Hepatoencephalopathy due to combined oxidative phosphorylation defect type 1

Summary

Hepatoencephalopathy due to combined oxidative phosphorylation defect type 1 (MONDO:0012191) is a disease caused by GFM1 (GenCC Definitive), with 7 cohort genes. The dominant Reactome pathway is Translation (6 cohort genes).

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: GFM1 (GenCC Definitive)
• Cohort genes: 7
• ClinVar variants: 326
• Phenotypes (HPO): 21

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		2	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

21 HPO clinical features (Orphanet curated; top 21 by frequency):

HPO ID	Term	Frequency
HP:0001250	Seizure	Frequent (30-79%)
HP:0001263	Global developmental delay	Frequent (30-79%)
HP:0001298	Encephalopathy	Frequent (30-79%)
HP:0001399	Hepatic failure	Frequent (30-79%)
HP:0002353	EEG abnormality	Frequent (30-79%)
HP:0003128	Lactic acidosis	Frequent (30-79%)
HP:0008872	Feeding difficulties in infancy	Frequent (30-79%)
HP:0008936	Axial hypotonia	Frequent (30-79%)
HP:0008972	Decreased activity of mitochondrial respiratory chain	Frequent (30-79%)
HP:0000047	Hypospadias	Occasional (5-29%)
HP:0000252	Microcephaly	Occasional (5-29%)
HP:0001257	Spasticity	Occasional (5-29%)
HP:0001332	Dystonia	Occasional (5-29%)
HP:0001511	Intrauterine growth retardation	Occasional (5-29%)
HP:0001622	Premature birth	Occasional (5-29%)
HP:0001943	Hypoglycemia	Occasional (5-29%)
HP:0002119	Ventriculomegaly	Occasional (5-29%)
HP:0002240	Hepatomegaly	Occasional (5-29%)
HP:0002910	Elevated circulating hepatic transaminase concentration	Occasional (5-29%)
HP:0003073	Hypoalbuminemia	Occasional (5-29%)
HP:0033725	Thin corpus callosum	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hepatoencephalopathy due to combined oxidative phosphorylation defect type 1
Mondo ID	MONDO:0012191
MeSH	C563797
OMIM	609060
Orphanet	137681
DOID	DOID:0111474
NCIT	C125663
SNOMED CT	764962002
UMLS	C1836797
MedGen	322999
GARD	0016949
Is cancer (heuristic)	no

Also known as: combined oxidative phosphorylation deficiency 1 · combined oxidative phosphorylation deficiency caused by mutation in GFM1 · combined oxidative phosphorylation deficiency type 1 · COXPD1 · GFM1 combined oxidative phosphorylation deficiency · hepatoencephalopathy due to combined oxidative phosphorylation defect type 1 · Hepatoencephalopathy due to COXPD1

Data availability: 326 ClinVar variants · 4 GenCC gene-disease records · 1 cell line.

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 › combined oxidative phosphorylation deficiency › hepatoencephalopathy due to combined oxidative phosphorylation defect type 1

Related subtypes (57): severe X-linked mitochondrial encephalomyopathy, combined oxidative phosphorylation defect type 2, fatal mitochondrial disease due to combined oxidative phosphorylation defect type 3, combined oxidative phosphorylation defect type 4, hypotonia with lactic acidemia and hyperammonemia, combined oxidative phosphorylation defect type 7, combined oxidative phosphorylation defect type 8, combined oxidative phosphorylation defect type 9, mitochondrial hypertrophic cardiomyopathy with lactic acidosis due to MTO1 deficiency, combined oxidative phosphorylation defect type 11, leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome, combined oxidative phosphorylation defect type 13, combined oxidative phosphorylation defect type 14, combined oxidative phosphorylation defect type 15, infantile hypertrophic cardiomyopathy due to MRPL44 deficiency, combined oxidative phosphorylation defect type 17, growth and developmental delay-hypotonia-vision impairment-lactic acidosis syndrome, combined oxidative phosphorylation deficiency 19, combined oxidative phosphorylation defect type 20, combined oxidative phosphorylation defect type 21, mitochondrial proton-transporting ATP synthase complex deficiency, combined oxidative phosphorylation defect type 23, combined oxidative phosphorylation defect type 24, combined oxidative phosphorylation defect type 25, combined oxidative phosphorylation defect type 26, combined oxidative phosphorylation defect type 27, combined oxidative phosphorylation deficiency 28, combined oxidative phosphorylation deficiency 29, combined oxidative phosphorylation defect type 30, lethal left ventricular non-compaction-seizures-hypotonia-cataract-developmental delay syndrome, combined oxidative phosphorylation deficiency 40, combined oxidative phosphorylation deficiency 41, combined oxidative phosphorylation deficiency 42, combined oxidative phosphorylation deficiency 43, combined oxidative phosphorylation deficiency 44, combined oxidative phosphorylation deficiency 52, combined oxidative phosphorylation deficiency 53, combined oxidative phosphorylation deficiency 54, combined oxidative phosphorylation deficiency 37, combined oxidative phosphorylation deficiency 38, combined oxidative phosphorylation deficiency 39, combined oxidative phosphorylation deficiency 45, combined oxidative phosphorylation deficiency 46, combined oxidative phosphorylation deficiency 47, combined oxidative phosphorylation deficiency 48, combined oxidative phosphorylation deficiency 51, combined oxidative phosphorylation deficiency 32, combined oxidative phosphorylation deficiency 33, combined oxidative phosphorylation deficiency 34, combined oxidative phosphorylation deficiency 35, combined oxidative phosphorylation deficiency 36, combined oxidative phosphorylation deficiency 55, combined oxidative phosphorylation deficiency 56, combined oxidative phosphorylation deficiency 57, combined oxidative phosphorylation deficiency 58, combined oxidative phosphorylation deficiency 59, combined oxidative phosphorylation deficiency 60

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

326 retrieved; paginated sample, class counts are floors:

96 uncertain significance, 80 likely pathogenic, 47 pathogenic/likely pathogenic, 33 conflicting classifications of pathogenicity, 25 benign, 18 pathogenic, 18 likely benign, 9 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
812088	NM_024996.7(GFM1):c.958C>G (p.Pro320Ala)		Pathogenic	criteria provided, single submitter
1028357	NM_024996.7(GFM1):c.1324G>T (p.Glu442Ter)	GFM1	Pathogenic	criteria provided, single submitter
1068827	NM_024996.7(GFM1):c.1595_1596del (p.Pro532fs)	GFM1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1069701	NM_024996.7(GFM1):c.1576C>T (p.Arg526Ter)	GFM1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1075664	NM_024996.7(GFM1):c.1090C>T (p.Arg364Ter)	GFM1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1119996	NM_024996.7(GFM1):c.1823G>A (p.Arg608Gln)	GFM1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1322995	NM_024996.7(GFM1):c.1510del (p.Tyr504fs)	GFM1	Pathogenic	criteria provided, single submitter
1357540	NM_024996.7(GFM1):c.890del (p.Leu297fs)	GFM1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1367819	NM_024996.7(GFM1):c.690_693del	GFM1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1425853	NM_024996.7(GFM1):c.1172del (p.Lys391fs)	GFM1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1450272	NM_024996.7(GFM1):c.1878del (p.Phe626fs)	GFM1	Pathogenic	criteria provided, multiple submitters, no conflicts
1453055	NM_024996.7(GFM1):c.1882C>T (p.Arg628Ter)	GFM1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1453256	NM_024996.7(GFM1):c.850C>T (p.Arg284Ter)	GFM1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1454007	NM_024996.7(GFM1):c.69G>A (p.Trp23Ter)	GFM1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1455378	NM_024996.7(GFM1):c.532C>T (p.Arg178Ter)	GFM1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1455901	NM_024996.7(GFM1):c.1532_1533del (p.Glu511fs)	GFM1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1456973	NM_024996.7(GFM1):c.89_99del (p.Trp30fs)	GFM1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1460255	NM_024996.7(GFM1):c.1642C>T (p.Gln548Ter)	GFM1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1460386	NM_024996.7(GFM1):c.1186C>T (p.Gln396Ter)	GFM1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1469533	NM_024996.7(GFM1):c.1765-2A>G	GFM1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1944995	NM_024996.7(GFM1):c.817dup (p.Ile273fs)	GFM1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1980192	NM_024996.7(GFM1):c.307C>T (p.Gln103Ter)	GFM1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2055507	NM_024996.7(GFM1):c.1831dup (p.Leu611fs)	GFM1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2077405	NM_024996.7(GFM1):c.303dup (p.Ile102fs)	GFM1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
214491	NM_024996.7(GFM1):c.3G>A (p.Met1Ile)	GFM1	Pathogenic	criteria provided, single submitter
214493	NM_024996.7(GFM1):c.688G>A (p.Gly230Ser)	GFM1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
214495	NM_024996.7(GFM1):c.700C>T (p.Arg234Ter)	GFM1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
214496	NM_024996.7(GFM1):c.273del (p.Met92fs)	GFM1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
214497	NM_024996.7(GFM1):c.1596del (p.Val533fs)	GFM1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
214500	NM_024996.7(GFM1):c.2011C>T (p.Arg671Cys)	GFM1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 9 · 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
GFM1	Definitive	Autosomal recessive	hepatoencephalopathy due to combined oxidative phosphorylation defect type 1	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GFM1	Orphanet:137681	Hepatoencephalopathy due to combined oxidative phosphorylation defect type 1
MRPS22	Orphanet:137908	Hypotonia with lactic acidemia and hyperammonemia
MRPS22	Orphanet:243	46,XX gonadal dysgenesis
MRPL44	Orphanet:352563	Infantile hypertrophic cardiomyopathy due to MRPL44 deficiency
VARS2	Orphanet:420728	Combined oxidative phosphorylation defect type 20
NARS2	Orphanet:444458	Combined oxidative phosphorylation defect type 24
NARS2	Orphanet:79134	DEND syndrome
NARS2	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB
GFM2	Orphanet:565624	Combined oxidative phosphorylation defect type 39

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
GFM1	HGNC:13780	ENSG00000168827	Q96RP9	Elongation factor G, mitochondrial	gencc,clinvar
VARS1	HGNC:12651	ENSG00000204394	P26640	Valine–tRNA ligase	clinvar
MRPS22	HGNC:14508	ENSG00000175110	P82650	Small ribosomal subunit protein mS22	clinvar
MRPL44	HGNC:16650	ENSG00000135900	Q9H9J2	Large ribosomal subunit protein mL44	clinvar
VARS2	HGNC:21642	ENSG00000137411	Q5ST30	Valine–tRNA ligase, mitochondrial	clinvar
NARS2	HGNC:26274	ENSG00000137513	Q96I59	Asparaginyl-tRNA synthetase	clinvar
GFM2	HGNC:29682	ENSG00000164347	Q969S9	Ribosome-releasing factor 2, mitochondrial	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GFM1	Elongation factor G, mitochondrial	Mitochondrial GTPase that catalyzes the GTP-dependent ribosomal translocation step during translation elongation.
VARS1	Valine–tRNA ligase	Catalyzes the attachment of valine to tRNA(Val).
MRPL44	Large ribosomal subunit protein mL44	Component of the 39S subunit of mitochondrial ribosome.
VARS2	Valine–tRNA ligase, mitochondrial	Catalyzes the attachment of valine to tRNA(Val) in a two-step reaction: valine is first activated by ATP to form Val-AMP and then transferred to the acceptor end of tRNA(Val).
NARS2	Asparaginyl-tRNA synthetase	Mitochondrial aminoacyl-tRNA synthetase that catalyzes the specific attachment of the asparagine amino acid (aa) to the homologous transfer RNA (tRNA), further participating in protein synthesis.
GFM2	Ribosome-releasing factor 2, mitochondrial	Mitochondrial GTPase that mediates the disassembly of ribosomes from messenger RNA at the termination of mitochondrial protein biosynthesis.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 5 · Druggable fraction: 0.29

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	3.4×	0.220
Other/Unknown	5	1.3×	0.332

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GFM1	Other/Unknown	no		EFG_V-like, T_Tr_GTP-bd_dom, EFTu-like_2
VARS1	Enzyme (other)	yes	6.1.1.9	aa-tRNA-synth_I_CS, aa-tRNA-synth_Ia, Valyl-tRNA_ligase
MRPS22	Other/Unknown	no		Ribosomal_mS22
MRPL44	Other/Unknown	no		dsRBD_dom, RNase_III_sf, Ribosomal_mL44_DSRM_metazoa
VARS2	Other/Unknown	no		aa-tRNA-synth_I_CS, aa-tRNA-synth_Ia, Valyl-tRNA_ligase
NARS2	Enzyme (other)	yes	6.1.1.22	Asp/Asn-tRNA-synth_IIb, Aa-tRNA-synt_II, NA-bd_OB_tRNA
GFM2	Other/Unknown	no		EFG_V-like, T_Tr_GTP-bd_dom, Small_GTP-bd

Expression context

Cohort genes with no expression data: 0.

6 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
adrenal tissue	2
oocyte	2
biceps brachii	1
endothelial cell	1
left testis	1
right testis	1
testis	1
right adrenal gland	1
right adrenal gland cortex	1
cortical plate	1
primordial germ cell in gonad	1
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1
secondary oocyte	1
skeletal muscle tissue of biceps brachii	1
bronchial epithelial cell	1
left ventricle myocardium	1
tibialis anterior	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GFM1	271	ubiquitous	marker	endothelial cell, biceps brachii, adrenal tissue
VARS1	134	ubiquitous	marker	right testis, left testis, testis
MRPS22	289	ubiquitous	marker	adrenal tissue, right adrenal gland, right adrenal gland cortex
MRPL44	253	ubiquitous	marker	oocyte, primordial germ cell in gonad, cortical plate
VARS2	134	ubiquitous	yes	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
NARS2	278	ubiquitous	marker	secondary oocyte, oocyte, skeletal muscle tissue of biceps brachii
GFM2	262	ubiquitous	marker	left ventricle myocardium, tibialis anterior, bronchial epithelial cell

Protein interactions among cohort

Intra-cohort edges: 2.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
VARS1	5,848
GFM1	5,789
MRPL44	4,429
MRPS22	2,985
VARS2	2,590
NARS2	2,248
GFM2	1,997

Intra-cohort edges

A	B	Sources
GFM1	MRPS22	string_interaction
MRPL44	MRPS22	string_interaction

Structural data

PDB: 4 · AlphaFold-only: 3 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MRPL44	Q9H9J2	85
MRPS22	P82650	77
GFM1	Q96RP9	5
GFM2	Q969S9	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
NARS2	Q96I59	91.59
VARS1	P26640	88.12
VARS2	Q5ST30	87.96

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 10. 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
Translation	6	53.2×	1e-09	VARS1, MRPS22, MRPL44, VARS2, NARS2, GFM2
tRNA Aminoacylation	3	122.4×	6e-06	VARS1, VARS2, NARS2
Metabolism of proteins	6	10.6×	6e-06	VARS1, MRPS22, MRPL44, VARS2, NARS2, GFM2
Mitochondrial translation	3	59.0×	3e-05	MRPS22, MRPL44, GFM2
Mitochondrial translation elongation	3	54.4×	3e-05	GFM1, MRPS22, MRPL44
Mitochondrial translation termination	3	47.1×	4e-05	MRPS22, MRPL44, GFM2
Mitochondrial tRNA aminoacylation	2	148.3×	1e-04	VARS2, NARS2
Mitochondrial translation initiation	2	36.2×	0.001	MRPS22, MRPL44
Mitochondrial ribosome-associated quality control	2	35.1×	0.001	MRPS22, MRPL44
Cytosolic tRNA aminoacylation	1	62.8×	0.016	VARS1

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
valyl-tRNA aminoacylation	2	2407.4×	1e-06	VARS1, VARS2
mitochondrial translational elongation	2	1203.7×	4e-06	GFM1, MRPL44
mitochondrial translation	3	74.5×	2e-05	MRPS22, MRPL44, GFM2
asparaginyl-tRNA aminoacylation	1	1203.7×	0.002	NARS2
mitochondrial translational termination	1	481.5×	0.003	GFM2
ribosome disassembly	1	141.6×	0.009	GFM2
tRNA aminoacylation for protein translation	1	120.4×	0.009	VARS1
RNA processing	1	31.3×	0.032	MRPL44

Therapeutics

Drug target analysis

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

Druggability breadth: 3 of 7 evidence-associated genes (43%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
GFM1	0	0
VARS1	0	0
MRPS22	0	0
MRPL44	0	0
VARS2	0	0
NARS2	0	0
GFM2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
VARS1	7	Binding:7
GFM1	1	Binding:1
MRPS22	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
VARS1	6.1.1.9	valine-tRNA ligase
NARS2	6.1.1.22	asparagine-tRNA ligase

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	2	VARS1, NARS2
E	Difficult family or no structure, no drug	5	GFM1, MRPS22, MRPL44, VARS2, GFM2

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)
GFM1	1	—
VARS1	7	—
MRPS22	1	—
MRPL44	0	—
VARS2	0	—
NARS2	0	—
GFM2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.