Autosomal recessive progressive external ophthalmoplegia

Summary

Autosomal recessive progressive external ophthalmoplegia (MONDO:0016810) is a disease with 2 cohort genes.

At a glance

• Cohort genes: 2
• ClinVar variants: 1
• Phenotypes (HPO): 42

Clinical features

Signs & symptoms

Clinical features (HPO)

42 HPO clinical features (Orphanet curated; top 42 by frequency):

HPO ID	Term	Frequency
HP:0000298	Mask-like facies	Frequent (30-79%)
HP:0000544	External ophthalmoplegia	Frequent (30-79%)
HP:0001638	Cardiomyopathy	Frequent (30-79%)
HP:0002015	Dysphagia	Frequent (30-79%)
HP:0003198	Myopathy	Frequent (30-79%)
HP:0003200	Ragged-red muscle fibers	Frequent (30-79%)
HP:0003390	Sensory axonal neuropathy	Frequent (30-79%)
HP:0003401	Paresthesia	Frequent (30-79%)
HP:0003688	Cytochrome C oxidase-negative muscle fibers	Frequent (30-79%)
HP:0003737	Mitochondrial myopathy	Frequent (30-79%)
HP:0009830	Peripheral neuropathy	Frequent (30-79%)
HP:0010628	Facial palsy	Frequent (30-79%)
HP:0000365	Hearing impairment	Occasional (5-29%)
HP:0000479	Abnormal retinal morphology	Occasional (5-29%)
HP:0000505	Visual impairment	Occasional (5-29%)
HP:0000508	Ptosis	Occasional (5-29%)
HP:0000648	Optic atrophy	Occasional (5-29%)
HP:0000716	Depression	Occasional (5-29%)
HP:0001251	Ataxia	Occasional (5-29%)
HP:0001265	Hyporeflexia	Occasional (5-29%)
HP:0001272	Cerebellar atrophy	Occasional (5-29%)
HP:0001621	Weak voice	Occasional (5-29%)
HP:0002059	Cerebral atrophy	Occasional (5-29%)
HP:0002067	Bradykinesia	Occasional (5-29%)
HP:0002345	Action tremor	Occasional (5-29%)
HP:0002362	Shuffling gait	Occasional (5-29%)
HP:0002396	Cogwheel rigidity	Occasional (5-29%)
HP:0002500	Abnormal cerebral white matter morphology	Occasional (5-29%)
HP:0002548	Parkinsonism with favorable response to dopaminergic medication	Occasional (5-29%)
HP:0002921	Abnormality of the cerebrospinal fluid	Occasional (5-29%)
HP:0002936	Distal sensory impairment	Occasional (5-29%)
HP:0003546	Exercise intolerance	Occasional (5-29%)
HP:0003552	Muscle stiffness	Occasional (5-29%)
HP:0003701	Proximal muscle weakness	Occasional (5-29%)
HP:0007641	Dyschromatopsia	Occasional (5-29%)
HP:0025403	Stooped posture	Occasional (5-29%)
HP:0030237	Hand muscle weakness	Occasional (5-29%)
HP:0100295	Muscle fiber atrophy	Occasional (5-29%)
HP:0100653	Optic neuritis	Occasional (5-29%)
HP:0003236	Elevated circulating creatine kinase concentration	Very rare (<1-4%)
HP:0003691	Scapular winging	Very rare (<1-4%)
HP:0100543	Cognitive impairment	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal recessive progressive external ophthalmoplegia
Mondo ID	MONDO:0016810
MeSH	C564926
Orphanet	254886
UMLS	C1850303
MedGen	340509
GARD	0001191
Is cancer (heuristic)	no

Also known as: arPEO · progressive external ophthalmoplegia, autosomal recessive

Data availability: 1 ClinVar variant · 2 GenCC gene-disease records.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › nervous system disorder › congenital nervous system disorder › progressive external ophthalmoplegia › autosomal recessive progressive external ophthalmoplegia

Related subtypes (2): progressive external ophthalmoplegia with mitochondrial DNA deletions, Kearns-Sayre syndrome

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

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 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
206484	NM_002693.3(POLG):c.126GCA[13] (p.Gln54_Gln55dup)	POLG	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 26 · Orphanet: 10 · 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
TK2	Supportive	Autosomal recessive	autosomal recessive progressive external ophthalmoplegia	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
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
TK2	Orphanet:254875	Mitochondrial DNA depletion syndrome, myopathic form
TK2	Orphanet:254886	Autosomal recessive progressive external ophthalmoplegia

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
POLG	HGNC:9179	ENSG00000140521	P54098	DNA polymerase subunit gamma-1	gencc,clinvar
TK2	HGNC:11831	ENSG00000166548	O00142	Thymidine kinase 2, mitochondrial	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
POLG	DNA polymerase subunit gamma-1	Catalytic subunit of DNA polymerase gamma solely responsible for replication of mitochondrial DNA (mtDNA).
TK2	Thymidine kinase 2, mitochondrial	Phosphorylates thymidine, deoxycytidine, and deoxyuridine in the mitochondrial matrix.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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
Kinase	1	13.9×	0.142
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
POLG	Other/Unknown	no		DNA-dir_DNA_pol_A_palm_dom, DNA-dir_DNA_pol_A_mt, RNaseH-like_sf
TK2	Kinase	yes	2.7.1.21	DCK/DGK, P-loop_NTPase, DNK_dom

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
granulocyte	1
small intestine Peyer’s patch	1
tibial nerve	1
adrenal tissue	1
calcaneal tendon	1
sural nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
POLG	295	ubiquitous	marker	granulocyte, small intestine Peyer’s patch, tibial nerve
TK2	280	ubiquitous	marker	calcaneal tendon, sural nerve, adrenal tissue

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
POLG	3,400
TK2	2,031

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
POLG	P54098	36

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TK2	O00142	85.01

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Nucleotide salvage	1	571.0×	0.003	TK2
Strand-asynchronous mitochondrial DNA replication	1	571.0×	0.003	POLG
Pyrimidine salvage	1	519.1×	0.003	TK2
Metabolism of nucleotides	1	150.3×	0.008	TK2
Metabolism	1	5.8×	0.165	TK2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
deoxycytidine metabolic process	1	8426.0×	9e-04	TK2
pyrimidine nucleoside salvage	1	4213.0×	9e-04	TK2
thymidine metabolic process	1	4213.0×	9e-04	TK2
DNA replication proofreading	1	2808.7×	1e-03	POLG
mitochondrial DNA replication	1	766.0×	0.003	POLG
base-excision repair, gap-filling	1	561.7×	0.003	POLG
DNA metabolic process	1	526.6×	0.003	POLG
DNA biosynthetic process	1	401.2×	0.003	TK2
DNA-templated DNA replication	1	280.9×	0.004	POLG
nucleobase-containing compound metabolic process	1	263.3×	0.004	TK2
base-excision repair	1	234.1×	0.004	POLG

Therapeutics

Drug target analysis

Approved (phase 4): 2 · Phase ≥3: 2 · Phased (≥1): 2 · Undrugged: 0

Druggability breadth: 2 of 2 evidence-associated genes (100%) 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
TK2	SORIVUDINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
POLG	1	4
TK2	1	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
ADEFOVIR DIPIVOXIL	4	POLG
SORIVUDINE	4	TK2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
POLG	33	Binding:30, ADMET:2, Functional:1
TK2	17	Binding:17

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
TK2	2.7.1.21	thymidine kinase

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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
SORIVUDINE	4	TK2

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	POLG, TK2
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	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.