COX18-Related COX Deficiency

Mendelian MONDO:0980970 Pathograph 7 Show in embeddings browser Mitochondrial Disease Inborn Error of Metabolism

COX18-related COX deficiency is a nuclear form of isolated cytochrome c oxidase (COX, Complex IV) deficiency caused by biallelic variants in COX18, an assembly factor required for maturation and membrane insertion of the mtDNA-encoded subunit COX2 (MT-CO2). Reported in 2023 in a single patient, it presents as a neonatal encephalo-cardio-myopathy with hypertrophic cardiomyopathy, infantile myopathy, axonal sensory neuropathy, and failure to thrive. It conforms to the conserved Complex IV assembly deficiency mechanism, with the defect localized to COX2 maturation.

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2
Pathophys.
4
Phenotypes
7
Pathograph
1
Genes
1
Medical Actions
🏷

Classifications

Harrison's Part
GENETICS ENVIRONMENT DISEASE ENDOCRINOLOGY METABOLISM
Mechanistic Nosology
mitochondrial disease
ICIMD (Inherited Metabolic Disorders)
complex iv subunits and assembly factors
⚙

Pathophysiology

2
COX18 Loss and Defective COX2 Maturation
Biallelic COX18 variants impair maturation and membrane insertion of the mtDNA-encoded COX2 subunit, preventing assembly of a functional Complex IV holoenzyme.
COX18 hgnc:26801 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves COX18 (hgnc:26801). hgnc:26801 is a gene from the HUGO Gene Nomenclature Committee.
mitochondrial respiratory chain complex IV assembly GO:0033617 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased mitochondrial respiratory chain complex IV assembly (GO:0033617). GO:0033617 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Impaired Terminal Electron Transfer and ATP Synthesis Failure to mature COX2 prevents formation of a catalytically competent enzyme.
Show evidence (1 reference)
PMID:37468577 SUPPORT In Vitro
"Biochemical and enzymatic studies in patient's myoblasts and in HEK293 cells after COX18 silencing showed a severe impairment of both COX activity and assembly."
Reports the direct biochemical measurement of impaired COX assembly in cultured patient myoblasts and an independent HEK293 COX18-silencing arm.
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 prominent cardiac, muscle, and peripheral nerve involvement.
cardiac muscle cell CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
mitochondrial electron transport, cytochrome c to oxygen GO:0006123 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased mitochondrial electron transport, cytochrome c to oxygen (GO:0006123). GO:0006123 is a biological process from the Gene Ontology. ↓ DECREASED ATP synthesis coupled electron transport GO:0042775 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased ATP synthesis coupled electron transport, annotated with mitochondrial ATP synthesis coupled electron transport (GO:0042775). GO:0042775 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Hypertrophic cardiomyopathy Energy failure in cardiomyocytes drives hypertrophic cardiomyopathy.
Peripheral neuropathy Bioenergetic deficit in peripheral nerve produces axonal sensory neuropathy.
Encephalopathy Bioenergetic failure in nervous tissue contributes to neonatal encephalopathy in COX18-related disease.
Failure to thrive Severe multisystem energy failure in neonatal COX18-related disease contributes to failure to thrive.
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 COX18-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 COX18-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

4
Cardiovascular 1
Hypertrophic cardiomyopathy HP:0001639 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypertrophic cardiomyopathy (HP:0001639). HP:0001639 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37468577 SUPPORT Human Clinical
"The proband is a 19-months old female displaying hypertrophic cardiomyopathy at birth and myopathy with axonal sensory neuropathy and failure to thrive"
Documents hypertrophic cardiomyopathy at birth in COX18-related disease.
Nervous System 2
Peripheral neuropathy HP:0009830 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Axonal sensory neuropathy, annotated with Peripheral neuropathy (HP:0009830). HP:0009830 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37468577 SUPPORT Human Clinical
"The proband is a 19-months old female displaying hypertrophic cardiomyopathy at birth and myopathy with axonal sensory neuropathy and failure to thrive"
Documents axonal sensory neuropathy in COX18-related disease.
Encephalopathy HP:0001298 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Encephalopathy (HP:0001298). HP:0001298 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37468577 SUPPORT Human Clinical
"The aim of this study is to describe a molecular defect in the COX assembly factor gene COX18 as the likely cause of a neonatal form of mitochondrial encephalo-cardio-myopathy and axonal sensory neuropathy."
Names the encephalopathy component within the compound disease designation the authors attribute to COX18. This is the study's aim statement, not a documented encephalopathy finding — the proband description in the same abstract reports cardiomyopathy, myopathy, axonal sensory neuropathy, and failure to thrive, so support for this specific phenotype rests on the disease name rather than a reported observation.
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:37468577 SUPPORT Human Clinical
"The proband is a 19-months old female displaying hypertrophic cardiomyopathy at birth and myopathy with axonal sensory neuropathy and failure to thrive"
Documents failure to thrive in COX18-related disease.
🧬

Genetic Associations

1
COX18 pathogenic variants causing COX deficiency
Gene: COX18 hgnc:26801 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is COX18 (hgnc:26801). hgnc:26801 is a gene from the HUGO Gene Nomenclature Committee.
Autosomal recessive
Show evidence (1 reference)
PMID:37468577 SUPPORT Human Clinical
"Whole exome sequencing allowed the prioritization of the unreported homozygous substitution NM_001297732.2:c.667 G > C p.(Asp223His) in COX18."
Identifies the specific homozygous COX18 variant establishing COX18 as the causal gene in this disorder.
💊

Medical Actions

1
Supportive and Metabolic Care
Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
No curative therapy; supportive management of cardiomyopathy, neuropathy, feeding difficulties, and metabolic decompensation.
{ }

Source YAML

click to show 
name: COX18-Related COX Deficiency
category: Mendelian
creation_date: "2026-05-30T00:00:00Z"
synonyms:
- COX18 deficiency
- COX18-related cytochrome c oxidase deficiency
- Isolated complex IV deficiency due to COX18
- mitochondrial complex 4 deficiency, nuclear type 25
- MC4DN25
description: >
  COX18-related COX deficiency is a nuclear form of isolated cytochrome c
  oxidase (COX, Complex IV) deficiency caused by biallelic variants in COX18, an
  assembly factor required for maturation and membrane insertion of the
  mtDNA-encoded subunit COX2 (MT-CO2). Reported in 2023 in a single patient, it
  presents as a neonatal encephalo-cardio-myopathy with hypertrophic
  cardiomyopathy, infantile myopathy, axonal sensory neuropathy, and failure to
  thrive. It conforms to the conserved Complex IV assembly deficiency mechanism,
  with the defect localized to COX2 maturation.
disease_term:
  preferred_term: COX18-related COX deficiency (MC4DN25)
  term:
    id: MONDO:0980970
    label: mitochondrial complex 4 deficiency, nuclear type 25
parents:
- Mitochondrial Disease
- Inborn Error of Metabolism
classifications:
  harrisons_chapter:
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    notes: >-
      Mendelian, autosomal recessive nuclear-gene mitochondrial disorder; Harrison's
      covers primary mitochondrial disease under the genetics/environment Part.
  - classification_value: ENDOCRINOLOGY_METABOLISM
    notes: >-
      An inborn error of energy metabolism (isolated respiratory chain Complex IV
      deficiency) presenting with lactic acidosis.
  mechanistic_category:
  - classification_value: mitochondrial disease
    notes: >-
      Nuclear-encoded defect of mitochondrial respiratory chain Complex IV
      biogenesis; a primary mitochondrial disease.
  icimd_category:
  - classification_value: complex_iv_subunits_and_assembly_factors
    notes: >-
      ICIMD (Ferreira et al. 2021, PMID:33340416): group "Nuclear-encoded complex IV
      subunit and assembly factor defects" under category "Disorders of
      nuclear-encoded oxidative phosphorylation". COX18 is a nuclear-encoded COX
      assembly factor required for maturation and membrane insertion of the
      mtDNA-encoded COX2 subunit.
pathophysiology:
- name: COX18 Loss and Defective COX2 Maturation
  conforms_to: "complex_iv_assembly_deficiency#Complex IV Biogenesis Failure"
  description: >
    Biallelic COX18 variants impair maturation and membrane insertion of the
    mtDNA-encoded COX2 subunit, preventing assembly of a functional Complex IV
    holoenzyme.
  genes:
  - preferred_term: COX18
    term:
      id: hgnc:26801
      label: COX18
  biological_processes:
  - preferred_term: mitochondrial respiratory chain complex IV assembly
    term:
      id: GO:0033617
      label: mitochondrial respiratory chain complex IV assembly
    modifier: DECREASED
  evidence:
  - reference: PMID:37468577
    reference_title: "A biallelic variant in COX18 cause isolated Complex IV deficiency associated with neonatal encephalo-cardio-myopathy and axonal sensory neuropathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Biochemical and enzymatic studies in patient's myoblasts and in HEK293 cells after COX18 silencing showed a severe impairment of both COX activity and assembly.
    explanation: Reports the direct biochemical measurement of impaired COX assembly in cultured patient myoblasts and an independent HEK293 COX18-silencing arm.
  downstream:
  - target: Impaired Terminal Electron Transfer and ATP Synthesis
    causal_link_type: DIRECT
    description: Failure to mature COX2 prevents formation of a catalytically competent enzyme.
    evidence:
    - reference: PMID:37468577
      reference_title: "A biallelic variant in COX18 cause isolated Complex IV deficiency associated with neonatal encephalo-cardio-myopathy and axonal sensory neuropathy."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Biochemical and enzymatic studies in patient's myoblasts and in HEK293 cells after COX18 silencing showed a severe impairment of both COX activity and assembly.
      explanation: Loss of COX18 impairs both assembly and catalytic COX activity, linking the biogenesis defect directly to loss of terminal electron transfer.
- 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 prominent
    cardiac, muscle, and peripheral nerve involvement.
  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 COX18-related COX deficiency.
  downstream:
  - target: Hypertrophic cardiomyopathy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Energy failure in cardiomyocytes drives hypertrophic cardiomyopathy.
    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: Review establishes hypertrophic cardiomyopathy as a recognised consequence of COX (Complex IV) deficiency arising from assembly-factor mutations.
  - target: Peripheral neuropathy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Bioenergetic deficit in peripheral nerve produces axonal sensory neuropathy.
    evidence:
    - reference: PMID:37468577
      reference_title: "A biallelic variant in COX18 cause isolated Complex IV deficiency associated with neonatal encephalo-cardio-myopathy and axonal sensory neuropathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The proband is a 19-months old female displaying hypertrophic cardiomyopathy at birth and myopathy with axonal sensory neuropathy and failure to thrive developing in the first months of life.
      explanation: Documents the axonal sensory neuropathy directly as an observed finding in the COX18 proband, rather than as a stated aim of the study.
  - target: Encephalopathy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Bioenergetic failure in nervous tissue contributes to neonatal encephalopathy in COX18-related disease.
    evidence:
    - reference: PMID:37468577
      reference_title: "A biallelic variant in COX18 cause isolated Complex IV deficiency associated with neonatal encephalo-cardio-myopathy and axonal sensory neuropathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Pathogenic variants impacting upon assembly of mitochondrial respiratory chain Complex IV (Cytochrome c Oxidase or COX) predominantly result in early onset mitochondrial disorders often leading to CNS, skeletal and cardiac muscle manifestations.
      explanation: Places CNS manifestations downstream of Complex IV assembly failure, the mechanism operating in COX18-related disease.
  - target: Failure to thrive
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Severe multisystem energy failure in neonatal COX18-related disease contributes to failure to thrive.
    evidence:
    - reference: PMID:37468577
      reference_title: "A biallelic variant in COX18 cause isolated Complex IV deficiency associated with neonatal encephalo-cardio-myopathy and axonal sensory neuropathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The proband is a 19-months old female displaying hypertrophic cardiomyopathy at birth and myopathy with axonal sensory neuropathy and failure to thrive developing in the first months of life.
      explanation: Documents failure to thrive developing alongside the multisystem energy-failure phenotype in the COX18 proband.
phenotypes:
- name: Hypertrophic cardiomyopathy
  description: Hypertrophic cardiomyopathy present at birth.
  phenotype_term:
    preferred_term: Hypertrophic cardiomyopathy
    term:
      id: HP:0001639
      label: Hypertrophic cardiomyopathy
  evidence:
  - reference: PMID:37468577
    reference_title: "A biallelic variant in COX18 cause isolated Complex IV deficiency associated with neonatal encephalo-cardio-myopathy and axonal sensory neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The proband is a 19-months old female displaying hypertrophic cardiomyopathy at birth and myopathy with axonal sensory neuropathy and failure to thrive
    explanation: Documents hypertrophic cardiomyopathy at birth in COX18-related disease.
- name: Peripheral neuropathy
  description: Axonal sensory neuropathy.
  phenotype_term:
    preferred_term: Axonal sensory neuropathy
    term:
      id: HP:0009830
      label: Peripheral neuropathy
  evidence:
  - reference: PMID:37468577
    reference_title: "A biallelic variant in COX18 cause isolated Complex IV deficiency associated with neonatal encephalo-cardio-myopathy and axonal sensory neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The proband is a 19-months old female displaying hypertrophic cardiomyopathy at birth and myopathy with axonal sensory neuropathy and failure to thrive
    explanation: Documents axonal sensory neuropathy in COX18-related disease.
- name: Failure to thrive
  description: Failure to thrive in infancy.
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: PMID:37468577
    reference_title: "A biallelic variant in COX18 cause isolated Complex IV deficiency associated with neonatal encephalo-cardio-myopathy and axonal sensory neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The proband is a 19-months old female displaying hypertrophic cardiomyopathy at birth and myopathy with axonal sensory neuropathy and failure to thrive
    explanation: Documents failure to thrive in COX18-related disease.
- name: Encephalopathy
  description: Encephalopathy as part of the neonatal encephalo-cardio-myopathy.
  phenotype_term:
    preferred_term: Encephalopathy
    term:
      id: HP:0001298
      label: Encephalopathy
  evidence:
  - reference: PMID:37468577
    reference_title: "A biallelic variant in COX18 cause isolated Complex IV deficiency associated with neonatal encephalo-cardio-myopathy and axonal sensory neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The aim of this study is to describe a molecular defect in the COX assembly factor gene COX18 as the likely cause of a neonatal form of mitochondrial encephalo-cardio-myopathy and axonal sensory neuropathy.
    explanation: >-
      Names the encephalopathy component within the compound disease designation
      the authors attribute to COX18. This is the study's aim statement, not a
      documented encephalopathy finding — the proband description in the same
      abstract reports cardiomyopathy, myopathy, axonal sensory neuropathy, and
      failure to thrive, so support for this specific phenotype rests on the
      disease name rather than a reported observation.
genetic:
- name: COX18 pathogenic variants causing COX deficiency
  gene_term:
    preferred_term: COX18
    term:
      id: hgnc:26801
      label: COX18
  inheritance:
  - name: Autosomal recessive
    evidence:
    - reference: PMID:37468577
      reference_title: "A biallelic variant in COX18 cause isolated Complex IV deficiency associated with neonatal encephalo-cardio-myopathy and axonal sensory neuropathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Whole exome sequencing allowed the prioritization of the unreported homozygous substitution NM_001297732.2:c.667 G > C p.(Asp223His) in COX18.
      explanation: >-
        Reports the homozygous COX18 substitution in the single proband, which is
        consistent with autosomal recessive inheritance; parental segregation is
        not stated in the abstract.
  features: >
    A biallelic COX18 variant impairs COX2 maturation, causing isolated Complex
    IV deficiency with neonatal encephalo-cardio-myopathy and axonal sensory
    neuropathy.
  evidence:
  - reference: PMID:37468577
    reference_title: "A biallelic variant in COX18 cause isolated Complex IV deficiency associated with neonatal encephalo-cardio-myopathy and axonal sensory neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Whole exome sequencing allowed the prioritization of the unreported homozygous substitution NM_001297732.2:c.667 G > C p.(Asp223His) in COX18.
    explanation: Identifies the specific homozygous COX18 variant establishing COX18 as the causal gene in this disorder.
treatments:
- name: Supportive and Metabolic Care
  description: >
    No curative therapy; supportive management of cardiomyopathy, neuropathy,
    feeding difficulties, and metabolic decompensation.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care