SCO2-Related Fatal Infantile Cardioencephalomyopathy

Mendelian MONDO:0011451 Pathograph 3 Mitochondrial Disease Inborn Error of Metabolism

SCO2-related fatal infantile cardioencephalomyopathy is a nuclear form of isolated cytochrome c oxidase (COX, Complex IV) deficiency caused by biallelic variants in SCO2, a copper-delivery metallochaperone required to assemble the CuA center of COX. Affected infants present with hypertrophic cardiomyopathy, encephalopathy, hypotonia, and lactic acidosis, and typically die in infancy. The disorder conforms to the conserved Complex IV assembly deficiency mechanism, with the assembly defect localized to copper delivery and the dominant tissue involvement being cardiac.

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2
Pathophys.
3
Phenotypes
3
Pathograph
1
Genes
1
Treatments
⚙

Pathophysiology

2
SCO2 Loss and Defective Copper Delivery to COX
Biallelic SCO2 variants impair copper delivery to the CuA center of COX2, preventing assembly of a catalytically competent Complex IV holoenzyme.
copper ion transport link ↓ DECREASED mitochondrial respiratory chain complex IV assembly link ↓ DECREASED
Downstream
Impaired Terminal Electron Transfer and ATP Synthesis Failure of CuA assembly yields a catalytically inactive enzyme.
Show evidence (1 reference)
PMID:10545952 SUPPORT Human Clinical
"we have identified mutations in the human homologue, SCO2, in three unrelated infants with a newly recognized fatal cardioencephalomyopathy and COX deficiency."
Original identification of SCO2 mutations as the cause of fatal infantile cardioencephalomyopathy with COX deficiency.
Impaired Terminal Electron Transfer and ATP Synthesis
Loss of functional COX blocks electron transfer from cytochrome c to oxygen and proton pumping, collapsing oxidative ATP synthesis, with greatest impact on cardiac and skeletal muscle.
cardiac muscle cell link
mitochondrial electron transport, cytochrome c to oxygen link ↓ DECREASED ATP synthesis coupled electron transport link ↓ DECREASED
Downstream
Hypertrophic cardiomyopathy Energy failure in cardiomyocytes drives hypertrophic cardiomyopathy.
Show evidence (1 reference)
PMID:10545952 SUPPORT Human Clinical
"Mammalian cytochrome c oxidase (COX) catalyses the transfer of reducing equivalents from cytochrome c to molecular oxygen and pumps protons across the inner mitochondrial membrane."
Defines the terminal electron-transfer and proton-pumping function lost in SCO2-related COX deficiency.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for SCO2-Related Fatal Infantile Cardioencephalomyopathy 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

3
Cardiovascular 1
Hypertrophic cardiomyopathy Hypertrophic cardiomyopathy (HP:0001639)
Show evidence (1 reference)
PMID:10545952 SUPPORT Human Clinical
"we have identified mutations in the human homologue, SCO2, in three unrelated infants with a newly recognized fatal cardioencephalomyopathy and COX deficiency."
SCO2 mutations cause fatal infantile cardioencephalomyopathy, of which hypertrophic cardiomyopathy is the cardinal feature.
Metabolism 1
Lactic acidosis Lactic acidosis (HP:0003128)
Show evidence (1 reference)
PMID:19682572 SUPPORT Other
"Human diseases associated with COX deficiency including encephalomyopathies, Leigh syndrome, hypertrophic cardiomyopathies, and fatal lactic acidosis are caused by mutations in COX subunits or assembly factors."
Fatal lactic acidosis and hypertrophic cardiomyopathy are recognized manifestations of COX deficiency.
Nervous System 1
Encephalopathy Encephalopathy (HP:0001298)
Show evidence (1 reference)
PMID:10545952 SUPPORT Human Clinical
"we have identified mutations in the human homologue, SCO2, in three unrelated infants with a newly recognized fatal cardioencephalomyopathy and COX deficiency."
The cardioencephalomyopathy phenotype includes encephalopathy.
🧬

Genetic Associations

1
SCO2 pathogenic variants causing cardioencephalomyopathy
Autosomal recessive
Show evidence (1 reference)
PMID:10545952 SUPPORT Human Clinical
"The clinical phenotype caused by mutations in human SCO2 differs from that caused by mutations in SURF1, the only other known COX assembly gene associated with a human disease, Leigh syndrome."
Establishes SCO2 as a distinct COX assembly gene with a cardioencephalomyopathy phenotype distinct from SURF1.
💊

Treatments

1
Supportive and Metabolic Care
Action: supportive care MAXO:0000950
No curative therapy; supportive management of cardiomyopathy, lactic acidosis, and metabolic decompensation.
{ }

Source YAML

click to show 
name: SCO2-Related Fatal Infantile Cardioencephalomyopathy
category: Mendelian
creation_date: "2026-05-30T00:00:00Z"
synonyms:
- SCO2 deficiency
- Fatal infantile cardioencephalomyopathy due to cytochrome c oxidase deficiency 1
- Cardioencephalomyopathy, fatal infantile, due to COX deficiency, SCO2-related
description: >
  SCO2-related fatal infantile cardioencephalomyopathy is a nuclear form of
  isolated cytochrome c oxidase (COX, Complex IV) deficiency caused by biallelic
  variants in SCO2, a copper-delivery metallochaperone required to assemble the
  CuA center of COX. Affected infants present with hypertrophic cardiomyopathy,
  encephalopathy, hypotonia, and lactic acidosis, and typically die in infancy.
  The disorder conforms to the conserved Complex IV assembly deficiency
  mechanism, with the assembly defect localized to copper delivery and the
  dominant tissue involvement being cardiac.
disease_term:
  preferred_term: SCO2-related fatal infantile cardioencephalomyopathy
  term:
    id: MONDO:0011451
    label: cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 1
parents:
- Mitochondrial Disease
- Inborn Error of Metabolism
pathophysiology:
- name: SCO2 Loss and Defective Copper Delivery to COX
  conforms_to: "complex_iv_assembly_deficiency#Complex IV Biogenesis Failure"
  description: >
    Biallelic SCO2 variants impair copper delivery to the CuA center of COX2,
    preventing assembly of a catalytically competent Complex IV holoenzyme.
  biological_processes:
  - preferred_term: copper ion transport
    term:
      id: GO:0006825
      label: copper ion transport
    modifier: DECREASED
  - preferred_term: mitochondrial respiratory chain complex IV assembly
    term:
      id: GO:0033617
      label: mitochondrial respiratory chain complex IV assembly
    modifier: DECREASED
  evidence:
  - reference: PMID:10545952
    reference_title: "Fatal infantile cardioencephalomyopathy with COX deficiency and mutations in SCO2, a COX assembly gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: we have identified mutations in the human homologue, SCO2, in three unrelated infants with a newly recognized fatal cardioencephalomyopathy and COX deficiency.
    explanation: Original identification of SCO2 mutations as the cause of fatal infantile cardioencephalomyopathy with COX deficiency.
  downstream:
  - target: Impaired Terminal Electron Transfer and ATP Synthesis
    causal_link_type: DIRECT
    description: Failure of CuA assembly yields a catalytically inactive enzyme.
- name: Impaired Terminal Electron Transfer and ATP Synthesis
  conforms_to: "complex_iv_assembly_deficiency#Impaired Terminal Electron Transfer and ATP Synthesis"
  description: >
    Loss of functional COX blocks electron transfer from cytochrome c to oxygen
    and proton pumping, collapsing oxidative ATP synthesis, with greatest impact
    on cardiac and skeletal muscle.
  cell_types:
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: mitochondrial electron transport, cytochrome c to oxygen
    term:
      id: GO:0006123
      label: mitochondrial electron transport, cytochrome c to oxygen
    modifier: DECREASED
  - preferred_term: ATP synthesis coupled electron transport
    term:
      id: GO:0042775
      label: mitochondrial ATP synthesis coupled electron transport
    modifier: DECREASED
  evidence:
  - reference: PMID:10545952
    reference_title: "Fatal infantile cardioencephalomyopathy with COX deficiency and mutations in SCO2, a COX assembly gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Mammalian cytochrome c oxidase (COX) catalyses the transfer of reducing equivalents from cytochrome c to molecular oxygen and pumps protons across the inner mitochondrial membrane.
    explanation: Defines the terminal electron-transfer and proton-pumping function lost in SCO2-related COX deficiency.
  downstream:
  - target: Hypertrophic cardiomyopathy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Energy failure in cardiomyocytes drives hypertrophic cardiomyopathy.
phenotypes:
- name: Hypertrophic cardiomyopathy
  description: Cardiac hypertrophy, the hallmark feature of SCO2-related disease.
  phenotype_term:
    preferred_term: Hypertrophic cardiomyopathy
    term:
      id: HP:0001639
      label: Hypertrophic cardiomyopathy
  evidence:
  - reference: PMID:10545952
    reference_title: "Fatal infantile cardioencephalomyopathy with COX deficiency and mutations in SCO2, a COX assembly gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: we have identified mutations in the human homologue, SCO2, in three unrelated infants with a newly recognized fatal cardioencephalomyopathy and COX deficiency.
    explanation: SCO2 mutations cause fatal infantile cardioencephalomyopathy, of which hypertrophic cardiomyopathy is the cardinal feature.
- name: Encephalopathy
  description: Encephalopathy as part of the cardioencephalomyopathy phenotype.
  phenotype_term:
    preferred_term: Encephalopathy
    term:
      id: HP:0001298
      label: Encephalopathy
  evidence:
  - reference: PMID:10545952
    reference_title: "Fatal infantile cardioencephalomyopathy with COX deficiency and mutations in SCO2, a COX assembly gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: we have identified mutations in the human homologue, SCO2, in three unrelated infants with a newly recognized fatal cardioencephalomyopathy and COX deficiency.
    explanation: The cardioencephalomyopathy phenotype includes encephalopathy.
- name: Lactic acidosis
  description: Elevated lactate from impaired oxidative metabolism.
  phenotype_term:
    preferred_term: Lactic acidosis
    term:
      id: HP:0003128
      label: Lactic acidosis
  evidence:
  - reference: PMID:19682572
    reference_title: "Cytochrome c oxidase deficiency: patients and animal models."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Human diseases associated with COX deficiency including encephalomyopathies, Leigh syndrome, hypertrophic cardiomyopathies, and fatal lactic acidosis are caused by mutations in COX subunits or assembly factors.
    explanation: Fatal lactic acidosis and hypertrophic cardiomyopathy are recognized manifestations of COX deficiency.
genetic:
- name: SCO2 pathogenic variants causing cardioencephalomyopathy
  gene_term:
    preferred_term: SCO2
    term:
      id: hgnc:10604
      label: SCO2
  inheritance:
  - name: Autosomal recessive
    evidence:
    - reference: PMID:10749987
      reference_title: "Mutations in SCO2 are associated with a distinct form of hypertrophic cardiomyopathy and cytochrome c oxidase deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: compound heterozygotes for the G1541A mutation
      explanation: Patients are compound heterozygous for SCO2 variants, indicating autosomal recessive inheritance.
  features: >
    Biallelic SCO2 variants impair copper delivery to the COX CuA center,
    causing fatal infantile cardioencephalomyopathy. The clinical phenotype
    differs from that caused by SURF1.
  evidence:
  - reference: PMID:10545952
    reference_title: "Fatal infantile cardioencephalomyopathy with COX deficiency and mutations in SCO2, a COX assembly gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The clinical phenotype caused by mutations in human SCO2 differs from that caused by mutations in SURF1, the only other known COX assembly gene associated with a human disease, Leigh syndrome.
    explanation: Establishes SCO2 as a distinct COX assembly gene with a cardioencephalomyopathy phenotype distinct from SURF1.
treatments:
- name: Supportive and Metabolic Care
  description: >
    No curative therapy; supportive management of cardiomyopathy, lactic
    acidosis, and metabolic decompensation.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care