Adult-onset chronic progressive external ophthalmoplegia with mitochondrial myopathy

Summary

Adult-onset chronic progressive external ophthalmoplegia with mitochondrial myopathy (MONDO:0018002) is a disease with 3 cohort genes.

At a glance

• Prevalence: Unknown (Worldwide)
• Cohort genes: 3
• Phenotypes (HPO): 32

Clinical features

Signs & symptoms

Clinical features (HPO)

32 HPO clinical features (Orphanet curated; top 32 by frequency):

HPO ID	Term	Frequency
HP:0000590	Progressive external ophthalmoplegia	Obligate (100%)
HP:0003546	Exercise intolerance	Very frequent (80-99%)
HP:0003690	Limb muscle weakness	Very frequent (80-99%)
HP:0000218	High palate	Frequent (30-79%)
HP:0000365	Hearing impairment	Frequent (30-79%)
HP:0001260	Dysarthria	Frequent (30-79%)
HP:0001488	Bilateral ptosis	Frequent (30-79%)
HP:0002015	Dysphagia	Frequent (30-79%)
HP:0002522	Areflexia of lower limbs	Frequent (30-79%)
HP:0002747	Respiratory insufficiency due to muscle weakness	Frequent (30-79%)
HP:0003202	Skeletal muscle atrophy	Frequent (30-79%)
HP:0003326	Myalgia	Frequent (30-79%)
HP:0003551	Difficulty climbing stairs	Frequent (30-79%)
HP:0003738	Exercise-induced myalgia	Frequent (30-79%)
HP:0011968	Feeding difficulties	Frequent (30-79%)
HP:0030196	Fatigable weakness of respiratory muscles	Frequent (30-79%)
HP:0030319	Weakness of facial musculature	Frequent (30-79%)
HP:0000565	Esotropia	Occasional (5-29%)
HP:0000580	Pigmentary retinopathy	Occasional (5-29%)
HP:0001638	Cardiomyopathy	Occasional (5-29%)
HP:0002076	Migraine	Occasional (5-29%)
HP:0002141	Gait imbalance	Occasional (5-29%)
HP:0002361	Psychomotor deterioration	Occasional (5-29%)
HP:0002406	Limb dysmetria	Occasional (5-29%)
HP:0002505	Loss of ambulation	Occasional (5-29%)
HP:0002549	Deficit in phonologic short-term memory	Occasional (5-29%)
HP:0002650	Scoliosis	Occasional (5-29%)
HP:0003133	Abnormality of the spinocerebellar tracts	Occasional (5-29%)
HP:0003722	Neck flexor weakness	Occasional (5-29%)
HP:0005150	Abnormal atrioventricular conduction	Occasional (5-29%)
HP:0007141	Sensorimotor neuropathy	Occasional (5-29%)
HP:0007256	Abnormal pyramidal sign	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	adult-onset chronic progressive external ophthalmoplegia with mitochondrial myopathy
Mondo ID	MONDO:0018002
Orphanet	329336
SNOMED CT	725464001
UMLS	C4511138
MedGen	1393682
GARD	0017503
Is cancer (heuristic)	no

Also known as: adult-onset CPEO with mitochondrial myopathy

Data availability: 2 GenCC gene-disease records.

Disease family

An umbrella term covering 1 Mondo subtype.

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › muscle tissue disorder › skeletal muscle disorder › myopathy › congenital myopathy › congenital structural myopathy › inborn mitochondrial myopathy › adult-onset chronic progressive external ophthalmoplegia with mitochondrial myopathy

Related subtypes (23): myopathy, lactic acidosis, and sideroblastic anemia, mitochondrial encephalomyopathy, progressive external ophthalmoplegia, mitochondrial myopathy with a defect in mitochondrial-protein transport, Barth syndrome, mitochondrial myopathy with diabetes, mitochondrial myopathy with reversible cytochrome C oxidase deficiency, lethal infantile mitochondrial myopathy, sensory ataxic neuropathy, dysarthria, and ophthalmoparesis, mitochondrial trifunctional protein deficiency, adenosine monophosphate deaminase deficiency, congenital cataract-progressive muscular hypotonia-hearing loss-developmental delay syndrome, autosomal dominant mitochondrial myopathy with exercise intolerance, fatal infantile encephalocardiomyopathy, mitochondrial myopathy-lactic acidosis-deafness syndrome, mitochondrial neurogastrointestinal encephalomyopathy, maternally-inherited progressive external ophthalmoplegia, mitochondrial myopathy, episodic, with optic atrophy and reversible leukoencephalopathy, mitochondrial complex II deficiency, nuclear type, mitochondrial myopathy-cerebellar ataxia-pigmentary retinopathy syndrome, X-linked recessive mitochondrial myopathy, mitochondrial complex I deficiency, nuclear type 1, COX deficiency, benign infantile mitochondrial myopathy

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

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

No tiered GWAS variants or ClinVar records for this disease.

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 16 · Orphanet: 6 · 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
RRM2B	Definitive	Autosomal recessive	mitochondrial DNA depletion syndrome 8a	10
RNASEH1	Strong	Autosomal recessive	progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 2	3
RNASEH1P1	Strong	Autosomal recessive	progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 2	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
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
RNASEH1	Orphanet:329336	Adult-onset chronic progressive external ophthalmoplegia with mitochondrial myopathy

Cohort genes → proteins

3 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
RNASEH1P1	HGNC:10049	ENSG00000265790		ribonuclease H1 pseudogene 1	gencc
RRM2B	HGNC:17296	ENSG00000048392	Q7LG56	Ribonucleoside-diphosphate reductase subunit M2 B	gencc
RNASEH1	HGNC:18466	ENSG00000171865	O60930	Ribonuclease H1	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RRM2B	Ribonucleoside-diphosphate reductase subunit M2 B	Plays a pivotal role in cell survival by repairing damaged DNA in a p53/TP53-dependent manner.
RNASEH1	Ribonuclease H1	Endonuclease that specifically degrades the RNA of RNA-DNA hybrids.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 1 · 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)	2	8.0×	0.039
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RNASEH1P1	Other/Unknown	no
RRM2B	Enzyme (other)	yes	1.17.4.1	RNR_small_fam, Ferritin-like_SF, RNR-like
RNASEH1	Enzyme (other)	yes	3.1.26.4	RNaseH_domain, Ribosomal_bL9/RNase_H1_N, RNase_H1_N

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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
oocyte	2
secondary oocyte	2
male germ line stem cell (sensu Vertebrata) in testis	1
primordial germ cell in gonad	1
testis	1
deltoid	1
endothelial cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RNASEH1P1	29	ubiquitous	yes	male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad, testis
RRM2B	254	ubiquitous	marker	secondary oocyte, oocyte, deltoid
RNASEH1	271	ubiquitous	marker	secondary oocyte, oocyte, endothelial cell

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RNASEH1	2,627
RRM2B	2,432
RNASEH1P1	0

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
RNASEH1	O60930	7
RRM2B	Q7LG56	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. Enrichment computed across 3 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
Strand-asynchronous mitochondrial DNA replication	1	571.0×	0.007	RNASEH1
Interconversion of nucleotide di- and triphosphates	1	178.4×	0.011	RRM2B
DNA Replication	1	119.0×	0.011	RNASEH1
TP53 Regulates Metabolic Genes	1	64.9×	0.015	RRM2B

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
deoxyribonucleoside triphosphate metabolic process	1	8426.0×	0.001	RRM2B
ribonucleoside diphosphate metabolic process	1	2808.7×	0.001	RRM2B
deoxyribonucleotide biosynthetic process	1	2808.7×	0.001	RRM2B
2’-deoxyribonucleotide biosynthetic process	1	2808.7×	0.001	RRM2B
DNA replication, removal of RNA primer	1	2106.5×	0.002	RNASEH1
positive regulation of G0 to G1 transition	1	1685.2×	0.002	RRM2B
negative regulation of intrinsic apoptotic signaling pathway by p53 class mediator	1	1203.7×	0.002	RRM2B
response to amine	1	936.2×	0.002	RRM2B
mitochondrial DNA replication	1	766.0×	0.002	RRM2B
renal system process	1	561.7×	0.003	RRM2B
DNA synthesis involved in DNA repair	1	468.1×	0.003	RRM2B
positive regulation of G2/M transition of mitotic cell cycle	1	300.9×	0.004	RRM2B
RNA catabolic process	1	227.7×	0.005	RNASEH1
kidney development	1	70.2×	0.016	RRM2B
response to oxidative stress	1	65.3×	0.016	RRM2B
DNA repair	1	31.9×	0.031	RRM2B

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 3 evidence-associated genes (67%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
RRM2B	1	3
RNASEH1P1	0	0
RNASEH1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
TRIAPINE	3	RRM2B

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
RRM2B	47	Binding:44, Functional:3
RNASEH1	3	Binding:3

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
RRM2B	1.17.4.1	ribonucleoside-diphosphate reductase
RNASEH1	3.1.26.4	ribonuclease H

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

1 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)
TRIAPINE	3	RRM2B

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	1	RRM2B
C	Druggable family + PDB, no drug	1	RNASEH1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	RNASEH1P1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
RNASEH1P1	0	—
RNASEH1	3	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.