Ethylmalonic encephalopathy

Summary

Ethylmalonic encephalopathy (MONDO:0011229) is a disease caused by ETHE1 (GenCC Definitive), with 2 cohort genes and 1 clinical trial. Top therapeutic interventions include esomeprazole.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: ETHE1 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 429
• Phenotypes (HPO): 18
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		80	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

18 HPO clinical features (Orphanet curated; top 18 by frequency):

HPO ID	Term	Frequency
HP:0001298	Encephalopathy	Very frequent (80-99%)
HP:0003219	Ethylmalonic aciduria	Very frequent (80-99%)
HP:0000967	Petechiae	Frequent (30-79%)
HP:0001063	Acrocyanosis	Frequent (30-79%)
HP:0001249	Intellectual disability	Frequent (30-79%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0001251	Ataxia	Frequent (30-79%)
HP:0001290	Generalized hypotonia	Frequent (30-79%)
HP:0001508	Failure to thrive	Frequent (30-79%)
HP:0002014	Diarrhea	Frequent (30-79%)
HP:0002071	Abnormality of extrapyramidal motor function	Frequent (30-79%)
HP:0002376	Developmental regression	Frequent (30-79%)
HP:0003128	Lactic acidosis	Frequent (30-79%)
HP:0007256	Abnormal pyramidal sign	Frequent (30-79%)
HP:0012751	Abnormal basal ganglia MRI signal intensity	Frequent (30-79%)
HP:0012758	Neurodevelopmental delay	Frequent (30-79%)
HP:0012841	Retinal vascular tortuosity	Frequent (30-79%)
HP:0012747	Abnormal brainstem MRI signal intensity	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	ethylmalonic encephalopathy
Mondo ID	MONDO:0011229
MeSH	C535737
OMIM	602473
Orphanet	51188
DOID	DOID:0060640
ICD-11	1966714550
SNOMED CT	723307008
UMLS	C1865349
MedGen	355966
GARD	0002198
Is cancer (heuristic)	no

Also known as: EE · eme · encephalopathy, ethylmalonic · encephalopathy, petechiae, and ethylmalonic aciduria · EPEMA syndrome · syndrome of encephalopathy, petechiae, and ethylmalonic aciduria

Data availability: 429 ClinVar variants · 18 ClinGen variant curations · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › mitochondrial disease › ethylmalonic encephalopathy

Related subtypes (11): inborn mitochondrial metabolism disorder, hereditary myopathy with lactic acidosis due to ISCU deficiency, Bjornstad syndrome, X-linked sideroblastic anemia with ataxia, GRACILE syndrome, mitochondrial short-chain Enoyl-Coa hydratase 1 deficiency, autosomal dominant optic atrophy plus syndrome, maternally-inherited cardiomyopathy and hearing loss, pure mitochondrial myopathy, FDXR-related optic atrophy mitochondrial dysfunction syndrome, ACO2-related optic atrophy with or without extraocular features

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

429 retrieved; paginated sample, class counts are floors:

211 likely benign, 78 uncertain significance, 52 likely pathogenic, 43 pathogenic, 14 benign, 11 pathogenic/likely pathogenic, 11 conflicting classifications of pathogenicity, 8 not provided, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1072741	NM_014297.5(ETHE1):c.43C>T (p.Gln15Ter)	ETHE1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1361099	NM_014297.5(ETHE1):c.622G>T (p.Glu208Ter)	ETHE1	Pathogenic	criteria provided, single submitter
1379077	NM_014297.5(ETHE1):c.413del (p.Gly138fs)	ETHE1	Pathogenic	criteria provided, single submitter
1396975	NM_014297.5(ETHE1):c.325C>T (p.Gln109Ter)	ETHE1	Pathogenic	criteria provided, single submitter
1412035	NM_014297.5(ETHE1):c.645_655del (p.Leu215_Thr216insTer)	ETHE1	Pathogenic	criteria provided, single submitter
1452053	NM_014297.5(ETHE1):c.254_258dup (p.Gly87fs)	ETHE1	Pathogenic	criteria provided, single submitter
1456400	NC_000019.9:g.(?44015579)(44031339_?)del	ETHE1	Pathogenic	criteria provided, single submitter
1460169	NM_014297.5(ETHE1):c.189del (p.Gln63fs)	ETHE1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1722427	NM_014297.5(ETHE1):c.702_703del (p.Gln235fs)	ETHE1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1936675	NM_014297.5(ETHE1):c.596-1G>A	ETHE1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1941827	NM_014297.5(ETHE1):c.43del (p.Gln15fs)	ETHE1	Pathogenic	criteria provided, single submitter
2012369	NM_014297.5(ETHE1):c.448_469dup (p.Leu157fs)	ETHE1	Pathogenic	criteria provided, single submitter
214322	NM_014297.5(ETHE1):c.488G>A (p.Arg163Gln)	ETHE1	Pathogenic	reviewed by expert panel
214323	NM_014297.5(ETHE1):c.221dup (p.Tyr74Ter)	ETHE1	Pathogenic	criteria provided, multiple submitters, no conflicts
2152319	NM_014297.5(ETHE1):c.2T>A (p.Met1Lys)	ETHE1	Pathogenic	criteria provided, single submitter
2317	NM_014297.5(ETHE1):c.487C>T (p.Arg163Trp)	ETHE1	Pathogenic	reviewed by expert panel
2318	NM_014297.5(ETHE1):c.3G>T (p.Met1Ile)	ETHE1	Pathogenic	criteria provided, multiple submitters, no conflicts
2675145	NM_014297.5(ETHE1):c.388del (p.Arg130fs)	ETHE1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2710594	NM_014297.5(ETHE1):c.401_402del (p.Gly134fs)	ETHE1	Pathogenic	criteria provided, single submitter
2711088	NM_014297.5(ETHE1):c.463dup (p.Ala155fs)	ETHE1	Pathogenic	criteria provided, single submitter
2734186	NM_014297.5(ETHE1):c.19_20dup (p.Val8fs)	ETHE1	Pathogenic	criteria provided, single submitter
2749492	NM_014297.5(ETHE1):c.418_419del (p.Val140fs)	ETHE1	Pathogenic	criteria provided, single submitter
2802892	NM_014297.5(ETHE1):c.129_132del (p.Arg43fs)	ETHE1	Pathogenic	criteria provided, single submitter
2833401	NM_014297.5(ETHE1):c.1A>C (p.Met1Leu)	ETHE1	Pathogenic	criteria provided, single submitter
2836024	NM_014297.5(ETHE1):c.241del (p.His81fs)	ETHE1	Pathogenic	criteria provided, single submitter
2843998	NM_014297.5(ETHE1):c.61del (p.Ala21fs)	ETHE1	Pathogenic	criteria provided, single submitter
2858077	NM_014297.5(ETHE1):c.252_253dup (p.Ile85fs)	ETHE1	Pathogenic	criteria provided, single submitter
2971554	NM_014297.5(ETHE1):c.396_397insAC (p.Pro133fs)	ETHE1	Pathogenic	criteria provided, single submitter
30725	NM_014297.5(ETHE1):c.554T>G (p.Leu185Arg)	ETHE1	Pathogenic	criteria provided, multiple submitters, no conflicts
3248451	NC_000019.9:g.(?44015569)(44015738_?)del	ETHE1	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 1 · 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
ETHE1	Definitive	Autosomal recessive	ethylmalonic encephalopathy	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ETHE1	Orphanet:51188	Ethylmalonic encephalopathy

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
ETHE1	HGNC:23287	ENSG00000105755	O95571	Persulfide dioxygenase ETHE1, mitochondrial	gencc,clinvar
CADM4	HGNC:30825	ENSG00000105767	Q8NFZ8	Cell adhesion molecule 4	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ETHE1	Persulfide dioxygenase ETHE1, mitochondrial	Sulfur dioxygenase that plays an essential role in hydrogen sulfide catabolism in the mitochondrial matrix.
CADM4	Cell adhesion molecule 4	Involved in the cell-cell adhesion.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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
Antibody/Immunoglobulin	1	14.6×	0.135
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ETHE1	Other/Unknown	no		Metallo-B-lactamas, RibonucZ/Hydroxyglut_hydro, POD-like_MBL-fold
CADM4	Antibody/Immunoglobulin	yes		Neurexin-like, Ig_sub2, Ig_sub

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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
colonic mucosa	1
ileal mucosa	1
mucosa of transverse colon	1
C1 segment of cervical spinal cord	1
cortical plate	1
nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ETHE1	276	ubiquitous	marker	mucosa of transverse colon, ileal mucosa, colonic mucosa
CADM4	218	ubiquitous	yes	cortical plate, C1 segment of cervical spinal cord, nerve

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ETHE1	1,603
CADM4	1,153

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ETHE1	O95571	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CADM4	Q8NFZ8	85.31

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 2 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Sulfide oxidation to sulfate	1	1903.3×	5e-04	ETHE1

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
hydrogen sulfide metabolic process	1	8426.0×	0.002	ETHE1
negative regulation of peptidyl-threonine phosphorylation	1	1685.2×	0.002	CADM4
negative regulation of peptidyl-tyrosine phosphorylation	1	1685.2×	0.002	CADM4
regulation of wound healing	1	1685.2×	0.002	CADM4
regulation of Rac protein signal transduction	1	936.2×	0.003	CADM4
negative regulation of vascular endothelial growth factor receptor signaling pathway	1	648.1×	0.003	CADM4
negative regulation of vascular endothelial growth factor signaling pathway	1	648.1×	0.003	CADM4
regulation of protein phosphorylation	1	561.7×	0.003	CADM4
regulation of cell motility	1	495.6×	0.003	CADM4
negative regulation of protein phosphorylation	1	290.6×	0.004	CADM4
glutathione metabolic process	1	175.5×	0.007	ETHE1
homophilic cell-cell adhesion	1	70.2×	0.015	CADM4
regulation of cell population proliferation	1	57.7×	0.017	CADM4

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 2 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ETHE1	0	0
CADM4	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	1	CADM4
E	Difficult family or no structure, no drug	1	ETHE1

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)
ETHE1	0	—
CADM4	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2/PHASE3	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00728481	PHASE2/PHASE3	COMPLETED	The Role Of Gastroesophageal Reflux Disease (GERD) in Eosinophilic Esophagitis

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
ESOMEPRAZOLE	4	1