Progressive external ophthalmoplegia

Summary

Progressive external ophthalmoplegia (MONDO:0005181) is a disease with 6 cohort genes and 3 clinical trials. Top therapeutic interventions include nicotinamide riboside.

At a glance

• Cohort genes: 6
• ClinVar variants: 8
• Clinical trials: 3

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	progressive external ophthalmoplegia
Mondo ID	MONDO:0005181
EFO	EFO:0002509
MeSH	D017246
Orphanet	520820
DOID	DOID:12558
ICD-10-CM	H49.4
ICD-11	1698427219
SNOMED CT	46252003
UMLS	C0162674
MedGen	102439
GARD	0004503
Is cancer (heuristic)	no

Also known as: chronic progressive external ophthalmoplegia [ambiguous] · progressive external ophthalmoplegia

Data availability: 8 ClinVar variants · 1 HPO phenotype.

Disease family

An umbrella term covering 3 Mondo subtypes.

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

Related subtypes (216): polymicrogyria, congenital myasthenic syndrome with tubular aggregates, prenatal-onset spinal muscular atrophy with congenital bone fractures, anencephaly, cerebral cavernous malformation, meningocele, congenital nystagmus, congenital toxoplasmosis, congenital contractural arachnodactyly, congenital trigeminal anesthesia, familial congenital palsy of trochlear nerve, Myhre syndrome, Aase-Smith syndrome, KBG syndrome, autosomal dominant primary microcephaly, Mobius syndrome, MYH7-related skeletal myopathy, congenital stationary night blindness autosomal dominant 2, Prader-Willi syndrome, congenital myopathy 7A, myosin storage, autosomal dominant, Smith-Magenis syndrome, spina bifida, Freeman-Sheldon syndrome, isolated cerebellar hypoplasia/agenesis, Chediak-Higashi syndrome, Cohen syndrome, multiple pterygium-malignant hyperthermia syndrome, corpus callosum, agenesis of, congenital lactic acidosis, Saguenay-Lac-Saint-Jean type, facial dysmorphism-macrocephaly-myopia-Dandy-Walker malformation syndrome, diastematomyelia, EEM syndrome, Mowat-Wilson syndrome, Johanson-Blizzard syndrome, intellectual disability, Buenos-Aires type, myasthenia, congenital, refractory to acetylcholinesterase inhibitors, congenital myasthenic syndrome 6, Bailey-Bloch congenital myopathy, congenital stationary night blindness 1B, radioulnar synostosis-developmental delay-hypotonia syndrome, Schinzel-Giedion syndrome, schizencephaly, intellectual disability, Wolff type, X-linked intellectual disability-plagiocephaly syndrome, X-linked adrenal hypoplasia congenita, syndromic X-linked intellectual disability 7, syndromic X-linked intellectual disability Shashi type, syndromic X-linked intellectual disability Lubs type, syndromic X-linked intellectual disability Abidi type, syndromic X-linked intellectual disability Siderius type, X-linked intellectual disability, Cabezas type, X-linked intellectual disability-cubitus valgus-dysmorphism syndrome, syndromic X-linked intellectual disability Claes-Jensen type, moyamoya angiopathy-short stature-facial dysmorphism-hypergonadotropic hypogonadism syndrome, multiple congenital anomalies-hypotonia-seizures syndrome 2, developmental and epileptic encephalopathy, 36, blepharophimosis - intellectual disability syndrome, MKB type, X-linked intellectual disability-short stature-overweight syndrome, intellectual disability, X-linked, syndromic 33, syndromic X-linked intellectual disability 34, infantile-onset X-linked spinal muscular atrophy, syndromic X-linked intellectual disability 5, holoprosencephaly-hypokinesia-congenital contractures syndrome, X-linked intellectual disability with marfanoid habitus, Wieacker-Wolff syndrome, MERRF syndrome, macrocephaly-spastic paraplegia-dysmorphism syndrome, intellectual disability-sparse hair-brachydactyly syndrome, myofibrillar myopathy 1, isolated hereditary congenital facial paralysis, fibrosis of extraocular muscles, congenital, 2, Pierpont syndrome, congenital cataracts-facial dysmorphism-neuropathy syndrome, Bohring-Opitz syndrome, PHACE syndrome, B4GALT1-congenital disorder of glycosylation, developmental malformations-deafness-dystonia syndrome, sensory ataxic neuropathy, dysarthria, and ophthalmoparesis, AICA-ribosiduria, myofibrillar myopathy 3, fibrosis of extraocular muscles, congenital, 3c, myofibrillar myopathy 4, myofibrillar myopathy 5, cone-rod synaptic disorder, congenital nonprogressive, congenital stationary night blindness autosomal dominant 3, congenital stationary night blindness autosomal dominant 1, intellectual disability, autosomal recessive 12, progressive myoclonic epilepsy type 3, chromosome 15q13.3 microdeletion syndrome, combined pituitary hormone deficiencies, genetic form, congenital stationary night blindness 1D, DYRK1A-related intellectual disability syndrome, Pitt-Hopkins-like syndrome 2, developmental and epileptic encephalopathy, 15, Schuurs-Hoeijmakers syndrome, severe intellectual disability-poor language-strabismus-grimacing face-long fingers syndrome, severe intellectual disability-progressive spastic diplegia syndrome, hypotonia, infantile, with psychomotor retardation and characteristic facies, developmental and epileptic encephalopathy, 18, CTCF-related neurodevelopmental disorder, autism spectrum disorder due to AUTS2 deficiency, developmental and epileptic encephalopathy, 23, ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder, Bardet-Biedl syndrome 11, cerebellar-facial-dental syndrome, fibrosis of extraocular muscles, congenital, 5, congenital myasthenic syndrome 15, lethal fetal cerebrorenogenitourinary agenesis/hypoplasia syndrome, autosomal dominant intellectual disability-craniofacial anomalies-cardiac defects syndrome, congenital myasthenic syndrome 18, autosomal recessive spinocerebellar ataxia 20, Houge-Janssens syndrome 1, intellectual disability-microcephaly-strabismus-behavioral abnormalities syndrome, congenital stationary night blindness 1G, hypomyelinating leukodystrophy 10, developmental and epileptic encephalopathy, 50, congenital insensitivity to pain-hypohidrosis syndrome, macrocephaly-intellectual disability-neurodevelopmental disorder-small thorax syndrome, SLC39A8-CDG, spastic paraplegia-severe developmental delay-epilepsy syndrome, cardiac anomalies - developmental delay - facial dysmorphism syndrome, severe intellectual disability-corpus callosum agenesis-facial dysmorphism-cerebellar ataxia syndrome, intellectual disability, autosomal recessive 53, TELO2-related intellectual disability-neurodevelopmental disorder, micrognathia-recurrent infections-behavioral abnormalities-mild intellectual disability syndrome, autosomal recessive limb-girdle muscular dystrophy type 2Y, myofibrillar myopathy 7, short stature-brachydactyly-obesity-global developmental delay syndrome, autosomal recessive limb-girdle muscular dystrophy type 2R1, severe microbrachycephaly-intellectual disability-athetoid cerebral palsy syndrome, congenital laryngeal palsy, congenital or early infantile CACH syndrome, congenital epulis, severe congenital nemaline myopathy, intermediate nemaline myopathy, typical nemaline myopathy, childhood-onset nemaline myopathy, adult-onset nemaline myopathy, qualitative or quantitative defects of protein involved in O-glycosylation of alpha-dystroglycan, holoprosencephaly, congenital insensitivity to pain with hyperhidrosis, congenital hydrocephalus, familial congenital mirror movements, macrocephaly-short stature-paraplegia syndrome, cephalocele, mitochondrial neurogastrointestinal encephalomyopathy, X-linked intellectual disability-hypogonadism-ichthyosis-obesity-short stature syndrome, 7p22.1 microduplication syndrome, congenital achiasma, congenital retinal arteriovenous communication, 3q27.3 microdeletion syndrome, Prader-Willi-like syndrome, 9q31.1q31.3 microdeletion syndrome, congenital oculomotor nerve palsy, congenital abducens nerve palsy, neurodevelopmental disorder-craniofacial dysmorphism-cardiac defect-hip dysplasia syndrome, congenital insensitivity to pain with severe intellectual disability, X-linked intellectual disability-cerebellar hypoplasia-spondylo-epiphyseal dysplasia syndrome, global developmental delay-visual anomalies-progressive cerebellar atrophy-truncal hypotonia syndrome, lissencephaly spectrum disorders, hyaline body myopathy, 22q11.2 deletion syndrome, craniorachischisis, Leber congenital amaurosis, Ritscher-Schinzel syndrome, Rubinstein-Taybi syndrome, X-linked intellectual disability-hypogammaglobulinemia-progressive neurological deterioration syndrome, X-linked intellectual disability-epilepsy-progressive joint contractures-dysmorphism syndrome, X-linked intellectual disability, Pai type, X-linked intellectual disability, Stevenson type, X-linked intellectual disability, Stoll type, congenital muscular dystrophy, congenital vitreoretinal dysplasia, periventricular nodular heterotopia, postsynaptic congenital myasthenic syndrome, subcortical band heterotopia, congenital fibrosis of extraocular muscles type 1, Al Gazali Khidr Prem Chandran syndrome, distal arthrogryposis Moore weaver type, congenital myotonic dystrophy, myasthenic syndrome, congenital, 7B, presynaptic, autosomal recessive, intellectual disability, autosomal dominant 47, intellectual disability, autosomal dominant 48, spondyloepiphyseal dysplasia, sensorineural hearing loss, impaired intellectual development, and leber congenital amaurosis, myasthenic syndrome, congenital, 23, presynaptic, myasthenic syndrome, congenital, 24, presynaptic, myasthenic syndrome, congenital, 25, presynaptic, developmental and epileptic encephalopathy, 77, night blindness, congenital stationary, type1i, neuropathy, congenital hypomelinating, congenital axonal neuropathy with encephalopathy, developmental and epileptic encephalopathy, 73, PHIP-related behavioral problems-intellectual disability-obesity-dysmorphic features syndrome, isolated exencephaly, myasthenic syndrome, congenital, 22, intellectual developmental disorder with gastrointestinal difficulties and high pain threshold, intellectual developmental disorder with dysmorphic facies, seizures, and distal limb anomalies, 9q33.3q34.11 microdeletion syndrome, congenital labioscrotal agenesis-cerebellar malformation-corneal dystrophy-facial dysmorphism syndrome, early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome, SIN3A-related intellectual disability syndrome, childhood-onset motor and cognitive regression syndrome with extrapyramidal movement disorder, X-linked congenital stationary night blindness, neurodevelopmental disorder with progressive microcephaly, spasticity, and brain anomalies, FOXG1 disorder, alpha-actinopathy, TPM3-related myopathy, X-linked recessive mitochondrial myopathy, RYR1-related myopathy, TTN-related myopathy, TPM2-related myopathy, myopathy caused by variation in POMGNT1, central hypoventilation syndrome, congenital, 1, with or without Hirschsprung disease, segmental spinal dysgenesis, myopathy, myofibrillar, 13, with rimmed vacuoles, congenital neuronal ceroid lipofuscinosis 10

Subtypes (3): progressive external ophthalmoplegia with mitochondrial DNA deletions, Kearns-Sayre syndrome, autosomal recessive progressive external ophthalmoplegia

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

8 retrieved; paginated sample, class counts are floors:

4 uncertain significance, 2 pathogenic, 1 not provided, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
3255383	NC_012920.1(MT-TI):m.4275G>A	MT-TI	Pathogenic	criteria provided, single submitter
3255385	NC_012920.1(MT-TY):m.5828G>A	MT-TY	Pathogenic	criteria provided, single submitter
426106	NM_021830.5(TWNK):c.1121G>A (p.Arg374Gln)	TWNK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
374215	NC_012920.1(MT-TS1):m.7486G>A	MT-TS1	Uncertain significance	no assertion criteria provided
30434	NM_015713.5(RRM2B):c.606T>A (p.Phe202Leu)	RRM2B	Uncertain significance	no assertion criteria provided
30435	NM_015713.5(RRM2B):c.817G>A (p.Gly273Ser)	RRM2B	Uncertain significance	criteria provided, multiple submitters, no conflicts
30436	NM_015713.5(RRM2B):c.97C>T (p.Pro33Ser)	RRM2B	Uncertain significance	criteria provided, multiple submitters, no conflicts
2501808	NC_012920.1(MT-CYB):m.15485C>T	MT-CYB	not provided	no classification provided

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
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
MT-CYB	Orphanet:104	Leber hereditary optic neuropathy
MT-CYB	Orphanet:137675	Histiocytoid cardiomyopathy
MT-CYB	Orphanet:1460	Isolated complex III deficiency
MT-TI	Orphanet:620371	Gitelman-like kidney tubulopathy due to mitochondrial DNA mutation
MT-TS1	Orphanet:2202	Palmoplantar keratoderma-deafness syndrome
MT-TS1	Orphanet:550	MELAS
MT-TS1	Orphanet:551	MERRF
MT-TS1	Orphanet:663	Mitochondrial DNA-related progressive external ophthalmoplegia
MT-TS1	Orphanet:90641	Rare mitochondrial non-syndromic sensorineural deafness

Cohort genes → proteins

6 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	6

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TWNK	HGNC:1160	ENSG00000107815	Q96RR1	Twinkle mtDNA helicase	clinvar
RRM2B	HGNC:17296	ENSG00000048392	Q7LG56	Ribonucleoside-diphosphate reductase subunit M2 B	clinvar
MT-CYB	HGNC:7427	ENSG00000198727	P00156	Cytochrome b	clinvar
MT-TI	HGNC:7488	ENSG00000210100		mitochondrially encoded tRNA-Ile (AUU/C)	clinvar
MT-TS1	HGNC:7497	ENSG00000210151		mitochondrially encoded tRNA-Ser (UCN) 1	clinvar
MT-TY	HGNC:7502	ENSG00000210144		mitochondrially encoded tRNA-Tyr (UAU/C)	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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.
MT-CYB	Cytochrome b	Component of the ubiquinol-cytochrome c reductase complex (complex III or cytochrome b-c1 complex) that is part of the mitochondrial respiratory chain.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 4 · Druggable fraction: 0.33

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	4.0×	0.166
Other/Unknown	4	1.2×	0.458

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
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
MT-CYB	Other/Unknown	no		Cyt_b/b6_N, Cyt_b/b6_C, Di-haem_cyt_TM
MT-TI	Other/Unknown	no
MT-TS1	Other/Unknown	no
MT-TY	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

3 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
skeletal muscle tissue	2
duodenum	2
gastrocnemius	1
male germ line stem cell (sensu Vertebrata) in testis	1
tendon of biceps brachii	1
deltoid	1
oocyte	1
secondary oocyte	1
pituitary gland	1
zone of skin	1
putamen	1
sural nerve	1
vermiform appendix	1
adrenal tissue	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
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
MT-CYB	134	ubiquitous	marker	apex of heart, pituitary gland, zone of skin
MT-TI	117	broad	yes	skeletal muscle tissue, sural nerve, putamen
MT-TS1	118	tissue_specific	yes	duodenum, apex of heart, vermiform appendix
MT-TY	118		marker	skeletal muscle tissue, duodenum, adrenal tissue

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MT-CYB	3,317
RRM2B	2,432
TWNK	1,390
MT-TI	0
MT-TS1	0
MT-TY	0

Intra-cohort edges

A	B	Sources
RRM2B	TWNK	string_interaction

Structural data

PDB: 3 · AlphaFold-only: 0 · No structure: 3

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MT-CYB	P00156	5
RRM2B	Q7LG56	3
TWNK	Q96RR1	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. Enrichment computed across 6 evidence-associated genes (3 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 3 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	380.7×	0.021	TWNK
Complex III assembly	1	146.4×	0.022	MT-CYB
Interconversion of nucleotide di- and triphosphates	1	119.0×	0.022	RRM2B
Transcriptional activation of mitochondrial biogenesis	1	68.0×	0.029	TWNK
TP53 Regulates Metabolic Genes	1	43.3×	0.031	RRM2B
Mitochondrial protein degradation	1	38.1×	0.031	TWNK
Mitochondrial translation termination	1	36.6×	0.031	MT-CYB
Respiratory electron transport	1	31.7×	0.031	MT-CYB

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 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	2	1021.3×	4e-05	TWNK, RRM2B
deoxyribonucleoside triphosphate metabolic process	1	5617.3×	0.002	RRM2B
response to D-galactosamine	1	5617.3×	0.002	MT-CYB
response to cobalamin	1	2808.7×	0.003	MT-CYB
ribonucleoside diphosphate metabolic process	1	1872.4×	0.003	RRM2B
deoxyribonucleotide biosynthetic process	1	1872.4×	0.003	RRM2B
2’-deoxyribonucleotide biosynthetic process	1	1872.4×	0.003	RRM2B
electron transport coupled proton transport	1	1404.3×	0.003	MT-CYB
positive regulation of G0 to G1 transition	1	1123.5×	0.003	RRM2B
mitochondrial transcription	1	802.5×	0.003	TWNK
response to mercury ion	1	802.5×	0.003	MT-CYB
negative regulation of intrinsic apoptotic signaling pathway by p53 class mediator	1	802.5×	0.003	RRM2B
response to amine	1	624.1×	0.004	RRM2B
response to glucagon	1	561.7×	0.004	MT-CYB
response to copper ion	1	510.7×	0.004	MT-CYB
protein hexamerization	1	468.1×	0.004	TWNK
mitochondrial electron transport, ubiquinol to cytochrome c	1	432.1×	0.004	MT-CYB
renal system process	1	374.5×	0.005	RRM2B
response to hyperoxia	1	374.5×	0.005	MT-CYB
DNA synthesis involved in DNA repair	1	312.1×	0.005	RRM2B
response to cadmium ion	1	244.2×	0.006	MT-CYB
positive regulation of G2/M transition of mitotic cell cycle	1	200.6×	0.007	RRM2B
animal organ regeneration	1	200.6×	0.007	MT-CYB
DNA-templated DNA replication	1	187.2×	0.007	TWNK
cellular respiration	1	144.0×	0.009	MT-CYB
response to calcium ion	1	106.0×	0.012	MT-CYB
response to toxic substance	1	70.2×	0.017	MT-CYB
response to ethanol	1	48.9×	0.024	MT-CYB
kidney development	1	46.8×	0.024	RRM2B
response to oxidative stress	1	43.5×	0.025	RRM2B

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 6 evidence-associated genes (17%) 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
TWNK	0	0
MT-CYB	0	0
MT-TI	0	0
MT-TS1	0	0
MT-TY	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

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
TWNK	3.6.4.12	DNA helicase
RRM2B	1.17.4.1	ribonucleoside-diphosphate reductase

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

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	TWNK
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	4	MT-CYB, MT-TI, MT-TS1, MT-TY

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)
TWNK	0	—
MT-CYB	0	—
MT-TI	0	—
MT-TS1	0	—
MT-TY	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 3.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	3

Top trials by phase / activity

NCT	Phase	Status	Title
NCT02161848	Not specified	COMPLETED	MRI Study - Chronic Progressive External Ophthalmoplegia
NCT03432871	Not specified	COMPLETED	Nicotinamide Riboside and Mitochondrial Biogenesis
NCT04678115	Not specified	COMPLETED	Clinical Trial Comparing Two Non-Surgical Treatments for Severe Blepharoptosis

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
NICOTINAMIDE RIBOSIDE	3	1