Ethylmalonic Encephalopathy

Mendelian MONDO:0011229 Pathograph 10 Show in embeddings browser Metabolic Disease Inborn Error of Metabolism

Ethylmalonic encephalopathy (EE) is a rare, autosomal recessive, "intoxication-type" inborn error of metabolism caused by loss-of-function mutations in ETHE1, which encodes a mitochondrial matrix sulfur dioxygenase (persulfide dioxygenase). ETHE1 is a key enzyme in the mitochondrial pathway that detoxifies hydrogen sulfide (H2S), a signalling gasotransmitter produced both endogenously in tissues and, in large amounts, by anaerobic bacteria of the gut. When ETHE1 activity is lost, H2S and its metabolite thiosulfate accumulate to toxic concentrations in critical tissues including colonic mucosa, liver, muscle, brain, and the endothelium of small blood vessels. H2S is a potent inhibitor of cytochrome c oxidase (COX, respiratory chain complex IV) and of short-chain fatty acid oxidation, and exerts vasoactive and vasotoxic effects. The result is the characteristic multisystem phenotype: early-onset encephalopathy with psychomotor regression, hypotonia and pyramidal signs, symmetric basal ganglia lesions on MRI, relapsing petechiae, orthostatic acrocyanosis and chronic diarrhea, together with the diagnostic biochemical signature of high urinary ethylmalonic acid and elevated C4 and C5 acylcarnitines. Classically fatal in early childhood, EE can be ameliorated by combined metronidazole (to lower colonic H2S-producing anaerobes) and N-acetylcysteine (to buffer sulfide via glutathione), with liver transplantation reported in some cases.

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1
Mappings
1
Inheritance
6
Pathophys.
10
Phenotypes
10
Pathograph
1
Genes
2
Medical Actions
5
References
🏷

Classifications

ICIMD (Inherited Metabolic Disorders)
sulfur containing amino acids
🔗

Mappings

MONDO
MONDO:0011229 ethylmalonic encephalopathy
skos:exactMatch OMIM:602473
MONDO:0011229 (ethylmalonic encephalopathy) cross-references OMIM:602473 and Orphanet:51188, the authoritative entries for ETHE1-deficiency ethylmalonic encephalopathy.
👪

Inheritance

1
Autosomal recessive HP:0000007
Ethylmalonic encephalopathy is caused by biallelic pathogenic variants in ETHE1; heterozygous carriers are asymptomatic.
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:19136963 SUPPORT Human Clinical
"Ethylmalonic encephalopathy is an autosomal recessive, invariably fatal disorder characterized by early-onset encephalopathy, microangiopathy, chronic diarrhea, defective cytochrome c oxidase (COX) in muscle and brain, high concentrations of C4 and C5 acylcarnitines in blood and high excretion..."
States the autosomal recessive inheritance and the defining multisystem/biochemical phenotype.
⚙

Pathophysiology

6
ETHE1 sulfur dioxygenase deficiency
Biallelic loss-of-function ETHE1 variants abolish the activity of the mitochondrial matrix sulfur (persulfide) dioxygenase, the enzyme that oxidizes sulfide within the mitochondrial pathway of H2S catabolism. The ETHE1 gene (formerly HSCO, GenBank D83198) encodes a beta-lactamase-like iron-coordinating metalloprotein imported into the mitochondrial matrix.
ETHE1 hgnc:23287 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves ETHE1 (hgnc:23287). hgnc:23287 is a gene from the HUGO Gene Nomenclature Committee.
sulfide oxidation GO:0019418 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased sulfide oxidation (GO:0019418). GO:0019418 is a biological process from the Gene Ontology. ↓ DECREASED
sulfur dioxygenase activity GO:0050313 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased sulfur dioxygenase activity (GO:0050313). GO:0050313 is a molecular function from the Gene Ontology. ↓ DECREASED
Downstream
Hydrogen sulfide accumulation Loss of sulfur dioxygenase activity prevents catabolism of sulfide, so H2S and its metabolite thiosulfate accumulate to toxic levels.
Show evidence (3 references)
PMID:14732903 SUPPORT Human Clinical
"we identified GenBank D83198 as the gene responsible for EE"
Identifies ETHE1 (GenBank D83198) as the gene mutated in ethylmalonic encephalopathy.
PMID:14732903 SUPPORT Human Clinical
"the D83198 protein product is targeted to mitochondria and internalized into the matrix after energy-dependent cleavage of a short leader peptide"
Establishes that the ETHE1 product is a mitochondrial matrix protein.
PMID:19136963 SUPPORT Model Organism
"ETHE1 is a mitochondrial sulfur dioxygenase involved in catabolism of sulfide that accumulates to toxic levels in ethylmalonic encephalopathy."
Defines ETHE1 as the mitochondrial sulfur dioxygenase of the sulfide catabolic pathway (demonstrated via the Ethe1-/- mouse and enzyme assays).
Hydrogen sulfide accumulation
In the absence of ETHE1-sulfur dioxygenase, hydrogen sulfide (H2S) accumulates in critical tissues — colonic mucosa, liver, muscle, and brain — and thiosulfate is excreted in massive amounts in urine. H2S is a powerful inhibitor of cytochrome c oxidase and of short-chain fatty acid oxidation and has vasoactive/vasotoxic effects, making it the central toxic species of the disease.
Downstream
Cytochrome c oxidase deficiency H2S inhibits and accelerates degradation of cytochrome c oxidase (complex IV).
Ethylmalonic aciduria and acylcarnitine elevation H2S inhibition of short-chain acyl-CoA dehydrogenase / short-chain fatty acid oxidation produces the ethylmalonic aciduria and C4/C5 acylcarnitine elevation that define the biochemical phenotype.
Microangiopathy and endothelial toxicity The vasoactive/vasotoxic action of H2S on the endothelium of small vessels produces the microangiopathy underlying petechiae and orthostatic acrocyanosis.
Chronic diarrhea Accumulation of H2S in the colonic mucosa drives the chronic diarrhea characteristic of the disease.
Show evidence (2 references)
PMID:20812865 SUPPORT Model Organism
"The main consequence of the absence of Ethe1-SDO is the accumulation of sulfide (H(2)S) in critical tissues, including colonic mucosa, liver, muscle, and brain."
Establishes tissue H2S accumulation as the direct consequence of ETHE1-SDO loss.
PMID:19136963 SUPPORT Human Clinical
"thiosulfate was excreted in massive amounts in urine of both Ethe1(-/-) mice and humans with ethylmalonic encephalopathy"
Documents massive thiosulfate excretion (the H2S metabolite) in both mice and affected humans.
Cytochrome c oxidase deficiency
Chronic sulfide exposure causes cytochrome c oxidase (complex IV) deficiency by rapid heme a inhibition and accelerated long-term degradation of COX subunits; COX activity is decreased in skeletal muscle and brain.
Downstream
Neurodevelopmental regression and encephalopathy Cerebral energy failure from complex IV deficiency (together with direct neurotoxicity of sulfide) drives the encephalopathy, psychomotor regression and symmetric basal ganglia lesions.
Show evidence (2 references)
PMID:20812865 SUPPORT Model Organism
"The mechanism by which H(2)S causes COX deficiency consists of rapid heme a inhibition and accelerated long-term degradation of COX subunits."
Describes the mechanism of the acquired complex IV deficiency.
PMID:14732903 SUPPORT Human Clinical
"cytochrome c oxidase activity is decreased in skeletal muscle"
Documents decreased COX activity in patient skeletal muscle.
Ethylmalonic aciduria and acylcarnitine elevation
The biochemical hallmark of EE: high urinary excretion of ethylmalonic acid and elevated blood C4 (butyryl-) and C5 acylcarnitines, reflecting inhibition of short-chain fatty acid oxidation.
Show evidence (2 references)
PMID:14732903 SUPPORT Human Clinical
"High levels of ethylmalonic acid are detected in the body fluids, and cytochrome c oxidase activity is decreased in skeletal muscle."
Documents the high ethylmalonic acid levels defining the biochemical phenotype.
PMID:19136963 SUPPORT Human Clinical
"high concentrations of C4 and C5 acylcarnitines in blood and high excretion of ethylmalonic acid in urine"
Documents the C4/C5 acylcarnitine and ethylmalonic acid signature.
Microangiopathy and endothelial toxicity
H2S toxicity to the endothelium of small vessels produces a microangiopathy that manifests as relapsing petechiae and orthostatic acrocyanosis.
Downstream
Petechiae Small-vessel microangiopathy produces relapsing petechiae.
Acrocyanosis Vasomotor instability produces orthostatic acrocyanosis.
Show evidence (1 reference)
PMID:19136963 SUPPORT Model Organism
"vasoactive and vasotoxic effects that explain the microangiopathy in ethylmalonic encephalopathy patients"
Attributes the microangiopathy to the vasotoxic action of sulfide.
Neurodevelopmental regression and encephalopathy
Progressive encephalopathy with psychomotor regression, hypotonia, pyramidal signs, developmental delay and symmetric basal ganglia signal abnormalities.
collection of basal ganglia UBERON:0010011 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in collection of basal ganglia (UBERON:0010011). UBERON:0010011 is an anatomical location from the Uberon multi-species anatomy ontology.
Show evidence (1 reference)
PMID:37458841 SUPPORT Human Clinical
"Basal ganglia signal alterations were detected in 42 cases."
Documents symmetric basal ganglia involvement on neuroimaging.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Ethylmalonic Encephalopathy Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

10
Blood 1
Petechiae HP:0000967 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Petechiae (HP:0000967). HP:0000967 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37458841 SUPPORT Human Clinical
"The common manifestations of EE are psychomotor regression, hypotonia, developmental delay, petechia, pyramidal signs, chronic diarrhoea, orthostatic acrocyanosis and failure to thrive, respectively."
Petechiae are listed as a common manifestation.
Digestive 1
Chronic diarrhea HP:0002028 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Chronic diarrhea (HP:0002028). HP:0002028 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:19136963 SUPPORT Human Clinical
"characterized by early-onset encephalopathy, microangiopathy, chronic diarrhea, defective cytochrome c oxidase (COX) in muscle and brain"
Chronic diarrhea is a defining feature of the disease.
Integument 1
Acrocyanosis HP:0001063 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Acrocyanosis (HP:0001063). HP:0001063 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37458841 SUPPORT Human Clinical
"The common manifestations of EE are psychomotor regression, hypotonia, developmental delay, petechia, pyramidal signs, chronic diarrhoea, orthostatic acrocyanosis and failure to thrive, respectively."
Orthostatic acrocyanosis is listed as a common manifestation.
Musculoskeletal 2
Hypotonia HP:0001252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypotonia (HP:0001252). HP:0001252 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37458841 SUPPORT Human Clinical
"The common manifestations of EE are psychomotor regression, hypotonia, developmental delay, petechia, pyramidal signs, chronic diarrhoea, orthostatic acrocyanosis and failure to thrive, respectively."
Hypotonia is listed as a common manifestation.
Spasticity HP:0001257 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Spasticity (HP:0001257). HP:0001257 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37458841 SUPPORT Human Clinical
"The common manifestations of EE are psychomotor regression, hypotonia, developmental delay, petechia, pyramidal signs, chronic diarrhoea, orthostatic acrocyanosis and failure to thrive, respectively."
Pyramidal signs (mapped to spasticity) are listed as a common manifestation.
Nervous System 3
Developmental regression HP:0002376 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Developmental regression (HP:0002376). HP:0002376 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37458841 SUPPORT Human Clinical
"The common manifestations of EE are psychomotor regression, hypotonia, developmental delay, petechia, pyramidal signs, chronic diarrhoea, orthostatic acrocyanosis and failure to thrive, respectively."
Psychomotor regression is listed as a common manifestation.
Global developmental delay HP:0001263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37458841 SUPPORT Human Clinical
"The common manifestations of EE are psychomotor regression, hypotonia, developmental delay, petechia, pyramidal signs, chronic diarrhoea, orthostatic acrocyanosis and failure to thrive, respectively."
Developmental delay is listed as a common manifestation.
Abnormal basal ganglia morphology HP:0002134 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal basal ganglia morphology (HP:0002134). HP:0002134 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37458841 SUPPORT Human Clinical
"Basal ganglia signal alterations were detected in 42 cases."
Basal ganglia involvement documented on MRI in the majority of imaged cases.
Growth 1
Failure to thrive HP:0001508 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Failure to thrive (HP:0001508). HP:0001508 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37458841 SUPPORT Human Clinical
"The common manifestations of EE are psychomotor regression, hypotonia, developmental delay, petechia, pyramidal signs, chronic diarrhoea, orthostatic acrocyanosis and failure to thrive, respectively."
Failure to thrive is listed as a common manifestation.
Other 1
Ethylmalonic aciduria HP:0003219 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ethylmalonic aciduria (HP:0003219). HP:0003219 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:19136963 SUPPORT Human Clinical
"high concentrations of C4 and C5 acylcarnitines in blood and high excretion of ethylmalonic acid in urine"
Documents high urinary ethylmalonic acid excretion.
🧬

Genetic Associations

1
ETHE1 deficiency
Gene: ETHE1 hgnc:23287 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is ETHE1 (hgnc:23287). hgnc:23287 is a gene from the HUGO Gene Nomenclature Committee.
Autosomal recessive
Show evidence (2 references)
PMID:19136963 SUPPORT Human Clinical
"ETHE1, a gene encoding a beta-lactamase-like, iron-coordinating metalloprotein, is mutated in ethylmalonic encephalopathy."
Describes the ETHE1 gene product mutated in the disease.
PMID:37458841 SUPPORT Human Clinical
"The most common ETHE1 gene homozygous state mutations were (p.R163Q) (c.488G>A), exon 4 deletion, (p.R163W)(c.487C>T), (p.Glu44ValfsTer62)(c.131_132delAG) and (p.M1I)(c.3G>T) mutations, respectively."
Lists the most common recurrent ETHE1 pathogenic variants across reported cases.
💊

Medical Actions

2
Metronidazole plus N-acetylcysteine
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: metronidazole CHEBI:6909 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses metronidazole (CHEBI:6909). CHEBI:6909 is a therapeutic agent from Chemical Entities of Biological Interest. N-acetylcysteine CHEBI:22198 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses N-acetylcysteine, annotated with acetylcysteine (CHEBI:22198). CHEBI:22198 is a therapeutic agent from Chemical Entities of Biological Interest.
Combined oral metronidazole (a bactericide that lowers the population of H2S-producing anaerobic gut bacteria) and N-acetylcysteine (a precursor of sulfide-buffering glutathione) is the mainstay disease-modifying therapy. The combination prolonged survival of Ethe1-deficient mice additively and produced marked clinical improvement in affected children.
Show evidence (2 references)
PMID:20657580 SUPPORT Human Clinical
"The same dual treatment caused marked clinical improvement in five affected children, with hardly any adverse or side effects."
Demonstrates clinical benefit of the combined metronidazole/NAC therapy in affected children.
PMID:20657580 SUPPORT Model Organism
"Metronidazole, a bactericide, or N-acetylcysteine, a precursor of sulfide-buffering glutathione, substantially prolonged the lifespan of Ethe1-deficient mice, with the combined treatment being additive."
Establishes the mechanistic rationale (reducing/buffering sulfide) and additive survival benefit in the mouse model.
Liver transplantation
Action: organ transplantationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is organ transplantation (NCIT:C15289). NCIT:C15289 is a clinical intervention from the NCI Thesaurus. Ontology label: Organ Transplantation NCIT:C15289
Liver transplantation has been used in EE to restore hepatic sulfur dioxygenase activity and lower systemic sulfide, with reported clinical benefit in some patients.
Show evidence (1 reference)
PMID:37458841 SUPPORT Human Clinical
"Reducing the accumulation and inducing detoxification of sulfide is the main long-term treatment strategy for EE, including metronidazole, N-acetylcysteine (NAC), dietary modification, liver transplantation and continuous renal replacement therapy (CRRT)."
Lists liver transplantation among the long-term sulfide-reducing treatment strategies.
🔬

Biochemical Markers

3
Urinary ethylmalonic acid (INCREASED)
Context: Markedly elevated urinary ethylmalonic acid is the diagnostic biomarker of EE and gives the disorder its name.
Show evidence (1 reference)
PMID:14732903 SUPPORT Human Clinical
"High levels of ethylmalonic acid are detected in the body fluids, and cytochrome c oxidase activity is decreased in skeletal muscle."
Documents high ethylmalonic acid in body fluids.
Blood C4/C5 acylcarnitines (INCREASED)
Context: Elevated blood C4 (butyryl-) and C5 acylcarnitines accompany the ethylmalonic aciduria and reflect impaired short-chain fatty acid oxidation.
Show evidence (1 reference)
PMID:19136963 SUPPORT Human Clinical
"high concentrations of C4 and C5 acylcarnitines in blood and high excretion of ethylmalonic acid in urine"
Documents the C4/C5 acylcarnitine elevation.
Urinary thiosulfate (INCREASED)
Context: Massive urinary thiosulfate excretion reflects the systemic accumulation of the H2S metabolite and is a biomarker of the sulfide detoxification defect.
Show evidence (1 reference)
PMID:19136963 SUPPORT Human Clinical
"thiosulfate was excreted in massive amounts in urine of both Ethe1(-/-) mice and humans with ethylmalonic encephalopathy"
Documents massive urinary thiosulfate excretion in affected humans.
📊

Prevalence

1
Reported cases in the literature
Cases In Literature Ultra Rare
Ethylmalonic encephalopathy is ultra-rare; a 2023 systematic review compiled the features of 70 reported cases worldwide.
Show evidence (1 reference)
PMID:37458841 SUPPORT Human Clinical
"This review focuses on the clinical, metabolic, genetic and neuroradiological features of 70 reported cases, including two new cases."
Documents that only ~70 cases have been reported, consistent with an ultra-rare disorder.
{ }

Source YAML

click to show 
name: Ethylmalonic Encephalopathy
category: Mendelian
creation_date: '2026-07-08T00:00:00Z'
synonyms:
- EE
- EPEMA syndrome
- Encephalopathy, petechiae, and ethylmalonic aciduria
- ETHE1 deficiency
- Mitochondrial sulfur dioxygenase deficiency
description: >
  Ethylmalonic encephalopathy (EE) is a rare, autosomal recessive, "intoxication-type"
  inborn error of metabolism caused by loss-of-function mutations in ETHE1, which
  encodes a mitochondrial matrix sulfur dioxygenase (persulfide dioxygenase). ETHE1
  is a key enzyme in the mitochondrial pathway that detoxifies hydrogen sulfide
  (H2S), a signalling gasotransmitter produced both endogenously in tissues and, in
  large amounts, by anaerobic bacteria of the gut. When ETHE1 activity is lost, H2S
  and its metabolite thiosulfate accumulate to toxic concentrations in critical
  tissues including colonic mucosa, liver, muscle, brain, and the endothelium of
  small blood vessels. H2S is a potent inhibitor of cytochrome c oxidase (COX,
  respiratory chain complex IV) and of short-chain fatty acid oxidation, and exerts
  vasoactive and vasotoxic effects. The result is the characteristic multisystem
  phenotype: early-onset encephalopathy with psychomotor regression, hypotonia and
  pyramidal signs, symmetric basal ganglia lesions on MRI, relapsing petechiae,
  orthostatic acrocyanosis and chronic diarrhea, together with the diagnostic
  biochemical signature of high urinary ethylmalonic acid and elevated C4 and C5
  acylcarnitines. Classically fatal in early childhood, EE can be ameliorated by
  combined metronidazole (to lower colonic H2S-producing anaerobes) and
  N-acetylcysteine (to buffer sulfide via glutathione), with liver transplantation
  reported in some cases.
disease_term:
  preferred_term: ethylmalonic encephalopathy
  term:
    id: MONDO:0011229
    label: ethylmalonic encephalopathy
parents:
- Metabolic Disease
- Inborn Error of Metabolism
classifications:
  icimd_category:
  - classification_value: sulfur_containing_amino_acids
    notes: >-
      ICIMD: EE is a disorder of sulfur-containing amino acid and hydrogen sulfide
      metabolism — ETHE1 encodes the mitochondrial sulfur dioxygenase of the H2S
      catabolic pathway. Grouped in this package (WP-002) under "Disorders of the
      metabolism of sulfur-containing amino acids and hydrogen sulfide".
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0011229
      label: ethylmalonic encephalopathy
    mapping_predicate: skos:exactMatch
    mapping_source: OMIM:602473
    mapping_justification: >
      MONDO:0011229 (ethylmalonic encephalopathy) cross-references OMIM:602473 and
      Orphanet:51188, the authoritative entries for ETHE1-deficiency ethylmalonic
      encephalopathy.
inheritance:
- name: Autosomal recessive
  description: >
    Ethylmalonic encephalopathy is caused by biallelic pathogenic variants in ETHE1;
    heterozygous carriers are asymptomatic.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:19136963
    reference_title: "Loss of ETHE1, a mitochondrial dioxygenase, causes fatal sulfide toxicity in ethylmalonic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ethylmalonic encephalopathy is an autosomal recessive, invariably fatal disorder characterized by early-onset encephalopathy, microangiopathy, chronic diarrhea, defective cytochrome c oxidase (COX) in muscle and brain, high concentrations of C4 and C5 acylcarnitines in blood and high excretion of ethylmalonic acid in urine."
    explanation: States the autosomal recessive inheritance and the defining multisystem/biochemical phenotype.
prevalence:
- population: Reported cases in the literature
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Ethylmalonic encephalopathy is ultra-rare; a 2023 systematic review compiled the
    features of 70 reported cases worldwide.
  evidence:
  - reference: PMID:37458841
    reference_title: "Ethylmalonic Encephalopathy: a literature review and two new cases of mild phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This review focuses on the clinical, metabolic, genetic and neuroradiological features of 70 reported cases, including two new cases."
    explanation: Documents that only ~70 cases have been reported, consistent with an ultra-rare disorder.
pathophysiology:
- name: ETHE1 sulfur dioxygenase deficiency
  description: >
    Biallelic loss-of-function ETHE1 variants abolish the activity of the
    mitochondrial matrix sulfur (persulfide) dioxygenase, the enzyme that oxidizes
    sulfide within the mitochondrial pathway of H2S catabolism. The ETHE1 gene
    (formerly HSCO, GenBank D83198) encodes a beta-lactamase-like iron-coordinating
    metalloprotein imported into the mitochondrial matrix.
  genes:
  - preferred_term: ETHE1
    term:
      id: hgnc:23287
      label: ETHE1
  molecular_functions:
  - preferred_term: sulfur dioxygenase activity
    term:
      id: GO:0050313
      label: sulfur dioxygenase activity
    modifier: DECREASED
  biological_processes:
  - preferred_term: sulfide oxidation
    term:
      id: GO:0019418
      label: sulfide oxidation
    modifier: DECREASED
  evidence:
  - reference: PMID:14732903
    reference_title: "Ethylmalonic encephalopathy is caused by mutations in ETHE1, a gene encoding a mitochondrial matrix protein."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we identified GenBank D83198 as the gene responsible for EE"
    explanation: Identifies ETHE1 (GenBank D83198) as the gene mutated in ethylmalonic encephalopathy.
  - reference: PMID:14732903
    reference_title: "Ethylmalonic encephalopathy is caused by mutations in ETHE1, a gene encoding a mitochondrial matrix protein."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the D83198 protein product is targeted to mitochondria and internalized into the matrix after energy-dependent cleavage of a short leader peptide"
    explanation: Establishes that the ETHE1 product is a mitochondrial matrix protein.
  - reference: PMID:19136963
    reference_title: "Loss of ETHE1, a mitochondrial dioxygenase, causes fatal sulfide toxicity in ethylmalonic encephalopathy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "ETHE1 is a mitochondrial sulfur dioxygenase involved in catabolism of sulfide that accumulates to toxic levels in ethylmalonic encephalopathy."
    explanation: Defines ETHE1 as the mitochondrial sulfur dioxygenase of the sulfide catabolic pathway (demonstrated via the Ethe1-/- mouse and enzyme assays).
  downstream:
  - target: Hydrogen sulfide accumulation
    description: >
      Loss of sulfur dioxygenase activity prevents catabolism of sulfide, so H2S and
      its metabolite thiosulfate accumulate to toxic levels.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:19136963
      reference_title: "Loss of ETHE1, a mitochondrial dioxygenase, causes fatal sulfide toxicity in ethylmalonic encephalopathy."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "ETHE1 is a mitochondrial sulfur dioxygenase involved in catabolism of sulfide that accumulates to toxic levels in ethylmalonic encephalopathy."
      explanation: Directly links loss of ETHE1 sulfur dioxygenase to toxic sulfide accumulation.
- name: Hydrogen sulfide accumulation
  description: >
    In the absence of ETHE1-sulfur dioxygenase, hydrogen sulfide (H2S) accumulates in
    critical tissues — colonic mucosa, liver, muscle, and brain — and thiosulfate is
    excreted in massive amounts in urine. H2S is a powerful inhibitor of cytochrome c
    oxidase and of short-chain fatty acid oxidation and has vasoactive/vasotoxic
    effects, making it the central toxic species of the disease.
  chemical_entities:
  - preferred_term: hydrogen sulfide
    term:
      id: CHEBI:16136
      label: hydrogen sulfide
    modifier: INCREASED
  - preferred_term: thiosulfate
    term:
      id: CHEBI:26977
      label: thiosulfate
    modifier: INCREASED
  evidence:
  - reference: PMID:20812865
    reference_title: "Chronic exposure to sulfide causes accelerated degradation of cytochrome c oxidase in ethylmalonic encephalopathy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The main consequence of the absence of Ethe1-SDO is the accumulation of sulfide (H(2)S) in critical tissues, including colonic mucosa, liver, muscle, and brain."
    explanation: Establishes tissue H2S accumulation as the direct consequence of ETHE1-SDO loss.
  - reference: PMID:19136963
    reference_title: "Loss of ETHE1, a mitochondrial dioxygenase, causes fatal sulfide toxicity in ethylmalonic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "thiosulfate was excreted in massive amounts in urine of both Ethe1(-/-) mice and humans with ethylmalonic encephalopathy"
    explanation: Documents massive thiosulfate excretion (the H2S metabolite) in both mice and affected humans.
  downstream:
  - target: Cytochrome c oxidase deficiency
    description: >
      H2S inhibits and accelerates degradation of cytochrome c oxidase (complex IV).
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:19136963
      reference_title: "Loss of ETHE1, a mitochondrial dioxygenase, causes fatal sulfide toxicity in ethylmalonic encephalopathy."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Sulfide is a powerful inhibitor of COX and short-chain fatty acid oxidation, with vasoactive and vasotoxic effects that explain the microangiopathy in ethylmalonic encephalopathy patients."
      explanation: Links sulfide to COX inhibition (and to short-chain fatty acid oxidation inhibition and microangiopathy).
  - target: Ethylmalonic aciduria and acylcarnitine elevation
    description: >
      H2S inhibition of short-chain acyl-CoA dehydrogenase / short-chain fatty acid
      oxidation produces the ethylmalonic aciduria and C4/C5 acylcarnitine elevation
      that define the biochemical phenotype.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:19136963
      reference_title: "Loss of ETHE1, a mitochondrial dioxygenase, causes fatal sulfide toxicity in ethylmalonic encephalopathy."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Sulfide is a powerful inhibitor of COX and short-chain fatty acid oxidation, with vasoactive and vasotoxic effects that explain the microangiopathy in ethylmalonic encephalopathy patients."
      explanation: Sulfide inhibition of short-chain fatty acid oxidation underlies the ethylmalonic acid / acylcarnitine biomarker profile.
  - target: Microangiopathy and endothelial toxicity
    description: >
      The vasoactive/vasotoxic action of H2S on the endothelium of small vessels
      produces the microangiopathy underlying petechiae and orthostatic acrocyanosis.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20812865
      reference_title: "Chronic exposure to sulfide causes accelerated degradation of cytochrome c oxidase in ethylmalonic encephalopathy."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "several toxic actions on a number of enzymatic activities in different tissues, including endothelial lining of the small vessels, leading to multiorgan failure."
      explanation: Attributes the small-vessel/endothelial injury to H2S toxicity.
  - target: Chronic diarrhea
    description: >
      Accumulation of H2S in the colonic mucosa drives the chronic diarrhea
      characteristic of the disease.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20812865
      reference_title: "Chronic exposure to sulfide causes accelerated degradation of cytochrome c oxidase in ethylmalonic encephalopathy."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "The main consequence of the absence of Ethe1-SDO is the accumulation of sulfide (H(2)S) in critical tissues, including colonic mucosa, liver, muscle, and brain."
      explanation: Colonic-mucosa H2S accumulation underlies the gastrointestinal (chronic diarrhea) involvement.
- name: Cytochrome c oxidase deficiency
  description: >
    Chronic sulfide exposure causes cytochrome c oxidase (complex IV) deficiency by
    rapid heme a inhibition and accelerated long-term degradation of COX subunits;
    COX activity is decreased in skeletal muscle and brain.
  evidence:
  - reference: PMID:20812865
    reference_title: "Chronic exposure to sulfide causes accelerated degradation of cytochrome c oxidase in ethylmalonic encephalopathy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The mechanism by which H(2)S causes COX deficiency consists of rapid heme a inhibition and accelerated long-term degradation of COX subunits."
    explanation: Describes the mechanism of the acquired complex IV deficiency.
  - reference: PMID:14732903
    reference_title: "Ethylmalonic encephalopathy is caused by mutations in ETHE1, a gene encoding a mitochondrial matrix protein."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "cytochrome c oxidase activity is decreased in skeletal muscle"
    explanation: Documents decreased COX activity in patient skeletal muscle.
  downstream:
  - target: Neurodevelopmental regression and encephalopathy
    description: >
      Cerebral energy failure from complex IV deficiency (together with direct
      neurotoxicity of sulfide) drives the encephalopathy, psychomotor regression and
      symmetric basal ganglia lesions.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - cerebral mitochondrial energy failure
    - basal ganglia injury
    evidence:
    - reference: PMID:19136963
      reference_title: "Loss of ETHE1, a mitochondrial dioxygenase, causes fatal sulfide toxicity in ethylmalonic encephalopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "characterized by early-onset encephalopathy, microangiopathy, chronic diarrhea, defective cytochrome c oxidase (COX) in muscle and brain"
      explanation: Links the brain COX defect to the early-onset encephalopathy.
- name: Ethylmalonic aciduria and acylcarnitine elevation
  description: >
    The biochemical hallmark of EE: high urinary excretion of ethylmalonic acid and
    elevated blood C4 (butyryl-) and C5 acylcarnitines, reflecting inhibition of
    short-chain fatty acid oxidation.
  chemical_entities:
  - preferred_term: ethylmalonic acid
    term:
      id: CHEBI:741548
      label: ethylmalonic acid
    modifier: INCREASED
  - preferred_term: C4 acylcarnitine (butyrylcarnitine)
    term:
      id: CHEBI:7676
      label: O-butanoylcarnitine
    modifier: INCREASED
  evidence:
  - reference: PMID:14732903
    reference_title: "Ethylmalonic encephalopathy is caused by mutations in ETHE1, a gene encoding a mitochondrial matrix protein."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "High levels of ethylmalonic acid are detected in the body fluids, and cytochrome c oxidase activity is decreased in skeletal muscle."
    explanation: Documents the high ethylmalonic acid levels defining the biochemical phenotype.
  - reference: PMID:19136963
    reference_title: "Loss of ETHE1, a mitochondrial dioxygenase, causes fatal sulfide toxicity in ethylmalonic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "high concentrations of C4 and C5 acylcarnitines in blood and high excretion of ethylmalonic acid in urine"
    explanation: Documents the C4/C5 acylcarnitine and ethylmalonic acid signature.
- name: Microangiopathy and endothelial toxicity
  description: >
    H2S toxicity to the endothelium of small vessels produces a microangiopathy that
    manifests as relapsing petechiae and orthostatic acrocyanosis.
  evidence:
  - reference: PMID:19136963
    reference_title: "Loss of ETHE1, a mitochondrial dioxygenase, causes fatal sulfide toxicity in ethylmalonic encephalopathy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "vasoactive and vasotoxic effects that explain the microangiopathy in ethylmalonic encephalopathy patients"
    explanation: Attributes the microangiopathy to the vasotoxic action of sulfide.
  downstream:
  - target: Petechiae
    description: Small-vessel microangiopathy produces relapsing petechiae.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:37458841
      reference_title: "Ethylmalonic Encephalopathy: a literature review and two new cases of mild phenotype."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The common manifestations of EE are psychomotor regression, hypotonia, developmental delay, petechia, pyramidal signs, chronic diarrhoea, orthostatic acrocyanosis and failure to thrive, respectively."
      explanation: Lists petechiae among the common manifestations of EE.
  - target: Acrocyanosis
    description: Vasomotor instability produces orthostatic acrocyanosis.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:37458841
      reference_title: "Ethylmalonic Encephalopathy: a literature review and two new cases of mild phenotype."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The common manifestations of EE are psychomotor regression, hypotonia, developmental delay, petechia, pyramidal signs, chronic diarrhoea, orthostatic acrocyanosis and failure to thrive, respectively."
      explanation: Lists orthostatic acrocyanosis among the common manifestations of EE.
- name: Neurodevelopmental regression and encephalopathy
  description: >
    Progressive encephalopathy with psychomotor regression, hypotonia, pyramidal
    signs, developmental delay and symmetric basal ganglia signal abnormalities.
  locations:
  - preferred_term: collection of basal ganglia
    term:
      id: UBERON:0010011
      label: collection of basal ganglia
  evidence:
  - reference: PMID:37458841
    reference_title: "Ethylmalonic Encephalopathy: a literature review and two new cases of mild phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Basal ganglia signal alterations were detected in 42 cases."
    explanation: Documents symmetric basal ganglia involvement on neuroimaging.
phenotypes:
- name: Developmental regression
  category: Neurologic
  description: Psychomotor/developmental regression is a cardinal feature.
  phenotype_term:
    preferred_term: Developmental regression
    term:
      id: HP:0002376
      label: Developmental regression
  evidence:
  - reference: PMID:37458841
    reference_title: "Ethylmalonic Encephalopathy: a literature review and two new cases of mild phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The common manifestations of EE are psychomotor regression, hypotonia, developmental delay, petechia, pyramidal signs, chronic diarrhoea, orthostatic acrocyanosis and failure to thrive, respectively."
    explanation: Psychomotor regression is listed as a common manifestation.
- name: Hypotonia
  category: Neurologic
  description: Central hypotonia is common, often with later pyramidal signs.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:37458841
    reference_title: "Ethylmalonic Encephalopathy: a literature review and two new cases of mild phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The common manifestations of EE are psychomotor regression, hypotonia, developmental delay, petechia, pyramidal signs, chronic diarrhoea, orthostatic acrocyanosis and failure to thrive, respectively."
    explanation: Hypotonia is listed as a common manifestation.
- name: Global developmental delay
  category: Neurologic
  description: Global developmental delay is a common feature.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:37458841
    reference_title: "Ethylmalonic Encephalopathy: a literature review and two new cases of mild phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The common manifestations of EE are psychomotor regression, hypotonia, developmental delay, petechia, pyramidal signs, chronic diarrhoea, orthostatic acrocyanosis and failure to thrive, respectively."
    explanation: Developmental delay is listed as a common manifestation.
- name: Spasticity
  category: Neurologic
  description: Pyramidal signs (spasticity) develop as the encephalopathy progresses.
  phenotype_term:
    preferred_term: Spasticity
    term:
      id: HP:0001257
      label: Spasticity
  evidence:
  - reference: PMID:37458841
    reference_title: "Ethylmalonic Encephalopathy: a literature review and two new cases of mild phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The common manifestations of EE are psychomotor regression, hypotonia, developmental delay, petechia, pyramidal signs, chronic diarrhoea, orthostatic acrocyanosis and failure to thrive, respectively."
    explanation: Pyramidal signs (mapped to spasticity) are listed as a common manifestation.
- name: Abnormal basal ganglia morphology
  category: Neurologic
  description: Symmetric basal ganglia signal alterations are seen on brain MRI.
  phenotype_term:
    preferred_term: Abnormal basal ganglia morphology
    term:
      id: HP:0002134
      label: Abnormal basal ganglia morphology
  evidence:
  - reference: PMID:37458841
    reference_title: "Ethylmalonic Encephalopathy: a literature review and two new cases of mild phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Basal ganglia signal alterations were detected in 42 cases."
    explanation: Basal ganglia involvement documented on MRI in the majority of imaged cases.
- name: Petechiae
  category: Dermatologic
  description: Relapsing petechiae from the small-vessel microangiopathy.
  phenotype_term:
    preferred_term: Petechiae
    term:
      id: HP:0000967
      label: Petechiae
  evidence:
  - reference: PMID:37458841
    reference_title: "Ethylmalonic Encephalopathy: a literature review and two new cases of mild phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The common manifestations of EE are psychomotor regression, hypotonia, developmental delay, petechia, pyramidal signs, chronic diarrhoea, orthostatic acrocyanosis and failure to thrive, respectively."
    explanation: Petechiae are listed as a common manifestation.
- name: Acrocyanosis
  category: Vascular
  description: Orthostatic acrocyanosis reflecting the microvascular toxicity.
  phenotype_term:
    preferred_term: Acrocyanosis
    term:
      id: HP:0001063
      label: Acrocyanosis
  evidence:
  - reference: PMID:37458841
    reference_title: "Ethylmalonic Encephalopathy: a literature review and two new cases of mild phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The common manifestations of EE are psychomotor regression, hypotonia, developmental delay, petechia, pyramidal signs, chronic diarrhoea, orthostatic acrocyanosis and failure to thrive, respectively."
    explanation: Orthostatic acrocyanosis is listed as a common manifestation.
- name: Chronic diarrhea
  category: Gastrointestinal
  description: Chronic diarrhea from colonic-mucosa H2S accumulation.
  phenotype_term:
    preferred_term: Chronic diarrhea
    term:
      id: HP:0002028
      label: Chronic diarrhea
  evidence:
  - reference: PMID:19136963
    reference_title: "Loss of ETHE1, a mitochondrial dioxygenase, causes fatal sulfide toxicity in ethylmalonic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "characterized by early-onset encephalopathy, microangiopathy, chronic diarrhea, defective cytochrome c oxidase (COX) in muscle and brain"
    explanation: Chronic diarrhea is a defining feature of the disease.
- name: Failure to thrive
  category: Constitutional
  description: Failure to thrive is common, often exacerbated by chronic diarrhea.
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: PMID:37458841
    reference_title: "Ethylmalonic Encephalopathy: a literature review and two new cases of mild phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The common manifestations of EE are psychomotor regression, hypotonia, developmental delay, petechia, pyramidal signs, chronic diarrhoea, orthostatic acrocyanosis and failure to thrive, respectively."
    explanation: Failure to thrive is listed as a common manifestation.
- name: Ethylmalonic aciduria
  category: Biochemical
  description: High urinary excretion of ethylmalonic acid is the diagnostic biomarker.
  phenotype_term:
    preferred_term: Ethylmalonic aciduria
    term:
      id: HP:0003219
      label: Ethylmalonic aciduria
  evidence:
  - reference: PMID:19136963
    reference_title: "Loss of ETHE1, a mitochondrial dioxygenase, causes fatal sulfide toxicity in ethylmalonic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "high concentrations of C4 and C5 acylcarnitines in blood and high excretion of ethylmalonic acid in urine"
    explanation: Documents high urinary ethylmalonic acid excretion.
biochemical:
- name: Urinary ethylmalonic acid
  presence: INCREASED
  context: >
    Markedly elevated urinary ethylmalonic acid is the diagnostic biomarker of EE and
    gives the disorder its name.
  biomarker_term:
    preferred_term: ethylmalonic acid
    term:
      id: CHEBI:741548
      label: ethylmalonic acid
  evidence:
  - reference: PMID:14732903
    reference_title: "Ethylmalonic encephalopathy is caused by mutations in ETHE1, a gene encoding a mitochondrial matrix protein."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "High levels of ethylmalonic acid are detected in the body fluids, and cytochrome c oxidase activity is decreased in skeletal muscle."
    explanation: Documents high ethylmalonic acid in body fluids.
- name: Blood C4/C5 acylcarnitines
  presence: INCREASED
  context: >
    Elevated blood C4 (butyryl-) and C5 acylcarnitines accompany the ethylmalonic
    aciduria and reflect impaired short-chain fatty acid oxidation.
  biomarker_term:
    preferred_term: C4 acylcarnitine (butyrylcarnitine)
    term:
      id: CHEBI:7676
      label: O-butanoylcarnitine
  evidence:
  - reference: PMID:19136963
    reference_title: "Loss of ETHE1, a mitochondrial dioxygenase, causes fatal sulfide toxicity in ethylmalonic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "high concentrations of C4 and C5 acylcarnitines in blood and high excretion of ethylmalonic acid in urine"
    explanation: Documents the C4/C5 acylcarnitine elevation.
- name: Urinary thiosulfate
  presence: INCREASED
  context: >
    Massive urinary thiosulfate excretion reflects the systemic accumulation of the
    H2S metabolite and is a biomarker of the sulfide detoxification defect.
  biomarker_term:
    preferred_term: thiosulfate
    term:
      id: CHEBI:26977
      label: thiosulfate
  evidence:
  - reference: PMID:19136963
    reference_title: "Loss of ETHE1, a mitochondrial dioxygenase, causes fatal sulfide toxicity in ethylmalonic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "thiosulfate was excreted in massive amounts in urine of both Ethe1(-/-) mice and humans with ethylmalonic encephalopathy"
    explanation: Documents massive urinary thiosulfate excretion in affected humans.
genetic:
- name: ETHE1 deficiency
  gene_term:
    preferred_term: ETHE1
    term:
      id: hgnc:23287
      label: ETHE1
  inheritance:
  - name: Autosomal recessive
    description: Biallelic pathogenic ETHE1 variants are required; carriers are asymptomatic.
    evidence:
    - reference: PMID:19136963
      reference_title: "Loss of ETHE1, a mitochondrial dioxygenase, causes fatal sulfide toxicity in ethylmalonic encephalopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Ethylmalonic encephalopathy is an autosomal recessive, invariably fatal disorder characterized by early-onset encephalopathy, microangiopathy, chronic diarrhea, defective cytochrome c oxidase (COX) in muscle and brain, high concentrations of C4 and C5 acylcarnitines in blood and high excretion of ethylmalonic acid in urine."
      explanation: States autosomal recessive inheritance.
  features: >
    ETHE1 encodes a beta-lactamase-like, iron-coordinating metalloprotein imported
    into the mitochondrial matrix that functions as a sulfur dioxygenase. Recurrent
    pathogenic variants reported in the literature include the homozygous p.R163Q,
    p.R163W, exon 4 deletion, p.Glu44ValfsTer62 and p.M1I alleles.
  evidence:
  - reference: PMID:19136963
    reference_title: "Loss of ETHE1, a mitochondrial dioxygenase, causes fatal sulfide toxicity in ethylmalonic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ETHE1, a gene encoding a beta-lactamase-like, iron-coordinating metalloprotein, is mutated in ethylmalonic encephalopathy."
    explanation: Describes the ETHE1 gene product mutated in the disease.
  - reference: PMID:37458841
    reference_title: "Ethylmalonic Encephalopathy: a literature review and two new cases of mild phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most common ETHE1 gene homozygous state mutations were (p.R163Q) (c.488G>A), exon 4 deletion, (p.R163W)(c.487C>T), (p.Glu44ValfsTer62)(c.131_132delAG) and (p.M1I)(c.3G>T) mutations, respectively."
    explanation: Lists the most common recurrent ETHE1 pathogenic variants across reported cases.
treatments:
- name: Metronidazole plus N-acetylcysteine
  description: >
    Combined oral metronidazole (a bactericide that lowers the population of
    H2S-producing anaerobic gut bacteria) and N-acetylcysteine (a precursor of
    sulfide-buffering glutathione) is the mainstay disease-modifying therapy. The
    combination prolonged survival of Ethe1-deficient mice additively and produced
    marked clinical improvement in affected children.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: metronidazole
      term:
        id: CHEBI:6909
        label: metronidazole
    - preferred_term: N-acetylcysteine
      term:
        id: CHEBI:22198
        label: acetylcysteine
  evidence:
  - reference: PMID:20657580
    reference_title: "Combined treatment with oral metronidazole and N-acetylcysteine is effective in ethylmalonic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The same dual treatment caused marked clinical improvement in five affected children, with hardly any adverse or side effects."
    explanation: Demonstrates clinical benefit of the combined metronidazole/NAC therapy in affected children.
  - reference: PMID:20657580
    reference_title: "Combined treatment with oral metronidazole and N-acetylcysteine is effective in ethylmalonic encephalopathy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Metronidazole, a bactericide, or N-acetylcysteine, a precursor of sulfide-buffering glutathione, substantially prolonged the lifespan of Ethe1-deficient mice, with the combined treatment being additive."
    explanation: Establishes the mechanistic rationale (reducing/buffering sulfide) and additive survival benefit in the mouse model.
- name: Liver transplantation
  description: >
    Liver transplantation has been used in EE to restore hepatic sulfur dioxygenase
    activity and lower systemic sulfide, with reported clinical benefit in some
    patients.
  treatment_term:
    preferred_term: organ transplantation
    term:
      id: NCIT:C15289
      label: Organ Transplantation
  evidence:
  - reference: PMID:37458841
    reference_title: "Ethylmalonic Encephalopathy: a literature review and two new cases of mild phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Reducing the accumulation and inducing detoxification of sulfide is the main long-term treatment strategy for EE, including metronidazole, N-acetylcysteine (NAC), dietary modification, liver transplantation and continuous renal replacement therapy (CRRT)."
    explanation: Lists liver transplantation among the long-term sulfide-reducing treatment strategies.
notes: >
  Ethylmalonic encephalopathy is a paradigm of a "gasotransmitter intoxication"
  disorder: the primary defect is not in amino-acid catabolism per se but in the
  mitochondrial detoxification of hydrogen sulfide, so the pathogenic species is H2S
  (and its metabolite thiosulfate) rather than a classic amino/organic acid. This
  explains two otherwise puzzling features — the therapeutic value of gut-directed
  antibiotics (metronidazole reduces bacterial H2S production) and the microvascular
  (petechiae, acrocyanosis) and gastrointestinal involvement alongside the
  mitochondrial encephalopathy. The ethylmalonic aciduria and C4/C5 acylcarnitine
  elevation are downstream consequences of sulfide inhibition of short-chain fatty
  acid oxidation, not the primary lesion. Most mechanistic detail derives from the
  Ethe1-/- mouse and tissue-specific conditional knockouts (Tiranti 2009; Di Meo
  2011), corroborated by patient biochemistry and the human treatment response.
references:
- reference: PMID:14732903
  title: "Ethylmalonic encephalopathy is caused by mutations in ETHE1, a gene encoding a mitochondrial matrix protein."
- reference: PMID:19136963
  title: "Loss of ETHE1, a mitochondrial dioxygenase, causes fatal sulfide toxicity in ethylmalonic encephalopathy."
- reference: PMID:20812865
  title: "Chronic exposure to sulfide causes accelerated degradation of cytochrome c oxidase in ethylmalonic encephalopathy."
- reference: PMID:20657580
  title: "Combined treatment with oral metronidazole and N-acetylcysteine is effective in ethylmalonic encephalopathy."
- reference: PMID:37458841
  title: "Ethylmalonic Encephalopathy: a literature review and two new cases of mild phenotype."
📚

References & Deep Research

References

5
PMID:14732903
Ethylmalonic encephalopathy is caused by mutations in ETHE1, a gene encoding a mitochondrial matrix protein.
No top-level findings curated for this source.
PMID:19136963
Loss of ETHE1, a mitochondrial dioxygenase, causes fatal sulfide toxicity in ethylmalonic encephalopathy.
No top-level findings curated for this source.
PMID:20812865
Chronic exposure to sulfide causes accelerated degradation of cytochrome c oxidase in ethylmalonic encephalopathy.
No top-level findings curated for this source.
PMID:20657580
Combined treatment with oral metronidazole and N-acetylcysteine is effective in ethylmalonic encephalopathy.
No top-level findings curated for this source.
PMID:37458841
Ethylmalonic Encephalopathy: a literature review and two new cases of mild phenotype.
No top-level findings curated for this source.