Autosomal dominant progressive external ophthalmoplegia

Summary

Autosomal dominant progressive external ophthalmoplegia (MONDO:0008003) is a disease (an umbrella term covering 5 Mondo subtypes) with 6 cohort genes. The dominant Reactome pathway is Strand-asynchronous mitochondrial DNA replication (4 cohort genes).

At a glance

• Umbrella term: 5 Mondo subtypes
• Cohort genes: 6
• ClinVar variants: 1
• Phenotypes (HPO): 81

Clinical features

Signs & symptoms

Clinical features (HPO)

81 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0000508	Ptosis	Very frequent (80-99%)
HP:0000544	External ophthalmoplegia	Very frequent (80-99%)
HP:0000338	Hypomimic face	Frequent (30-79%)
HP:0000496	Abnormality of eye movement	Frequent (30-79%)
HP:0000597	Ophthalmoparesis	Frequent (30-79%)
HP:0000602	Ophthalmoplegia	Frequent (30-79%)
HP:0002067	Bradykinesia	Frequent (30-79%)
HP:0002322	Resting tremor	Frequent (30-79%)
HP:0003198	Myopathy	Frequent (30-79%)
HP:0003200	Ragged-red muscle fibers	Frequent (30-79%)
HP:0003458	EMG: myopathic abnormalities	Frequent (30-79%)
HP:0003546	Exercise intolerance	Frequent (30-79%)
HP:0003547	Shoulder girdle muscle weakness	Frequent (30-79%)
HP:0003688	Cytochrome C oxidase-negative muscle fibers	Frequent (30-79%)
HP:0003690	Limb muscle weakness	Frequent (30-79%)
HP:0003731	Quadriceps muscle weakness	Frequent (30-79%)
HP:0003737	Mitochondrial myopathy	Frequent (30-79%)
HP:0010628	Facial palsy	Frequent (30-79%)
HP:0012103	Abnormality of the mitochondrion	Frequent (30-79%)
HP:0012378	Fatigue	Frequent (30-79%)
HP:0000365	Hearing impairment	Occasional (5-29%)
HP:0000505	Visual impairment	Occasional (5-29%)
HP:0000518	Cataract	Occasional (5-29%)
HP:0000716	Depression	Occasional (5-29%)
HP:0000739	Anxiety	Occasional (5-29%)
HP:0001251	Ataxia	Occasional (5-29%)
HP:0001254	Lethargy	Occasional (5-29%)
HP:0001260	Dysarthria	Occasional (5-29%)
HP:0001265	Hyporeflexia	Occasional (5-29%)
HP:0001272	Cerebellar atrophy	Occasional (5-29%)
HP:0001288	Gait disturbance	Occasional (5-29%)
HP:0001290	Generalized hypotonia	Occasional (5-29%)
HP:0001337	Tremor	Occasional (5-29%)
HP:0001349	Facial diplegia	Occasional (5-29%)
HP:0001508	Failure to thrive	Occasional (5-29%)
HP:0001644	Dilated cardiomyopathy	Occasional (5-29%)
HP:0001712	Left ventricular hypertrophy	Occasional (5-29%)
HP:0001952	Glucose intolerance	Occasional (5-29%)
HP:0002015	Dysphagia	Occasional (5-29%)
HP:0002019	Constipation	Occasional (5-29%)
HP:0002020	Gastroesophageal reflux	Occasional (5-29%)
HP:0002063	Rigidity	Occasional (5-29%)
HP:0002066	Gait ataxia	Occasional (5-29%)
HP:0002071	Abnormality of extrapyramidal motor function	Occasional (5-29%)
HP:0002093	Respiratory insufficiency	Occasional (5-29%)
HP:0002151	Increased circulating lactate concentration	Occasional (5-29%)
HP:0002359	Frequent falls	Occasional (5-29%)
HP:0002375	Hypokinesia	Occasional (5-29%)
HP:0002396	Cogwheel rigidity	Occasional (5-29%)
HP:0002578	Gastroparesis	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal dominant progressive external ophthalmoplegia
Mondo ID	MONDO:0008003
MeSH	C563575
Orphanet	254892
UMLS	C5231255
MedGen	1686757
GARD	0016486
Is cancer (heuristic)	no

Also known as: adPEO · PEOA1 · progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1 · progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant type 1 · progressive external ophthalmoplegia, autosomal dominant

Data availability: 1 ClinVar variant · 5 GenCC gene-disease records.

Disease family

An umbrella term covering 5 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › nervous system disorder › congenital nervous system disorder › progressive external ophthalmoplegia › progressive external ophthalmoplegia with mitochondrial DNA deletions › autosomal dominant progressive external ophthalmoplegia

Related subtypes (7): progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1, mitochondrial DNA deletion syndrome with progressive myopathy, progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 2, progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 3, progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 4, progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 5, progressive external ophthalmoplegia with mitochondrial dna deletions, autosomal recessive 6

Subtypes (5): progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 2, progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 3, progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4, progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 5, progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1

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

1 retrieved; paginated sample, class counts are floors:

1 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
2441977	NM_005035.4(POLRMT):c.719C>T (p.Pro240Leu)	POLRMT	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 63 · Orphanet: 22 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
POLG	Definitive	Autosomal dominant	progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1	21
POLG2	Strong	Autosomal dominant	progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4	8
RRM2B	Strong	Autosomal dominant	progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 5	10
SLC25A4	Strong	Autosomal dominant	progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 2	14
TWNK	Strong	Autosomal dominant	progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 3	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SLC25A4	Orphanet:1369	Congenital cataract-hypertrophic cardiomyopathy-mitochondrial myopathy syndrome
SLC25A4	Orphanet:254892	Autosomal dominant progressive external ophthalmoplegia
TWNK	Orphanet:1186	Infantile-onset spinocerebellar ataxia
TWNK	Orphanet:254892	Autosomal dominant progressive external ophthalmoplegia
TWNK	Orphanet:363534	Mitochondrial DNA depletion syndrome, hepatocerebrorenal form
TWNK	Orphanet:642945	Perrault syndrome type 1
TWNK	Orphanet:642976	Perrault syndrome type 2
TWNK	Orphanet:70595	Sensory ataxic neuropathy-dysarthria-ophthalmoparesis syndrome
RRM2B	Orphanet:254892	Autosomal dominant progressive external ophthalmoplegia
RRM2B	Orphanet:255235	Mitochondrial DNA depletion syndrome, encephalomyopathic form with renal tubulopathy
RRM2B	Orphanet:298	Mitochondrial neurogastrointestinal encephalomyopathy
RRM2B	Orphanet:329336	Adult-onset chronic progressive external ophthalmoplegia with mitochondrial myopathy
RRM2B	Orphanet:480	Kearns-Sayre syndrome
POLG	Orphanet:254881	Spinocerebellar ataxia with epilepsy
POLG	Orphanet:254886	Autosomal recessive progressive external ophthalmoplegia
POLG	Orphanet:254892	Autosomal dominant progressive external ophthalmoplegia
POLG	Orphanet:298	Mitochondrial neurogastrointestinal encephalomyopathy
POLG	Orphanet:402082	Progressive myoclonic epilepsy type 5
POLG	Orphanet:70595	Sensory ataxic neuropathy-dysarthria-ophthalmoparesis syndrome
POLG	Orphanet:726	Alpers-Huttenlocher syndrome
POLG	Orphanet:94125	Recessive mitochondrial ataxia syndrome
POLG2	Orphanet:254892	Autosomal dominant progressive external ophthalmoplegia

Cohort genes → proteins

6 cohort genes, 6 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	6

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SLC25A4	HGNC:10990	ENSG00000151729	P12235	ADP/ATP translocase 1	gencc
TWNK	HGNC:1160	ENSG00000107815	Q96RR1	Twinkle mtDNA helicase	gencc
RRM2B	HGNC:17296	ENSG00000048392	Q7LG56	Ribonucleoside-diphosphate reductase subunit M2 B	gencc
POLG	HGNC:9179	ENSG00000140521	P54098	DNA polymerase subunit gamma-1	gencc
POLG2	HGNC:9180	ENSG00000256525	Q9UHN1	DNA polymerase subunit gamma-2	gencc
POLRMT	HGNC:9200	ENSG00000099821	O00411	DNA-directed RNA polymerase, mitochondrial	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SLC25A4	ADP/ATP translocase 1	ADP:ATP antiporter that mediates import of ADP into the mitochondrial matrix for ATP synthesis, and export of ATP out to fuel the cell.
TWNK	Twinkle mtDNA helicase	Mitochondrial helicase involved in mtDNA replication and repair.
RRM2B	Ribonucleoside-diphosphate reductase subunit M2 B	Plays a pivotal role in cell survival by repairing damaged DNA in a p53/TP53-dependent manner.
POLG	DNA polymerase subunit gamma-1	Catalytic subunit of DNA polymerase gamma solely responsible for replication of mitochondrial DNA (mtDNA).
POLG2	DNA polymerase subunit gamma-2	Accessory subunit of DNA polymerase gamma solely responsible for replication of mitochondrial DNA (mtDNA).
POLRMT	DNA-directed RNA polymerase, mitochondrial	DNA-dependent RNA polymerase catalyzes the transcription of mitochondrial DNA into RNA using the four ribonucleoside triphosphates as substrates.

Protein-family classification

Druggable: 4 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.67

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
Enzyme (other)	4	8.0×	0.001
Other/Unknown	2	0.6×	0.936

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SLC25A4	Other/Unknown	no		MCP, ADT_euk_type, MCP_transmembrane
TWNK	Enzyme (other)	yes	3.6.4.12	DNA_helicase_DnaB-like_C, Twinkle-like, P-loop_NTPase
RRM2B	Enzyme (other)	yes	1.17.4.1	RNR_small_fam, Ferritin-like_SF, RNR-like
POLG	Other/Unknown	no		DNA-dir_DNA_pol_A_palm_dom, DNA-dir_DNA_pol_A_mt, RNaseH-like_sf
POLG2	Enzyme (other)	yes	2.7.7.7	Anticodon-bd, Gly-tRNA_synthase/POLG2, Anticodon-bd_dom_sf
POLRMT	Enzyme (other)	yes	2.7.7.6	DNA-dir_Rpol_phage-type, TPR-like_helical_dom_sf, RPOL_N

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)	6
unknown	0

Top tissues across cohort

Tissue	Cohort genes
apex of heart	2
oocyte	2
secondary oocyte	2
left testis	2
heart right ventricle	1
left ventricle myocardium	1
gastrocnemius	1
male germ line stem cell (sensu Vertebrata) in testis	1
tendon of biceps brachii	1
deltoid	1
granulocyte	1
small intestine Peyer’s patch	1
tibial nerve	1
right testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SLC25A4	292	ubiquitous	marker	left ventricle myocardium, heart right ventricle, apex of heart
TWNK	211	ubiquitous	yes	male germ line stem cell (sensu Vertebrata) in testis, tendon of biceps brachii, gastrocnemius
RRM2B	254	ubiquitous	marker	secondary oocyte, oocyte, deltoid
POLG	295	ubiquitous	marker	granulocyte, small intestine Peyer’s patch, tibial nerve
POLG2	249	ubiquitous	marker	secondary oocyte, oocyte, left testis
POLRMT	251	ubiquitous	marker	left testis, right testis, apex of heart

Protein interactions among cohort

Intra-cohort edges: 13.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
POLG	3,400
SLC25A4	3,085
POLRMT	2,630
RRM2B	2,432
POLG2	1,557
TWNK	1,390

Intra-cohort edges

A	B	Sources
POLG	POLG2	biogrid_interaction, intact, string_interaction
POLG	POLRMT	string_interaction
POLG	RRM2B	string_interaction
POLG	SLC25A4	string_interaction
POLG	TWNK	string_interaction
POLG2	POLRMT	string_interaction
POLG2	RRM2B	string_interaction
POLG2	SLC25A4	string_interaction
POLG2	TWNK	string_interaction
POLRMT	TWNK	string_interaction
RRM2B	SLC25A4	string_interaction
RRM2B	TWNK	string_interaction
SLC25A4	TWNK	string_interaction

Structural data

PDB: 5 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
POLG2	Q9UHN1	38
POLG	P54098	36
POLRMT	O00411	25
RRM2B	Q7LG56	3
TWNK	Q96RR1	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SLC25A4	P12235	92.07

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 27. Enrichment computed across 6 evidence-associated genes (6 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 6 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Strand-asynchronous mitochondrial DNA replication	4	761.3×	1e-10	TWNK, POLG, POLG2, POLRMT
Transcriptional activation of mitochondrial biogenesis	3	102.0×	3e-05	TWNK, POLG2, POLRMT
Mitochondrial Uncoupling	1	951.7×	0.009	SLC25A4
Mitochondrial transcription initiation	1	634.4×	0.009	POLRMT
Vpr-mediated induction of apoptosis by mitochondrial outer membrane permeabilization	1	634.4×	0.009	SLC25A4
Transcription from mitochondrial promoters	1	475.8×	0.009	POLRMT
Interactions of Vpr with host cellular proteins	1	237.9×	0.016	SLC25A4
Transport of nucleosides and free purine and pyrimidine bases across the plasma membrane	1	158.6×	0.021	SLC25A4
Interconversion of nucleotide di- and triphosphates	1	59.5×	0.048	RRM2B
Host Interactions of HIV factors	1	56.0×	0.048	SLC25A4
Transport of vitamins, nucleosides, and related molecules	1	45.3×	0.054	SLC25A4
DNA Replication	1	39.6×	0.056	POLRMT
Protein localization	1	31.7×	0.063	SLC25A4
Mitochondrial protein import	1	28.0×	0.063	SLC25A4
Mitochondrial biogenesis	1	28.0×	0.063	POLRMT
TP53 Regulates Metabolic Genes	1	21.6×	0.077	RRM2B
HIV Infection	1	19.8×	0.077	SLC25A4
Mitochondrial protein degradation	1	19.0×	0.077	TWNK
Aerobic respiration and respiratory electron transport	1	14.8×	0.094	SLC25A4
Organelle biogenesis and maintenance	1	11.0×	0.118	POLRMT
SLC-mediated transmembrane transport	1	9.9×	0.125	SLC25A4
Viral Infection Pathways	1	5.1×	0.221	SLC25A4
Transport of small molecules	1	4.2×	0.246	SLC25A4
Infectious disease	1	4.1×	0.246	SLC25A4
Gene expression (Transcription)	1	3.0×	0.316	POLRMT
Disease	1	2.2×	0.394	SLC25A4
Metabolism	1	1.9×	0.417	SLC25A4

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 6 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
mitochondrial DNA replication	5	1276.7×	9e-15	TWNK, RRM2B, POLG, POLG2, POLRMT
DNA-templated DNA replication	3	280.9×	2e-06	TWNK, POLG, POLG2
mitochondrial transcription	2	802.5×	3e-05	TWNK, POLRMT
deoxyribonucleoside triphosphate metabolic process	1	2808.7×	0.003	RRM2B
ribonucleoside diphosphate metabolic process	1	936.2×	0.005	RRM2B
deoxyribonucleotide biosynthetic process	1	936.2×	0.005	RRM2B
2’-deoxyribonucleotide biosynthetic process	1	936.2×	0.005	RRM2B
DNA replication proofreading	1	936.2×	0.005	POLG
transcription initiation at mitochondrial promoter	1	702.2×	0.006	POLRMT
positive regulation of G0 to G1 transition	1	561.7×	0.006	RRM2B
mitochondrial ADP transmembrane transport	1	561.7×	0.006	SLC25A4
negative regulation of intrinsic apoptotic signaling pathway by p53 class mediator	1	401.2×	0.007	RRM2B
ADP transport	1	351.1×	0.007	SLC25A4
positive regulation of DNA-directed DNA polymerase activity	1	351.1×	0.007	POLG2
response to amine	1	312.1×	0.007	RRM2B
mitochondrial ATP transmembrane transport	1	312.1×	0.007	SLC25A4
protein hexamerization	1	234.1×	0.008	TWNK
regulation of mitochondrial membrane permeability	1	234.1×	0.008	SLC25A4
renal system process	1	187.2×	0.008	RRM2B
base-excision repair, gap-filling	1	187.2×	0.008	POLG
positive regulation of mitophagy	1	187.2×	0.008	SLC25A4
DNA metabolic process	1	175.5×	0.008	POLG
negative regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway	1	175.5×	0.008	SLC25A4
adaptive thermogenesis	1	175.5×	0.008	SLC25A4
negative regulation of necroptotic process	1	165.2×	0.008	SLC25A4
DNA synthesis involved in DNA repair	1	156.0×	0.009	RRM2B
apoptotic mitochondrial changes	1	147.8×	0.009	SLC25A4
positive regulation of G2/M transition of mitotic cell cycle	1	100.3×	0.012	RRM2B
base-excision repair	1	78.0×	0.015	POLG
generation of precursor metabolites and energy	1	57.3×	0.020	SLC25A4

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 2 · Phased (≥1): 2 · Undrugged: 4

Druggability breadth: 5 of 6 evidence-associated genes (83%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
POLG	ADEFOVIR DIPIVOXIL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
RRM2B	1	3
POLG	1	4
SLC25A4	0	0
TWNK	0	0
POLG2	0	0
POLRMT	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
ADEFOVIR DIPIVOXIL	4	POLG
TRIAPINE	3	RRM2B

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 4.

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

Symbol	Assays	Type breakdown
RRM2B	47	Binding:44, Functional:3
POLG	33	Binding:30, ADMET:2, Functional:1
POLRMT	20	Binding:12, ADMET:7, Functional:1
SLC25A4	1	Binding:1
POLG2	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
TWNK	3.6.4.12	DNA helicase
RRM2B	1.17.4.1	ribonucleoside-diphosphate reductase
POLG2	2.7.7.7	DNA-directed DNA polymerase
POLRMT	2.7.7.6	DNA-directed RNA polymerase

Pharmacogenomics

Cohort genes with a PharmGKB record: 6; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

2 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.

Compound	Max phase	Cohort target (bioactivity)
ADEFOVIR DIPIVOXIL	4	POLG
TRIAPINE	3	RRM2B

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	POLG
B	Phased (≥1) drug, not yet approved	1	RRM2B
C	Druggable family + PDB, no drug	3	TWNK, POLG2, POLRMT
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	SLC25A4

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SLC25A4	1	POLG
TWNK	0	POLG
POLG2	1	POLG, RRM2B
POLRMT	20	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.