NARP syndrome

Summary

NARP syndrome (MONDO:0010794) is a disease caused by MT-ATP6 (GenCC Definitive), with 2 cohort genes and 3 clinical trials.

At a glance

• Prevalence: 1-9 / 100 000 (Europe) [Orphanet-validated]
• Causal gene: MT-ATP6 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 12
• Phenotypes (HPO): 28
• Clinical trials: 3

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000		Europe	Validated

Signs & symptoms

Clinical features (HPO)

28 HPO clinical features (Orphanet curated; top 28 by frequency):

HPO ID	Term	Frequency
HP:0000365	Hearing impairment	Frequent (30-79%)
HP:0000510	Rod-cone dystrophy	Frequent (30-79%)
HP:0000543	Optic disc pallor	Frequent (30-79%)
HP:0000618	Blindness	Frequent (30-79%)
HP:0000639	Nystagmus	Frequent (30-79%)
HP:0000726	Dementia	Frequent (30-79%)
HP:0000737	Irritability	Frequent (30-79%)
HP:0000763	Sensory neuropathy	Frequent (30-79%)
HP:0001133	Constriction of peripheral visual field	Frequent (30-79%)
HP:0001136	Retinal arteriolar tortuosity	Frequent (30-79%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0001251	Ataxia	Frequent (30-79%)
HP:0001263	Global developmental delay	Frequent (30-79%)
HP:0002119	Ventriculomegaly	Frequent (30-79%)
HP:0002120	Cerebral cortical atrophy	Frequent (30-79%)
HP:0002315	Headache	Frequent (30-79%)
HP:0003394	Muscle spasm	Frequent (30-79%)
HP:0003487	Babinski sign	Frequent (30-79%)
HP:0003701	Proximal muscle weakness	Frequent (30-79%)
HP:0003739	Myoclonic spasms	Frequent (30-79%)
HP:0004322	Short stature	Frequent (30-79%)
HP:0007117	Corticospinal tract atrophy	Frequent (30-79%)
HP:0007240	Progressive gait ataxia	Frequent (30-79%)
HP:0007814	Retinal pigment epithelial mottling	Frequent (30-79%)
HP:0010864	Intellectual disability, severe	Frequent (30-79%)
HP:0012751	Abnormal basal ganglia MRI signal intensity	Frequent (30-79%)
HP:0030588	Abnormal visual field test	Frequent (30-79%)
HP:0008316	Abnormal mitochondria in muscle tissue	Excluded (0%)

Identifiers

Disease identifiers

Field	Value
Canonical name	NARP syndrome
Mondo ID	MONDO:0010794
MeSH	C537396
OMIM	551500
Orphanet	644
DOID	DOID:0111273
ICD-11	2089784682
UMLS	C1328349
MedGen	231285
GARD	0000262
MedDRA	10062940
Is cancer (heuristic)	no

Also known as: NARP · NARP syndrome · neurogenic muscle weakness-ataxia-retinitis pigmentosa syndrome · neuropathy ataxia retinitis pigmentosa syndrome · neuropathy-ataxia-retinitis pigmentosa syndrome

Data availability: 12 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › metabolic disease › developmental anomaly of metabolic origin › inborn mitochondrial metabolism disorder › mitochondrial oxidative phosphorylation disorder › NARP syndrome

Related subtypes (47): mitochondrial respiratory chain complex deficiency, combined oxidative phosphorylation deficiency, myopathy, lactic acidosis, and sideroblastic anemia, optic atrophy 3, autosomal dominant optic atrophy, classic form, Leigh syndrome, mitochondrial non-syndromic sensorineural hearing loss, maternally-inherited diabetes and deafness, chronic diarrhea with villous atrophy, Kearns-Sayre syndrome, Leber hereditary optic neuropathy, deafness, aminoglycoside-induced, hereditary spastic paraplegia 7, spinocerebellar ataxia type 28, leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome, spastic ataxia 3, pontocerebellar hypoplasia type 6, autosomal recessive optic atrophy, OPA7 type, acute infantile liver failure due to synthesis defect of mtDNA-encoded proteins, congenital cataract-progressive muscular hypotonia-hearing loss-developmental delay syndrome, spastic ataxia 4, hyperuricemia-pulmonary hypertension-renal failure-alkalosis syndrome, hereditary spastic paraplegia 55, cataract-growth hormone deficiency-sensory neuropathy-sensorineural hearing loss-skeletal dysplasia syndrome, Charcot-Marie-Tooth disease recessive intermediate D, autosomal dominant mitochondrial myopathy with exercise intolerance, Charcot-Marie-Tooth disease type 4K, hydrops-lactic acidosis-sideroblastic anemia-multisystemic failure syndrome, hereditary spastic paraplegia 77, fatal infantile encephalocardiomyopathy, FASTKD2-related infantile mitochondrial encephalomyopathy, autosomal dominant optic atrophy and peripheral neuropathy, ataxia neuropathy spectrum, maternally-inherited mitochondrial dystonia, Perrault syndrome, hypertrophic cardiomyopathy and renal tubular disease due to mitochondrial DNA mutation, adult-onset chronic progressive external ophthalmoplegia with mitochondrial myopathy, mitochondrial DNA maintenance syndrome, coenzyme Q10 deficiency, mitochondrial DNA depletion syndrome, periodic paralysis with later-onset distal motor neuropathy, non-progressive predominantly posterior cavitating leukoencephalopathy with peripheral neuropathy, Zellweger-like syndrome without peroxisomal anomalies, maternally-inherited progressive external ophthalmoplegia, Leber plus disease, encephalopathy due to mitochondrial and peroxisomal fission defect, severe neonatal lactic acidosis due to NFS1-ISD11 complex deficiency

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

12 retrieved; paginated sample, class counts are floors:

4 uncertain significance, 4 pathogenic, 3 likely pathogenic, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
9641	NC_012920.1(MT-ATP6):m.8993T>G	MT-ATP6	Pathogenic	reviewed by expert panel
9642	NC_012920.1(MT-ATP6):m.8993T>C	MT-ATP6	Pathogenic	reviewed by expert panel
9644	NC_012920.1(MT-ATP6):m.9176T>C	MT-ATP6	Pathogenic	reviewed by expert panel
9647	NC_012920.1(MT-ATP6):m.9185T>C	MT-ATP6	Pathogenic	reviewed by expert panel
690280	NC_012920.1(MT-ATP6):m.9035T>C	MT-ATP6	Likely pathogenic	reviewed by expert panel
693047	NC_012920.1(MT-ATP6):m.8993_8994inv	MT-ATP6	Likely pathogenic	reviewed by expert panel
9648	NC_012920.1(MT-ATP6):m.8618dup	MT-ATP6	Likely pathogenic	reviewed by expert panel
585120	NC_012920.1(MT-ATP6):m.8686T>C	MT-ATP6	Uncertain significance	criteria provided, single submitter
692983	NC_012920.1(MT-ATP6):m.8783G>A	MT-ATP6	Uncertain significance	reviewed by expert panel
693061	NC_012920.1(MT-ATP6):m.9032T>C	MT-ATP6	Uncertain significance	reviewed by expert panel
9645	NC_012920.1(MT-ATP6):m.8851T>C	MT-ATP6	Uncertain significance	reviewed by expert panel
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: 8 · 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
MT-ATP6	Definitive	Mitochondrial	NARP syndrome	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MT-ATP6	Orphanet:104	Leber hereditary optic neuropathy
MT-ATP6	Orphanet:225154	Familial infantile bilateral striatal necrosis
MT-ATP6	Orphanet:254913	Isolated ATP synthase deficiency
MT-ATP6	Orphanet:255210	Mitochondrial DNA-associated Leigh syndrome
MT-ATP6	Orphanet:320360	MT-ATP6-related mitochondrial spastic paraplegia
MT-ATP6	Orphanet:397750	Periodic paralysis with later-onset distal motor neuropathy
MT-ATP6	Orphanet:644	NARP syndrome
MT-CYB	Orphanet:104	Leber hereditary optic neuropathy
MT-CYB	Orphanet:137675	Histiocytoid cardiomyopathy
MT-CYB	Orphanet:1460	Isolated complex III deficiency

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
MT-ATP6	HGNC:7414	ENSG00000198899	P00846	ATP synthase F(0) complex subunit a	gencc,clinvar
MT-CYB	HGNC:7427	ENSG00000198727	P00156	Cytochrome b	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MT-ATP6	ATP synthase F(0) complex subunit a	Subunit a, of the mitochondrial membrane ATP synthase complex (F(1)F(0) ATP synthase or Complex V) that produces ATP from ADP in the presence of a proton gradient across the membrane which is generated by electron transport complexes of th…
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: 0 · Difficult: 0 · Unknown: 2 · 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	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MT-ATP6	Other/Unknown	no		ATP_synth_F0_asu, ATP_synth_F0_asu_AS, F0_ATP_A_sf
MT-CYB	Other/Unknown	no		Cyt_b/b6_N, Cyt_b/b6_C, Di-haem_cyt_TM

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
descending thoracic aorta	1
left uterine tube	1
mucosa of stomach	1
apex of heart	1
pituitary gland	1
zone of skin	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MT-ATP6	134	ubiquitous	marker	mucosa of stomach, left uterine tube, descending thoracic aorta
MT-CYB	134	ubiquitous	marker	apex of heart, pituitary gland, zone of skin

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MT-CYB	3,317
MT-ATP6	2,869

Intra-cohort edges

A	B	Sources
MT-ATP6	MT-CYB	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MT-ATP6	P00846	10
MT-CYB	P00156	5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 11. 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
Mitochondrial translation termination	2	109.8×	9e-04	MT-ATP6, MT-CYB
Formation of ATP by chemiosmotic coupling	1	285.5×	0.016	MT-ATP6
Complex III assembly	1	219.6×	0.016	MT-CYB
Cristae formation	1	173.0×	0.016	MT-ATP6
Mitochondrial biogenesis	1	84.0×	0.026	MT-ATP6
Mitochondrial protein degradation	1	57.1×	0.031	MT-ATP6
Respiratory electron transport	1	47.6×	0.031	MT-CYB
Aerobic respiration and respiratory electron transport	1	44.3×	0.031	MT-ATP6
Organelle biogenesis and maintenance	1	33.0×	0.037	MT-ATP6
Metabolism of proteins	1	6.2×	0.165	MT-ATP6
Metabolism	1	5.8×	0.165	MT-ATP6

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
response to hyperoxia	2	1123.5×	1e-05	MT-ATP6, MT-CYB
response to D-galactosamine	1	8426.0×	0.001	MT-CYB
response to cobalamin	1	4213.0×	0.002	MT-CYB
electron transport coupled proton transport	1	2106.5×	0.002	MT-CYB
response to mercury ion	1	1203.7×	0.003	MT-CYB
response to glucagon	1	842.6×	0.004	MT-CYB
response to copper ion	1	766.0×	0.004	MT-CYB
mitochondrial electron transport, ubiquinol to cytochrome c	1	648.1×	0.004	MT-CYB
proton motive force-driven ATP synthesis	1	401.2×	0.005	MT-ATP6
response to cadmium ion	1	366.4×	0.005	MT-CYB
animal organ regeneration	1	300.9×	0.006	MT-CYB
cellular respiration	1	216.1×	0.007	MT-CYB
response to calcium ion	1	159.0×	0.009	MT-CYB
proton transmembrane transport	1	156.0×	0.009	MT-ATP6
proton motive force-driven mitochondrial ATP synthesis	1	131.7×	0.010	MT-ATP6
response to toxic substance	1	105.3×	0.011	MT-CYB
response to ethanol	1	73.3×	0.015	MT-CYB
response to hypoxia	1	47.9×	0.022	MT-CYB
response to xenobiotic stimulus	1	34.5×	0.029	MT-CYB

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MT-ATP6	0	0
MT-CYB	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-ATP6	1	Binding:1

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

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	2	MT-ATP6, MT-CYB

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)
MT-ATP6	1	—
MT-CYB	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
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT01803906	Not specified	ENROLLING_BY_INVITATION	Tissue Sample Study for Mitochondrial Disorders
NCT05554835	Not specified	RECRUITING	Global Registry and Natural History Study for Mitochondrial Disorders