COX15-Related COX Deficiency

Mendelian MONDO:0014051 Pathograph 3 Mitochondrial Disease Inborn Error of Metabolism

COX15-related COX deficiency is a nuclear form of isolated cytochrome c oxidase (COX, Complex IV) deficiency caused by biallelic variants in COX15, which encodes heme A synthase, the final enzyme of heme A biosynthesis that generates the heme a prosthetic group of COX. Loss of COX15 produces a defect in heme A biosynthesis and classically causes early-onset fatal hypertrophic cardiomyopathy; Leigh syndrome has also been reported. It conforms to the conserved Complex IV assembly deficiency mechanism, with the defect localized to heme A biosynthesis and dominant cardiac involvement.

Ask OpenScientist

Ask a research question about COX15-Related COX Deficiency. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).

Submitting...

Do not include personal health information in your question. Questions and results are cached in your browser's local storage.

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

Pathophysiology

2
COX15 Loss and Defective Heme A Biosynthesis
Biallelic COX15 variants disrupt heme A synthase, the final step of heme A biosynthesis, depriving COX of its heme a prosthetic group and preventing assembly of a functional holoenzyme.
heme A biosynthetic process link ↓ DECREASED mitochondrial respiratory chain complex IV assembly link ↓ DECREASED
Downstream
Impaired Terminal Electron Transfer and ATP Synthesis Loss of the heme a cofactor yields a catalytically inactive enzyme.
Show evidence (1 reference)
PMID:12474143 SUPPORT In Vitro
"COX15, a protein involved in the synthesis of heme A, the heme prosthetic group for COX, can functionally complement the isolated COX deficiency"
Establishes COX15 as a heme A synthesis protein whose loss causes isolated COX deficiency, rescued by complementation.
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 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 early-onset 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 function lost in COX15-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 COX15-Related COX 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

2
Cardiovascular 1
Hypertrophic cardiomyopathy Hypertrophic cardiomyopathy (HP:0001639)
Show evidence (1 reference)
PMID:12474143 SUPPORT Human Clinical
"Mutations in COX15 produce a defect in the mitochondrial heme biosynthetic pathway, causing early-onset fatal hypertrophic cardiomyopathy."
COX15 mutations cause early-onset fatal hypertrophic cardiomyopathy.
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."
Hypertrophic cardiomyopathy and fatal lactic acidosis are recognized manifestations of COX deficiency.
🧬

Genetic Associations

1
COX15 pathogenic variants causing COX deficiency
Autosomal recessive
Show evidence (1 reference)
PMID:12474143 SUPPORT Human Clinical
"Mutations in COX15 produce a defect in the mitochondrial heme biosynthetic pathway, causing early-onset fatal hypertrophic cardiomyopathy."
Identifies COX15 as a heme A biosynthesis gene whose mutations cause COX deficiency with hypertrophic cardiomyopathy.
💊

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: COX15-Related COX Deficiency
category: Mendelian
creation_date: "2026-05-30T00:00:00Z"
synonyms:
- COX15 deficiency
- Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 2
- COX15-related cytochrome c oxidase deficiency
description: >
  COX15-related COX deficiency is a nuclear form of isolated cytochrome c
  oxidase (COX, Complex IV) deficiency caused by biallelic variants in COX15,
  which encodes heme A synthase, the final enzyme of heme A biosynthesis that
  generates the heme a prosthetic group of COX. Loss of COX15 produces a defect
  in heme A biosynthesis and classically causes early-onset fatal hypertrophic
  cardiomyopathy; Leigh syndrome has also been reported. It conforms to the
  conserved Complex IV assembly deficiency mechanism, with the defect localized
  to heme A biosynthesis and dominant cardiac involvement.
disease_term:
  preferred_term: COX15-related fatal infantile hypertrophic cardiomyopathy
  term:
    id: MONDO:0014051
    label: cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 2
parents:
- Mitochondrial Disease
- Inborn Error of Metabolism
pathophysiology:
- name: COX15 Loss and Defective Heme A Biosynthesis
  conforms_to: "complex_iv_assembly_deficiency#Complex IV Biogenesis Failure"
  description: >
    Biallelic COX15 variants disrupt heme A synthase, the final step of heme A
    biosynthesis, depriving COX of its heme a prosthetic group and preventing
    assembly of a functional holoenzyme.
  biological_processes:
  - preferred_term: heme A biosynthetic process
    term:
      id: GO:0006784
      label: heme A biosynthetic process
    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:12474143
    reference_title: "Mutations in COX15 produce a defect in the mitochondrial heme biosynthetic pathway, causing early-onset fatal hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: COX15, a protein involved in the synthesis of heme A, the heme prosthetic group for COX, can functionally complement the isolated COX deficiency
    explanation: Establishes COX15 as a heme A synthesis protein whose loss causes isolated COX deficiency, rescued by complementation.
  downstream:
  - target: Impaired Terminal Electron Transfer and ATP Synthesis
    causal_link_type: DIRECT
    description: Loss of the heme a cofactor 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 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 function lost in COX15-related COX deficiency.
  downstream:
  - target: Hypertrophic cardiomyopathy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Energy failure in cardiomyocytes drives early-onset hypertrophic cardiomyopathy.
phenotypes:
- name: Hypertrophic cardiomyopathy
  description: Early-onset fatal hypertrophic cardiomyopathy, the classic COX15 phenotype.
  phenotype_term:
    preferred_term: Hypertrophic cardiomyopathy
    term:
      id: HP:0001639
      label: Hypertrophic cardiomyopathy
  evidence:
  - reference: PMID:12474143
    reference_title: "Mutations in COX15 produce a defect in the mitochondrial heme biosynthetic pathway, causing early-onset fatal hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Mutations in COX15 produce a defect in the mitochondrial heme biosynthetic pathway, causing early-onset fatal hypertrophic cardiomyopathy.
    explanation: COX15 mutations cause early-onset fatal hypertrophic cardiomyopathy.
- 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: Hypertrophic cardiomyopathy and fatal lactic acidosis are recognized manifestations of COX deficiency.
genetic:
- name: COX15 pathogenic variants causing COX deficiency
  gene_term:
    preferred_term: COX15
    term:
      id: hgnc:2263
      label: COX15
  inheritance:
  - name: Autosomal recessive
    evidence:
    - reference: PMID:12474143
      reference_title: "Mutations in COX15 produce a defect in the mitochondrial heme biosynthetic pathway, causing early-onset fatal hypertrophic cardiomyopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: a splice-site mutation in intron 3 on the other allele
      explanation: The patient carried a missense variant on one allele and a splice-site variant on the other (compound heterozygous), indicating autosomal recessive inheritance.
  features: >
    Biallelic COX15 (heme A synthase) variants impair heme A biosynthesis,
    causing isolated COX deficiency with early-onset fatal hypertrophic
    cardiomyopathy and, in some patients, Leigh syndrome.
  evidence:
  - reference: PMID:12474143
    reference_title: "Mutations in COX15 produce a defect in the mitochondrial heme biosynthetic pathway, causing early-onset fatal hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Mutations in COX15 produce a defect in the mitochondrial heme biosynthetic pathway, causing early-onset fatal hypertrophic cardiomyopathy.
    explanation: Identifies COX15 as a heme A biosynthesis gene whose mutations cause COX deficiency with hypertrophic cardiomyopathy.
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