COX4I1-Related COX Deficiency

Mendelian MONDO:0033651 Pathograph 9 Show in embeddings browser Mitochondrial Disease Inborn Error of Metabolism

COX4I1-related COX deficiency (mitochondrial complex IV deficiency nuclear type 16, MC4DN16) is a rare autosomal recessive nuclear form of isolated cytochrome c oxidase (COX, Complex IV) deficiency caused by biallelic variants in COX4I1. COX4I1 encodes the ubiquitously expressed common isoform of cytochrome c oxidase subunit 4 (COX4-1), a nuclear-encoded structural and regulatory subunit of the Complex IV holoenzyme, the terminal oxidase of the mitochondrial respiratory chain. Loss of functional COX4-1 destabilizes the holoenzyme and produces an isolated Complex IV deficiency with reduced COX activity, impaired oxidative ATP production, and elevated reactive oxygen species. The clinical spectrum is variable: the first reported individual (homozygous K101N) presented with short stature, poor weight gain, dysmorphic features, and increased chromosomal breakage that simulated Fanconi anemia, while subsequently reported siblings (homozygous P152T) presented with encephalopathy, developmental regression, hypotonia, and pathognomonic Leigh-syndrome-like brain imaging. It conforms to the conserved Complex IV assembly-deficiency mechanism, with the lesion localized to loss of a structural COX subunit, and adds a distinctive oxidative-stress / chromosomal-instability branch.

Ask OpenScientist

Ask a research question about COX4I1-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.

5
Pathophys.
11
Phenotypes
9
Pathograph
1
Genes
1
Medical Actions
1
References
⚙

Pathophysiology

5
COX4-1 Subunit Loss and Failed Complex IV Assembly
COX4I1 encodes the common (ubiquitous) isoform of cytochrome c oxidase subunit 4, a nuclear-encoded structural and regulatory subunit of Complex IV. Biallelic COX4I1 variants reduce or abolish COX4-1 expression; in the index case the COX4I1 mRNA was decreased and the COX4 protein undetectable. Loss of this core subunit destabilizes the holoenzyme and yields an isolated Complex IV biogenesis defect.
COX4I1 hgnc:2265 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves COX4I1 (hgnc:2265). hgnc:2265 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 Loss of the COX4-1 subunit yields a catalytically deficient holoenzyme.
Oxidative Stress and Chromosomal Instability A dysfunctional Complex IV leaks reactive oxygen species, driving oxidative stress and genomic instability.
Show evidence (2 references)
PMID:28766551 SUPPORT Human Clinical
"This nuclear gene encodes the common isoform of cytochrome c oxidase (COX) subunit 4 (COX 4-1), an integral regulatory part of COX (respiratory chain complex IV) the terminal electron acceptor of the mitochondrial respiratory chain."
Establishes COX4I1/COX4-1 as a structural and regulatory subunit of Complex IV, the terminal oxidase whose loss causes the defect.
PMID:28766551 SUPPORT In Vitro
"decreased expression of COX4I1 mRNA and undetectable (COX4) protein"
Patient fibroblasts show loss of COX4I1 mRNA and COX4 protein, the molecular lesion that destabilizes Complex IV.
Impaired Terminal Electron Transfer and ATP Synthesis
Deficient Complex IV blocks transfer of electrons from cytochrome c to molecular oxygen and the coupled proton pumping, reducing oxidative ATP synthesis. Patient fibroblasts showed decreased COX activity and impaired ATP production, both rescued by re-expression of wild-type COX4I1.
neuron CL:0000540 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neuron (CL:0000540). CL:0000540 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
Lactic Acidosis and Metabolic Decompensation Loss of oxidative ATP synthesis forces anaerobic glycolysis and lactate accumulation.
High-Energy Tissue Dysfunction The bioenergetic deficit is most damaging in high oxidative-demand tissues, notably the brain.
Show evidence (2 references)
PMID:28766551 SUPPORT In Vitro
"The patient's fibroblasts disclosed decreased COX activity, impaired ATP production, elevated ROS production"
Patient fibroblasts show decreased COX activity and impaired ATP production, the biochemical basis for failed terminal electron transfer.
PMID:28766551 SUPPORT In Vitro
"COX activity and ATP production were restored by lentiviral transfection with the wild-type gene."
Rescue of COX activity and ATP production by wild-type COX4I1 confirms the bioenergetic defect is caused by COX4I1 loss.
Oxidative Stress and Chromosomal Instability
A distinctive feature of COX4-1 deficiency is elevated reactive oxygen species production accompanying the respiratory-chain defect. In the index case this was associated with increased chromosomal breakage that clinically simulated Fanconi anemia, illustrating how a primary Complex IV subunit defect can mimic a nuclear DNA-repair disorder.
reactive oxygen species metabolic process GO:0072593 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased reactive oxygen species metabolic process (GO:0072593). GO:0072593 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Increased chromosomal breakage Oxidative stress is associated with increased chromosomal breaks that simulate Fanconi anemia.
Show evidence (2 references)
PMID:28766551 SUPPORT In Vitro
"The patient's fibroblasts disclosed decreased COX activity, impaired ATP production, elevated ROS production"
Documents elevated reactive oxygen species production in COX4I1-deficient patient fibroblasts.
PMID:28766551 SUPPORT Human Clinical
"We describe a novel autosomal recessive form of mitochondrial disease in a child with short stature, poor weight gain, and mild dysmorphic features with highly suspected Fanconi anemia due to a mutation in COX4I1 gene."
Links the oxidative phenotype to a clinically Fanconi-anemia-like presentation with increased chromosomal breakage.
Lactic Acidosis and Metabolic Decompensation
With oxidative phosphorylation impaired, pyruvate is shunted to lactate, elevating blood and CSF lactate; metabolic stress can precipitate decompensation in the encephalopathic (Leigh-like) presentation.
lactate biosynthetic process GO:0019249 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased lactate biosynthetic process (GO:0019249). GO:0019249 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Lactic acidosis Lactate overproduction manifests clinically as lactic acidosis.
Show evidence (1 reference)
PMID:31290619 SUPPORT Human Clinical
"Defective production of cytochrome c oxidase leads to a variable phenotypic spectrum ranging from isolated myopathy to Leigh syndrome."
Establishes that defective COX (the source of the bioenergetic block driving lactate accumulation) produces a spectrum that includes Leigh syndrome.
High-Energy Tissue Dysfunction
Energy failure is most damaging in high oxidative-demand tissues. In COX4I1-related disease the dominant tropism in the severe presentation is the central nervous system, producing encephalopathy, developmental regression, and Leigh-syndrome-like brain imaging; growth failure reflects systemic energy deficit.
neuron CL:0000540 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neuron (CL:0000540). CL:0000540 is a cell type from the Cell Ontology.
aerobic respiration GO:0009060 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased aerobic respiration (GO:0009060). GO:0009060 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Encephalopathy Bioenergetic failure in the brain produces encephalopathy and developmental regression.
Show evidence (1 reference)
PMID:31290619 SUPPORT Human Clinical
"we describe two siblings, born to consanguineous parents, who presented with encephalopathy, developmental regression, hypotonia, pathognomonic brain imaging findings resembling Leigh-syndrome, and a novel homozygous variant on COX4I1"
Documents the CNS-predominant high-energy-tissue dysfunction (encephalopathy, regression, Leigh-like imaging) of the severe COX4I1 presentation.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for COX4I1-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

11
Head and Neck 1
Abnormal facial shape HP:0001999 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal facial shape (HP:0001999). HP:0001999 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28766551 SUPPORT Human Clinical
"a child with short stature, poor weight gain, and mild dysmorphic features"
Mild dysmorphic features are documented in the first reported COX4I1 patient.
Metabolism 1
Lactic acidosis HP:0003128 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Lactic acidosis (HP:0003128). HP:0003128 is a phenotype from the Human Phenotype Ontology.
Resolves the downstream "Lactic acidosis" target of the Lactic Acidosis and Metabolic Decompensation pathophysiology node. No snippet-backed evidence is attached here because none of the cached COX4I1 abstracts (PMID:28766551, PMID:31290619, PMID:26425749) quote lactic acidosis directly; the mechanistic basis is carried by the pathophysiology node, which cites PMID:31290619 and the GeneReviews Leigh syndrome spectrum overview (PMID:26425749), where elevated lactate is the defining biochemical hallmark.
Musculoskeletal 1
Hypotonia HP:0001252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypotonia (HP:0001252). HP:0001252 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31290619 SUPPORT Human Clinical
"two siblings, born to consanguineous parents, who presented with encephalopathy, developmental regression, hypotonia"
Hypotonia is documented in the COX4I1 siblings.
Nervous System 4
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:31290619 SUPPORT Human Clinical
"two siblings, born to consanguineous parents, who presented with encephalopathy, developmental regression, hypotonia"
Encephalopathy is documented in the COX4I1 siblings with the Leigh-like presentation.
Developmental regression HP:0002376 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Developmental regression (HP:0002376). HP:0002376 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31290619 SUPPORT Human Clinical
"two siblings, born to consanguineous parents, who presented with encephalopathy, developmental regression, hypotonia"
Developmental regression is documented in the COX4I1 siblings.
Intellectual disability HP:0001249 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intellectual disability (HP:0001249). HP:0001249 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31290619 SUPPORT Human Clinical
"a novel phenotype resembling Leigh syndrome with developmental regression, intellectual disability, and seizures"
Intellectual disability is part of the expanded COX4I1 phenotype.
Seizures HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31290619 SUPPORT Human Clinical
"a novel phenotype resembling Leigh syndrome with developmental regression, intellectual disability, and seizures"
Seizures are part of the expanded COX4I1 phenotype.
Growth 2
Short stature HP:0004322 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short stature (HP:0004322). HP:0004322 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28766551 SUPPORT Human Clinical
"a child with short stature, poor weight gain, and mild dysmorphic features"
Short stature is a core feature of the first reported COX4I1 patient.
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:28766551 SUPPORT Human Clinical
"a child with short stature, poor weight gain, and mild dysmorphic features"
Poor weight gain (failure to thrive) is documented in the first reported COX4I1 patient.
Other 2
Increased chromosomal breakage Chromosome breakage HP:0040012 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Chromosome breakage (HP:0040012). HP:0040012 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28766551 SUPPORT Human Clinical
"Mutation in the COX4I1 gene is associated with short stature, poor weight gain and increased chromosomal breaks, simulating Fanconi anemia."
Increased chromosomal breakage simulating Fanconi anemia is a distinctive feature of COX4I1 deficiency.
Bilateral basal ganglia lesions HP:0007146 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bilateral basal ganglia lesions (HP:0007146). HP:0007146 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31290619 SUPPORT Human Clinical
"pathognomonic brain imaging findings resembling Leigh-syndrome"
The Leigh-like neuroimaging (basal ganglia/brainstem lesions) is documented in the COX4I1 siblings.
🧬

Genetic Associations

1
COX4I1 pathogenic variants causing MC4DN16
Gene: COX4I1 hgnc:2265 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is COX4I1 (hgnc:2265). hgnc:2265 is a gene from the HUGO Gene Nomenclature Committee.
Autosomal recessive
Show evidence (2 references)
PMID:28766551 SUPPORT Human Clinical
"Whole Exome Sequencing was performed then followed by Sanger confirmation, identified a K101N mutation in COX4I1, segregating with the disease."
Identifies a homozygous K101N COX4I1 variant segregating with disease, establishing COX4I1 as the causal gene.
PMID:28766551 SUPPORT Human Clinical
"Our results demonstrate the first human mutation in the COX4I1 gene linked to diseases and confirm its role in the pathogenesis."
Establishes the first human COX4I1 disease association and confirms its causal role.
💊

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
There is no disease-modifying therapy for COX4I1-related COX deficiency. Management of the nuclear gene-encoded Leigh syndrome spectrum is largely supportive, with surveillance and symptomatic treatment of seizures, feeding difficulties, and metabolic decompensation.
Show evidence (1 reference)
PMID:26425749 SUPPORT Other
"Review management of nuclear gene-encoded LSS with a focus on disorders with targeted therapies"
The GeneReviews overview frames management of the nuclear gene-encoded Leigh syndrome spectrum, the clinical context for supportive care.
{ }

Source YAML

click to show 
name: COX4I1-Related COX Deficiency
category: Mendelian
creation_date: "2026-06-19T00:00:00Z"
synonyms:
- COX4I1 deficiency
- Mitochondrial complex IV deficiency, nuclear type 16
- MC4DN16
- COX4I1-related cytochrome c oxidase deficiency
- Cytochrome c oxidase subunit 4 isoform 1 deficiency
description: >
  COX4I1-related COX deficiency (mitochondrial complex IV deficiency nuclear
  type 16, MC4DN16) is a rare autosomal recessive nuclear form of isolated
  cytochrome c oxidase (COX, Complex IV) deficiency caused by biallelic variants
  in COX4I1. COX4I1 encodes the ubiquitously expressed common isoform of
  cytochrome c oxidase subunit 4 (COX4-1), a nuclear-encoded structural and
  regulatory subunit of the Complex IV holoenzyme, the terminal oxidase of the
  mitochondrial respiratory chain. Loss of functional COX4-1 destabilizes the
  holoenzyme and produces an isolated Complex IV deficiency with reduced COX
  activity, impaired oxidative ATP production, and elevated reactive oxygen
  species. The clinical spectrum is variable: the first reported individual
  (homozygous K101N) presented with short stature, poor weight gain, dysmorphic
  features, and increased chromosomal breakage that simulated Fanconi anemia,
  while subsequently reported siblings (homozygous P152T) presented with
  encephalopathy, developmental regression, hypotonia, and pathognomonic
  Leigh-syndrome-like brain imaging. It conforms to the conserved Complex IV
  assembly-deficiency mechanism, with the lesion localized to loss of a
  structural COX subunit, and adds a distinctive oxidative-stress /
  chromosomal-instability branch.
disease_term:
  preferred_term: COX4I1-related COX deficiency (MC4DN16)
  term:
    id: MONDO:0033651
    label: mitochondrial complex IV deficiency, nuclear type 16
parents:
- Mitochondrial Disease
- Inborn Error of Metabolism
references:
- reference: PMID:26425749
  title: "Nuclear Gene-Encoded Leigh Syndrome Spectrum Overview."
  tags:
  - GeneReviews
genetic:
- name: COX4I1 pathogenic variants causing MC4DN16
  gene_term:
    preferred_term: COX4I1
    term:
      id: hgnc:2265
      label: COX4I1
  inheritance:
  - name: Autosomal recessive
    evidence:
    - reference: PMID:28766551
      reference_title: "Mutation in the COX4I1 gene is associated with short stature, poor weight gain and increased chromosomal breaks, simulating Fanconi anemia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "We describe a novel autosomal recessive form of mitochondrial disease in a child with short stature, poor weight gain, and mild dysmorphic features with highly suspected Fanconi anemia due to a mutation in COX4I1 gene."
      explanation: A novel autosomal recessive mitochondrial disease caused by a homozygous COX4I1 variant establishes recessive inheritance.
  features: >
    Biallelic (homozygous) pathogenic missense variants in COX4I1 cause
    autosomal recessive isolated Complex IV deficiency. Reported alleles include
    K101N (Abu-Libdeh et al. 2017) and P152T (Pillai et al. 2019).
  evidence:
  - reference: PMID:28766551
    reference_title: "Mutation in the COX4I1 gene is associated with short stature, poor weight gain and increased chromosomal breaks, simulating Fanconi anemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Whole Exome Sequencing was performed then followed by Sanger confirmation, identified a K101N mutation in COX4I1, segregating with the disease."
    explanation: Identifies a homozygous K101N COX4I1 variant segregating with disease, establishing COX4I1 as the causal gene.
  - reference: PMID:28766551
    reference_title: "Mutation in the COX4I1 gene is associated with short stature, poor weight gain and increased chromosomal breaks, simulating Fanconi anemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our results demonstrate the first human mutation in the COX4I1 gene linked to diseases and confirm its role in the pathogenesis."
    explanation: Establishes the first human COX4I1 disease association and confirms its causal role.
pathophysiology:
- name: COX4-1 Subunit Loss and Failed Complex IV Assembly
  conforms_to: "complex_iv_assembly_deficiency#Complex IV Biogenesis Failure"
  description: >
    COX4I1 encodes the common (ubiquitous) isoform of cytochrome c oxidase
    subunit 4, a nuclear-encoded structural and regulatory subunit of Complex
    IV. Biallelic COX4I1 variants reduce or abolish COX4-1 expression; in the
    index case the COX4I1 mRNA was decreased and the COX4 protein undetectable.
    Loss of this core subunit destabilizes the holoenzyme and yields an isolated
    Complex IV biogenesis defect.
  genes:
  - preferred_term: COX4I1
    term:
      id: hgnc:2265
      label: COX4I1
  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:28766551
    reference_title: "Mutation in the COX4I1 gene is associated with short stature, poor weight gain and increased chromosomal breaks, simulating Fanconi anemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This nuclear gene encodes the common isoform of cytochrome c oxidase (COX) subunit 4 (COX 4-1), an integral regulatory part of COX (respiratory chain complex IV) the terminal electron acceptor of the mitochondrial respiratory chain."
    explanation: Establishes COX4I1/COX4-1 as a structural and regulatory subunit of Complex IV, the terminal oxidase whose loss causes the defect.
  - reference: PMID:28766551
    reference_title: "Mutation in the COX4I1 gene is associated with short stature, poor weight gain and increased chromosomal breaks, simulating Fanconi anemia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "decreased expression of COX4I1 mRNA and undetectable (COX4) protein"
    explanation: Patient fibroblasts show loss of COX4I1 mRNA and COX4 protein, the molecular lesion that destabilizes Complex IV.
  downstream:
  - target: Impaired Terminal Electron Transfer and ATP Synthesis
    causal_link_type: DIRECT
    description: Loss of the COX4-1 subunit yields a catalytically deficient holoenzyme.
  - target: Oxidative Stress and Chromosomal Instability
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: A dysfunctional Complex IV leaks reactive oxygen species, driving oxidative stress and genomic instability.
- name: Impaired Terminal Electron Transfer and ATP Synthesis
  conforms_to: "complex_iv_assembly_deficiency#Impaired Terminal Electron Transfer and ATP Synthesis"
  description: >
    Deficient Complex IV blocks transfer of electrons from cytochrome c to
    molecular oxygen and the coupled proton pumping, reducing oxidative ATP
    synthesis. Patient fibroblasts showed decreased COX activity and impaired
    ATP production, both rescued by re-expression of wild-type COX4I1.
  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:28766551
    reference_title: "Mutation in the COX4I1 gene is associated with short stature, poor weight gain and increased chromosomal breaks, simulating Fanconi anemia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The patient's fibroblasts disclosed decreased COX activity, impaired ATP production, elevated ROS production"
    explanation: Patient fibroblasts show decreased COX activity and impaired ATP production, the biochemical basis for failed terminal electron transfer.
  - reference: PMID:28766551
    reference_title: "Mutation in the COX4I1 gene is associated with short stature, poor weight gain and increased chromosomal breaks, simulating Fanconi anemia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "COX activity and ATP production were restored by lentiviral transfection with the wild-type gene."
    explanation: Rescue of COX activity and ATP production by wild-type COX4I1 confirms the bioenergetic defect is caused by COX4I1 loss.
  downstream:
  - target: Lactic Acidosis and Metabolic Decompensation
    causal_link_type: DIRECT
    description: Loss of oxidative ATP synthesis forces anaerobic glycolysis and lactate accumulation.
  - target: High-Energy Tissue Dysfunction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: The bioenergetic deficit is most damaging in high oxidative-demand tissues, notably the brain.
- name: Oxidative Stress and Chromosomal Instability
  description: >
    A distinctive feature of COX4-1 deficiency is elevated reactive oxygen
    species production accompanying the respiratory-chain defect. In the index
    case this was associated with increased chromosomal breakage that clinically
    simulated Fanconi anemia, illustrating how a primary Complex IV subunit
    defect can mimic a nuclear DNA-repair disorder.
  biological_processes:
  - preferred_term: reactive oxygen species metabolic process
    term:
      id: GO:0072593
      label: reactive oxygen species metabolic process
    modifier: INCREASED
  evidence:
  - reference: PMID:28766551
    reference_title: "Mutation in the COX4I1 gene is associated with short stature, poor weight gain and increased chromosomal breaks, simulating Fanconi anemia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The patient's fibroblasts disclosed decreased COX activity, impaired ATP production, elevated ROS production"
    explanation: Documents elevated reactive oxygen species production in COX4I1-deficient patient fibroblasts.
  - reference: PMID:28766551
    reference_title: "Mutation in the COX4I1 gene is associated with short stature, poor weight gain and increased chromosomal breaks, simulating Fanconi anemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe a novel autosomal recessive form of mitochondrial disease in a child with short stature, poor weight gain, and mild dysmorphic features with highly suspected Fanconi anemia due to a mutation in COX4I1 gene."
    explanation: Links the oxidative phenotype to a clinically Fanconi-anemia-like presentation with increased chromosomal breakage.
  downstream:
  - target: Increased chromosomal breakage
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Oxidative stress is associated with increased chromosomal breaks that simulate Fanconi anemia.
- name: Lactic Acidosis and Metabolic Decompensation
  conforms_to: "complex_iv_assembly_deficiency#Lactic Acidosis and Metabolic Decompensation"
  description: >
    With oxidative phosphorylation impaired, pyruvate is shunted to lactate,
    elevating blood and CSF lactate; metabolic stress can precipitate
    decompensation in the encephalopathic (Leigh-like) presentation.
  biological_processes:
  - preferred_term: lactate biosynthetic process
    term:
      id: GO:0019249
      label: lactate biosynthetic process
    modifier: INCREASED
  evidence:
  - reference: PMID:31290619
    reference_title: "Biallelic variants in COX4I1 associated with a novel phenotype resembling Leigh syndrome with developmental regression, intellectual disability, and seizures."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Defective production of cytochrome c oxidase leads to a variable phenotypic spectrum ranging from isolated myopathy to Leigh syndrome."
    explanation: Establishes that defective COX (the source of the bioenergetic block driving lactate accumulation) produces a spectrum that includes Leigh syndrome.
  downstream:
  - target: Lactic acidosis
    causal_link_type: DIRECT
    description: Lactate overproduction manifests clinically as lactic acidosis.
- name: High-Energy Tissue Dysfunction
  conforms_to: "complex_iv_assembly_deficiency#High-Energy Tissue Dysfunction"
  description: >
    Energy failure is most damaging in high oxidative-demand tissues. In
    COX4I1-related disease the dominant tropism in the severe presentation is the
    central nervous system, producing encephalopathy, developmental regression,
    and Leigh-syndrome-like brain imaging; growth failure reflects systemic
    energy deficit.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: aerobic respiration
    term:
      id: GO:0009060
      label: aerobic respiration
    modifier: DECREASED
  evidence:
  - reference: PMID:31290619
    reference_title: "Biallelic variants in COX4I1 associated with a novel phenotype resembling Leigh syndrome with developmental regression, intellectual disability, and seizures."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we describe two siblings, born to consanguineous parents, who presented with encephalopathy, developmental regression, hypotonia, pathognomonic brain imaging findings resembling Leigh-syndrome, and a novel homozygous variant on COX4I1"
    explanation: Documents the CNS-predominant high-energy-tissue dysfunction (encephalopathy, regression, Leigh-like imaging) of the severe COX4I1 presentation.
  downstream:
  - target: Encephalopathy
    causal_link_type: DIRECT
    description: Bioenergetic failure in the brain produces encephalopathy and developmental regression.
phenotypes:
- name: Short stature
  description: >
    Short stature with poor overall growth, a prominent feature of the index
    (K101N) presentation.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:28766551
    reference_title: "Mutation in the COX4I1 gene is associated with short stature, poor weight gain and increased chromosomal breaks, simulating Fanconi anemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a child with short stature, poor weight gain, and mild dysmorphic features"
    explanation: Short stature is a core feature of the first reported COX4I1 patient.
- name: Failure to thrive
  description: >
    Poor weight gain / failure to thrive, reported in the index presentation.
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: PMID:28766551
    reference_title: "Mutation in the COX4I1 gene is associated with short stature, poor weight gain and increased chromosomal breaks, simulating Fanconi anemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a child with short stature, poor weight gain, and mild dysmorphic features"
    explanation: Poor weight gain (failure to thrive) is documented in the first reported COX4I1 patient.
- name: Abnormal facial shape
  description: >
    Mild dysmorphic facial features, reported in the index presentation.
  phenotype_term:
    preferred_term: Abnormal facial shape
    term:
      id: HP:0001999
      label: Abnormal facial shape
  evidence:
  - reference: PMID:28766551
    reference_title: "Mutation in the COX4I1 gene is associated with short stature, poor weight gain and increased chromosomal breaks, simulating Fanconi anemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a child with short stature, poor weight gain, and mild dysmorphic features"
    explanation: Mild dysmorphic features are documented in the first reported COX4I1 patient.
- name: Increased chromosomal breakage
  description: >
    Increased chromosomal breaks simulating Fanconi anemia, the distinctive
    finding that delayed the genetic diagnosis in the index case.
  phenotype_term:
    preferred_term: Chromosome breakage
    term:
      id: HP:0040012
      label: Chromosome breakage
  evidence:
  - reference: PMID:28766551
    reference_title: "Mutation in the COX4I1 gene is associated with short stature, poor weight gain and increased chromosomal breaks, simulating Fanconi anemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutation in the COX4I1 gene is associated with short stature, poor weight gain and increased chromosomal breaks, simulating Fanconi anemia."
    explanation: Increased chromosomal breakage simulating Fanconi anemia is a distinctive feature of COX4I1 deficiency.
- name: Encephalopathy
  description: >
    Encephalopathy, a core feature of the severe (P152T) sibling presentation.
  phenotype_term:
    preferred_term: Encephalopathy
    term:
      id: HP:0001298
      label: Encephalopathy
  evidence:
  - reference: PMID:31290619
    reference_title: "Biallelic variants in COX4I1 associated with a novel phenotype resembling Leigh syndrome with developmental regression, intellectual disability, and seizures."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "two siblings, born to consanguineous parents, who presented with encephalopathy, developmental regression, hypotonia"
    explanation: Encephalopathy is documented in the COX4I1 siblings with the Leigh-like presentation.
- name: Developmental regression
  description: >
    Developmental regression in the severe Leigh-like presentation.
  phenotype_term:
    preferred_term: Developmental regression
    term:
      id: HP:0002376
      label: Developmental regression
  evidence:
  - reference: PMID:31290619
    reference_title: "Biallelic variants in COX4I1 associated with a novel phenotype resembling Leigh syndrome with developmental regression, intellectual disability, and seizures."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "two siblings, born to consanguineous parents, who presented with encephalopathy, developmental regression, hypotonia"
    explanation: Developmental regression is documented in the COX4I1 siblings.
- name: Intellectual disability
  description: >
    Intellectual disability, part of the novel Leigh-like phenotype expanding the
    COX4I1 spectrum.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:31290619
    reference_title: "Biallelic variants in COX4I1 associated with a novel phenotype resembling Leigh syndrome with developmental regression, intellectual disability, and seizures."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a novel phenotype resembling Leigh syndrome with developmental regression, intellectual disability, and seizures"
    explanation: Intellectual disability is part of the expanded COX4I1 phenotype.
- name: Seizures
  description: >
    Seizures, part of the novel Leigh-like phenotype in the COX4I1 siblings.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:31290619
    reference_title: "Biallelic variants in COX4I1 associated with a novel phenotype resembling Leigh syndrome with developmental regression, intellectual disability, and seizures."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a novel phenotype resembling Leigh syndrome with developmental regression, intellectual disability, and seizures"
    explanation: Seizures are part of the expanded COX4I1 phenotype.
- name: Hypotonia
  description: >
    Hypotonia in the severe Leigh-like sibling presentation.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:31290619
    reference_title: "Biallelic variants in COX4I1 associated with a novel phenotype resembling Leigh syndrome with developmental regression, intellectual disability, and seizures."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "two siblings, born to consanguineous parents, who presented with encephalopathy, developmental regression, hypotonia"
    explanation: Hypotonia is documented in the COX4I1 siblings.
- name: Bilateral basal ganglia lesions
  description: >
    Pathognomonic brain imaging findings resembling Leigh syndrome, with lesions
    typically in the basal ganglia and brainstem.
  phenotype_term:
    preferred_term: Bilateral basal ganglia lesions
    term:
      id: HP:0007146
      label: Bilateral basal ganglia lesions
  evidence:
  - reference: PMID:31290619
    reference_title: "Biallelic variants in COX4I1 associated with a novel phenotype resembling Leigh syndrome with developmental regression, intellectual disability, and seizures."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "pathognomonic brain imaging findings resembling Leigh-syndrome"
    explanation: The Leigh-like neuroimaging (basal ganglia/brainstem lesions) is documented in the COX4I1 siblings.
- name: Lactic acidosis
  description: >
    Elevated blood and CSF lactate from the bioenergetic block in cytochrome c
    oxidase, the clinical manifestation of the "Lactic Acidosis and Metabolic
    Decompensation" pathophysiology node and a defining biochemical feature of
    the Leigh-syndrome-spectrum presentation of COX4I1 deficiency.
  phenotype_term:
    preferred_term: Lactic acidosis
    term:
      id: HP:0003128
      label: Lactic acidosis
  notes: >
    Resolves the downstream "Lactic acidosis" target of the Lactic Acidosis and
    Metabolic Decompensation pathophysiology node. No snippet-backed evidence is
    attached here because none of the cached COX4I1 abstracts (PMID:28766551,
    PMID:31290619, PMID:26425749) quote lactic acidosis directly; the mechanistic
    basis is carried by the pathophysiology node, which cites PMID:31290619 and
    the GeneReviews Leigh syndrome spectrum overview (PMID:26425749), where
    elevated lactate is the defining biochemical hallmark.
treatments:
- name: Supportive and Metabolic Care
  description: >
    There is no disease-modifying therapy for COX4I1-related COX deficiency.
    Management of the nuclear gene-encoded Leigh syndrome spectrum is largely
    supportive, with surveillance and symptomatic treatment of seizures, feeding
    difficulties, and metabolic decompensation.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:26425749
    reference_title: "Nuclear Gene-Encoded Leigh Syndrome Spectrum Overview."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Review management of nuclear gene-encoded LSS with a focus on disorders with targeted therapies"
    explanation: The GeneReviews overview frames management of the nuclear gene-encoded Leigh syndrome spectrum, the clinical context for supportive care.
notes: >
  COX4I1 (MC4DN16, MONDO:0033651, OMIM:619060) is one of the nuclear-type
  isolated Complex IV deficiencies tracked by issue #4239. It is distinctive
  among the COX-subunit/assembly-factor disorders in that the index case
  presented with increased chromosomal breakage simulating Fanconi anemia,
  attributed to oxidative stress from the respiratory-chain defect. Reported
  alleles to date are the missense variants K101N (Abu-Libdeh et al. 2017) and
  P152T (Pillai et al. 2019). The entry conforms to the
  complex_iv_assembly_deficiency module and should be added as a member of the
  Mitochondrial_Complex_IV_Deficiency grouping.
📚

References & Deep Research

References

1
PMID:26425749
Nuclear Gene-Encoded Leigh Syndrome Spectrum Overview.
No top-level findings curated for this source.