COX18-Related COX Deficiency

Mendelian MONDO:0033885 Pathograph 4 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
4
Pathograph
1
Genes
1
Treatments
⚙

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.
mitochondrial respiratory chain complex IV assembly link ↓ 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 Human Clinical
"A biallelic variant in COX18 cause isolated Complex IV deficiency associated with neonatal encephalo-cardio-myopathy and axonal sensory neuropathy."
Identifies COX18 as a cause of isolated Complex IV deficiency via defective COX assembly.
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 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.
Peripheral neuropathy Bioenergetic deficit in peripheral nerve produces axonal sensory neuropathy.
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 Hypertrophic cardiomyopathy (HP:0001639)
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 Peripheral neuropathy (HP:0009830)
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 Encephalopathy (HP:0001298)
Show evidence (1 reference)
PMID:37468577 SUPPORT Human Clinical
"A biallelic variant in COX18 cause isolated Complex IV deficiency associated with neonatal encephalo-cardio-myopathy and axonal sensory neuropathy."
The neonatal encephalo-cardio-myopathy phenotype includes encephalopathy.
Growth 1
Failure to thrive Failure to thrive (HP:0001508)
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
Autosomal recessive
💊

Treatments

1
Supportive and Metabolic Care
Action: supportive care MAXO:0000950
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
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
  term:
    id: MONDO:0033885
    label: mitochondrial complex IV deficiency, nuclear-type
notes: >
  COX18-related disease was first reported in 2023 (PMID:37468577) and does not
  yet have a dedicated MONDO/OMIM (MC4DN) class. The nuclear-type grouping
  MONDO:0033885 is used as the closest available term; an NTR for a
  COX18-specific class would allow a precise mapping.
parents:
- Mitochondrial Disease
- Inborn Error of Metabolism
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.
  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: HUMAN_CLINICAL
    snippet: A biallelic variant in COX18 cause isolated Complex IV deficiency associated with neonatal encephalo-cardio-myopathy and axonal sensory neuropathy.
    explanation: Identifies COX18 as a cause of isolated Complex IV deficiency via defective COX assembly.
  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.
- 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.
  - target: Peripheral neuropathy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Bioenergetic deficit in peripheral nerve produces axonal sensory neuropathy.
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: A biallelic variant in COX18 cause isolated Complex IV deficiency associated with neonatal encephalo-cardio-myopathy and axonal sensory neuropathy.
    explanation: The neonatal encephalo-cardio-myopathy phenotype includes encephalopathy.
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: A biallelic variant in COX18 cause isolated Complex IV deficiency associated with neonatal encephalo-cardio-myopathy and axonal sensory neuropathy.
      explanation: A biallelic COX18 variant indicates autosomal recessive inheritance.
  features: >
    A biallelic COX18 variant impairs COX2 maturation, causing isolated Complex
    IV deficiency with neonatal encephalo-cardio-myopathy and axonal sensory
    neuropathy.
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: MAXO:0000950
      label: supportive care