Optic neuritis

Summary

Optic neuritis (MONDO:0005885) is a disease (an umbrella term covering 5 Mondo subtypes) with 1 cohort gene (7 GWAS associations across 8 studies) and 63 clinical trials. Top therapeutic interventions include phenytoin, clemastine, and amiloride.

At a glance

• Umbrella term: 5 Mondo subtypes
• Cohort genes: 1
• GWAS associations: 7
• ClinVar variants: 1
• Clinical trials: 63

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	optic neuritis
Mondo ID	MONDO:0005885
EFO	EFO:0007405
MeSH	D009902
DOID	DOID:1210
ICD-10-CM	H46
ICD-11	210935787
NCIT	C84950
SNOMED CT	66760008
UMLS	C0029134
MedGen	18181
GARD	0027731
Is cancer (heuristic)	no

Data availability: 1 ClinVar variant · 7 GWAS associations (8 studies).

Disease family

An umbrella term covering 5 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › optic nerve disorder › optic neuritis

Related subtypes (7): optic disk drusen, optic nerve neoplasm, optic atrophy, anterior ischemic optic neuropathy, low tension glaucoma, extensive peripapillary myelinated nerve fibers, isolated optic nerve aplasia

Subtypes (5): toxic or nutritional optic neuropathy, toxic optic neuropathy, optic papillitis, retrobulbar neuritis, autoimmune optic neuritis

Genetics & variants

GWAS landscape

7 GWAS associations across 8 studies. Top hits map to 4 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs12464737	7e-23	PNPT1 - EFEMP1	G	0.23
rs12615158	5e-21	PNPT1 - EFEMP1	C	0.23
rs6475604	2e-13	CDKN2B-AS1	T	0.16
rs944801	2e-12	CDKN2B-AS1	G	0.15
chr14:60957171	6e-12		G	0.16
rs185185149	2e-11	ATP7B	G	1.74
rs183184686	2e-08	LINC01102, LINC01103	?

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST90475897	Verma A	2024	4,487	442,099	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90477764	Verma A	2024	1,313	118,949	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90480095	Verma A	2024	1,313	118,949	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90473444	UK Biobank Whole-Genome Sequencing Consortium	2025	536	457,904	Whole-genome sequencing of 490,640 UK Biobank participants.
GCST90481937	Verma A	2024	411	58,932	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90651541	Liu TY	2025	380	213,222	Diversity and longitudinal records: Genetic architecture of disease associations and polygenic risk in the Taiwanese Han population.
GCST90436017	Zhou W	2018	125	401,245	Efficiently controlling for case-control imbalance and sample relatedness in large-scale genetic association studies.
GCST90043802	Jiang L	2021	105	456,243	A generalized linear mixed model association tool for biobank-scale data.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	0
Tier 2: splice/UTR	0
Tier 3: regulatory	0
Tier 4: intronic/intergenic	7

MAF distribution

Bucket	Variants
common (>=0.05)	5
low_freq (0.01-0.05)	0
rare (<0.01)	1
unknown	1

Functional consequences

Consequence	Count
intron_variant	4
intergenic_variant	2
unknown	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs12464737	2	55802703	G>A,C,T	0.193	intergenic_variant	PNPT1 - EFEMP1	7e-23	Tier 4: intronic/intergenic
rs12615158	2	55805864	C>G,T	0.238	intergenic_variant	PNPT1 - EFEMP1	5e-21	Tier 4: intronic/intergenic
rs6475604	9	22052735	T>A,C,G	0.422	intron_variant	CDKN2B-AS1	2e-13	Tier 4: intronic/intergenic
rs944801	9	22051671	G>A,C	0.344	intron_variant	CDKN2B-AS1	2e-12	Tier 4: intronic/intergenic
chr14:60957171				0.45			6e-12	Tier 4: intronic/intergenic
rs185185149	13	51949060	G>T	0	intron_variant	ATP7B	2e-11	Tier 4: intronic/intergenic
rs183184686	2	104501965	G>A,T		intron_variant	LINC01102, LINC01103	2e-08	Tier 4: intronic/intergenic

ClinVar germline variants

1 retrieved; paginated sample, class counts are floors:

1 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
523305	NC_012920.1:m.11443A>C	MT-ND4	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 5 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MT-ND4	Orphanet:104	Leber hereditary optic neuropathy
MT-ND4	Orphanet:255210	Mitochondrial DNA-associated Leigh syndrome
MT-ND4	Orphanet:550	MELAS
MT-ND4	Orphanet:90641	Rare mitochondrial non-syndromic sensorineural deafness
MT-ND4	Orphanet:99718	Leber plus disease

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MT-ND4	HGNC:7459	ENSG00000198886	C0HME5	Mitochondrial alternative ND4 protein	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MT-ND4	Mitochondrial alternative ND4 protein	Regulates mitochondrial respiration by decreasing oxygen consumption.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MT-ND4	Other/Unknown	no		NADH4_N, ND/Mrp_TM, NADH_UbQ_OxRdtase

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
apex of heart	1
right uterine tube	1
zone of skin	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MT-ND4	134	ubiquitous	marker	right uterine tube, apex of heart, zone of skin

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MT-ND4	0

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MT-ND4	C0HME5	7

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Complex I biogenesis	1	165.5×	0.011	MT-ND4
Mitochondrial translation termination	1	109.8×	0.011	MT-ND4
Respiratory electron transport	1	95.2×	0.011	MT-ND4

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
electron transport coupled proton transport	1	4213.0×	0.002	MT-ND4
response to nicotine	1	421.3×	0.006	MT-ND4
mitochondrial respiratory chain complex I assembly	1	411.0×	0.006	MT-ND4
mitochondrial electron transport, NADH to ubiquinone	1	358.6×	0.006	MT-ND4
cerebellum development	1	358.6×	0.006	MT-ND4
proton motive force-driven mitochondrial ATP synthesis	1	263.3×	0.006	MT-ND4
aerobic respiration	1	247.8×	0.006	MT-ND4
response to ethanol	1	146.5×	0.009	MT-ND4
response to hypoxia	1	95.8×	0.012	MT-ND4
in utero embryonic development	1	72.0×	0.014	MT-ND4

Therapeutics

Drugs indicated for this disease

3 approved, 4 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Dexamethasone	Approved (phase 4)
Prednisolone	Approved (phase 4)
Prednisone	Approved (phase 4)
Epoetin Beta	Phase 3 (in late-stage trials)
Glatiramer Acetate	Phase 3 (in late-stage trials)
Methylprednisolone	Phase 3 (in late-stage trials)
Simvastatin	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Amiloride, Atacicept, Cholecalciferol, Clemastine, Efgartigimod Alfa, Ergocalciferol, Fingolimod, Methylprednisolone Acetate, Phenytoin.

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MT-ND4	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	MT-ND4

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
MT-ND4	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 63.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	32
PHASE2	15
PHASE3	6
PHASE2/PHASE3	3
PHASE1	3
PHASE4	2
EARLY_PHASE1	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00037115	PHASE4	WITHDRAWN	Induction Therapy With a Single High Dose Bolus of Intravenous Methotrexate With Leucovorin Rescue, Prior to Initiation of AVONEX® Treatment, in Patients Presenting With a First Acute Demyelinating Event.
NCT00179478	PHASE4	COMPLETED	Long Term Study of Avonex Therapy Following a First Attack of Multiple Sclerosis
NCT07100990	PHASE3	RECRUITING	Treatment of Inflammatory Myelitis and Optic Neuritis With Early vs Rescue Plasma Exchange (TIMELY-PLEX)
NCT00000117	PHASE3	COMPLETED	Intravenous Immunoglobulin Therapy in Optic Neuritis
NCT00000146	PHASE3	UNKNOWN	Optic Neuritis Treatment Trial (ONTT)
NCT00261326	PHASE3	UNKNOWN	Simvastatin Treatment of Patients With Acute Optic Neuritis
NCT00856635	PHASE3	COMPLETED	A Randomized, Double-blind, Placebo-controlled, Multicenter Study of the Effects of Glatiramer Acetate (GA) on the Retinal Nerve Fiber Layer (RNFL) and Visual Function in Patients With a First Episode of Acute Optic Neuritis (AON). (Octagon)
NCT01337986	PHASE2/PHASE3	COMPLETED	Ampyra for Optic Neuritis in Multiple Sclerosis
NCT01524250	PHASE2/PHASE3	COMPLETED	Optic Neuritis Recovery After Oral or IV Corticosteroids
NCT01962571	PHASE3	COMPLETED	Treatment of Optic Neuritis With Erythropoietin: a Randomised, Double-blind, Placebo-controlled Trial
NCT04942002	PHASE2/PHASE3	UNKNOWN	Retrobulbar Methylprednisolone as Adjunctive Treatment in Optic Neuritis Trial
NCT02521311	PHASE2	RECRUITING	Assessment of Clemastine Fumarate as a Remyelinating Agent in Acute Optic Neuritis (ReCOVER)
NCT06453694	PHASE2	RECRUITING	Efgartigimod for the Treatment of Acute Optic Neuritis
NCT00355095	PHASE2	COMPLETED	Safety and Efficacy Study of Erythropoietin as add-on Therapy of Methylprednisolone to Treat Acute Optic Neuritis
NCT00624468	PHASE2	TERMINATED	Atacicept in Subjects With Optic Neuritis
NCT01073813	PHASE2	TERMINATED	Neuroprotection and Repair in Optic Neuritis
NCT01274702	PHASE2	COMPLETED	Visual Reconstitution Therapy After Optic Neuritis
NCT01451593	PHASE2	COMPLETED	Neuroprotection With Phenytoin in Optic Neuritis
NCT01465893	PHASE2	UNKNOWN	Effect of Vitamin D on Retinal Changes in Patient With Optic Neuritis by Optic Coherence Tomography
NCT01721161	PHASE2	COMPLETED	BIIB033 In Acute Optic Neuritis (AON)
NCT01802489	PHASE2	COMPLETED	Amiloride Clinical Trial In Optic Neuritis
NCT02657915	PHASE2	COMPLETED	Long-Term Assessment of Remyelinating Therapy
NCT02939937	PHASE2	COMPLETED	Effect of Phenytoin on the Ganglion Cell Layer in Patients With Optic Neuritis
NCT02976766	PHASE2	TERMINATED	Adjunctive Gypenosides for Acute Optic Neuritis
NCT03302585	PHASE2	TERMINATED	High-Dose Vitamin D Induction in Optic Neuritis
NCT04762017	PHASE2	COMPLETED	OCS-05 in Patients With Optic Neuritis
NCT01294176	PHASE1	COMPLETED	Lipoic Acid as a Treatment for Acute Optic Neuritis
NCT02833142	PHASE1	COMPLETED	Pharmacokinetics, Safety and Tolerability of Single Doses of BIIB033 (Opicinumab) Produced by 2 Manufacturing Processes
NCT03630497	PHASE1	COMPLETED	BN201 SAD MAD Study in Healthy Subjects
NCT01987167	EARLY_PHASE1	COMPLETED	Defining the Functional and Neuro-Protective Potential of ACTHAR in Acute Optic Neuritis
NCT04148781	EARLY_PHASE1	UNKNOWN	Fampridine-SR and Optic Neuritis Recovery
NCT00445367	Not specified	ACTIVE_NOT_RECRUITING	Biobank For MS And Other Demyelinating Diseases
NCT01623076	Not specified	ACTIVE_NOT_RECRUITING	The Longitudinal CONQUER Study of Rare Neuroimmunologic Disorders
NCT03401879	Not specified	RECRUITING	Retinal Neuro-vascular Coupling in Patients With Multiple Sclerosis
NCT05017142	Not specified	RECRUITING	Swiss Pediatric Inflammatory Brain Disease Registry (Swiss-Ped-IBrainD)
NCT05487989	Not specified	RECRUITING	VIsual Pathways Model in Neuro-inflammatory Disorders
NCT05540262	Not specified	RECRUITING	Edaravone in the Treatment of Optic Neuritis
NCT06389968	Not specified	RECRUITING	Light Stimulation to Improve Visual Function After Optic Neuritis in Persons with Multiple Sclerosis
NCT06916182	Not specified	NOT_YET_RECRUITING	Evaluation of Optic Neuritis Using Synthetic Quantitative MRI
NCT00000147	Not specified	UNKNOWN	Longitudinal Optic Neuritis Study (LONS)

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
PHENYTOIN	4	4
CLEMASTINE	4	3
AMILORIDE	4	1
CORTICOTROPIN	4	1
DALFAMPRIDINE	4	1
EDARAVONE	4	1
EFGARTIGIMOD ALFA	4	1
EPOETIN ALFA	4	1
GLATIRAMER ACETATE	4	1
METHOTREXATE	4	1
METHYLPREDNISOLONE	4	1
MINOCYCLINE	4	1
INTERFERON BETA	3	2
ATACICEPT	3	1
LIPOIC ACID, ALPHA	3	1
OPICINUMAB	2	3
CHEMBL426	0	1
THIOCTIC ACID	0	1