| domain | verified finding | quantitative details | evidence type/strength |
|---|---|---|---|
| disease identity | Optic atrophy 14 is a very rare inherited optic neuropathy associated with **MIEF1** (MID51); MONDO disease mapping supports the association. | MONDO:0957824; MIEF1 Ensembl **ENSG00000100335**; Open Targets association score **0.5659** with 4 evidence items tied to PMID 33632269. (pqac-00000009, pqac-00000000) | Curated disease-target database + primary human report; moderate for identity, limited by few cases. |
| Patient 1 | Female with late-adult onset, non-syndromic optic neuropathy featuring peripheral visual field loss progressing to central loss, optic disc pallor/excavation, abnormal VEP, normal ERG/retina. | Age **55**; origin **Maghreb**; first noted visual problem in **2002**; right-eye BVA **10/20** initially, by **2015** right eye **1/20**, left eye **18/20**; elevated sedimentation rate **44 mm**; no peripheral neuropathy reported. (pqac-00000006, pqac-00000005) | Primary human case report; strong for phenotype in this individual. |
| Patient 2 | Female with late-adult onset optic neuropathy after cesarean delivery, superior altitudinal/peripheral field loss, optic disc pallor/excavation, macular microcysts, severe RNFL loss, abnormal VEP, normal brain MRI/ENT. | Age **47**; born in **Egypt**; onset **2002**, **1 month after cesarean**; initial BVA right **3/20**, left **10/20**; by **2012** right **2/20**, left **8/20**; by **2015** right **hand moving**, left **4/20**; IOP right **9 mmHg**, left **10 mmHg**. (pqac-00000006, pqac-00000005) | Primary human case report; strong for phenotype in this individual. |
| genetics | Two heterozygous missense MIEF1 variants were identified and confirmed by Sanger sequencing; inheritance interpreted as dominant/monoallelic, but familial segregation data were not reported. | Patient 1: **c.718T>A, p.Y240N**, absent from cited databases; Patient 2: **c.436C>T, p.R146W**, **rs778124994**, gnomAD frequency **1.99e-5**; variants predicted damaging by **SIFT/PolyPhen** and disease-causing by **MutationTaster**. ClinVar records **RCV003387453/RCV003387454** released **2023-10-28**. (pqac-00000005, pqac-00000009) | Primary human genetics + curated variant database; moderate-high for variant-disease link, limited by n=2 and absent segregation. |
| functional mechanism | Disease-linked MID51 variants do **not** disrupt mitochondrial localization or oligomerization, but **do** impair mitochondrial network dynamics/fusion in cell assays; p.Y240N lies in the DRP1-binding region. | Mutant proteins localized to mitochondria similarly to WT; oligomerization pattern retained; mito-PAGFP assays showed significantly reduced fusion versus WT; p.Y240 located in DRP1-binding loop **238-242**; MID51 is an outer mitochondrial membrane DRP1 adaptor. (pqac-00000005, pqac-00000007, pqac-00000011, pqac-00000012) | Disease-specific in vitro functional evidence + broader mechanistic literature; moderate-high for mechanism, indirect for retinal tissue. |
| epidemiology | Extremely rare cause of hereditary optic neuropathy; no population prevalence or incidence established. | In the original French unsolved ION cohort, **2/200** cases carried MIEF1 variants (**1.0%**). In a larger 2023 hereditary optic neuropathy dataset, MIEF1 accounted for **2 individuals** and ~**1.08%** of positive optic atrophy diagnoses in the relevant subgroup; overall positive diagnostic rate across 2,186 probands was **30%**. (pqac-00000010, pqac-00000014, pqac-00000015) | Cohort-based observational evidence; moderate for rarity within referral cohorts, low for general-population frequency. |
| diagnosis | Current diagnosis relies on ophthalmic phenotyping plus molecular testing after exclusion of more common optic neuropathy causes; expanded gene panels improve detection of rare genes like MIEF1. | In both cases: normal retina, pale moderately excavated optic discs, abnormal VEP; Patient 2 had OCT evidence of RNFL collapse in all quadrants. Negative/normal workup included OPA1/OPA3/WFS1 and primary LHON mtDNA mutations, SNP array (no CNV/chromosomal abnormality/large ROH), anti-NMO and anti-MOG serology in Patient 2, and glaucoma-compatible findings absent at presentation. Initial study panel covered **22 genes** with **>95%** of bases at **>100X** coverage. (pqac-00000006, pqac-00000007, pqac-00000014) | Primary clinical diagnostic evidence + cohort practice data; high for reported cases. |
| treatment | No disease-specific therapy, clinical trial, or formal management guideline was identified for MIEF1-related optic atrophy; care is supportive. | No treatment response data reported in the two cases. Reviews of inherited optic neuropathies discuss **idebenone** (approved for LHON in Europe), antioxidants, gene/RNA-based therapies, cysteamine, and NAD+ strategies, but **not as established therapy for MIEF1 optic atrophy**. (pqac-00000017, pqac-00000018, pqac-00000020) | Direct evidence absent for MIEF1; only low-strength extrapolation from broader optic neuropathy literature. |
| evidence gaps | Major unanswered questions remain on natural history, penetrance, segregation, sex effects, modifier genes, environmental triggers, pathology outside the optic nerve, and translational models. | Only **2 published disease-defining patients** were identified in retrieved evidence; no validated prevalence/incidence, no mortality/prognosis statistics, no disease-specific animal/iPSC/omics studies, no preventive factors, and no interventional trials found. (pqac-00000010, pqac-00000020) | Strong evidence of knowledge scarcity; conclusions limited by ultra-rare case count. |


*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.*