| domain | key facts | ontology/identifier suggestions | evidence/source |
|---|---|---|---|
| Disease definition | Primary inherited optic neuropathy causing rapid, painless, usually sequential bilateral central vision loss due to selective retinal ganglion cell degeneration and mitochondrial dysfunction | MONDO: **MONDO:0010788**; OMIM: **535000**; MeSH: **D029242** (“Optic Atrophy, Hereditary, Leber”); Category: Mendelian, mitochondrial; autosomal-recessive subtype noted separately | (pqac-00000000, pqac-00000003, pqac-00000012) |
| Disease identifiers / subtypes | Classical form is maternally inherited mtDNA disease; autosomal-recessive LHON also recognized | OMIM arLHON: **619382**; MONDO arLHON: **MONDO:0030309**; “Leber-like hereditary optic neuropathy, autosomal recessive 1/2” MONDOs available via Open Targets context; ICD-10/ICD-11: **uncertain—verify in OMIM/Orphanet/WHO** | (pqac-00000000, pqac-00000010, pqac-00000011) |
| Synonyms | Leber hereditary optic neuropathy; Leber hereditary optic atrophy; hereditary optic atrophy, Leber type; LHON | Synonym curation term set; MeSH disease heading above | (pqac-00000012, pqac-00000015) |
| Causal genes / variants | >90–95% of cases due to three mtDNA missense variants affecting complex I: **m.11778G>A (MT-ND4)**, **m.3460G>A (MT-ND1)**, **m.14484T>C (MT-ND6)** | Genes: **MT-ND4, MT-ND1, MT-ND6**; variant class: missense, germline mtDNA; inheritance: mitochondrial | (pqac-00000003, pqac-00000006, pqac-00000014) |
| Additional genetic causes | Nuclear autosomal-recessive LHON genes recently implicated: **DNAJC30, NDUFS2, NDUFAF5**; 2023 review also lists **MCAT, NDUFA12** in unresolved LHON phenotype | OMIM gene IDs available for DNAJC30 **618202**, NDUFS2 **612985**, NDUFAF5 **612360**; inheritance: autosomal recessive | (pqac-00000010, pqac-00000002) |
| Modifier biology | Incomplete penetrance; male bias; estrogen proposed as protective for mitochondrial function; treatment response may be modified by **NQO1** levels | Modifier genes/factors: **NQO1** (pharmacogenetic response modifier), sex-related hormonal effect; haplogroup/heteroplasmy details **not fully resolved in gathered evidence** | (pqac-00000004, pqac-00000010, pqac-00000013) |
| Environmental risk factors | Smoking, excessive alcohol use, and toxic medications/exposures are advised against in carriers; environmental triggers modulate disease expression | CHEBI/Exposures: tobacco smoke **uncertain CHEBI mapping here**; ethanol **CHEBI:16236** (verify if needed); exposure ontology terms **uncertain—verify** | (pqac-00000003, pqac-00000011, pqac-00000013) |
| Protective / preventive factors | Avoid oxidative stressors; family screening/counseling; early recognition may enable treatment; vitamin B12 screening may be relevant in carriers because deficiency is enriched | Prevention annotations: cascade screening; genetic counseling; vitamin B12 monitoring (**CHEBI:176843 cyanocobalamin class mapping uncertain**) | (pqac-00000003, pqac-00000013) |
| Core phenotype | Bilateral painless subacute central visual loss, often sequential; dyschromatopsia; dense central/centrocecal scotoma; poor acuity often worse than 20/200 | HPO suggestions: **central scotoma (HP term verify)**, **decreased visual acuity (HP term verify)**, **dyschromatopsia/color vision defect (HP term verify)**, **optic atrophy (HP:0000648 likely, verify)** | (pqac-00000002, pqac-00000003, pqac-00000004, pqac-00000006) |
| Fundus / structural ocular findings | Acute/subacute phase may show optic disc hyperemia, peripapillary telangiectasia, vascular tortuosity, RNFL swelling; chronic phase shows RNFL and ganglion cell thinning with temporal then diffuse optic pallor | HPO suggestions: **optic disc pallor (verify)**, **retinal nerve fiber layer thinning (verify)**, **abnormality of color vision (verify)** | (pqac-00000002, pqac-00000003, pqac-00000006, pqac-00000014) |
| Disease stages / temporal development | Stages commonly described as asymptomatic carrier, subacute **<6 months**, dynamic **6–12 months**, chronic **>12 months**; second eye usually affected within weeks to months | Temporal annotations for KB; onset: adolescent/young adult; pattern: subacute progressive bilateral sequential | (pqac-00000002, pqac-00000004, pqac-00000007) |
| Age / sex distribution | Peak onset typically **15–30/35 years**; onset can range from childhood to late adulthood; male predominance; penetrance estimates in gathered evidence range around **17.5% males, 5.4% females** or older estimates **40–50% males, ~10% females** | Demography fields: male-biased expression; age-at-onset = adolescent/young adult | (pqac-00000003, pqac-00000004, pqac-00000006, pqac-00000010) |
| Epidemiology | Prevalence estimates vary by population: approximately **1/30,000 to 1/50,000** commonly cited; Madrid population study estimated **0.55/100,000 confirmed**, **0.79/100,000 capture-recapture**; susceptibility allele prevalence may be **1 in 800–1000** | Epidemiology fields: prevalence, sex-stratified prevalence; disease rarity | (pqac-00000003, pqac-00000006, pqac-00000011) |
| Extraocular / LHON-plus manifestations | Some patients have neurologic/systemic disease: dystonia, epilepsy, cerebellar ataxia, parkinsonism, myoclonus, peripheral neuropathy, encephalopathy; cardiac/endocrine dysfunction; overlap with multiple sclerosis (“Harding disease”) | HPO suggestions: **ataxia (verify)**, **peripheral neuropathy (verify)**, **dystonia (verify)**; disease note: LHON-plus / Harding disease | (pqac-00000004, pqac-00000014) |
| Molecular mechanism | Primary lesion is **complex I dysfunction** in oxidative phosphorylation, reducing ATP generation and increasing reactive oxygen species; this initiates retinal ganglion cell dysfunction/apoptosis | GO suggestions: **oxidative phosphorylation (GO:0006119)**, **mitochondrial electron transport, NADH to ubiquinone (GO term verify)**, **ATP synthesis coupled electron transport (GO:0042773 verify)**, **reactive oxygen species metabolic process (GO:0072593 verify)**, **apoptotic process (GO:0006915)** | (pqac-00000011, pqac-00000014) |
| Selective vulnerability | Preferential involvement of small axons in the **papillomacular bundle** serving central vision; degeneration extends along optic pathways | Anatomy/process links: papillomacular bundle **anatomy term uncertain—verify**; optic nerve degeneration | (pqac-00000002, pqac-00000014) |
| Cell types involved | Primary affected cells are **retinal ganglion cells** and their axons; glial involvement/demyelination inferred in visual pathways on MRI/histopathology | CL suggestions: **retinal ganglion cell (CL term verify)**; oligodendrocyte/astrocyte involvement **secondary, verify** | (pqac-00000003, pqac-00000014) |
| Anatomy affected | Retina, retinal nerve fiber layer, ganglion cell layer, optic disc, optic nerve, optic chiasm/tracts, lateral geniculate nucleus, visual cortex | UBERON suggestions: **retina (UBERON:0000966 likely, verify)**, **optic nerve (UBERON term verify)**, **optic chiasm (verify)**, **lateral geniculate nucleus (verify)**, **visual cortex (verify)** | (pqac-00000014) |
| Subcellular localization | Inner mitochondrial membrane / respiratory chain complex I are central sites of dysfunction | GO Cellular Component suggestions: **mitochondrion (GO:0005739)**, **mitochondrial inner membrane (GO:0005743)**, **respiratory chain complex I (GO term verify)** | (pqac-00000011, pqac-00000014) |
| Diagnostic workflow | Clinical recognition plus targeted genetic testing for three common mtDNA variants first; if negative but suspicion persists, comprehensive mtDNA sequencing; consider nuclear arLHON genes if unresolved | Diagnostic concepts: targeted mtDNA testing; full mtDNA sequencing; nuclear gene panel incl. **DNAJC30/NDUFS2/NDUFAF5** and others | (pqac-00000002, pqac-00000006) |
| Diagnostic tests | Ophthalmic evaluation includes ETDRS visual acuity, OCT (RNFL/GCL changes), visual field testing with central/centrocecal scotoma, contrast sensitivity, color vision testing | LOINC-specific mappings **not gathered**; functional tests: OCT, Humphrey visual field, Pelli-Robson, Farnsworth-Munsell | (pqac-00000003, pqac-00000015, pqac-00000016) |
| Differential diagnosis | Frequently misdiagnosed as inflammatory optic neuritis; also other optic neuropathies/toxic-metabolic causes should be excluded | Differential disease concepts: optic neuritis, NMOSD/MOGAD-related optic neuritis, toxic/nutritional optic neuropathy | (pqac-00000006) |
| Prognosis / natural history | Visual acuity often plateaus by ~4 months at severe impairment; spontaneous recovery depends strongly on genotype, best with **m.14484T>C**; chronic deficits common | Prognosis fields: genotype-dependent recovery; early childhood onset may have better prognosis | (pqac-00000004, pqac-00000008) |
| Variant-specific recovery | Spontaneous recovery estimates in gathered evidence: **m.14484T>C up to 70%** (or 37–71% in older review) vs **m.11778G>A ~4–23% / ~15%** and **m.3460G>A ~15–25% / ~15%** | Genotype–phenotype annotation | (pqac-00000006, pqac-00000008) |
| Quality of life / burden | Vision-related QoL is markedly impaired; Slovenian 2024 patient study reported mean **VFQ-25 = 30.4 (SD 12.9)** and annual productivity loss **EUR 11,608/person** | Outcome concepts: VFQ-25 composite score; disability/productivity loss | (pqac-00000017) |
| Standard treatment | **Idebenone** is the main approved disease-specific therapy in Europe; commonly dosed **300 mg three times daily (900 mg/day)**, usually for **≥1 year**, ideally within **12 months** of onset | NCIT suggestions: **Idebenone (NCIT term verify)**; treatment class: antioxidant / quinone analog | (pqac-00000004, pqac-00000008, pqac-00000009) |
| Idebenone evidence | RHODOS secondary endpoints favored idebenone; LEROS showed higher clinically relevant benefit at 12 months versus natural history cohort; longer treatment may improve chance of recovery | NCIT concept: pharmacologic intervention; pharmacogenetic modifier: **NQO1** low-level variants associated with poorer response | (pqac-00000013) |
| Gene therapy | **Lenadogene nolparvovec / GS010 / rAAV2/2-ND4** studied in RESCUE, REVERSE, REFLECT, RESTORE; unilateral and bilateral intravitreal approaches investigated | NCIT suggestions: **Gene Therapy (NCIT:C15238)**; **Intravitreal Injection (NCIT term verify)**; vector: AAV2-based ND4 allotopic expression | (pqac-00000015, pqac-00000017, pqac-00000018) |
| Gene-therapy trial details | RESCUE enrolled **39**; RESTORE long-term follow-up enrolled **62**; REFLECT enrolled **98**; outcomes included BCVA, OCT GCL/RNFL, visual field, contrast sensitivity, color vision, QoL | ClinicalTrials.gov IDs: **NCT02652767 (RESCUE)**, **NCT03406104 (RESTORE)**, **NCT03293524 (REFLECT)** | (pqac-00000015, pqac-00000017, pqac-00000018) |
| Supportive care | Visual rehabilitation and psychological support are recommended for all patients; counseling to avoid smoking/alcohol/toxic medications in carriers | NCIT suggestions: **Rehabilitation (verify)**, **Psychological Support (verify)** | (pqac-00000013) |
| Prevention / counseling | No established pharmacologic prophylaxis for unaffected carriers in gathered evidence; emphasize maternal inheritance/arLHON counseling, cascade testing, avoidance of triggers, and timely diagnosis | Genetic counseling; family screening; reproductive counseling | (pqac-00000003, pqac-00000011, pqac-00000013) |
| Model systems | Cybrids, patient-derived fibroblasts, iPSC-derived retinal ganglion cells, and retinal organoids model LHON; models show increased RGC death, ATP/membrane-potential deficits, and rescue with correction or idebenone in some systems | Model annotations: **in vitro cybrid**, **iPSC-RGC**, **retinal organoid**; animal models mentioned but robust human-like models remain limited | (pqac-00000003, pqac-00000009) |
| Model readouts / limitations | iPSC/cybrid-corrected systems help test causality and rescue; limitations include incomplete reproduction of whole visual pathway and scarcity of robust animal models for selective human RGC degeneration | Evidence type labels: human cell model, organoid, translational preclinical model | (pqac-00000009) |


*Table: This compact table organizes gathered Leber hereditary optic neuropathy facts into knowledge-base-ready domains, including identifiers, genetics, phenotypes, mechanisms, diagnostics, treatment, epidemiology, and models. Ontology and identifier fields are suggested conservatively, with uncertain IDs clearly marked for later verification.*