rather than therapeutic. The 2023, 2,186-proband study showed that comprehensive sequencing produces a 30% overall diagnostic rate, while MIEF1 remains among the individually rare contributors; this supports retaining MIEF1 on broad optic-neuropathy panels rather than using it as first-line single-gene testing. (rocatcher2023thetop10 pages 2-3, rocatcher2023thetop10 pages 1-1)

A 2024 review reinforced high energetic demand, mitochondrial dysfunction and oxidative stress as central to RGC vulnerability and highlighted genotype–phenotype integration and emerging molecular therapies. None of those advances has yet produced an OPA14-specific intervention. (d’esposito2024insightsonthe pages 11-12, d’esposito2024insightsonthe pages 1-2, d’esposito2024insightsonthe pages 2-4)

Knowledge-base confidence statement

High confidence: MIEF1 association; the two reported variants and patient phenotypes; bilateral late-onset peripheral-field-predominant optic neuropathy; abnormal MID51 network regulation in HeLa-cell assays.

Moderate confidence: autosomal-dominant mechanism and nonsyndromic classification, because familial segregation and broader natural history remain unavailable.

Low or insufficient evidence: penetrance, population epidemiology, sex/ancestry effects, variant-specific prognosis, environmental triggers, protective factors, biochemical biomarkers, treatment, prevention of progression, advanced omics and organismal models.

Key primary-source quotation

The disease-defining abstract states: “Using targeted sequencing of genes involved in mitochondrial dynamics, we report the first heterozygous variants in MIEF1 linked to disease, which cause an unusual form of late-onset progressive optic neuropathy characterized by the initial loss of peripheral visual fields.” It further reports that the variants “do not disrupt MID51’s localization to the outer mitochondrial membrane or its oligomerization, but rather, significantly disrupt mitochondrial network dynamics.” (charif2021dominantmutationsin pages 1-3)

References

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2. (charif2021dominantmutationsin pages 1-3): Majida Charif, Yvette C. Wong, Soojin Kim, Agnès Guichet, Catherine Vignal, Xavier Zanlonghi, Philippe Bensaid, Vincent Procaccio, Dominique Bonneau, Patrizia Amati-Bonneau, Pascal Reynier, Dimitri Krainc, and Guy Lenaers. Dominant mutations in mief1 affect mitochondrial dynamics and cause a singular late onset optic neuropathy. Molecular Neurodegeneration, Feb 2021. URL: https://doi.org/10.1186/s13024-021-00431-w, doi:10.1186/s13024-021-00431-w. This article has 20 citations and is from a highest quality peer-reviewed journal.

3. (charif2021dominantmutationsin pages 4-6): Majida Charif, Yvette C. Wong, Soojin Kim, Agnès Guichet, Catherine Vignal, Xavier Zanlonghi, Philippe Bensaid, Vincent Procaccio, Dominique Bonneau, Patrizia Amati-Bonneau, Pascal Reynier, Dimitri Krainc, and Guy Lenaers. Dominant mutations in mief1 affect mitochondrial dynamics and cause a singular late onset optic neuropathy. Molecular Neurodegeneration, Feb 2021. URL: https://doi.org/10.1186/s13024-021-00431-w, doi:10.1186/s13024-021-00431-w. This article has 20 citations and is from a highest quality peer-reviewed journal.

4. (charif2021dominantmutationsin pages 3-4): Majida Charif, Yvette C. Wong, Soojin Kim, Agnès Guichet, Catherine Vignal, Xavier Zanlonghi, Philippe Bensaid, Vincent Procaccio, Dominique Bonneau, Patrizia Amati-Bonneau, Pascal Reynier, Dimitri Krainc, and Guy Lenaers. Dominant mutations in mief1 affect mitochondrial dynamics and cause a singular late onset optic neuropathy. Molecular Neurodegeneration, Feb 2021. URL: https://doi.org/10.1186/s13024-021-00431-w, doi:10.1186/s13024-021-00431-w. This article has 20 citations and is from a highest quality peer-reviewed journal.

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7. (atkins2016theroleof pages 8-9): Kathleen Atkins, Asish Dasgupta, Kuang-Hueih Chen, Jeff Mewburn, and Stephen L. Archer. The role of drp1 adaptor proteins mid49 and mid51 in mitochondrial fission: implications for human disease. Clinical science, 130 21:1861-74, Nov 2016. URL: https://doi.org/10.1042/cs20160030, doi:10.1042/cs20160030. This article has 142 citations and is from a peer-reviewed journal.

8. (rocatcher2023thetop10 pages 2-3): Aude Rocatcher, Valérie Desquiret-Dumas, Majida Charif, Marc Ferré, Philippe Gohier, Delphine Mirebeau-Prunier, Christophe Verny, Dan Milea, Guy Lenaers, Catherine Vignal, Cédric Lamirel, Rabih Hage, Hélène Dollfus, Isabelle Meunier, Xavier Zanlonghi, Valérie Touitou, Pierre Lebranchu, Sylvie Odent, Caroline Froment Tilikete, Luc Jeanjean, Sabine Defoort-Dhellemmes, Isabelle Drumare-Bouvet, Vasily Smirnov, Catherine Vincent-Delorme, Damien Biotti, Fanny Varenne, Patrick Calvas, Nicolas Chassaing, Mickael Cohen, Christophe Orssaud, Fanny Mochel, Agathe Roubertie, Annick Toutain, Frédéric Pollet-Villard, Marie Noelle Bonnet Dupeyron, Céline Boulicot, Béatrice Cochener, Alice Goldenberg, Marie Line Jacquemont, Christine Francannet, Dominique Bonneau, Pascal Reynier, and Patrizia Amati-Bonneau. The top 10 most frequently involved genes in hereditary optic neuropathies in 2186 probands. Brain : a journal of neurology, 146:455-460, Nov 2023. URL: https://doi.org/10.1093/brain/awac395, doi:10.1093/brain/awac395. This article has 53 citations.

9. (rocatcher2023thetop10 pages 1-1): Aude Rocatcher, Valérie Desquiret-Dumas, Majida Charif, Marc Ferré, Philippe Gohier, Delphine Mirebeau-Prunier, Christophe Verny, Dan Milea, Guy Lenaers, Catherine Vignal, Cédric Lamirel, Rabih Hage, Hélène Dollfus, Isabelle Meunier, Xavier Zanlonghi, Valérie Touitou, Pierre Lebranchu, Sylvie Odent, Caroline Froment Tilikete, Luc Jeanjean, Sabine Defoort-Dhellemmes, Isabelle Drumare-Bouvet, Vasily Smirnov, Catherine Vincent-Delorme, Damien Biotti, Fanny Varenne, Patrick Calvas, Nicolas Chassaing, Mickael Cohen, Christophe Orssaud, Fanny Mochel, Agathe Roubertie, Annick Toutain, Frédéric Pollet-Villard, Marie Noelle Bonnet Dupeyron, Céline Boulicot, Béatrice Cochener, Alice Goldenberg, Marie Line Jacquemont, Christine Francannet, Dominique Bonneau, Pascal Reynier, and Patrizia Amati-Bonneau. The top 10 most frequently involved genes in hereditary optic neuropathies in 2186 probands. Brain : a journal of neurology, 146:455-460, Nov 2023. URL: https://doi.org/10.1093/brain/awac395, doi:10.1093/brain/awac395. This article has 53 citations.

10. (d’esposito2024insightsonthe pages 11-12): Fabiana D’Esposito, Marco Zeppieri, Maria Francesca Cordeiro, Matteo Capobianco, Alessandro Avitabile, Giuseppe Gagliano, Mutali Musa, Piero Barboni, and Caterina Gagliano. Insights on the genetic and phenotypic complexities of optic neuropathies. Genes, 15(12):1559, Nov 2024. URL: https://doi.org/10.3390/genes15121559, doi:10.3390/genes15121559. This article has 12 citations.

11. (d’esposito2024insightsonthe pages 1-2): Fabiana D’Esposito, Marco Zeppieri, Maria Francesca Cordeiro, Matteo Capobianco, Alessandro Avitabile, Giuseppe Gagliano, Mutali Musa, Piero Barboni, and Caterina Gagliano. Insights on the genetic and phenotypic complexities of optic neuropathies. Genes, 15(12):1559, Nov 2024. URL: https://doi.org/10.3390/genes15121559, doi:10.3390/genes15121559. This article has 12 citations.

12. (d’esposito2024insightsonthe pages 12-14): Fabiana D’Esposito, Marco Zeppieri, Maria Francesca Cordeiro, Matteo Capobianco, Alessandro Avitabile, Giuseppe Gagliano, Mutali Musa, Piero Barboni, and Caterina Gagliano. Insights on the genetic and phenotypic complexities of optic neuropathies. Genes, 15(12):1559, Nov 2024. URL: https://doi.org/10.3390/genes15121559, doi:10.3390/genes15121559. This article has 12 citations.

13. (d’esposito2024insightsonthe pages 2-4): Fabiana D’Esposito, Marco Zeppieri, Maria Francesca Cordeiro, Matteo Capobianco, Alessandro Avitabile, Giuseppe Gagliano, Mutali Musa, Piero Barboni, and Caterina Gagliano. Insights on the genetic and phenotypic complexities of optic neuropathies. Genes, 15(12):1559, Nov 2024. URL: https://doi.org/10.3390/genes15121559, doi:10.3390/genes15121559. This article has 12 citations.

14. (simpson2023posttranslationalcontrolof pages 52-57): Post-translational control of mitochondria by Fbxo7 in Parkinson's disease This article has 0 citations.

Artifacts

• Edison artifact artifact-00

Reference Validation

Checked with linkml-reference-validator 0.2.1.

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

• MONDO:0957824 (3 mentions) - the report calls it "if available"; MONDO calls it optic atrophy 14

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

• CL:0000740 (1 mention) - the report calls it "Cell Ontology: retinal ganglion cell"; CL calls it retinal ganglion cell