Leber optic atrophy and dystonia

Summary

Leber optic atrophy and dystonia (MONDO:0010772) is a disease with 5 cohort genes. The dominant Reactome pathway is Complex I biogenesis (5 cohort genes).

At a glance

• Cohort genes: 5
• ClinVar variants: 9

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Leber optic atrophy and dystonia
Mondo ID	MONDO:0010772
MeSH	C536024
OMIM	500001
DOID	DOID:0111755
UMLS	C1839040
MedGen	333240
GARD	0015311
Is cancer (heuristic)	no

Also known as: dystonia familial, with visual failure and striatal lucencies · dystonia, familial, with visual failure and striatal lucencies · LDYT · Leber Hereditary optic neuropathy with dystonia · Leber optic atrophy and dystonia · Leber’s hereditary optic neuropathy with dystonia · LHON and dystonia

Data availability: 9 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › muscle tissue disorder › cardiomyopathy › intrinsic cardiomyopathy › dilated cardiomyopathy › familial dilated cardiomyopathy › Leber hereditary optic neuropathy › Leber optic atrophy and dystonia

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

9 retrieved; paginated sample, class counts are floors:

4 pathogenic, 3 likely pathogenic, 1 uncertain significance, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
9722	NC_012920.1(MT-ND1):m.3460G>A	MT-ND1	Pathogenic	reviewed by expert panel
9715	NC_012920.1(MT-ND3):m.10197G>A	MT-ND3	Pathogenic	reviewed by expert panel
9689	NC_012920.1(MT-ND6):m.14459G>A	MT-ND5	Pathogenic	reviewed by expert panel
9688	NC_012920.1(MT-ND6):m.14484T>C	MT-ND6	Pathogenic	reviewed by expert panel
65518	NC_012920.1(MT-ND1):m.3635G>A	MT-ND1	Likely pathogenic	reviewed by expert panel
9733	NC_012920.1(MT-ND1):m.3697G>A	MT-ND1	Likely pathogenic	reviewed by expert panel
9711	NC_012920.1(MT-ND4):m.11777C>A	MT-ND4	Likely pathogenic	reviewed by expert panel
9690	NC_012920.1(MT-ND6):m.14596A>T	MT-ND6	Uncertain significance	reviewed by expert panel
9710	NC_012920.1(MT-ND4):m.11696G>A	MT-ND4	Benign	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 20 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MT-ND1	Orphanet:104	Leber hereditary optic neuropathy
MT-ND1	Orphanet:255210	Mitochondrial DNA-associated Leigh syndrome
MT-ND1	Orphanet:2609	Isolated complex I deficiency
MT-ND1	Orphanet:550	MELAS
MT-ND3	Orphanet:255210	Mitochondrial DNA-associated Leigh syndrome
MT-ND3	Orphanet:2609	Isolated complex I deficiency
MT-ND3	Orphanet:99718	Leber plus 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
MT-ND5	Orphanet:104	Leber hereditary optic neuropathy
MT-ND5	Orphanet:255210	Mitochondrial DNA-associated Leigh syndrome
MT-ND5	Orphanet:550	MELAS
MT-ND5	Orphanet:551	MERRF
MT-ND6	Orphanet:104	Leber hereditary optic neuropathy
MT-ND6	Orphanet:255210	Mitochondrial DNA-associated Leigh syndrome
MT-ND6	Orphanet:550	MELAS
MT-ND6	Orphanet:99718	Leber plus disease

Cohort genes → proteins

5 cohort genes, 5 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MT-ND1	HGNC:7455	ENSG00000198888	P03886	NADH-ubiquinone oxidoreductase chain 1	clinvar
MT-ND3	HGNC:7458	ENSG00000198840	P03897	NADH-ubiquinone oxidoreductase chain 3	clinvar
MT-ND4	HGNC:7459	ENSG00000198886	C0HME5	Mitochondrial alternative ND4 protein	clinvar
MT-ND5	HGNC:7461	ENSG00000198786	P03915	NADH-ubiquinone oxidoreductase chain 5	clinvar
MT-ND6	HGNC:7462	ENSG00000198695	P03923	NADH-ubiquinone oxidoreductase chain 6	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MT-ND1	NADH-ubiquinone oxidoreductase chain 1	Core subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) which catalyzes electron transfer from NADH through the respiratory chain, using ubiquinone as an electron acceptor.
MT-ND3	NADH-ubiquinone oxidoreductase chain 3	Core subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) which catalyzes electron transfer from NADH through the respiratory chain, using ubiquinone as an electron acceptor.
MT-ND4	Mitochondrial alternative ND4 protein	Regulates mitochondrial respiration by decreasing oxygen consumption.
MT-ND5	NADH-ubiquinone oxidoreductase chain 5	Core subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) which catalyzes electron transfer from NADH through the respiratory chain, using ubiquinone as an electron acceptor.
MT-ND6	NADH-ubiquinone oxidoreductase chain 6	Core subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) which catalyzes electron transfer from NADH through the respiratory chain, using ubiquinone as an electron acceptor.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 5 · 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	5	1.8×	0.054

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MT-ND1	Other/Unknown	no		NADH_UbQ_OxRdtase_su1/FPO, NADH_UbQ_OxRdtase_su1_CS
MT-ND3	Other/Unknown	no		NADH_UbQ/plastoQ_OxRdtase_su3, NDAH_ubi_oxred_su3_sf
MT-ND4	Other/Unknown	no		NADH4_N, ND/Mrp_TM, NADH_UbQ_OxRdtase
MT-ND5	Other/Unknown	no		Proton_antipo_N, ND/Mrp_TM, NU5C-like
MT-ND6	Other/Unknown	no		NADH_UbQ/plastoQ_OxRdtase_su6, ComplexI_Subunit6

Expression context

Cohort genes with no expression data: 0.

5 cohort genes 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)	5
unknown	0

Top tissues across cohort

Tissue	Cohort genes
adipose tissue	2
right uterine tube	2
frontal cortex	1
gastrocnemius	1
granulocyte	1
left lobe of thyroid gland	1
apex of heart	1
zone of skin	1
heart right ventricle	1
lateral nuclear group of thalamus	1
postcentral gyrus	1
left uterine tube	1
mucosa of stomach	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MT-ND1	134	ubiquitous	marker	adipose tissue, gastrocnemius, frontal cortex
MT-ND3	134	ubiquitous	marker	granulocyte, adipose tissue, left lobe of thyroid gland
MT-ND4	134	ubiquitous	marker	right uterine tube, apex of heart, zone of skin
MT-ND5	247	ubiquitous	marker	heart right ventricle, postcentral gyrus, lateral nuclear group of thalamus
MT-ND6	134	ubiquitous	marker	mucosa of stomach, left uterine tube, right uterine tube

Protein interactions among cohort

Intra-cohort edges: 6.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MT-ND1	3,537
MT-ND3	2,923
MT-ND5	2,825
MT-ND6	1,208
MT-ND4	0

Intra-cohort edges

A	B	Sources
MT-ND1	MT-ND3	string_interaction
MT-ND1	MT-ND5	string_interaction
MT-ND1	MT-ND6	string_interaction
MT-ND3	MT-ND5	string_interaction
MT-ND3	MT-ND6	string_interaction
MT-ND5	MT-ND6	string_interaction

Structural data

PDB: 5 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MT-ND4	C0HME5	7
MT-ND5	P03915	7
MT-ND1	P03886	5
MT-ND3	P03897	5
MT-ND6	P03923	5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. Enrichment computed across 5 evidence-associated genes (5 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 5 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	5	165.5×	3e-11	MT-ND1, MT-ND3, MT-ND4, MT-ND5, MT-ND6
Mitochondrial translation termination	5	109.8×	1e-10	MT-ND1, MT-ND3, MT-ND4, MT-ND5, MT-ND6
Respiratory electron transport	5	95.2×	2e-10	MT-ND1, MT-ND3, MT-ND4, MT-ND5, MT-ND6
Mitochondrial protein degradation	3	68.5×	6e-06	MT-ND1, MT-ND5, MT-ND6

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
mitochondrial electron transport, NADH to ubiquinone	5	358.6×	2e-12	MT-ND1, MT-ND3, MT-ND4, MT-ND5, MT-ND6
proton motive force-driven mitochondrial ATP synthesis	5	263.3×	5e-12	MT-ND1, MT-ND3, MT-ND4, MT-ND5, MT-ND6
aerobic respiration	5	247.8×	5e-12	MT-ND1, MT-ND3, MT-ND4, MT-ND5, MT-ND6
mitochondrial respiratory chain complex I assembly	4	328.8×	6e-10	MT-ND1, MT-ND4, MT-ND5, MT-ND6
electron transport coupled proton transport	2	1685.2×	1e-06	MT-ND4, MT-ND5
response to hypoxia	3	57.5×	3e-05	MT-ND1, MT-ND4, MT-ND5
response to light intensity	1	421.3×	0.005	MT-ND3
response to hydroperoxide	1	337.0×	0.006	MT-ND1
cellular response to glucocorticoid stimulus	1	124.8×	0.014	MT-ND3
response to hydrogen peroxide	1	93.6×	0.017	MT-ND5
response to nicotine	1	84.3×	0.017	MT-ND4
cerebellum development	1	71.7×	0.018	MT-ND4
response to ethanol	1	29.3×	0.041	MT-ND4
response to oxidative stress	1	26.1×	0.043	MT-ND3
in utero embryonic development	1	14.4×	0.070	MT-ND4
response to xenobiotic stimulus	1	13.8×	0.070	MT-ND1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 5

Druggability breadth: 5 of 5 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-ND1	0	0
MT-ND3	0	0
MT-ND4	0	0
MT-ND5	0	0
MT-ND6	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
MT-ND1	5	Binding:5
MT-ND3	4	Binding:4
MT-ND5	4	Binding:4
MT-ND6	4	Binding:4

Pharmacogenomics

Cohort genes with a PharmGKB record: 5; 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	5	MT-ND1, MT-ND3, MT-ND4, MT-ND5, MT-ND6

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
MT-ND1	5	—
MT-ND3	4	—
MT-ND4	0	—
MT-ND5	4	—
MT-ND6	4	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.