ECHS1 Deficiency

Mendelian MONDO:0014563 Pathograph 9 Show in embeddings browser Mitochondrial Disease Inborn Error of Metabolism

ECHS1 deficiency is an autosomal-recessive mitochondrial disorder caused by biallelic pathogenic variants in ECHS1, which encodes short-chain enoyl-CoA hydratase (SCEH, crotonase), a multifunctional enzyme of the mitochondrial matrix. SCEH catalyzes the second step of the fatty-acid beta-oxidation spiral (hydration of 2-trans-enoyl-CoA to 3-hydroxyacyl-CoA) and also an early step of valine catabolism (hydration of methacrylyl-CoA and acryloyl-CoA). Affected individuals typically present in infancy with a Leigh syndrome / Leigh-like mitochondrial encephalopathy: bilateral symmetric basal ganglia (putaminal) lesions, developmental delay or regression, dystonia, hypotonia, and elevated lactate, often with sensorineural hearing loss, epilepsy, optic atrophy, and cardiomyopathy; a paroxysmal exercise-induced dyskinesia phenotype is also described. Although ECHS1 is a beta-oxidation-spiral enzyme, the prevailing view is that the neurotoxicity is driven mainly by accumulation of toxic valine-pathway intermediates — the highly reactive metabolites methacrylyl-CoA and acryloyl-CoA, which spontaneously react with sulfhydryl groups (cysteine, glutathione, cysteamine) and damage mitochondrial proteins including the pyruvate dehydrogenase complex — rather than by impaired fatty-acid oxidation flux. Mitochondrial fatty-acid beta-oxidation is largely preserved because of overlapping enzyme activities (palmitate loading of patient fibroblasts is typically normal, and routine serum acylcarnitine profiles are usually unremarkable), which distinguishes ECHS1 deficiency from classical fatty-acid oxidation disorders and explains why a valine-restricted diet is being explored therapeutically.

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4
Pathophys.
9
Phenotypes
9
Pathograph
1
Genes
1
Medical Actions
3
Datasets
⚙

Pathophysiology

4
ECHS1 (short-chain enoyl-CoA hydratase) enzyme deficiency
Biallelic pathogenic variants in ECHS1 markedly reduce short-chain enoyl-CoA hydratase (SCEH/crotonase) protein and enzyme activity in the mitochondrial matrix. SCEH is a multifunctional hydratase acting on substrates from several pathways, catalyzing the second step of the fatty-acid beta-oxidation spiral and an early hydration step of valine catabolism.
ECHS1 hgnc:3151
enoyl-CoA hydratase activity GO:0004300 ↓ DECREASED
mitochondrial matrix GO:0005759
Downstream
Impaired valine catabolism and reactive-metabolite accumulation Loss of SCEH blocks the valine catabolic pathway at the hydration of methacrylyl-CoA and acryloyl-CoA, causing these reactive intermediates to accumulate.
Largely preserved fatty-acid beta-oxidation Despite SCEH being a beta-oxidation-spiral enzyme, mitochondrial fatty-acid oxidation flux is largely preserved because of overlapping hydratase activities.
Show evidence (3 references)
PMID:25393721 SUPPORT Human Clinical
"The human ECHS1 gene encodes the short-chain enoyl coenzyme A hydratase, the enzyme that catalyzes the second step of β-oxidation of fatty acids in the mitochondrial matrix."
Defines the gene product and its localization to the mitochondrial matrix as the second-step beta-oxidation hydratase.
PMID:25393721 SUPPORT In Vitro
"ECHS1 protein expression was severely depleted in the patient's skeletal muscle and patient-derived myoblasts; a marked decrease in enzyme activity was also evident in patient-derived myoblasts."
Patient tissue and myoblast studies confirm loss of ECHS1 protein and enzyme activity.
PMID:25125611 SUPPORT In Vitro
"ECHS1 activity was markedly decreased in cultured fibroblasts from both siblings, ECHS1 protein was undetectable by immunoblot analysis and transfection of patient cells with wild-type ECHS1 rescued ECHS1 activity."
Loss of ECHS1 activity with wild-type rescue establishes pathogenicity of the enzyme deficiency.
Impaired valine catabolism and reactive-metabolite accumulation
SCEH deficiency blocks valine catabolism at the hydration of the reactive thioesters methacrylyl-CoA and acryloyl-CoA. These highly reactive intermediates accumulate and are considered the principal drivers of neurotoxicity, in parallel with the biochemically and clinically similar HIBCH deficiency of the adjacent valine-pathway step.
L-valine catabolic process GO:0006574 ↓ DECREASED branched-chain amino acid catabolic process GO:0009083 ↓ DECREASED
mitochondrial matrix GO:0005759
Downstream
Reactive-metabolite mitochondrial and pyruvate dehydrogenase toxicity The accumulated reactive thioesters covalently react with sulfhydryl groups (cysteine, glutathione, cysteamine) and damage mitochondrial proteins, including the pyruvate dehydrogenase complex.
Show evidence (1 reference)
PMID:25125611 SUPPORT Human Clinical
"The highly reactive metabolites methacrylyl-CoA and acryloyl-CoA accumulate in deficiencies of both ECHS1 and HIBCH and are probably responsible for the brain pathology in both disorders."
Identifies accumulating reactive valine-pathway intermediates as the probable cause of brain pathology in ECHS1 deficiency.
Reactive-metabolite mitochondrial and pyruvate dehydrogenase toxicity
Reactive valine-pathway intermediates deplete cellular thiol pools and damage mitochondrial proteins, producing a secondary pyruvate dehydrogenase (PDH) deficiency and secondary respiratory-chain dysfunction. This bioenergetic failure links the primary enzyme defect to the Leigh-like neurodegeneration, mirroring other mitochondrial energy-metabolism disorders.
pyruvate dehydrogenase (acetyl-transferring) activity GO:0004739 ↓ DECREASED
mitochondrial matrix GO:0005759
Downstream
Leigh-like basal ganglia neurodegeneration Secondary PDH and respiratory-chain dysfunction, together with direct metabolite toxicity, produce bilateral symmetric basal ganglia (putaminal) necrotizing lesions characteristic of Leigh / Leigh-like disease.
Show evidence (2 references)
PMID:26081110 SUPPORT Human Clinical
"In severely affected patients SCEH deficiency can cause a secondary pyruvate dehydrogenase deficiency contributing to the clinical presentation."
Directly supports secondary PDH deficiency as a contributor to the clinical phenotype.
PMID:26081110 SUPPORT Human Clinical
"Pyruvate dehydrogenase activity was markedly reduced in particular in muscle from the most severely affected patients, which was caused by reduced expression of E2 protein"
Documents reduced PDH activity due to loss of the E2 component in affected tissue.
Leigh-like basal ganglia neurodegeneration
The convergent bioenergetic and toxic insult manifests as bilateral symmetric basal ganglia (especially putaminal) degeneration with necrotizing/cavitating lesions, the neuropathological substrate of the Leigh-syndrome phenotype and its motor and developmental sequelae.
neuron CL:0000540
putamen UBERON:0001874 basal ganglion UBERON:0002420
Downstream
Dystonia Basal ganglia degeneration produces dystonia, a hallmark motor feature.
Developmental regression Progressive basal ganglia and white-matter injury manifests as developmental delay and regression.
Show evidence (2 references)
PMID:26081110 SUPPORT Human Clinical
"All patients presented with lactic acidosis. The first two patients presented with vacuolating leukoencephalopathy and basal ganglia abnormalities."
Documents basal ganglia abnormalities and lactic acidosis in ECHS1 deficiency patients.
PMID:36064416 SUPPORT Human Clinical
"The Leigh syndrome phenotype is the most frequently reported form of the disease."
Confirms Leigh syndrome as the predominant clinical phenotype of ECHS1 deficiency.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Referential integrity issues (1):
  • Target 'Largely preserved fatty-acid beta-oxidation' (from 'ECHS1 (short-chain enoyl-CoA hydratase) enzyme deficiency') not found in named elements
Pathograph: causal mechanism network for ECHS1 Deficiency 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

9
Cardiovascular 1
Cardiomyopathy OCCASIONAL Cardiomyopathy HP:0001638
Show evidence (1 reference)
PMID:26000322 SUPPORT Human Clinical
"The most prominent clinical features were encephalopathy (10/10), deafness (9/9), epilepsy (6/9), optic atrophy (6/10), and cardiomyopathy (4/10)."
Documents cardiomyopathy in 4/10 patients.
Ear 1
Sensorineural hearing impairment FREQUENT Sensorineural hearing impairment HP:0000407
Show evidence (1 reference)
PMID:26000322 SUPPORT Human Clinical
"The most prominent clinical features were encephalopathy (10/10), deafness (9/9), epilepsy (6/9), optic atrophy (6/10), and cardiomyopathy (4/10)."
Documents deafness in 9/9 tested patients as one of the most prominent features.
Eye 1
Optic atrophy OCCASIONAL Optic atrophy HP:0000648
Show evidence (1 reference)
PMID:26000322 SUPPORT Human Clinical
"The most prominent clinical features were encephalopathy (10/10), deafness (9/9), epilepsy (6/9), optic atrophy (6/10), and cardiomyopathy (4/10)."
Documents optic atrophy in 6/10 patients.
Metabolism 1
Lactic acidosis FREQUENT Lactic acidosis HP:0003128
Show evidence (1 reference)
PMID:26081110 SUPPORT Human Clinical
"All patients presented with lactic acidosis."
Documents lactic acidosis in all patients of the case series.
Musculoskeletal 1
Generalized hypotonia FREQUENT Generalized hypotonia HP:0001290
Show evidence (1 reference)
PMID:25393721 SUPPORT Human Clinical
"The patient presented with hypotonia, metabolic acidosis, and developmental delay."
Documents hypotonia as a presenting feature.
Nervous System 3
Developmental regression FREQUENT Developmental regression HP:0002376
Show evidence (1 reference)
PMID:25393721 SUPPORT Human Clinical
"The patient presented with hypotonia, metabolic acidosis, and developmental delay."
Documents developmental delay as a presenting feature.
Dystonia FREQUENT Dystonia HP:0001332
Show evidence (1 reference)
PMID:36064416 SUPPORT Human Clinical
"He presented severe dystonia, hyperlordosis, moderate to severe kyphoscoliosis, great difficulty in walking, and severe dysarthria."
Documents severe dystonia as a presenting feature of ECHS1 deficiency.
Seizure OCCASIONAL Seizure HP:0001250
Show evidence (1 reference)
PMID:26000322 SUPPORT Human Clinical
"The most prominent clinical features were encephalopathy (10/10), deafness (9/9), epilepsy (6/9), optic atrophy (6/10), and cardiomyopathy (4/10)."
Documents epilepsy in 6/9 patients.
Other 1
Bilateral basal ganglia lesions FREQUENT Bilateral basal ganglia lesions HP:0007146
Show evidence (2 references)
PMID:26000322 SUPPORT Human Clinical
"Serum lactate was elevated and brain magnetic resonance imaging showed white matter changes or a Leigh-like pattern resembling disorders of mitochondrial energy metabolism."
Documents Leigh-like brain MRI patterns characteristic of the disorder.
PMID:26081110 SUPPORT Human Clinical
"The first two patients presented with vacuolating leukoencephalopathy and basal ganglia abnormalities."
Documents basal ganglia abnormalities in ECHS1-deficient patients.
🧬

Genetic Associations

1
ECHS1 gene variants
Gene: ECHS1 hgnc:3151
Autosomal recessive
Show evidence (1 reference)
PMID:25125611 SUPPORT Human Clinical
"Both children were compound heterozygous for a c.473C > A (p.A158D) missense mutation and a c.414+3G>C splicing mutation in ECHS1."
Documents compound heterozygous ECHS1 variants in the index siblings.
💊

Medical Actions

1
Valine- and fat-restricted diet
Action: dietary intervention MAXO:0000088
Diet:
Because the neurotoxicity is attributed to accumulation of valine-pathway intermediates (methacrylyl-CoA and acryloyl-CoA), a valine-restricted (and fat-restricted) diet is being explored as a mechanism-directed, investigational therapy aimed at reducing production of the toxic metabolites. Reported outcomes are variable; in one pediatric case a valine- and fat-restricted diet was associated with improvement in dystonia and appeared to limit disease progression, but evidence remains limited to small case reports.
Show evidence (2 references)
PMID:36064416 SUPPORT Human Clinical
"A valine-restricted and total fat-restricted diet was considered as a therapeutic option after the genetic diagnosis."
Documents the valine- and fat-restricted diet as a therapeutic approach in ECHS1 deficiency.
PMID:36064416 PARTIAL Human Clinical
"After three years, the patient noticed an improvement in dystonia, especially in walking."
Single-case improvement in dystonia after dietary therapy; supports an investigational benefit while highlighting the limited evidence base.
🔬

Biochemical Markers

2
Blood lactate (INCREASED)
Context: Elevated blood (and CSF) lactate is a characteristic biochemical finding, reflecting secondary pyruvate dehydrogenase and respiratory-chain dysfunction rather than a primary fatty-acid oxidation block.
Pathograph Readouts
Readout Of Reactive-metabolite mitochondrial and pyruvate dehydrogenase toxicity Positive Diagnostic
Elevated lactate reports the secondary bioenergetic (PDH and respiratory-chain) dysfunction downstream of the enzyme defect.
Show evidence (1 reference)
PMID:26000322 SUPPORT Human Clinical
"Serum lactate was elevated and brain magnetic resonance imaging showed white matter changes or a Leigh-like pattern resembling disorders of mitochondrial energy metabolism."
Documents elevated serum lactate as a readout of mitochondrial energy dysfunction.
Show evidence (1 reference)
PMID:26081110 SUPPORT Human Clinical
"All patients presented with lactic acidosis."
All patients in the case series had lactic acidosis (elevated lactate).
Serum acylcarnitine profile (NORMAL)
Context: In contrast to classical fatty-acid oxidation disorders, routine serum acylcarnitine profiles are usually normal in ECHS1 deficiency; the fatty-acid oxidation defect is only unmasked by in vitro palmitate loading (increased butyrylcarnitine), consistent with largely preserved fatty-acid oxidation flux.
Show evidence (1 reference)
PMID:26000322 SUPPORT Human Clinical
"While serum acylcarnitine profiles were largely normal, in vitro palmitate loading of patient fibroblasts revealed increased butyrylcarnitine, unmasking the functional defect in mitochondrial β-oxidation of short-chain fatty acids."
Documents largely normal routine acylcarnitines with the FAO defect only unmasked by palmitate loading.
📊

Related Datasets

3
Loss of Mitochondrial Fatty Acid Beta-Oxidation Protein Short Chain Enoyl-CoA Hydratase Disrupts Oxidative Phosphorylation Protein Complex Stability and Function geo:GSE200252
Bulk RNA-seq of ECHS1-null human cells and patient fibroblasts showing secondary disruption of the TCA cycle, mitophagy, nucleotide synthesis, and OXPHOS complexes I and IV — evidence for the secondary mitochondrial/OXPHOS destabilization underlying the Leigh-like phenotype.
BULK RNA SEQ
PMID:35962613
Organism: human (CRISPR-edited cells and patient fibroblasts). NCBI GEO.
Loss of Mitochondrial Fatty Acid beta-Oxidation Protein Short Chain Enoyl-CoA Hydratase Disrupts Oxidative Phosphorylation Protein Complex Stability and Function pride:PXD032761
Proteomics companion to GSE200252 showing that ECHS1 loss compromises OXPHOS complex stability, especially complex I, supporting the secondary-mitochondrial mechanism of ECHS1 deficiency.
PROTEOMICS
PMID:35962613
Organism: human and mouse. PRIDE/ProteomeXchange.
Bulk RNA-seq analysis of the effects of ECHS1 knockdown on cardiomyocyte transcriptome geo:GSE159039
Bulk RNA-seq of ECHS1-knockdown versus control neonatal cardiomyocytes, linking ECHS1 loss to altered histone crotonylation — an example of acyl-CoA-driven protein and histone lysine-acylation effects.
BULK RNA SEQ
PMID:33683949
Organism: rat (Rattus norvegicus), neonatal cardiomyocytes (siECHS1 vs control).
{ }

Source YAML

click to show 
name: ECHS1 Deficiency
creation_date: '2026-07-02T00:00:00Z'
category: Mendelian
synonyms:
- Short-chain enoyl-CoA hydratase deficiency
- SCEH deficiency
- Mitochondrial short-chain enoyl-CoA hydratase 1 deficiency
- ECHS1D
description: >
  ECHS1 deficiency is an autosomal-recessive mitochondrial disorder caused by
  biallelic pathogenic variants in ECHS1, which encodes short-chain enoyl-CoA
  hydratase (SCEH, crotonase), a multifunctional enzyme of the mitochondrial
  matrix. SCEH catalyzes the second step of the fatty-acid beta-oxidation
  spiral (hydration of 2-trans-enoyl-CoA to 3-hydroxyacyl-CoA) and also an
  early step of valine catabolism (hydration of methacrylyl-CoA and
  acryloyl-CoA). Affected individuals typically present in infancy with a
  Leigh syndrome / Leigh-like mitochondrial encephalopathy: bilateral
  symmetric basal ganglia (putaminal) lesions, developmental delay or
  regression, dystonia, hypotonia, and elevated lactate, often with
  sensorineural hearing loss, epilepsy, optic atrophy, and cardiomyopathy; a
  paroxysmal exercise-induced dyskinesia phenotype is also described.

  Although ECHS1 is a beta-oxidation-spiral enzyme, the prevailing view is that
  the neurotoxicity is driven mainly by accumulation of toxic valine-pathway
  intermediates — the highly reactive metabolites methacrylyl-CoA and
  acryloyl-CoA, which spontaneously react with sulfhydryl groups (cysteine,
  glutathione, cysteamine) and damage mitochondrial proteins including the
  pyruvate dehydrogenase complex — rather than by impaired fatty-acid oxidation
  flux. Mitochondrial fatty-acid beta-oxidation is largely preserved because of
  overlapping enzyme activities (palmitate loading of patient fibroblasts is
  typically normal, and routine serum acylcarnitine profiles are usually
  unremarkable), which distinguishes ECHS1 deficiency from classical
  fatty-acid oxidation disorders and explains why a valine-restricted diet is
  being explored therapeutically.
disease_term:
  preferred_term: mitochondrial short-chain enoyl-CoA hydratase 1 deficiency
  term:
    id: MONDO:0014563
    label: mitochondrial short-chain Enoyl-Coa hydratase 1 deficiency
parents:
- Mitochondrial Disease
- Inborn Error of Metabolism
prevalence:
- notes: >-
    ECHS1 deficiency is a rare inborn error of metabolism. It was first
    described in 2014, and subsequent case series and reviews have reported a
    growing but still small number of patients worldwide; a precise population
    prevalence has not been established. Haack et al. identified ten unrelated
    individuals by exome sequencing across three diagnostic centers screening
    cohorts with suspected mitochondrial disease.
  evidence:
  - reference: PMID:26000322
    reference_title: "Deficiency of ECHS1 causes mitochondrial encephalopathy with cardiac involvement."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Using exome sequencing, we identified ten unrelated individuals carrying
      compound heterozygous or homozygous mutations in ECHS1.
    explanation: >-
      Haack et al. report the size of the initial multi-center ECHS1-deficiency
      cohort, reflecting the rarity of the disorder.
pathophysiology:
- name: ECHS1 (short-chain enoyl-CoA hydratase) enzyme deficiency
  description: >
    Biallelic pathogenic variants in ECHS1 markedly reduce short-chain
    enoyl-CoA hydratase (SCEH/crotonase) protein and enzyme activity in the
    mitochondrial matrix. SCEH is a multifunctional hydratase acting on
    substrates from several pathways, catalyzing the second step of the
    fatty-acid beta-oxidation spiral and an early hydration step of valine
    catabolism.
  genes:
  - preferred_term: ECHS1
    term:
      id: hgnc:3151
      label: ECHS1
  molecular_functions:
  - preferred_term: enoyl-CoA hydratase activity
    term:
      id: GO:0004300
      label: enoyl-CoA hydratase activity
    modifier: DECREASED
  locations:
  - preferred_term: mitochondrial matrix
    term:
      id: GO:0005759
      label: mitochondrial matrix
  evidence:
  - reference: PMID:25393721
    reference_title: "ECHS1 mutations cause combined respiratory chain deficiency resulting in Leigh syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The human ECHS1 gene encodes the short-chain enoyl coenzyme A hydratase,
      the enzyme that catalyzes the second step of β-oxidation of fatty acids in
      the mitochondrial matrix.
    explanation: >-
      Defines the gene product and its localization to the mitochondrial matrix
      as the second-step beta-oxidation hydratase.
  - reference: PMID:25393721
    reference_title: "ECHS1 mutations cause combined respiratory chain deficiency resulting in Leigh syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      ECHS1 protein expression was severely depleted in the patient's skeletal
      muscle and patient-derived myoblasts; a marked decrease in enzyme activity
      was also evident in patient-derived myoblasts.
    explanation: >-
      Patient tissue and myoblast studies confirm loss of ECHS1 protein and
      enzyme activity.
  - reference: PMID:25125611
    reference_title: "ECHS1 mutations in Leigh disease: a new inborn error of metabolism affecting valine metabolism."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      ECHS1 activity was markedly decreased in cultured fibroblasts from both
      siblings, ECHS1 protein was undetectable by immunoblot analysis and
      transfection of patient cells with wild-type ECHS1 rescued ECHS1 activity.
    explanation: >-
      Loss of ECHS1 activity with wild-type rescue establishes pathogenicity of
      the enzyme deficiency.
  downstream:
  - target: Impaired valine catabolism and reactive-metabolite accumulation
    description: >-
      Loss of SCEH blocks the valine catabolic pathway at the hydration of
      methacrylyl-CoA and acryloyl-CoA, causing these reactive intermediates to
      accumulate.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:25125611
      reference_title: "ECHS1 mutations in Leigh disease: a new inborn error of metabolism affecting valine metabolism."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        This mitochondrial enzyme is active in several metabolic pathways
        involving fatty acids and amino acids, including valine, and is
        immediately upstream of HIBCH in the valine pathway.
      explanation: >-
        Places SCEH in the valine catabolic pathway immediately upstream of
        HIBCH.
  - target: Largely preserved fatty-acid beta-oxidation
    description: >-
      Despite SCEH being a beta-oxidation-spiral enzyme, mitochondrial
      fatty-acid oxidation flux is largely preserved because of overlapping
      hydratase activities.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:26081110
      reference_title: "Clinical and biochemical characterization of four patients with mutations in ECHS1."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Despite its activity towards substrates from different metabolic
        pathways, SCEH appears to be only crucial in valine metabolism, but not
        in isoleucine metabolism, and only of limited importance for
        mitochondrial fatty acid oxidation.
      explanation: >-
        Directly supports that SCEH is only of limited importance for
        mitochondrial fatty-acid oxidation.
- name: Impaired valine catabolism and reactive-metabolite accumulation
  description: >
    SCEH deficiency blocks valine catabolism at the hydration of the reactive
    thioesters methacrylyl-CoA and acryloyl-CoA. These highly reactive
    intermediates accumulate and are considered the principal drivers of
    neurotoxicity, in parallel with the biochemically and clinically similar
    HIBCH deficiency of the adjacent valine-pathway step.
  biological_processes:
  - preferred_term: L-valine catabolic process
    term:
      id: GO:0006574
      label: L-valine catabolic process
    modifier: DECREASED
  - preferred_term: branched-chain amino acid catabolic process
    term:
      id: GO:0009083
      label: branched-chain amino acid catabolic process
    modifier: DECREASED
  chemical_entities:
  - preferred_term: methacrylyl-CoA
    term:
      id: CHEBI:27754
      label: methacrylyl-CoA
    modifier: INCREASED
  - preferred_term: acryloyl-CoA
    term:
      id: CHEBI:15513
      label: acryloyl-CoA
    modifier: INCREASED
  - preferred_term: L-valine
    term:
      id: CHEBI:16414
      label: L-valine
  locations:
  - preferred_term: mitochondrial matrix
    term:
      id: GO:0005759
      label: mitochondrial matrix
  evidence:
  - reference: PMID:25125611
    reference_title: "ECHS1 mutations in Leigh disease: a new inborn error of metabolism affecting valine metabolism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The highly reactive metabolites methacrylyl-CoA and acryloyl-CoA
      accumulate in deficiencies of both ECHS1 and HIBCH and are probably
      responsible for the brain pathology in both disorders.
    explanation: >-
      Identifies accumulating reactive valine-pathway intermediates as the
      probable cause of brain pathology in ECHS1 deficiency.
  downstream:
  - target: Reactive-metabolite mitochondrial and pyruvate dehydrogenase toxicity
    description: >-
      The accumulated reactive thioesters covalently react with sulfhydryl
      groups (cysteine, glutathione, cysteamine) and damage mitochondrial
      proteins, including the pyruvate dehydrogenase complex.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Reactive methacrylyl-CoA/acryloyl-CoA adduct formation on sulfhydryl-bearing mitochondrial proteins
    evidence:
    - reference: PMID:26000322
      reference_title: "Deficiency of ECHS1 causes mitochondrial encephalopathy with cardiac involvement."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Accumulation of toxic methacrylyl-CoA and acryloyl-CoA, two highly
        reactive intermediates that spontaneously react with sulfhydryl groups
        of, for example, cysteine and cysteamine, is suspected to cause brain
        pathology and biochemical phenotype in β-hydroxyisobutyryl-CoA hydrolase
        (HIBCH) deficiency
      explanation: >-
        Describes the reactive-thioester sulfhydryl-adduct mechanism proposed to
        cause brain pathology.
- name: Reactive-metabolite mitochondrial and pyruvate dehydrogenase toxicity
  description: >
    Reactive valine-pathway intermediates deplete cellular thiol pools and
    damage mitochondrial proteins, producing a secondary pyruvate dehydrogenase
    (PDH) deficiency and secondary respiratory-chain dysfunction. This
    bioenergetic failure links the primary enzyme defect to the Leigh-like
    neurodegeneration, mirroring other mitochondrial energy-metabolism
    disorders.
  molecular_functions:
  - preferred_term: pyruvate dehydrogenase (acetyl-transferring) activity
    term:
      id: GO:0004739
      label: pyruvate dehydrogenase (acetyl-transferring) activity
    modifier: DECREASED
  chemical_entities:
  - preferred_term: glutathione
    term:
      id: CHEBI:16856
      label: glutathione
    modifier: DECREASED
  locations:
  - preferred_term: mitochondrial matrix
    term:
      id: GO:0005759
      label: mitochondrial matrix
  evidence:
  - reference: PMID:26081110
    reference_title: "Clinical and biochemical characterization of four patients with mutations in ECHS1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In severely affected patients SCEH deficiency can cause a secondary
      pyruvate dehydrogenase deficiency contributing to the clinical
      presentation.
    explanation: >-
      Directly supports secondary PDH deficiency as a contributor to the
      clinical phenotype.
  - reference: PMID:26081110
    reference_title: "Clinical and biochemical characterization of four patients with mutations in ECHS1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Pyruvate dehydrogenase activity was markedly reduced in particular in
      muscle from the most severely affected patients, which was caused by
      reduced expression of E2 protein
    explanation: >-
      Documents reduced PDH activity due to loss of the E2 component in affected
      tissue.
  downstream:
  - target: Leigh-like basal ganglia neurodegeneration
    description: >-
      Secondary PDH and respiratory-chain dysfunction, together with direct
      metabolite toxicity, produce bilateral symmetric basal ganglia
      (putaminal) necrotizing lesions characteristic of Leigh / Leigh-like
      disease.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Secondary pyruvate dehydrogenase and respiratory-chain deficiency causing neuronal energy failure
    evidence:
    - reference: PMID:26000322
      reference_title: "Deficiency of ECHS1 causes mitochondrial encephalopathy with cardiac involvement."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Serum lactate was elevated and brain magnetic resonance imaging showed
        white matter changes or a Leigh-like pattern resembling disorders of
        mitochondrial energy metabolism.
      explanation: >-
        Links the bioenergetic defect to Leigh-like brain imaging patterns.
- name: Leigh-like basal ganglia neurodegeneration
  description: >
    The convergent bioenergetic and toxic insult manifests as bilateral
    symmetric basal ganglia (especially putaminal) degeneration with
    necrotizing/cavitating lesions, the neuropathological substrate of the
    Leigh-syndrome phenotype and its motor and developmental sequelae.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  locations:
  - preferred_term: putamen
    term:
      id: UBERON:0001874
      label: putamen
  - preferred_term: basal ganglion
    term:
      id: UBERON:0002420
      label: basal ganglion
  evidence:
  - reference: PMID:26081110
    reference_title: "Clinical and biochemical characterization of four patients with mutations in ECHS1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients presented with lactic acidosis. The first two patients
      presented with vacuolating leukoencephalopathy and basal ganglia
      abnormalities.
    explanation: >-
      Documents basal ganglia abnormalities and lactic acidosis in ECHS1
      deficiency patients.
  - reference: PMID:36064416
    reference_title: "Clinical improvements after treatment with a low-valine and low-fat diet in a pediatric patient with enoyl-CoA hydratase, short chain 1 (ECHS1) deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The Leigh syndrome phenotype is the most frequently reported form of the
      disease.
    explanation: >-
      Confirms Leigh syndrome as the predominant clinical phenotype of ECHS1
      deficiency.
  downstream:
  - target: Dystonia
    description: Basal ganglia degeneration produces dystonia, a hallmark motor feature.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:36064416
      reference_title: "Clinical improvements after treatment with a low-valine and low-fat diet in a pediatric patient with enoyl-CoA hydratase, short chain 1 (ECHS1) deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        He presented severe dystonia, hyperlordosis, moderate to severe
        kyphoscoliosis, great difficulty in walking, and severe dysarthria.
      explanation: >-
        Documents severe dystonia as a presenting feature of ECHS1 deficiency.
  - target: Developmental regression
    description: >-
      Progressive basal ganglia and white-matter injury manifests as
      developmental delay and regression.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Progressive neuronal loss in basal ganglia and associated structures
    evidence:
    - reference: PMID:25393721
      reference_title: "ECHS1 mutations cause combined respiratory chain deficiency resulting in Leigh syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The patient presented with hypotonia, metabolic acidosis, and
        developmental delay. A combined respiratory chain deficiency was also
        observed.
      explanation: >-
        Documents developmental delay accompanying the metabolic and
        respiratory-chain defect.
phenotypes:
- name: Bilateral basal ganglia lesions
  frequency: FREQUENT
  description: >
    Bilateral symmetric basal ganglia (especially putaminal) lesions on brain
    MRI, the Leigh / Leigh-like imaging hallmark of the disorder.
  phenotype_term:
    preferred_term: Bilateral basal ganglia lesions
    term:
      id: HP:0007146
      label: Bilateral basal ganglia lesions
  evidence:
  - reference: PMID:26000322
    reference_title: "Deficiency of ECHS1 causes mitochondrial encephalopathy with cardiac involvement."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Serum lactate was elevated and brain magnetic resonance imaging showed
      white matter changes or a Leigh-like pattern resembling disorders of
      mitochondrial energy metabolism.
    explanation: >-
      Documents Leigh-like brain MRI patterns characteristic of the disorder.
  - reference: PMID:26081110
    reference_title: "Clinical and biochemical characterization of four patients with mutations in ECHS1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The first two patients presented with vacuolating leukoencephalopathy and
      basal ganglia abnormalities.
    explanation: >-
      Documents basal ganglia abnormalities in ECHS1-deficient patients.
- name: Developmental regression
  frequency: FREQUENT
  description: >
    Developmental delay or loss of previously acquired milestones as the
    encephalopathy progresses.
  phenotype_term:
    preferred_term: Developmental regression
    term:
      id: HP:0002376
      label: Developmental regression
  evidence:
  - reference: PMID:25393721
    reference_title: "ECHS1 mutations cause combined respiratory chain deficiency resulting in Leigh syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient presented with hypotonia, metabolic acidosis, and
      developmental delay.
    explanation: >-
      Documents developmental delay as a presenting feature.
- name: Dystonia
  frequency: FREQUENT
  description: >
    Dystonia arising from basal ganglia degeneration; a hallmark movement
    disorder and a target of dietary therapy.
  phenotype_term:
    preferred_term: Dystonia
    term:
      id: HP:0001332
      label: Dystonia
  evidence:
  - reference: PMID:36064416
    reference_title: "Clinical improvements after treatment with a low-valine and low-fat diet in a pediatric patient with enoyl-CoA hydratase, short chain 1 (ECHS1) deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He presented severe dystonia, hyperlordosis, moderate to severe
      kyphoscoliosis, great difficulty in walking, and severe dysarthria.
    explanation: >-
      Documents severe dystonia as a presenting feature of ECHS1 deficiency.
- name: Generalized hypotonia
  frequency: FREQUENT
  description: >
    Central hypotonia is a common early feature of the infantile
    encephalopathy.
  phenotype_term:
    preferred_term: Generalized hypotonia
    term:
      id: HP:0001290
      label: Generalized hypotonia
  evidence:
  - reference: PMID:25393721
    reference_title: "ECHS1 mutations cause combined respiratory chain deficiency resulting in Leigh syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient presented with hypotonia, metabolic acidosis, and
      developmental delay.
    explanation: >-
      Documents hypotonia as a presenting feature.
- name: Lactic acidosis
  frequency: FREQUENT
  description: >
    Elevated lactate with metabolic acidosis reflects the secondary
    bioenergetic (PDH and respiratory-chain) dysfunction.
  phenotype_term:
    preferred_term: Lactic acidosis
    term:
      id: HP:0003128
      label: Lactic acidosis
  evidence:
  - reference: PMID:26081110
    reference_title: "Clinical and biochemical characterization of four patients with mutations in ECHS1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients presented with lactic acidosis.
    explanation: >-
      Documents lactic acidosis in all patients of the case series.
- name: Sensorineural hearing impairment
  frequency: FREQUENT
  description: >
    Sensorineural deafness is a frequent feature and was present in nearly all
    tested patients in the initial cohort.
  phenotype_term:
    preferred_term: Sensorineural hearing impairment
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
  evidence:
  - reference: PMID:26000322
    reference_title: "Deficiency of ECHS1 causes mitochondrial encephalopathy with cardiac involvement."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The most prominent clinical features were encephalopathy (10/10), deafness
      (9/9), epilepsy (6/9), optic atrophy (6/10), and cardiomyopathy (4/10).
    explanation: >-
      Documents deafness in 9/9 tested patients as one of the most prominent
      features.
- name: Optic atrophy
  frequency: OCCASIONAL
  description: >
    Optic atrophy occurs in a substantial subset of patients.
  phenotype_term:
    preferred_term: Optic atrophy
    term:
      id: HP:0000648
      label: Optic atrophy
  evidence:
  - reference: PMID:26000322
    reference_title: "Deficiency of ECHS1 causes mitochondrial encephalopathy with cardiac involvement."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The most prominent clinical features were encephalopathy (10/10), deafness
      (9/9), epilepsy (6/9), optic atrophy (6/10), and cardiomyopathy (4/10).
    explanation: >-
      Documents optic atrophy in 6/10 patients.
- name: Seizure
  frequency: OCCASIONAL
  description: >
    Epilepsy/seizures occur in a subset of patients, sometimes with neonatal
    onset.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:26000322
    reference_title: "Deficiency of ECHS1 causes mitochondrial encephalopathy with cardiac involvement."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The most prominent clinical features were encephalopathy (10/10), deafness
      (9/9), epilepsy (6/9), optic atrophy (6/10), and cardiomyopathy (4/10).
    explanation: >-
      Documents epilepsy in 6/9 patients.
- name: Cardiomyopathy
  frequency: OCCASIONAL
  description: >
    Hypertrophic or dilated cardiomyopathy occurs in a subset, and can dominate
    the severe neonatal presentation.
  phenotype_term:
    preferred_term: Cardiomyopathy
    term:
      id: HP:0001638
      label: Cardiomyopathy
  evidence:
  - reference: PMID:26000322
    reference_title: "Deficiency of ECHS1 causes mitochondrial encephalopathy with cardiac involvement."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The most prominent clinical features were encephalopathy (10/10), deafness
      (9/9), epilepsy (6/9), optic atrophy (6/10), and cardiomyopathy (4/10).
    explanation: >-
      Documents cardiomyopathy in 4/10 patients.
biochemical:
- name: Blood lactate
  presence: INCREASED
  context: >
    Elevated blood (and CSF) lactate is a characteristic biochemical finding,
    reflecting secondary pyruvate dehydrogenase and respiratory-chain
    dysfunction rather than a primary fatty-acid oxidation block.
  biomarker_term:
    preferred_term: lactate
    term:
      id: CHEBI:24996
      label: lactate
  readouts:
  - target: Reactive-metabolite mitochondrial and pyruvate dehydrogenase toxicity
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Elevated lactate reports the secondary bioenergetic (PDH and
      respiratory-chain) dysfunction downstream of the enzyme defect.
    evidence:
    - reference: PMID:26000322
      reference_title: "Deficiency of ECHS1 causes mitochondrial encephalopathy with cardiac involvement."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Serum lactate was elevated and brain magnetic resonance imaging showed
        white matter changes or a Leigh-like pattern resembling disorders of
        mitochondrial energy metabolism.
      explanation: >-
        Documents elevated serum lactate as a readout of mitochondrial energy
        dysfunction.
  evidence:
  - reference: PMID:26081110
    reference_title: "Clinical and biochemical characterization of four patients with mutations in ECHS1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients presented with lactic acidosis.
    explanation: >-
      All patients in the case series had lactic acidosis (elevated lactate).
- name: Serum acylcarnitine profile
  presence: NORMAL
  context: >
    In contrast to classical fatty-acid oxidation disorders, routine serum
    acylcarnitine profiles are usually normal in ECHS1 deficiency; the
    fatty-acid oxidation defect is only unmasked by in vitro palmitate loading
    (increased butyrylcarnitine), consistent with largely preserved
    fatty-acid oxidation flux.
  biomarker_term:
    preferred_term: acylcarnitine
    term:
      id: CHEBI:75659
      label: O-acyl-L-carnitine
  evidence:
  - reference: PMID:26000322
    reference_title: "Deficiency of ECHS1 causes mitochondrial encephalopathy with cardiac involvement."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      While serum acylcarnitine profiles were largely normal, in vitro palmitate
      loading of patient fibroblasts revealed increased butyrylcarnitine,
      unmasking the functional defect in mitochondrial β-oxidation of
      short-chain fatty acids.
    explanation: >-
      Documents largely normal routine acylcarnitines with the FAO defect only
      unmasked by palmitate loading.
genetic:
- name: ECHS1 gene variants
  gene_term:
    preferred_term: ECHS1
    term:
      id: hgnc:3151
      label: ECHS1
  inheritance:
  - name: Autosomal recessive
    evidence:
    - reference: PMID:26000322
      reference_title: "Deficiency of ECHS1 causes mitochondrial encephalopathy with cardiac involvement."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Here, we describe the broad phenotypic spectrum and pathobiochemistry of
        individuals with autosomal-recessive ECHS1 deficiency.
      explanation: >-
        States autosomal-recessive inheritance of ECHS1 deficiency.
  features: >
    ECHS1 deficiency results from biallelic (homozygous or compound
    heterozygous) pathogenic variants in ECHS1. A broad allelic spectrum has
    been reported, with several recurrent missense variants; genotype only
    loosely predicts phenotype, which ranges from fatal neonatal disease to
    survival into adulthood.
  evidence:
  - reference: PMID:25125611
    reference_title: "ECHS1 mutations in Leigh disease: a new inborn error of metabolism affecting valine metabolism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Both children were compound heterozygous for a c.473C > A (p.A158D)
      missense mutation and a c.414+3G>C splicing mutation in ECHS1.
    explanation: >-
      Documents compound heterozygous ECHS1 variants in the index siblings.
treatments:
- name: Valine- and fat-restricted diet
  description: >
    Because the neurotoxicity is attributed to accumulation of valine-pathway
    intermediates (methacrylyl-CoA and acryloyl-CoA), a valine-restricted (and
    fat-restricted) diet is being explored as a mechanism-directed,
    investigational therapy aimed at reducing production of the toxic
    metabolites. Reported outcomes are variable; in one pediatric case a
    valine- and fat-restricted diet was associated with improvement in dystonia
    and appeared to limit disease progression, but evidence remains limited to
    small case reports.
  treatment_term:
    preferred_term: dietary intervention
    term:
      id: MAXO:0000088
      label: dietary intervention
    dietary_modifications:
    - action: RESTRICT
      description: Restriction of dietary valine (and branched-chain amino acids) to reduce toxic valine-pathway metabolite production.
    - action: RESTRICT
      description: Restriction of total and dairy fat intake as an adjunct in the reported regimen.
  evidence:
  - reference: PMID:36064416
    reference_title: "Clinical improvements after treatment with a low-valine and low-fat diet in a pediatric patient with enoyl-CoA hydratase, short chain 1 (ECHS1) deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A valine-restricted and total fat-restricted diet was considered as a
      therapeutic option after the genetic diagnosis.
    explanation: >-
      Documents the valine- and fat-restricted diet as a therapeutic approach
      in ECHS1 deficiency.
  - reference: PMID:36064416
    reference_title: "Clinical improvements after treatment with a low-valine and low-fat diet in a pediatric patient with enoyl-CoA hydratase, short chain 1 (ECHS1) deficiency."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      After three years, the patient noticed an improvement in dystonia,
      especially in walking.
    explanation: >-
      Single-case improvement in dystonia after dietary therapy; supports an
      investigational benefit while highlighting the limited evidence base.
notes: >
  Framing note: ECHS1 is included among fatty-acid beta-oxidation-spiral
  enzymes (it catalyzes the second, hydration step of the spiral), which is why
  it appears in beta-oxidation sweeps. However, functional studies indicate
  that ECHS1/SCEH is only of limited importance for mitochondrial fatty-acid
  oxidation flux (palmitate loading of patient fibroblasts is typically normal
  and routine serum acylcarnitines are usually unremarkable), while it is
  crucial for valine catabolism. The prevailing pathomechanistic model is that
  disease is driven mainly by accumulation of the toxic, highly reactive
  valine-pathway intermediates methacrylyl-CoA and acryloyl-CoA — which react
  with sulfhydryl groups and impair the pyruvate dehydrogenase complex and
  respiratory chain — producing a Leigh / Leigh-like basal ganglia
  encephalopathy, rather than by impaired fatty-acid oxidation.
datasets:
- accession: geo:GSE200252
  title: "Loss of Mitochondrial Fatty Acid Beta-Oxidation Protein Short Chain Enoyl-CoA Hydratase Disrupts Oxidative Phosphorylation Protein Complex Stability and Function"
  description: "Bulk RNA-seq of ECHS1-null human cells and patient fibroblasts showing secondary disruption of the TCA cycle, mitophagy, nucleotide synthesis, and OXPHOS complexes I and IV — evidence for the secondary mitochondrial/OXPHOS destabilization underlying the Leigh-like phenotype."
  data_type: BULK_RNA_SEQ
  publication: PMID:35962613
  notes: "Organism: human (CRISPR-edited cells and patient fibroblasts). NCBI GEO."
- accession: pride:PXD032761
  title: "Loss of Mitochondrial Fatty Acid beta-Oxidation Protein Short Chain Enoyl-CoA Hydratase Disrupts Oxidative Phosphorylation Protein Complex Stability and Function"
  description: "Proteomics companion to GSE200252 showing that ECHS1 loss compromises OXPHOS complex stability, especially complex I, supporting the secondary-mitochondrial mechanism of ECHS1 deficiency."
  data_type: PROTEOMICS
  publication: PMID:35962613
  notes: "Organism: human and mouse. PRIDE/ProteomeXchange."
- accession: geo:GSE159039
  title: "Bulk RNA-seq analysis of the effects of ECHS1 knockdown on cardiomyocyte transcriptome"
  description: "Bulk RNA-seq of ECHS1-knockdown versus control neonatal cardiomyocytes, linking ECHS1 loss to altered histone crotonylation — an example of acyl-CoA-driven protein and histone lysine-acylation effects."
  data_type: BULK_RNA_SEQ
  publication: PMID:33683949
  notes: "Organism: rat (Rattus norvegicus), neonatal cardiomyocytes (siECHS1 vs control)."