maternally-inherited Leigh syndrome

Summary

maternally-inherited Leigh syndrome (MONDO:0016814) is a disease with 7 cohort genes and 1 clinical trial. The dominant Reactome pathway is Mitochondrial translation termination (7 cohort genes).

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Cohort genes: 7
• Phenotypes (HPO): 53
• Clinical trials: 1

Clinical features

Signs & symptoms

Clinical features (HPO)

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

HPO ID	Term	Frequency
HP:0000816	Abnormality of Krebs cycle metabolism	Very frequent (80-99%)
HP:0002490	Increased CSF lactate	Very frequent (80-99%)
HP:0000580	Pigmentary retinopathy	Frequent (30-79%)
HP:0000597	Ophthalmoparesis	Frequent (30-79%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0001251	Ataxia	Frequent (30-79%)
HP:0001257	Spasticity	Frequent (30-79%)
HP:0001276	Hypertonia	Frequent (30-79%)
HP:0001324	Muscle weakness	Frequent (30-79%)
HP:0001332	Dystonia	Frequent (30-79%)
HP:0001508	Failure to thrive	Frequent (30-79%)
HP:0002066	Gait ataxia	Frequent (30-79%)
HP:0002069	Bilateral tonic-clonic seizure	Frequent (30-79%)
HP:0002072	Chorea	Frequent (30-79%)
HP:0002123	Generalized myoclonic seizure	Frequent (30-79%)
HP:0002151	Increased circulating lactate concentration	Frequent (30-79%)
HP:0002572	Episodic vomiting	Frequent (30-79%)
HP:0003648	Lacticaciduria	Frequent (30-79%)
HP:0007141	Sensorimotor neuropathy	Frequent (30-79%)
HP:0007183	Focal T2 hyperintense basal ganglia lesion	Frequent (30-79%)
HP:0008947	Floppy infant	Frequent (30-79%)
HP:0011344	Severe global developmental delay	Frequent (30-79%)
HP:0100660	Dyskinesia	Frequent (30-79%)
HP:0002104	Apnea	Occasional (5-29%)
HP:0002240	Hepatomegaly	Occasional (5-29%)
HP:0002376	Developmental regression	Occasional (5-29%)
HP:0002483	Bulbar signs	Occasional (5-29%)
HP:0002883	Hyperventilation	Occasional (5-29%)
HP:0003348	Hyperalaninemia	Occasional (5-29%)
HP:0003481	Segmental peripheral demyelination/remyelination	Occasional (5-29%)
HP:0003737	Mitochondrial myopathy	Occasional (5-29%)
HP:0004885	Episodic respiratory distress	Occasional (5-29%)
HP:0007108	Demyelinating peripheral neuropathy	Occasional (5-29%)
HP:0012469	Infantile spasms	Occasional (5-29%)
HP:0031434	Abnormal speech prosody	Occasional (5-29%)
HP:0031546	Cardiac conduction abnormality	Occasional (5-29%)
HP:0100611	Multiple glomerular cysts	Occasional (5-29%)
HP:0000091	Abnormal renal tubule morphology	Occasional (5-29%)
HP:0000407	Sensorineural hearing impairment	Occasional (5-29%)
HP:0000510	Rod-cone dystrophy	Occasional (5-29%)
HP:0000639	Nystagmus	Occasional (5-29%)
HP:0000648	Optic atrophy	Occasional (5-29%)
HP:0001265	Hyporeflexia	Occasional (5-29%)
HP:0001347	Hyperreflexia	Occasional (5-29%)
HP:0001399	Hepatic failure	Occasional (5-29%)
HP:0001639	Hypertrophic cardiomyopathy	Occasional (5-29%)
HP:0001644	Dilated cardiomyopathy	Occasional (5-29%)
HP:0001945	Fever	Occasional (5-29%)
HP:0002015	Dysphagia	Occasional (5-29%)
HP:0002045	Hypothermia	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	maternally-inherited Leigh syndrome
Mondo ID	MONDO:0016814
MeSH	C536035
Orphanet	255210
SNOMED CT	717052002
UMLS	C2931092
MedGen	443976
GARD	0003671
Is cancer (heuristic)	no

Also known as: Leigh disease, maternally inherited · maternally inherited Leigh syndrome · maternally-inherited infantile subacute necrotizing encephalopathy · maternally-inherited Leigh disease · MILS · mitochondrial DNA-associated Leigh syndrome · Subacute necrotizing encephalomyelopathy maternally inherited

Data availability: 7 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 › Leigh syndrome › maternally-inherited Leigh syndrome

Related subtypes (3): necrotizing encephalomyelopathy, subacute, of Leigh, adult, congenital lactic acidosis, Saguenay-Lac-Saint-Jean type, Leigh syndrome with cardiomyopathy

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: 34 · Orphanet: 30 · 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	Supportive	Mitochondrial	maternally-inherited Leigh syndrome	8
MT-ND1	Supportive	Mitochondrial	maternally-inherited Leigh syndrome	5
MT-ND2	Supportive	Mitochondrial	maternally-inherited Leigh syndrome	3
MT-ND3	Supportive	Mitochondrial	maternally-inherited Leigh syndrome	3
MT-ND4	Supportive	Mitochondrial	maternally-inherited Leigh syndrome	5
MT-ND5	Supportive	Mitochondrial	maternally-inherited Leigh syndrome	5
MT-ND6	Supportive	Mitochondrial	maternally-inherited Leigh syndrome	5

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-ND1	Orphanet:104	Leber hereditary optic neuropathy
MT-ND1	Orphanet:255210	Mitochondrial DNA-associated Leigh syndrome
MT-ND1	Orphanet:2609	Isolated complex I deficiency
MT-ND1	Orphanet:550	MELAS
MT-ND2	Orphanet:104	Leber hereditary optic neuropathy
MT-ND2	Orphanet:255210	Mitochondrial DNA-associated Leigh syndrome
MT-ND2	Orphanet:2609	Isolated complex I deficiency
MT-ND3	Orphanet:255210	Mitochondrial DNA-associated Leigh syndrome
MT-ND3	Orphanet:2609	Isolated complex I deficiency
MT-ND3	Orphanet:99718	Leber plus disease
MT-ND4	Orphanet:104	Leber hereditary optic neuropathy
MT-ND4	Orphanet:255210	Mitochondrial DNA-associated Leigh syndrome
MT-ND4	Orphanet:550	MELAS
MT-ND4	Orphanet:90641	Rare mitochondrial non-syndromic sensorineural deafness
MT-ND4	Orphanet:99718	Leber plus disease
MT-ND5	Orphanet:104	Leber hereditary optic neuropathy
MT-ND5	Orphanet:255210	Mitochondrial DNA-associated Leigh syndrome
MT-ND5	Orphanet:550	MELAS
MT-ND5	Orphanet:551	MERRF
MT-ND6	Orphanet:104	Leber hereditary optic neuropathy
MT-ND6	Orphanet:255210	Mitochondrial DNA-associated Leigh syndrome
MT-ND6	Orphanet:550	MELAS
MT-ND6	Orphanet:99718	Leber plus disease

Cohort genes → proteins

7 cohort genes, 7 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	7

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MT-ATP6	HGNC:7414	ENSG00000198899	P00846	ATP synthase F(0) complex subunit a	gencc
MT-ND1	HGNC:7455	ENSG00000198888	P03886	NADH-ubiquinone oxidoreductase chain 1	gencc
MT-ND2	HGNC:7456	ENSG00000198763	P03891	NADH-ubiquinone oxidoreductase chain 2	gencc
MT-ND3	HGNC:7458	ENSG00000198840	P03897	NADH-ubiquinone oxidoreductase chain 3	gencc
MT-ND4	HGNC:7459	ENSG00000198886	C0HME5	Mitochondrial alternative ND4 protein	gencc
MT-ND5	HGNC:7461	ENSG00000198786	P03915	NADH-ubiquinone oxidoreductase chain 5	gencc
MT-ND6	HGNC:7462	ENSG00000198695	P03923	NADH-ubiquinone oxidoreductase chain 6	gencc

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-ND1	NADH-ubiquinone oxidoreductase chain 1	Core subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) which catalyzes electron transfer from NADH through the respiratory chain, using ubiquinone as an electron acceptor.
MT-ND2	NADH-ubiquinone oxidoreductase chain 2	Core subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) which catalyzes electron transfer from NADH through the respiratory chain, using ubiquinone as an electron acceptor.
MT-ND3	NADH-ubiquinone oxidoreductase chain 3	Core subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) which catalyzes electron transfer from NADH through the respiratory chain, using ubiquinone as an electron acceptor.
MT-ND4	Mitochondrial alternative ND4 protein	Regulates mitochondrial respiration by decreasing oxygen consumption.
MT-ND5	NADH-ubiquinone oxidoreductase chain 5	Core subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) which catalyzes electron transfer from NADH through the respiratory chain, using ubiquinone as an electron acceptor.
MT-ND6	NADH-ubiquinone oxidoreductase chain 6	Core subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) which catalyzes electron transfer from NADH through the respiratory chain, using ubiquinone as an electron acceptor.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 7 · 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	7	1.8×	0.017

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-ND1	Other/Unknown	no		NADH_UbQ_OxRdtase_su1/FPO, NADH_UbQ_OxRdtase_su1_CS
MT-ND2	Other/Unknown	no		ND/Mrp_TM, NADH_UbQ_OxRdtase_chain2, NADH_DH_su2_C
MT-ND3	Other/Unknown	no		NADH_UbQ/plastoQ_OxRdtase_su3, NDAH_ubi_oxred_su3_sf
MT-ND4	Other/Unknown	no		NADH4_N, ND/Mrp_TM, NADH_UbQ_OxRdtase
MT-ND5	Other/Unknown	no		Proton_antipo_N, ND/Mrp_TM, NU5C-like
MT-ND6	Other/Unknown	no		NADH_UbQ/plastoQ_OxRdtase_su6, ComplexI_Subunit6

Expression context

Cohort genes with no expression data: 0.

7 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)	7
unknown	0

Top tissues across cohort

Tissue	Cohort genes
left uterine tube	3
adipose tissue	3
right uterine tube	3
mucosa of stomach	2
descending thoracic aorta	1
frontal cortex	1
gastrocnemius	1
granulocyte	1
left lobe of thyroid gland	1
apex of heart	1
zone of skin	1
heart right ventricle	1
lateral nuclear group of thalamus	1
postcentral gyrus	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-ND1	134	ubiquitous	marker	adipose tissue, gastrocnemius, frontal cortex
MT-ND2	134	broad	marker	adipose tissue, right uterine tube, left uterine tube
MT-ND3	134	ubiquitous	marker	granulocyte, adipose tissue, left lobe of thyroid gland
MT-ND4	134	ubiquitous	marker	right uterine tube, apex of heart, zone of skin
MT-ND5	247	ubiquitous	marker	heart right ventricle, postcentral gyrus, lateral nuclear group of thalamus
MT-ND6	134	ubiquitous	marker	mucosa of stomach, left uterine tube, right uterine tube

Protein interactions among cohort

Intra-cohort edges: 15.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MT-ND1	3,537
MT-ND3	2,923
MT-ATP6	2,869
MT-ND5	2,825
MT-ND2	2,658
MT-ND6	1,208
MT-ND4	0

Intra-cohort edges

A	B	Sources
MT-ATP6	MT-ND1	string_interaction
MT-ATP6	MT-ND2	string_interaction
MT-ATP6	MT-ND3	string_interaction
MT-ATP6	MT-ND5	string_interaction
MT-ATP6	MT-ND6	string_interaction
MT-ND1	MT-ND2	string_interaction
MT-ND1	MT-ND3	string_interaction
MT-ND1	MT-ND5	string_interaction
MT-ND1	MT-ND6	string_interaction
MT-ND2	MT-ND3	string_interaction
MT-ND2	MT-ND5	string_interaction
MT-ND2	MT-ND6	string_interaction
MT-ND3	MT-ND5	string_interaction
MT-ND3	MT-ND6	string_interaction
MT-ND5	MT-ND6	string_interaction

Structural data

PDB: 7 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MT-ATP6	P00846	10
MT-ND2	P03891	7
MT-ND4	C0HME5	7
MT-ND5	P03915	7
MT-ND1	P03886	5
MT-ND3	P03897	5
MT-ND6	P03923	5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 11. Enrichment computed across 7 evidence-associated genes (7 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 7 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	7	109.8×	5e-14	MT-ATP6, MT-ND1, MT-ND2, MT-ND3, MT-ND4, MT-ND5, MT-ND6
Complex I biogenesis	6	141.9×	1e-12	MT-ND1, MT-ND2, MT-ND3, MT-ND4, MT-ND5, MT-ND6
Respiratory electron transport	6	81.6×	3e-11	MT-ND1, MT-ND2, MT-ND3, MT-ND4, MT-ND5, MT-ND6
Mitochondrial protein degradation	5	81.6×	3e-09	MT-ATP6, MT-ND1, MT-ND2, MT-ND5, MT-ND6
Formation of ATP by chemiosmotic coupling	1	81.6×	0.027	MT-ATP6
Cristae formation	1	49.4×	0.037	MT-ATP6
Mitochondrial biogenesis	1	24.0×	0.064	MT-ATP6
Aerobic respiration and respiratory electron transport	1	12.7×	0.105	MT-ATP6
Organelle biogenesis and maintenance	1	9.4×	0.124	MT-ATP6
Metabolism of proteins	1	1.8×	0.468	MT-ATP6
Metabolism	1	1.7×	0.468	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 7 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
proton motive force-driven mitochondrial ATP synthesis	7	263.3×	2e-16	MT-ATP6, MT-ND1, MT-ND2, MT-ND3, MT-ND4, MT-ND5, MT-ND6
mitochondrial electron transport, NADH to ubiquinone	6	307.3×	2e-14	MT-ND1, MT-ND2, MT-ND3, MT-ND4, MT-ND5, MT-ND6
aerobic respiration	6	212.4×	2e-13	MT-ND1, MT-ND2, MT-ND3, MT-ND4, MT-ND5, MT-ND6
mitochondrial respiratory chain complex I assembly	5	293.6×	7e-12	MT-ND1, MT-ND2, MT-ND4, MT-ND5, MT-ND6
response to hypoxia	4	54.7×	2e-06	MT-ND1, MT-ND2, MT-ND4, MT-ND5
electron transport coupled proton transport	2	1203.7×	3e-06	MT-ND4, MT-ND5
response to light intensity	1	300.9×	0.009	MT-ND3
response to hydroperoxide	1	240.7×	0.010	MT-ND1
response to hyperoxia	1	160.5×	0.014	MT-ATP6
proton motive force-driven ATP synthesis	1	114.6×	0.017	MT-ATP6
cellular response to glucocorticoid stimulus	1	89.2×	0.020	MT-ND3
response to hydrogen peroxide	1	66.9×	0.023	MT-ND5
reactive oxygen species metabolic process	1	66.9×	0.023	MT-ND2
response to nicotine	1	60.2×	0.024	MT-ND4
cerebellum development	1	51.2×	0.026	MT-ND4
proton transmembrane transport	1	44.6×	0.028	MT-ATP6
response to ethanol	1	20.9×	0.055	MT-ND4
response to oxidative stress	1	18.7×	0.058	MT-ND3
in utero embryonic development	1	10.3×	0.097	MT-ND4
response to xenobiotic stimulus	1	9.9×	0.097	MT-ND1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 7

Druggability breadth: 7 of 7 evidence-associated genes (100%) 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-ND1	0	0
MT-ND2	0	0
MT-ND3	0	0
MT-ND4	0	0
MT-ND5	0	0
MT-ND6	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-ND1	5	Binding:5
MT-ND2	4	Binding:4
MT-ND3	4	Binding:4
MT-ND5	4	Binding:4
MT-ND6	4	Binding:4
MT-ATP6	1	Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 7; 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	7	MT-ATP6, MT-ND1, MT-ND2, MT-ND3, MT-ND4, MT-ND5, MT-ND6

Undrugged target profiles

7 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-ND1	5	—
MT-ND2	4	—
MT-ND3	4	—
MT-ND4	0	—
MT-ND5	4	—
MT-ND6	4	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

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