COX10-Related COX Deficiency

Mendelian MONDO:0033635 Pathograph 3 Mitochondrial Disease Inborn Error of Metabolism

COX10-related COX deficiency (mitochondrial complex IV deficiency nuclear type 3, MC4DN3) is a nuclear form of isolated cytochrome c oxidase (COX, Complex IV) deficiency caused by biallelic variants in COX10, which encodes heme O synthase, the first committed enzyme of the heme A biosynthetic pathway that supplies the heme a cofactor of COX. Loss of COX10 produces a defect in heme A biosynthesis and a range of early-onset phenotypes including Leigh syndrome and multisystem mitochondrial disease. It conforms to the conserved Complex IV assembly deficiency mechanism, with the defect localized to heme A biosynthesis.

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

Pathophysiology

2
COX10 Loss and Defective Heme A Biosynthesis
Biallelic COX10 variants disrupt heme O synthase, the first step of heme A biosynthesis, depriving COX of its heme a cofactor 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 (2 references)
PMID:12928484 SUPPORT In Vitro
"Mutations in COX10 result in a defect in mitochondrial heme A biosynthesis"
Establishes that COX10 variants impair heme A biosynthesis, the step localized in this node.
PMID:38846886 SUPPORT Human Clinical
"This mutation led to a deficiency in COX10, which is a component of mitochondrial complex IV."
Confirms a pathogenic COX10 variant causing Complex IV deficiency in a patient.
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.
neuron link
mitochondrial electron transport, cytochrome c to oxygen link ↓ DECREASED ATP synthesis coupled electron transport link ↓ DECREASED
Downstream
Encephalopathy Energy deficit in the CNS produces Leigh-type encephalopathy.
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 COX10-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 COX10-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

3
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."
Lactic acidosis is a recognized manifestation of COX deficiency.
Musculoskeletal 1
Muscle weakness Muscle weakness (HP:0001324)
Show evidence (1 reference)
PMID:38846886 SUPPORT Human Clinical
"A 3-year-old girl was admitted due to muscle weakness"
Muscle weakness was a presenting feature of COX10-related complex mitochondrial disease.
Nervous System 1
Encephalopathy Encephalopathy (HP:0001298)
Show evidence (1 reference)
PMID:36176336 SUPPORT Human Clinical
"Biallelic COX10 Mutations and PMP22 Deletion in a Family With Leigh Syndrome and Hereditary Neuropathy With Liability to Pressure Palsy."
Documents biallelic COX10 mutations causing Leigh syndrome (the neuropathy in this family was attributable to the co-occurring PMP22 deletion).
🧬

Genetic Associations

1
COX10 pathogenic variants causing MC4DN3
Autosomal recessive
Show evidence (1 reference)
PMID:12928484 SUPPORT In Vitro
"Mutations in COX10 result in a defect in mitochondrial heme A biosynthesis"
Identifies COX10 as a heme A biosynthesis gene whose mutations cause COX deficiency.
💊

Treatments

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

Source YAML

click to show 
name: COX10-Related COX Deficiency
category: Mendelian
creation_date: "2026-05-30T00:00:00Z"
synonyms:
- COX10 deficiency
- Mitochondrial complex IV deficiency, nuclear type 3
- MC4DN3
- COX10-related cytochrome c oxidase deficiency
description: >
  COX10-related COX deficiency (mitochondrial complex IV deficiency nuclear type
  3, MC4DN3) is a nuclear form of isolated cytochrome c oxidase (COX, Complex
  IV) deficiency caused by biallelic variants in COX10, which encodes heme O
  synthase, the first committed enzyme of the heme A biosynthetic pathway that
  supplies the heme a cofactor of COX. Loss of COX10 produces a defect in heme A
  biosynthesis and a range of early-onset phenotypes including Leigh syndrome
  and multisystem mitochondrial disease. It conforms to the conserved Complex IV
  assembly deficiency mechanism, with the defect localized to heme A
  biosynthesis.
disease_term:
  preferred_term: COX10-related COX deficiency (MC4DN3)
  term:
    id: MONDO:0033635
    label: mitochondrial complex IV deficiency, nuclear type 3
parents:
- Mitochondrial Disease
- Inborn Error of Metabolism
pathophysiology:
- name: COX10 Loss and Defective Heme A Biosynthesis
  conforms_to: "complex_iv_assembly_deficiency#Complex IV Biogenesis Failure"
  description: >
    Biallelic COX10 variants disrupt heme O synthase, the first step of heme A
    biosynthesis, depriving COX of its heme a cofactor 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:12928484
    reference_title: "Mutations in COX10 result in a defect in mitochondrial heme A biosynthesis and account for multiple, early-onset clinical phenotypes."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Mutations in COX10 result in a defect in mitochondrial heme A biosynthesis
    explanation: Establishes that COX10 variants impair heme A biosynthesis, the step localized in this node.
  - reference: PMID:38846886
    reference_title: "Complex mitochondrial disease caused by the mutation of COX10 in a toddler: a case-report study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: This mutation led to a deficiency in COX10, which is a component of mitochondrial complex IV.
    explanation: Confirms a pathogenic COX10 variant causing Complex IV deficiency in a patient.
  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.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  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 COX10-related COX deficiency.
  downstream:
  - target: Encephalopathy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Energy deficit in the CNS produces Leigh-type encephalopathy.
phenotypes:
- name: Encephalopathy
  description: Leigh syndrome / progressive encephalopathy due to COX10-related COX deficiency.
  phenotype_term:
    preferred_term: Encephalopathy
    term:
      id: HP:0001298
      label: Encephalopathy
  evidence:
  - reference: PMID:36176336
    reference_title: "Biallelic COX10 Mutations and PMP22 Deletion in a Family With Leigh Syndrome and Hereditary Neuropathy With Liability to Pressure Palsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Biallelic COX10 Mutations and PMP22 Deletion in a Family With Leigh Syndrome and Hereditary Neuropathy With Liability to Pressure Palsy.
    explanation: Documents biallelic COX10 mutations causing Leigh syndrome (the neuropathy in this family was attributable to the co-occurring PMP22 deletion).
- name: Muscle weakness
  description: Muscle weakness, a presenting feature in a COX10-deficient toddler.
  phenotype_term:
    preferred_term: Muscle weakness
    term:
      id: HP:0001324
      label: Muscle weakness
  evidence:
  - reference: PMID:38846886
    reference_title: "Complex mitochondrial disease caused by the mutation of COX10 in a toddler: a case-report study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: A 3-year-old girl was admitted due to muscle weakness
    explanation: Muscle weakness was a presenting feature of COX10-related complex mitochondrial disease.
- 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: Lactic acidosis is a recognized manifestation of COX deficiency.
genetic:
- name: COX10 pathogenic variants causing MC4DN3
  gene_term:
    preferred_term: COX10
    term:
      id: hgnc:2260
      label: COX10
  inheritance:
  - name: Autosomal recessive
    evidence:
    - reference: PMID:36176336
      reference_title: "Biallelic COX10 Mutations and PMP22 Deletion in a Family With Leigh Syndrome and Hereditary Neuropathy With Liability to Pressure Palsy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: caused by biallelic COX10 mutations coexisting with HNPP caused by heterozygous PMP22 deletion
      explanation: Leigh syndrome in this family was caused by biallelic COX10 mutations (autosomal recessive); the co-occurring neuropathy was attributable to a separate heterozygous PMP22 deletion.
  features: >
    Biallelic COX10 (heme O synthase) variants impair heme A biosynthesis,
    causing isolated COX deficiency with Leigh syndrome and multisystem disease.
  evidence:
  - reference: PMID:12928484
    reference_title: "Mutations in COX10 result in a defect in mitochondrial heme A biosynthesis and account for multiple, early-onset clinical phenotypes."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Mutations in COX10 result in a defect in mitochondrial heme A biosynthesis
    explanation: Identifies COX10 as a heme A biosynthesis gene whose mutations cause COX deficiency.
treatments:
- name: Supportive and Metabolic Care
  description: >
    No curative therapy; supportive management of encephalopathy, lactic
    acidosis, and metabolic decompensation.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care