COX6A2-Related COX Deficiency

name: COX6A2-Related COX Deficiency
category: Mendelian
creation_date: "2026-06-23T00:00:00Z"
synonyms:
- COX6A2 deficiency
- Mitochondrial complex IV deficiency, nuclear type 18
- MC4DN18
- COX6A2-related cytochrome c oxidase deficiency
- Muscle-specific cytochrome c oxidase deficiency
description: >
  COX6A2-related COX deficiency (mitochondrial complex IV deficiency nuclear
  type 18, MC4DN18) is a rare autosomal recessive nuclear form of isolated
  cytochrome c oxidase (COX, Complex IV) deficiency caused by biallelic variants
  in COX6A2. COX6A2 encodes the heart/skeletal-muscle isoform of structural
  subunit VIa of the holoenzyme and is expressed only in striated muscle, which
  gives this disorder its distinctive tissue-restricted presentation. Unlike most
  members of the nuclear complex IV deficiency group, which arise from
  assembly-factor or metallochaperone defects, the lesion here destabilizes a
  nuclear-encoded *structural* subunit, impairing assembly of Complex IV and its
  incorporation into respiratory supercomplexes specifically in striated muscle.
  It was first defined by Inoue et al. (2019) in two unrelated Japanese
  individuals diagnosed with congenital myopathy and COX deficiency on muscle
  pathology, carrying biallelic missense variants (p.Ser39Arg homozygous in one,
  and compound heterozygous p.Ser39Arg/p.Cys43Arg in the other). Both presented
  with limb and facial muscle weakness and hypotonia, one with cardiomyopathy,
  and neither had involvement of other organs. It conforms to the conserved
  Complex IV assembly-deficiency mechanism, with the lesion localized to a
  destabilized muscle-specific structural subunit.
disease_term:
  preferred_term: COX6A2-related COX deficiency (MC4DN18)
  term:
    id: MONDO:0033653
    label: mitochondrial complex IV deficiency, nuclear type 18
parents:
- Mitochondrial Disease
- Inborn Error of Metabolism
references:
- reference: PMID:31155743
  title: "COX6A2 variants cause a muscle-specific cytochrome c oxidase deficiency."
pathophysiology:
- name: COX6A2 Structural Subunit Loss and Failed Complex IV Assembly
  conforms_to: "complex_iv_assembly_deficiency#Complex IV Biogenesis Failure"
  description: >
    Biallelic COX6A2 missense variants disrupt the heart/skeletal-muscle isoform
    of the nuclear-encoded structural subunit VIa of Complex IV. Because COX6A2
    is expressed only in striated muscle, the consequence is a tissue-restricted
    failure of Complex IV biogenesis: assembly of the holoenzyme and its
    incorporation into respiratory supercomplexes is impaired in muscle, while
    other organs are spared.
  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:31155743
    reference_title: "COX6A2 variants cause a muscle-specific cytochrome c oxidase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Whole exome sequencing identified biallelic missense variants in COX6A2, which is expressed only in the skeletal muscle and heart."
    explanation: Establishes COX6A2 as a striated-muscle-restricted Complex IV subunit, the protein affected in this disorder.
  - reference: PMID:31155743
    reference_title: "COX6A2 variants cause a muscle-specific cytochrome c oxidase deficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Assembly of complex IV and its supercomplex formation were impaired in the muscle."
    explanation: Impaired Complex IV assembly and supercomplex formation in patient muscle demonstrates failed holoenzyme biogenesis.
  downstream:
  - target: Impaired Terminal Electron Transfer and ATP Synthesis
    causal_link_type: DIRECT
    description: Failure to assemble Complex IV yields a catalytically deficient holoenzyme in muscle.
- name: Impaired Terminal Electron Transfer and ATP Synthesis
  conforms_to: "complex_iv_assembly_deficiency#Impaired Terminal Electron Transfer and ATP Synthesis"
  description: >
    Reduced amounts and activity of assembled Complex IV block electron transfer
    from cytochrome c to oxygen and proton pumping, impairing oxidative ATP
    synthesis in striated muscle. In both COX6A2-deficient individuals, Complex
    IV activity was specifically reduced in skeletal muscle.
  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:31155743
    reference_title: "COX6A2 variants cause a muscle-specific cytochrome c oxidase deficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We found specific reductions in complex IV activities in the skeletal muscle of both individuals."
    explanation: Reduced Complex IV enzymatic activity in patient skeletal muscle establishes the functional terminal-electron-transfer deficit.
  downstream:
  - target: High-Energy Tissue Dysfunction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: The muscle bioenergetic deficit injures high-demand striated muscle, producing myopathy and cardiomyopathy.
- name: High-Energy Tissue Dysfunction
  conforms_to: "complex_iv_assembly_deficiency#High-Energy Tissue Dysfunction"
  description: >
    The bioenergetic deficit manifests selectively in striated muscle, the only
    tissue expressing COX6A2. Both reported individuals had limb and facial
    muscle weakness with hypotonia, and one had cardiomyopathy, with no
    involvement of other organs — distinguishing this entity from the
    encephalopathic and multisystem presentations of other nuclear COX
    deficiencies.
  biological_processes:
  - preferred_term: aerobic respiration
    term:
      id: GO:0009060
      label: aerobic respiration
    modifier: DECREASED
  evidence:
  - reference: PMID:31155743
    reference_title: "COX6A2 variants cause a muscle-specific cytochrome c oxidase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both patients presented muscle weakness and hypotonia in 4 limbs along with facial muscle weakness."
    explanation: Skeletal muscle weakness and hypotonia are the dominant high-energy-tissue manifestations of the muscle bioenergetic deficit.
  - reference: PMID:31155743
    reference_title: "COX6A2 variants cause a muscle-specific cytochrome c oxidase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "One patient had cardiomyopathy."
    explanation: Cardiac muscle, which also expresses COX6A2, can be affected, manifesting as cardiomyopathy.
  downstream:
  - target: Muscle weakness
    causal_link_type: DIRECT
    description: Striated muscle energy failure manifests as limb and facial muscle weakness.
  - target: Cardiomyopathy
    causal_link_type: DIRECT
    description: Cardiac muscle involvement manifests as cardiomyopathy in a subset of patients.
phenotypes:
- name: Muscle weakness
  description: >
    Limb and facial muscle weakness in all reported COX6A2-deficient individuals,
    reflecting the striated-muscle-specific Complex IV deficiency.
  phenotype_term:
    preferred_term: Muscle weakness
    term:
      id: HP:0001324
      label: Muscle weakness
    onset:
      onset_category: INFANTILE
  evidence:
  - reference: PMID:31155743
    reference_title: "COX6A2 variants cause a muscle-specific cytochrome c oxidase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both patients presented muscle weakness and hypotonia in 4 limbs along with facial muscle weakness."
    explanation: Both reported individuals had muscle weakness affecting the limbs and face.
- name: Hypotonia
  description: >
    Hypotonia of the four limbs, present in both reported individuals.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:31155743
    reference_title: "COX6A2 variants cause a muscle-specific cytochrome c oxidase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both patients presented muscle weakness and hypotonia in 4 limbs along with facial muscle weakness."
    explanation: Both individuals presented with hypotonia in the four limbs.
- name: Facial muscle weakness
  description: >
    Facial muscle weakness accompanying the limb weakness and hypotonia.
  phenotype_term:
    preferred_term: Weakness of facial musculature
    term:
      id: HP:0030319
      label: Weakness of facial musculature
  evidence:
  - reference: PMID:31155743
    reference_title: "COX6A2 variants cause a muscle-specific cytochrome c oxidase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both patients presented muscle weakness and hypotonia in 4 limbs along with facial muscle weakness."
    explanation: Facial muscle weakness was a presenting feature in both individuals.
- name: Cardiomyopathy
  description: >
    Cardiomyopathy in one of the two reported individuals, reflecting involvement
    of cardiac striated muscle, which also expresses COX6A2.
  phenotype_term:
    preferred_term: Cardiomyopathy
    term:
      id: HP:0001638
      label: Cardiomyopathy
  evidence:
  - reference: PMID:31155743
    reference_title: "COX6A2 variants cause a muscle-specific cytochrome c oxidase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "One patient had cardiomyopathy."
    explanation: One of the two reported individuals had cardiomyopathy.
genetic:
- name: COX6A2 pathogenic variants causing MC4DN18
  gene_term:
    preferred_term: COX6A2
    term:
      id: hgnc:2279
      label: COX6A2
  inheritance:
  - name: Autosomal recessive
    evidence:
    - reference: PMID:31155743
      reference_title: "COX6A2 variants cause a muscle-specific cytochrome c oxidase deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The variants detected were homozygous c.117C > A (p.Ser39Arg) and compound heterozygous c.117C > A (p.Ser39Arg) and c.127T > C (p.Cys43Arg)."
      explanation: Homozygous and compound heterozygous biallelic COX6A2 variants establish autosomal recessive inheritance.
  features: >
    Biallelic missense COX6A2 variants cause MC4DN18. One individual was
    homozygous for c.117C>A (p.Ser39Arg); the other was compound heterozygous
    for c.117C>A (p.Ser39Arg) and c.127T>C (p.Cys43Arg). The variants affect a
    subunit expressed only in skeletal muscle and heart, accounting for the
    striated-muscle-specific phenotype.
  evidence:
  - reference: PMID:31155743
    reference_title: "COX6A2 variants cause a muscle-specific cytochrome c oxidase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This study indicates that biallelic variants in COX6A2 cause a striated muscle-specific form of COX deficiency."
    explanation: Identifies biallelic COX6A2 variants as the cause of a striated-muscle-specific Complex IV deficiency.
  - reference: PMID:31155743
    reference_title: "COX6A2 variants cause a muscle-specific cytochrome c oxidase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Whole exome sequencing identified biallelic missense variants in COX6A2, which is expressed only in the skeletal muscle and heart."
    explanation: Whole exome sequencing identified the causal biallelic COX6A2 variants.
treatments:
- name: Supportive and Multidisciplinary Care
  description: >
    No curative therapy exists; management is supportive, addressing the
    muscle weakness, hypotonia, and cardiomyopathy with multidisciplinary
    supportive care.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care