COX4I1-Related COX Deficiency

Mendelian MONDO:0033651 Pathograph 47 Show in embeddings browser Mitochondrial Disease Inborn Error of Metabolism

COX4I1-related mitochondrial complex IV deficiency is an autosomal recessive disorder caused by biallelic COX4I1 variants. Reduced abundance or function of the COX4-1 structural and regulatory subunit impairs complex IV assembly and respiratory-chain function. Presentations range from severe growth failure with chromosome breakage and mild hematologic abnormalities to infantile encephalopathy with regression and epilepsy, or later progressive spastic-dystonic motor and cognitive impairment with Leigh-like basal ganglia lesions. Normal lactate, normal chromosome-breakage studies, or initially normal development do not exclude the disorder. Nuclear DNA-repair defects and replication-associated DNA damage have been demonstrated in cell models; excess reactive oxygen species alone does not explain this branch of the disease mechanism.

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15
Pathophys.
33
Phenotypes
47
Pathograph
1
Genes
5
Variants
8
Medical Actions
2
Datasets
5
Models
15
References
⚙

Pathophysiology

15
Aberrant COX4I1 Splicing
The deep-intronic c.73+1511A>G variant activates cryptic splicing. Patient transcripts retain 82 intronic bases while losing the first two bases of exon 3, predicting p.Glu25ValfsTer9. Residual correctly processed transcripts indicate leaky splicing. Splicing was only hypothesized, not demonstrated, for the founding complex substitution.
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.
Genetic context COX4I1 hgnc:2265 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns COX4I1 (hgnc:2265). hgnc:2265 is a gene from the HUGO Gene Nomenclature Committee. Variant type: single nucleotide variant Genomic context: intron
c.73+1511A>G in intron 2, in trans with c.64C>T (p.Arg22Ter).
Experimental models
HAP1 COX4I1 intronic-variant minigene CELL LINE
Downstream
COX4I1 Protein Deficiency Aberrant transcripts reduce the pool of functional COX4I1.
Show evidence (1 reference)
url:https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download SUPPORT In Vitro
"the c.73 + 1511A > G variant promotes the aberrant incorporation of an intronic sequence into COX4I1 mRNA."
Patient RNA and a HAP1 minigene assay support cryptic splice activation.
COX4I1 Protein Deficiency
Biallelic variants reduce functional COX4-1. Protein was undetectable in the founding fibroblasts and substantially reduced, with residual protein, in the later nonsense/intronic case. A deletion of one COX4I1 allele can contribute when a pathogenic variant affects the other allele.
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.
COX4-1 contribution to cytochrome-c oxidase activity GO:0004129 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased COX4-1 contribution to cytochrome-c oxidase activity, annotated with cytochrome-c oxidase activity (GO:0004129). GO:0004129 is a molecular function from the Gene Ontology.
Experimental models
Patient-derived COX4I1 fibroblasts PRIMARY CELL CULTURE
Downstream
Impaired Complex IV Assembly Loss of a core structural subunit impairs complex IV biogenesis.
Impaired Nuclear DNA Repair COX4I1 deficiency is associated with impaired repair, but the mitochondrion-to-nucleus intermediates remain unresolved.
Conditional Oxidative Stress Deficient fibroblasts accumulate ROS under oxidative-phosphorylation-dependent culture conditions.
HIF1A Stabilization Normoxic deficient fibroblasts accumulate nuclear HIF-1α through an unresolved signal.
Show evidence (2 references)
PMID:28766551 SUPPORT In Vitro
"Western blot analysis revealed undetectable COX 4 protein while complexes I and II were comparable to controls"
Patient fibroblast immunoblotting demonstrates loss of detectable COX4 protein.
url:https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download SUPPORT In Vitro
"Western blot analysis in patients ’ fibroblasts showed a marked reduction of COX4I1 protein."
The later genotype leaves reduced rather than universally absent protein.
Impaired Complex IV Assembly
Reduced COX4-1 impairs assembly of the cytochrome c oxidase holoenzyme. In the 2026 case, assembly was modestly reduced in fibroblasts but nearly undetectable in muscle; other respiratory complexes remained assembled.
mitochondrial respiratory chain complex IV assembly GO:0033617 ↓ DECREASED 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.
Experimental models
COX4 isoform knockout and rescue in HEK293 CELL LINE
Downstream
Reduced Complex IV Activity Fewer assembled complexes reduce cytochrome c oxidase activity.
Reduced Mitochondrial Translation Complete COX4 loss in HEK293 cells disrupts mitochondrial translation; the exact assembly-to-translation signal is unresolved.
Show evidence (1 reference)
url:https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download SUPPORT In Vitro
"showed a strong complex IV assembly defect as it was almost undetectable by BN-PAGE"
Muscle extracts showed a much greater assembly defect than cultured fibroblasts.
Reduced Complex IV Activity
Complex IV electron transfer is reduced in patient fibroblasts and muscle. One P152T sibling had muscle complex IV activity at 16% of control. The biochemical defect and its detectability depend on tissue and assay.
mitochondrial electron transport, cytochrome c to oxygen GO:0006123 ↓ DECREASED 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.
Experimental models
Patient-derived COX4I1 fibroblasts PRIMARY CELL CULTURE
Downstream
Impaired Oxidative ATP Production Deficient terminal electron transfer can limit oxidative ATP production.
Show evidence (2 references)
url:https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download SUPPORT In Vitro
"in-gel activity analysis displayed a significant reduction of complex IV activity in patient cells compared to controls"
Fibroblast activity assays demonstrate impaired complex IV function.
url:https://scholarworks.indianapolis.iu.edu/bitstreams/b9b37f63-6e5e-4563-b086-880db5d3d66b/download SUPPORT In Vitro
"cytochrome c oxidase activity was reduced to 16% residual activity compared to control values"
Muscle respiratory-chain enzymology quantified reduced activity in the older sibling.
Impaired Oxidative ATP Production
The founding patient fibroblasts had reduced ATP production that was rescued by wild-type COX4I1. Later assays found relatively preserved ATP-linked respiration in the same patient line, and glycolysis can compensate in culture. Complete cellular ATP collapse is not a uniform finding.
mitochondrial ATP synthesis coupled electron transport GO:0042775 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased mitochondrial ATP synthesis coupled electron transport (GO:0042775). GO:0042775 is a biological process from the Gene Ontology.
Experimental models
Patient-derived COX4I1 fibroblasts PRIMARY CELL CULTURE
Downstream
Neurologic Dysfunction Respiratory dysfunction is a plausible contributor to brain injury, although neural vulnerability was not directly tested in patient neurons.
Increased circulating lactate Altered oxidative metabolism can favor lactate accumulation; normal lactate also occurs.
Increased Glycolysis Cultures adapt to respiratory impairment by favoring glycolysis; the upstream signaling is not fully resolved.
Show evidence (2 references)
PMID:28766551 SUPPORT In Vitro
"COX activity and ATP production were restored by lentiviral transfection with the wild-type gene."
Restoration in patient fibroblasts supports a causal bioenergetic effect of COX4I1 deficiency.
PMID:33672589 SUPPORT In Vitro
"the comparable ATP-linked OCRs in the patient’s and control fibroblasts"
Later respirometry demonstrates that impairment depends on the assay and metabolic context.
Neurologic Dysfunction
The neurologic spectrum includes infantile regression and epileptic encephalopathy, or later progressive motor and cognitive dysfunction with Leigh-like basal ganglia lesions. The growth-predominant founding case had adequate development and no seizures at follow-up.
Downstream
Encephalopathy The P152T siblings had encephalopathy as part of their central nervous system presentation.
Developmental regression Neurologic deterioration can cause loss of previously acquired developmental abilities; age and tempo vary.
Intellectual disability Cognitive impairment accompanies severe neurodevelopmental involvement in some patients.
Seizures Cerebral involvement can manifest as epilepsy, with infantile seizure onset documented in the deletion/missense case.
Infantile spasms The older P152T sibling developed infantile spasms with hypsarrhythmia at 12 months.
Hypotonia Central neurologic disease can contribute to hypotonia, although a peripheral or muscle contribution has not been excluded.
Bilateral basal ganglia lesions MRI demonstrates bilateral caudate and lenticular signal abnormalities in the later-onset neurologic presentation.
Cerebral atrophy Progressive cerebral volume loss documents structural brain involvement in the deletion/missense case.
Spasticity The later-onset motor disorder includes progressive lower-limb spasticity.
Dystonia The later-onset case has a mixed spastic-dystonic movement disorder.
Orofacial dyskinesia Involuntary orofacial movements occur in the later-onset neurologic presentation.
Dysarthria Orofacial motor dysfunction is associated with impaired pronunciation in the later-onset case.
Dysphagia Orofacial motor dysfunction is associated with swallowing difficulty in the later-onset case.
Show evidence (2 references)
PMID:31290619 SUPPORT Human Clinical
"two siblings, born to consanguineous parents, who presented with encephalopathy, developmental regression, hypotonia"
The sibling report establishes the neurologic presentation.
url:https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download SUPPORT Human Clinical
"he experienced a progressive deterioration of motor skills, with increasing spasticity of the lower limbs"
The later-onset case expands the motor phenotype.
Impaired Nuclear DNA Repair
Mechanism confidence: Provisional
Patient fibroblasts and COX4I1-knockdown HFF cells recover poorly from etoposide-induced DNA damage and have reduced expression of DNA-repair genes. A separate HEK293 knockdown reporter showed reduced homologous recombination. The molecular link between COX4-1 and nuclear repair is unresolved.
DNA repair GO:0006281 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased DNA repair (GO:0006281). GO:0006281 is a biological process from the Gene Ontology.
Experimental models
COX4I1 knockdown in human foreskin fibroblasts PRIMARY CELL CULTURE
COX4I1 knockdown HEK293 homologous-recombination reporter CELL LINE
Downstream
Replication-Associated DNA Damage Impaired repair provides a candidate explanation for damage accumulating in proliferating deficient cells.
Show evidence (2 references)
PMID:35456968 SUPPORT In Vitro
"both HFF-shCOX4I1 and the patient’s cells displayed a significant prolongation of the γH2AX foci signal"
Persistent damage after etoposide recovery supports impaired nuclear DNA-damage repair.
PMID:35456968 SUPPORT In Vitro
"detecting a 28% significant decrease in the HR efficiency compared to the control."
The homologous-recombination reporter was measured in COX4I1-silenced HEK293 cells, not directly in patient fibroblasts.
Replication-Associated DNA Damage
Double-stranded DNA breaks occur in COX4I1-deficient cultures and are enriched in proliferating cells. Experiments in COX-inhibited control fibroblasts found damage despite normal ROS and ATP, arguing against a solely oxidative-stress explanation. An NAD+ deficit is proposed, not established as the intermediate.
Downstream
Increased chromosomal breakage Cellular DNA damage provides a plausible link to the founding clinical breakage phenotype; the intermediate steps are not established.
Reduced Cell Proliferation Persistent DNA damage may contribute to reduced proliferation; alternative causes remain possible.
Show evidence (3 references)
PMID:35456968 SUPPORT In Vitro
"We demonstrated that COX4-1 deficiency coincides with accumulative DNA damage, primarily in Ki-67-positive cells"
Damage was enriched in proliferating cells, consistent with replication stress.
PMID:29886046 SUPPORT In Vitro
"We now quantified the DSB by phospho histone H2AX Ser139 staining of COX4-1 and COX6B1 deficient fibroblasts (225% and 215% of normal, respectively) and confirmed their occurrence by neutral comet assay."
The cultured-cell study confirmed double-stranded DNA breaks with an orthogonal assay.
PMID:29886046 SUPPORT In Vitro
"Present results demonstrate elevated nuclear DSB in cells treated with 50 μM KCN for 24 h (170% of normal) in high-glucose medium conditions where ROS and ATP remain normal"
Pharmacologic complex IV inhibition separates nuclear damage from elevated ROS or ATP depletion in this model.
Reduced Cell Proliferation
Mechanism confidence: Provisional
COX4I1-knockdown fibroblasts grow poorly and show telomere shortening and increased senescence-associated beta-galactosidase. Other senescence markers did not confirm a complete senescence program. A contribution to clinical growth failure remains provisional.
Downstream
Short stature Reduced cellular proliferation may contribute to growth failure; this extrapolation has not been demonstrated in vivo.
Show evidence (2 references)
PMID:35456968 SUPPORT In Vitro
"The reduced proliferation observed in COX4-1-deficient cells could be related to premature senescence"
The authors present senescence as a possible explanation rather than a proven exclusive mechanism.
PMID:35456968 SUPPORT In Vitro
"we failed to confirm premature senescence by other means"
The authors explicitly qualify their senescence interpretation.
Conditional Oxidative Stress
ROS accumulation was evident when deficient fibroblasts were grown in glucose-free galactose medium, and was reduced by ascorbate or N-acetylcysteine. This culture-dependent result does not establish ROS as the cause of nuclear DNA breaks.
reactive oxygen species metabolic process GO:0072593 ↑ INCREASED 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.
Show evidence (1 reference)
url:https://pmc.ncbi.nlm.nih.gov/articles/PMC5891488/ SUPPORT In Vitro
"both ascorbate and NAC normalized the ROS production on GAL."
Oxidative stress was conditional on galactose medium and responsive to antioxidants in culture.
HIF1A Stabilization
Nuclear HIF-1α accumulation occurs in the founding patient fibroblasts and HFF knockdown cells under normoxia. The upstream signal is unknown.
HIF1A hgnc:4910 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves HIF1A (hgnc:4910). hgnc:4910 is a gene from the HUGO Gene Nomenclature Committee.
DNA-binding transcription factor activity, RNA polymerase II-specific GO:0000981 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves increased DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981). GO:0000981 is a molecular function from the Gene Ontology.
Downstream
COX4I2 Upregulation HIF-1α-associated transcription is proposed to drive the compensatory isoform response.
Show evidence (1 reference)
PMID:33672589 SUPPORT In Vitro
"the COX4-1-deficient cells displayed increased levels of HIF-1α localized in their nuclei"
Patient and knockdown fibroblasts showed nuclear HIF-1α accumulation under normoxia.
COX4I2 Upregulation
Mechanism confidence: Provisional
COX4-2 expression increases in the founding patient fibroblasts and HFF knockdown models and may partially preserve complex IV function. It was not induced spontaneously in complete-knockout HEK293 cells and could not be reliably detected in the 2026 patient fibroblasts. It is not a demonstrated universal clinical modifier.
COX4I2 hgnc:16232 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves COX4I2 (hgnc:16232). hgnc:16232 is a gene from the HUGO Gene Nomenclature Committee.
COX4-2 contribution to cytochrome-c oxidase activity GO:0004129 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves COX4-2 contribution to cytochrome-c oxidase activity, annotated with cytochrome-c oxidase activity (GO:0004129). GO:0004129 is a molecular function from the Gene Ontology.
Experimental models
COX4I1 knockdown in human foreskin fibroblasts PRIMARY CELL CULTURE
Show evidence (3 references)
PMID:33672589 SUPPORT INDIRECT In Vitro
"we conclude that COX4-2 is upregulated and partially rescues COX4-1 deficiency through HIF-1α activation induced by a yet-to-be-characterized, noncanonical pathway."
The authors propose a compensatory pathway from their fibroblast assays; its upstream signal and clinical impact remain uncertain.
PMID:33578848 SUPPORT In Vitro
"COX4I1 KO in HEK293 cells did not trigger expression of the alternative isoform COX4I2"
The compensation is model-dependent.
url:https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download SUPPORT In Vitro
"COX4I2 mRNA could not be reliably detected by quantitative PCR"
The later patient did not reproduce a detectable isoform switch.
Reduced Mitochondrial Translation
Complete COX4 knockout in HEK293 cells reduces synthesis of mitochondrial-encoded complex I and IV subunits and mitoribosomal protein abundance. The 2026 patient proteome also showed reduced mitoribosomal components, but did not directly measure mitochondrial translation.
mitochondrial translation GO:0032543 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased mitochondrial translation (GO:0032543). GO:0032543 is a biological process from the Gene Ontology.
Experimental models
COX4 isoform knockout and rescue in HEK293 CELL LINE
Downstream
Secondary Complex I Assembly Defect Attenuated mitochondrial protein synthesis is a proposed contributor to complex I biogenesis failure in complete-knockout cells.
Show evidence (2 references)
PMID:33578848 SUPPORT In Vitro
"Pulse-chase metabolic labeling of mitochondrial DNA (mtDNA)-encoded proteins uncovered a decrease in the translation of cIV and cI subunits."
Direct pulse-chase measurements were made in complete-knockout HEK293 models.
PMID:33578848 SUPPORT In Vitro
"partial impairment of mitochondrial protein synthesis correlated with decreased content of mitochondrial ribosomal proteins."
Protein synthesis and ribosomal abundance covary in the knockout model.
Secondary Complex I Assembly Defect
Mechanism confidence: Provisional
Complex I assembly intermediates accumulate in complete COX4-knockout HEK293 cells. This model finding is not a universal patient biochemical phenotype; the founding fibroblasts and 2026 muscle/fibroblast studies retained other respiratory complexes.
mitochondrial respiratory chain complex I assembly GO:0032981 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased mitochondrial respiratory chain complex I assembly (GO:0032981). GO:0032981 is a biological process from the Gene Ontology.
Experimental models
COX4 isoform knockout and rescue in HEK293 CELL LINE
Show evidence (1 reference)
PMID:33578848 SUPPORT In Vitro
"complexome profiling revealed accumulation of cI assembly intermediates, indicating that cI biogenesis, rather than stability, was affected."
The complete-knockout model had a secondary complex I assembly defect.
Increased Glycolysis
The founding patient fibroblasts and COX4I1-knockdown HFF cells shift toward glycolysis, with increased extracellular acidification. This metabolic adaptation can preserve ATP despite impaired respiration, but does not establish clinical protection.
glycolytic process GO:0006096 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased glycolytic process (GO:0006096). GO:0006096 is a biological process from the Gene Ontology.
Show evidence (1 reference)
PMID:33672589 SUPPORT In Vitro
"The energy maps, combining decreased basal OCRs with increased ECARs, clearly showed a tendency towards favoring glycolysis over OXPHOS"
Extracellular flux measurements support a glycolytic shift in patient and knockdown fibroblasts.
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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.
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Phenotypes

33
Blood 2
Increased mean corpuscular volume HP:0005518 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Increased mean corpuscular volume (HP:0005518). HP:0005518 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28766551 SUPPORT Human Clinical
"Investigations were positive only for RBC macrocytosis and delayed bone age."
The founding investigation documented macrocytosis and delayed skeletal maturation.
Normocytic anemia HP:0001897 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Normocytic anemia (HP:0001897). HP:0001897 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35456968 SUPPORT Human Clinical
"Her last blood counts showed mild normocytic anemia, with normal WBC and platelet counts"
The follow-up clinical results distinguish anemia from pancytopenia.
Cardiovascular 1
Aortic coarctation Coarctation of aorta HP:0001680 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Coarctation of aorta (HP:0001680). HP:0001680 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download SUPPORT Human Clinical
"In the neonatal period he underwent surgery for aortic coarctation without remarkable complications."
The case documents co-occurring congenital heart disease without demonstrating COX4I1 causation.
Digestive 2
Dysphagia HP:0002015 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dysphagia (HP:0002015). HP:0002015 is a phenotype from the Human Phenotype Ontology.
Sequelae: Feeding difficulties
Show evidence (1 reference)
url:https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download SUPPORT Human Clinical
"associated with pronunciation difficulties, tongue movement and swal - lowing"
The same clinical description includes swallowing difficulty.
Feeding difficulties HP:0011968 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Feeding difficulties (HP:0011968). HP:0011968 is a phenotype from the Human Phenotype Ontology.
Sequelae: Failure to thrive
Show evidence (2 references)
PMID:40095452 SUPPORT Human Clinical
"He exhibits global developmental delays and generalized hypotonia, with an inability to sit unassisted, speak, recognize family members, maintain visual tracking, or chew solid food."
The deletion/missense case could not chew solid food.
url:https://scholarworks.indianapolis.iu.edu/bitstreams/b9b37f63-6e5e-4563-b086-880db5d3d66b/download SUPPORT Human Clinical
"He had profound hypotonia and required gastrostomy tube placement for feedings."
The younger sibling required tube feeding.
Eye 2
Hypermetropia HP:0000540 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypermetropia (HP:0000540). HP:0000540 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download SUPPORT BACKGROUND Human Clinical
"Moderate hyperopia but no evidence of retinopathy or optic nerve atrophy"
The 2026 table summarizes an ocular finding from the earlier sibling report.
Exotropia HP:0000577 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Exotropia (HP:0000577). HP:0000577 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download SUPPORT BACKGROUND Human Clinical
"Intermittent alternating exotropia with no evidence of retinopathy or optic nerve atrophy"
The 2026 comparison table describes the earlier sibling phenotype.
Head and Neck 3
Prominent nasal bridge HP:0000426 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Prominent nasal bridge (HP:0000426). HP:0000426 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28766551 SUPPORT Human Clinical
"minor dysmorphic features including prominent nasal bridge, frontal bossing, and short 5th fingers bilaterally"
The founding examination specifies these features rather than a generic facial-shape abnormality.
Frontal bossing HP:0002007 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Frontal bossing (HP:0002007). HP:0002007 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28766551 SUPPORT Human Clinical
"minor dysmorphic features including prominent nasal bridge, frontal bossing, and short 5th fingers bilaterally"
The founding examination specifies these features rather than a generic facial-shape abnormality.
Microcephaly HP:0000252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Microcephaly (HP:0000252). HP:0000252 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40095452 SUPPORT Human Clinical
"the patient presents with normal stature (height of 117 cm, 50th percentile), microcephaly (head circumference of 45 cm, −3 SD)"
The clinical head circumference establishes microcephaly.
Limbs 2
Short fifth fingers Short 5th finger HP:0009237 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short 5th finger (HP:0009237). HP:0009237 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28766551 SUPPORT Human Clinical
"minor dysmorphic features including prominent nasal bridge, frontal bossing, and short 5th fingers bilaterally"
The founding examination specifies these features rather than a generic facial-shape abnormality.
Distal toe phalanx hypoplasia Aplasia/Hypoplasia of the distal phalanges of the toes HP:0010185 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Aplasia/Hypoplasia of the distal phalanges of the toes (HP:0010185). HP:0010185 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://scholarworks.indianapolis.iu.edu/bitstreams/b9b37f63-6e5e-4563-b086-880db5d3d66b/download SUPPORT Human Clinical
"Physical examination did not show any dysmorphic features except bilateral hypoplasia of the distal phalanges of the 2nd-5th toes"
The finding is anatomically localized to the distal toe phalanges.
Metabolism 1
Increased circulating lactate Increased circulating lactate concentration HP:0002151 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Increased circulating lactate concentration (HP:0002151). HP:0002151 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download SUPPORT Human Clinical
"Biochemical studies showed high levels of plasma lactate, with normal pyruvate"
The later-onset patient had increased plasma lactate; this does not alone demonstrate acidosis.
Musculoskeletal 3
Delayed skeletal maturation HP:0002750 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Delayed skeletal maturation (HP:0002750). HP:0002750 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28766551 SUPPORT Human Clinical
"Investigations were positive only for RBC macrocytosis and delayed bone age."
The founding investigation documented macrocytosis and delayed skeletal maturation.
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"
The sibling report establishes the neurologic presentation.
Spasticity HP:0001257 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Spasticity (HP:0001257). HP:0001257 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download SUPPORT Human Clinical
"progressive deterioration of motor skills, with increasing spasticity of the lower limbs"
Spasticity accompanied progressive motor impairment.
Nervous System 14
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"
The sibling report establishes the neurologic 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"
The sibling report establishes the neurologic presentation.
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:40095452 SUPPORT Human Clinical
"The patient presents with developmental regression, intellectual disability, epileptic seizures, microcephaly, and progressive cerebral atrophy"
The case discussion summarizes the directly observed neurodevelopmental 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:40095452 SUPPORT Human Clinical
"By the eleventh month, the child began experiencing epileptic seizures characterized by upward eye deviation, spasm‐like nodding, and embracing motions."
Seizures began during infancy in this child.
Infantile spasms HP:0012469 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Infantile spasms (HP:0012469). HP:0012469 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://scholarworks.indianapolis.iu.edu/bitstreams/b9b37f63-6e5e-4563-b086-880db5d3d66b/download SUPPORT Human Clinical
"Infantile spasms associated with hypsarrhythmia on EEG started at 12 months"
The older sibling had infantile spasms with hypsarrhythmia.
Hyperreflexia HP:0001347 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hyperreflexia (HP:0001347). HP:0001347 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://scholarworks.indianapolis.iu.edu/bitstreams/b9b37f63-6e5e-4563-b086-880db5d3d66b/download SUPPORT Human Clinical
"He also had axial and appendicular hypotonia and patellar hyperreflexia."
The examination directly documents hyperreflexia.
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)
url:https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download SUPPORT Human Clinical
"Brain MRI revealed T2 hyperintensities in both caudate and lenticular nuclei"
MRI directly establishes bilateral basal ganglia involvement.
Cerebral atrophy HP:0002059 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cerebral atrophy (HP:0002059). HP:0002059 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40095452 SUPPORT Human Clinical
"MRI reveals significant enlargement of the ventricles and marked deepening and widening of the cerebral sulci, suggesting progressive cerebral atrophy"
Serial imaging supports cerebral volume loss.
Cerebellar atrophy HP:0001272 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cerebellar atrophy (HP:0001272). HP:0001272 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://scholarworks.indianapolis.iu.edu/bitstreams/b9b37f63-6e5e-4563-b086-880db5d3d66b/download SUPPORT Human Clinical
"Brain MRI showed mild to moderate generalized cerebral/cerebellar atrophy and evidence of bilateral hypertrophic olivary degeneration"
The younger sibling had both cerebral and cerebellar atrophy.
Olivary degeneration HP:0008303 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Olivary degeneration (HP:0008303). HP:0008303 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://scholarworks.indianapolis.iu.edu/bitstreams/b9b37f63-6e5e-4563-b086-880db5d3d66b/download SUPPORT Human Clinical
"Brain MRI showed mild to moderate generalized cerebral/cerebellar atrophy and evidence of bilateral hypertrophic olivary degeneration"
The MRI documents the specific olivary finding.
Inferior cerebellar vermis hypoplasia HP:0007068 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Inferior cerebellar vermis hypoplasia (HP:0007068). HP:0007068 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://scholarworks.indianapolis.iu.edu/bitstreams/b9b37f63-6e5e-4563-b086-880db5d3d66b/download SUPPORT Human Clinical
"diffuse cerebral and cerebellar volume loss, and congenital hypoplasia of the inferior vermis"
The report distinguishes inferior vermis hypoplasia from diffuse atrophy.
Dystonia HP:0001332 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dystonia (HP:0001332). HP:0001332 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download SUPPORT Human Clinical
"He also showed spastic-dystonic triparesis, mainly affecting right extremities"
The later-onset patient had dystonic as well as spastic motor signs.
Orofacial dyskinesia HP:0002310 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Orofacial dyskinesia (HP:0002310). HP:0002310 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download SUPPORT Human Clinical
"he showed orofacial invol - untary movements, including blinking and dyskinesias"
The report specifies the anatomic distribution of dyskinesia.
Dysarthria HP:0001260 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dysarthria (HP:0001260). HP:0001260 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download SUPPORT Human Clinical
"associated with pronunciation difficulties, tongue movement and swal - lowing"
The source links speech difficulty to orofacial motor dysfunction.
Cellular 1
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
"The result showed normal female karyotype and 29% of the cells showed ≥1 break/cell."
The diagnostic chromosome-breakage assay was abnormal.
Context-specific annotations (1)
Genetic COX4I1
Homozygous p.Pro152Thr in the two reported siblings
Neither sibling had abnormal chromosome-breakage studies; this observation does not exclude breakage in other genotypes.
Show evidence (1 reference)
url:https://scholarworks.indianapolis.iu.edu/bitstreams/b9b37f63-6e5e-4563-b086-880db5d3d66b/download SUPPORT Human Clinical
"both siblings described here did not have hematological features and abnormal chromosome breakage studies consistent with Fanconi anemia"
The primary report documents normal breakage studies in these two siblings.
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"
The founding patient had growth failure.
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"
The founding patient had growth failure.
🧬

Genetic Associations

1
COX4I1
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 (4 references)
PMID:28766551 SUPPORT Human Clinical
"we focused on chr16: g.85839400_85839401delinsTT, NM_001861.3:c.303_304delinsTT, p.(Lys101_Thr102delinsAsnSer) in the COX4I1 gene."
The founding allele is a complex substitution, although the paper uses K101N as shorthand.
url:https://scholarworks.indianapolis.iu.edu/bitstreams/b9b37f63-6e5e-4563-b086-880db5d3d66b/download SUPPORT Human Clinical
"A homozygous c.454C>A (p.P152T) variant in COX4I1 was detected by trio exome sequencing in Patient 1 and confirmed by familial mutation testing in Patient 2."
The two siblings carried the same homozygous missense allele.
PMID:40095452 SUPPORT Human Clinical
"The analysis revealed that the patient harbors a heterozygous deletion of approximately 0.13 Mb (chr16:85706011–85 840 495) in the 16q24.1 region, encompassing eight genes, including COX4I1"
The deletion includes COX4I1 and additional genes; it is not a demonstrated isolated regulatory lesion.
+ 1 more reference
Variants (5)
NM_001861.3:c.303_304delinsTT (p.Lys101_Thr102delinsAsnSer)
Gene: COX4I1 hgnc:2265 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in COX4I1 (hgnc:2265). hgnc:2265 is a gene from the HUGO Gene Nomenclature Committee. Complex coding substitution
Genomic context: coding sequence
Founding homozygous allele, often abbreviated K101N. The measured transcript reduction does not by itself establish a splicing defect.
Show evidence (2 references)
PMID:28766551 SUPPORT Human Clinical
"we focused on chr16: g.85839400_85839401delinsTT, NM_001861.3:c.303_304delinsTT, p.(Lys101_Thr102delinsAsnSer) in the COX4I1 gene."
The founding allele is a complex substitution, although the paper uses K101N as shorthand.
PMID:28766551 SUPPORT In Vitro
"Western blot analysis revealed undetectable COX 4 protein while complexes I and II were comparable to controls"
Patient fibroblast immunoblotting demonstrates loss of detectable COX4 protein.
c.454C>A (p.Pro152Thr)
Gene: COX4I1 hgnc:2265 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in COX4I1 (hgnc:2265). hgnc:2265 is a gene from the HUGO Gene Nomenclature Committee. single nucleotide variant
Genomic context: coding sequence
Homozygous in two siblings with neurologic disease and in trans with a COX4I1-containing deletion in a later child.
Show evidence (2 references)
url:https://scholarworks.indianapolis.iu.edu/bitstreams/b9b37f63-6e5e-4563-b086-880db5d3d66b/download SUPPORT Human Clinical
"A homozygous c.454C>A (p.P152T) variant in COX4I1 was detected by trio exome sequencing in Patient 1 and confirmed by familial mutation testing in Patient 2."
The two siblings carried the same homozygous missense allele.
PMID:40095452 SUPPORT Human Clinical
"Compound heterozygosity for a de novo 16q24.1 deletion and a P152T missense mutation in the COX4I1 was detected."
The later child carried the recurrent missense allele opposite a deletion.
16q24.1 deletion encompassing COX4I1
Gene: COX4I1 hgnc:2265 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in COX4I1 (hgnc:2265). hgnc:2265 is a gene from the HUGO Gene Nomenclature Committee. deletion
Genomic context: coding sequence intron
Affected regions (reference genome)
16q24.1 multigene interval 16q24.1
Overlaps genes: COX4I1 hgnc:2265
Reported de novo approximately 0.13-Mb deletion, GRCh37 chr16:85706011-85840495, in trans with paternal p.Pro152Thr. Eight genes are encompassed; contributions from other deleted genes cannot be excluded.
Show evidence (1 reference)
PMID:40095452 SUPPORT Human Clinical
"The analysis revealed that the patient harbors a heterozygous deletion of approximately 0.13 Mb (chr16:85706011–85 840 495) in the 16q24.1 region, encompassing eight genes, including COX4I1"
The deletion includes COX4I1 and additional genes; it is not a demonstrated isolated regulatory lesion.
c.64C>T (p.Arg22Ter)
Gene: COX4I1 hgnc:2265 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in COX4I1 (hgnc:2265). hgnc:2265 is a gene from the HUGO Gene Nomenclature Committee. single nucleotide variant
Genomic context: coding sequence
De novo early nonsense variant phased in trans with paternal c.73+1511A>G. Detection in multiple tissues did not establish parental origin or an exact developmental time of occurrence.
Show evidence (2 references)
url:https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download SUPPORT Human Clinical
"identified a heterozygous nonsense variant (c.64C > T, p.Arg22Ter) in COX4I1 gene"
Exome sequencing identified the nonsense allele.
url:https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download SUPPORT Human Clinical
"Phasing analysis of long sequencing data showed that the two variants were in trans"
Targeted long-read sequencing placed the nonsense and intronic variants on opposite alleles.
c.73+1511A>G
Gene: COX4I1 hgnc:2265 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in COX4I1 (hgnc:2265). hgnc:2265 is a gene from the HUGO Gene Nomenclature Committee. single nucleotide variant
Genomic context: intron
Paternally inherited intron-2 variant causing leaky cryptic splicing, an 82-base intronic insertion with loss of the first two exon-3 bases, and predicted p.Glu25ValfsTer9. Patient RNA and a minigene assay establish the splice effect.
Functional effects
Aberrant splicing
Cryptic splice activation reduces productive COX4I1 transcripts; residual normally spliced transcript remains.
Show evidence (2 references)
url:https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download SUPPORT In Vitro
"the c.73 + 1511A > G variant promotes the aberrant incorporation of an intronic sequence into COX4I1 mRNA."
Patient RNA and a HAP1 minigene assay support cryptic splice activation.
url:https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download SUPPORT Human Clinical
"Phasing analysis of long sequencing data showed that the two variants were in trans"
Targeted long-read sequencing placed the nonsense and intronic variants on opposite alleles.
💊

Medical Actions

8
Nutritional and feeding support
Action: Nutritional SupportNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Nutritional Support (NCIT:C15433). NCIT:C15433 is a clinical intervention from the NCI Thesaurus. NCIT:C15433
Assess growth, oral intake and swallowing safety; use feeding therapy, caloric support and gastrostomy when needed. Both P152T siblings required gastrostomy. General Leigh syndrome guidance supports individualized nutritional care.
Target Phenotypes: Feeding difficulties HP:0011968 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Feeding difficulties (HP:0011968). HP:0011968 is a phenotype from the Human Phenotype Ontology. Dysphagia HP:0002015 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Dysphagia (HP:0002015). HP:0002015 is a phenotype from the Human Phenotype Ontology. Failure to thrive HP:0001508 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Failure to thrive (HP:0001508). HP:0001508 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/ SUPPORT REVIEW SYNTHESIS Other
"Feeding therapy as needed; gastrostomy tube placement may improve nutritional intake for those w/persistent feeding issues, choking, or aspiration risk due to dysphagia"
GeneReviews supports tube feeding according to feeding safety and nutritional need.
url:https://scholarworks.indianapolis.iu.edu/bitstreams/b9b37f63-6e5e-4563-b086-880db5d3d66b/download SUPPORT Human Clinical
"Like his brother, he also required gastrostomy tube for feedings."
Both siblings required gastrostomy feeding.
Seizure management
Action: Anticonvulsant TherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Anticonvulsant Therapy (NCIT:C64172). NCIT:C64172 is a clinical intervention from the NCI Thesaurus. NCIT:C64172
An experienced neurologist should individualize antiseizure treatment. ACTH, topiramate, valproate, zonisamide, levetiracetam and clonazepam have been used in reported cases, with refractory seizures in the deletion/missense case. Historical valproate use is not a recommendation: general mitochondrial guidance advises avoiding it if possible; the absolute POLG contraindication should not be misattributed to COX4I1.
Target Phenotypes: Seizure HP:0001250 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology. Infantile spasms HP:0012469 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Infantile spasms (HP:0012469). HP:0012469 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/ SUPPORT REVIEW SYNTHESIS Other
"Treatment w/ASM by experienced neurologist ... Sodium valproate should be avoided because of its inhibitory effects on the mitochondrial respiratory chain."
GeneReviews recommends specialist seizure management.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/ SUPPORT REVIEW SYNTHESIS Other
"Sodium valproate should be avoided if possible, because of its inhibitory effect on respiratory chain enzymes."
GeneReviews distinguishes preferred avoidance from the separate POLG-specific absolute contraindication.
url:https://scholarworks.indianapolis.iu.edu/bitstreams/b9b37f63-6e5e-4563-b086-880db5d3d66b/download SUPPORT Human Clinical
"Currently, his antiepileptic treatment includes zonisamide and levetiracetam."
The younger sibling received these agents; this sentence does not establish efficacy.
Rehabilitation and communication support
Action: RehabilitationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Rehabilitation (NCIT:C15315). NCIT:C15315 is a clinical intervention from the NCI Thesaurus. NCIT:C15315
Physical, occupational and communication therapies and mobility aids address functional needs. An eye-tracking communication system had a positive reported effect in the later-onset case. Motor progression continued despite botulinum toxin treatment; this is not evidence of a disease-modifying benefit.
Target Phenotypes: Spasticity HP:0001257 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Spasticity (HP:0001257). HP:0001257 is a phenotype from the Human Phenotype Ontology. Dystonia HP:0001332 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Dystonia (HP:0001332). HP:0001332 is a phenotype from the Human Phenotype Ontology. Dysarthria HP:0001260 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Dysarthria (HP:0001260). HP:0001260 is a phenotype from the Human Phenotype Ontology. Hypotonia HP:0001252 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Hypotonia (HP:0001252). HP:0001252 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/ SUPPORT REVIEW SYNTHESIS Other
"Equipment to prevent falling, maintain independent mobility as appropriate"
GeneReviews describes supportive mobility equipment.
url:https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download SUPPORT Human Clinical
"use of an eye-tracking system to facilitate communication, with very positive results."
The later-onset patient benefited from assisted communication.
url:https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download SUPPORT Human Clinical
"increasing spasticity of the lower limbs despite botulinum toxin treatment"
Motor progression occurred despite symptomatic botulinum treatment.
Empirical ubiquinol supplementation
Action: Nutritional SupportNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Nutritional Support (NCIT:C15433). NCIT:C15433 is a clinical intervention from the NCI Thesaurus. NCIT:C15433
Agent: ubiquinol-10 CHEBI:64183 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses ubiquinol-10 (CHEBI:64183). CHEBI:64183 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Parents of the P152T siblings reported modest improvement in head control/tone or visual focus after four months of coenzyme Q10 treatment. These uncontrolled observations do not establish sustained or disease-modifying efficacy.
Show evidence (2 references)
url:https://scholarworks.indianapolis.iu.edu/bitstreams/b9b37f63-6e5e-4563-b086-880db5d3d66b/download SUPPORT Human Clinical
"Four months after initiation of therapy with Coenzyme Q10, parents reported improvement in head control and tone."
The younger sibling had a parent-reported response.
url:https://scholarworks.indianapolis.iu.edu/bitstreams/b9b37f63-6e5e-4563-b086-880db5d3d66b/download SUPPORT Human Clinical
"Parents reported improvement in visual focus four months after initiation of Coenzyme Q10 therapy."
The older sibling had a parent-reported response.
Empirical vitamin C supplementation
Action: Nutritional SupportNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Nutritional Support (NCIT:C15433). NCIT:C15433 is a clinical intervention from the NCI Thesaurus. NCIT:C15433
Agent: L-ascorbic acid CHEBI:29073 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses L-ascorbic acid (CHEBI:29073). CHEBI:29073 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
The founding patient was maintained on vitamin C after antioxidant findings in fibroblasts. The follow-up did not establish a clinical treatment effect. N-acetylcysteine and nicotinamide riboside results remain cell-culture observations.
Show evidence (2 references)
PMID:35456968 SUPPORT Human Clinical
"She is maintained only on a daily dose of 100 mg vitamin C"
Follow-up documents use, not proven efficacy.
url:https://pmc.ncbi.nlm.nih.gov/articles/PMC5891488/ SUPPORT In Vitro
"both ascorbate and NAC normalized the ROS production on GAL."
Oxidative stress was conditional on galactose medium and responsive to antioxidants in culture.
Perioperative metabolic support
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. NCIT:C15747
General mitochondrial guidance supports minimizing fasting, considering intravenous glucose during prolonged anesthesia when appropriate, and careful respiratory monitoring. Prolonged propofol and lactate-containing fluids require particular caution in patients at risk of acidosis.
Show evidence (2 references)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/ SUPPORT REVIEW SYNTHESIS Other
"Catabolism should be prevented by minimizing preoperative fasting and considering intravenous glucose perioperatively during prolonged anesthesia (unless the individual is on a ketogenic diet)."
The general LSS recommendation supports an individualized perioperative plan.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/ SUPPORT REVIEW SYNTHESIS Other
"Prolonged propofol use during maintenance anesthesia may increase the risk of lactic acidosis."
The chapter identifies a perioperative risk; this is not a claim that all COX4I1 patients have acidosis.
Longitudinal multidisciplinary surveillance
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. NCIT:C15747
Monitor neurologic function, development, movement disorders, nutrition, swallowing and blood counts. General LSS guidance supports regular ophthalmologic, audiologic and cardiac assessments, adapted to the individual; it does not establish those complications as frequent COX4I1 phenotypes.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/ SUPPORT REVIEW SYNTHESIS Other
"Affected individuals should be followed at regular intervals (typically every 6-12 months) to monitor progression of known manifestations and the appearance of new manifestations."
GeneReviews recommends repeated assessment across the LSS spectrum.
Genetic counseling
Action: Genetic CounselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic Counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. NCIT:C15240
Confirm familial alleles and phase. If both parents carry a causal allele, each pregnancy has a 25% affected risk; families with a de novo allele require individualized recurrence assessment, including residual parental mosaicism risk. Prenatal and preimplantation testing become possible after causal variants are identified.
Show evidence (3 references)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/ SUPPORT REVIEW SYNTHESIS Other
"If both parents are known to be ... heterozygous ... for an LSS-related ... pathogenic variant ... each sib of an affected individual has at conception a 25% chance of being affected"
The 25% figure is conditional on both parents being carriers.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/ SUPPORT REVIEW SYNTHESIS Other
"Once the LSS-related ... pathogenic variant ... (s) have been identified in an affected family member, prenatal and ... preimplantation genetic testing ... are possible."
GeneReviews supports reproductive testing after molecular diagnosis.
url:https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download SUPPORT Human Clinical
"Phasing analysis of long sequencing data showed that the two variants were in trans"
Targeted long-read sequencing placed the nonsense and intronic variants on opposite alleles.
🔬

Biochemical Markers

1
Medium- and long-chain acylcarnitine elevation (Elevated)
Context: Plasma in the later-onset nonsense/intronic case
Show evidence (1 reference)
url:https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download SUPPORT Human Clinical
"consistently increased levels of medium- and long- chain acylcarnitine species"
The case reports a persistent acylcarnitine abnormality.
🔬

Diagnosis

5
Molecular diagnosis and segregation
Identify biallelic causative COX4I1 alleles by exome/genome or a suitable panel, and test parents. Apparent homozygosity inconsistent with segregation warrants deletion analysis. A single identified allele can require RNA studies and intronic sequencing; long reads can resolve phase. General LSS guidance favors genome sequencing when available and consideration of trio testing in children.
DNA Sequencing NCIT:C153598 NCI Thesaurus (NCIT)
Show evidence (6 references)
url:https://scholarworks.indianapolis.iu.edu/bitstreams/b9b37f63-6e5e-4563-b086-880db5d3d66b/download SUPPORT Human Clinical
"A homozygous c.454C>A (p.P152T) variant in COX4I1 was detected by trio exome sequencing in Patient 1 and confirmed by familial mutation testing in Patient 2."
The two siblings carried the same homozygous missense allele.
PMID:40095452 SUPPORT Human Clinical
"The analysis revealed that the patient harbors a heterozygous deletion of approximately 0.13 Mb (chr16:85706011–85 840 495) in the 16q24.1 region, encompassing eight genes, including COX4I1"
The deletion includes COX4I1 and additional genes; it is not a demonstrated isolated regulatory lesion.
url:https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download SUPPORT Human Clinical
"Phasing analysis of long sequencing data showed that the two variants were in trans"
Targeted long-read sequencing placed the nonsense and intronic variants on opposite alleles.
+ 3 more references
Brain MRI
Assess basal ganglia and brainstem lesions, cerebral/cerebellar atrophy and other neurologic abnormalities. Imaging can remain stable despite clinical deterioration or be normal in the growth-predominant presentation.
Magnetic Resonance Imaging NCIT:C16809 NCI Thesaurus (NCIT)
Show evidence (2 references)
url:https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download SUPPORT Human Clinical
"Brain MRI revealed T2 hyperintensities in both caudate and lenticular nuclei"
The patient MRI localizes characteristic lesions.
PMID:28766551 SUPPORT Human Clinical
"Brain MRI was performed and found normal without any indication of mitochondrial disease"
The founding case had normal brain imaging.
Lactate measurement
Lactate supports the metabolic assessment but normal plasma or CSF lactate does not exclude COX4I1 disease.
Lactic Acid Measurement NCIT:C79450 NCI Thesaurus (NCIT)
Show evidence (4 references)
url:https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download SUPPORT Human Clinical
"Biochemical studies showed high levels of plasma lactate, with normal pyruvate"
The later-onset patient had increased plasma lactate; this does not alone demonstrate acidosis.
url:https://scholarworks.indianapolis.iu.edu/bitstreams/b9b37f63-6e5e-4563-b086-880db5d3d66b/download SUPPORT Human Clinical
"He had a normal comprehensive work up including CK, plasma amino acids, urine organic acid analysis, carbohydrate deficient transferrin, lactate and pyruvate."
The older sibling had normal lactate and pyruvate.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/ SUPPORT REVIEW SYNTHESIS Other
"Elevated blood and/or cerebrospinal fluid (CSF) lactate concentrations may strongly support the diagnosis of nuclear-encoded LSS."
General LSS guidance supports lactate as a diagnostic clue rather than a gene-specific test.
+ 1 more reference
Respiratory-chain and RNA functional studies
Enzymology, immunoblotting, blue-native electrophoresis and transcript/minigene analysis can support variant interpretation. Tissue differences are substantial; a relatively mild fibroblast assembly defect can coexist with a severe muscle defect. Invasive tissue enzymology is generally reserved for selected unresolved cases or variants, after genomic evaluation.
Respiratory-chain and RNA functional studies
Show evidence (4 references)
url:https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download SUPPORT In Vitro
"showed a strong complex IV assembly defect as it was almost undetectable by BN-PAGE"
Muscle extracts showed a much greater assembly defect than cultured fibroblasts.
url:https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download SUPPORT In Vitro
"in-gel activity analysis displayed a significant reduction of complex IV activity in patient cells compared to controls"
Fibroblast activity assays demonstrate impaired complex IV function.
url:https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download SUPPORT In Vitro
"the c.73 + 1511A > G variant promotes the aberrant incorporation of an intronic sequence into COX4I1 mRNA."
Patient RNA and a HAP1 minigene assay support cryptic splice activation.
+ 1 more reference
Chromosome-breakage and hematologic assessment
Chromosome-breakage testing may be abnormal in the growth-predominant presentation but normal in neurologic cases. Follow blood counts and growth; a breakage phenotype alone does not establish Fanconi anemia.
Chromosome-breakage and hematologic assessment
Show evidence (2 references)
PMID:28766551 SUPPORT Human Clinical
"The result showed normal female karyotype and 29% of the cells showed ≥1 break/cell."
DEB testing detected chromosome breakage in the founding case.
PMID:35456968 SUPPORT Human Clinical
"Her last blood counts showed mild normocytic anemia, with normal WBC and platelet counts"
Follow-up blood counts specify the hematologic involvement.
📊

Related Datasets

2
Upregulation of COX4-2 via HIF-1α stabilization in COX4-1 deficiency geo:GSE166429
CEL-Seq2 transcriptomic study of COX4I1-downregulated human foreskin fibroblasts, with metabolic/hypoxia-pathway analysis and later reanalysis of DNA-repair genes. This is a disease-mechanism cell model rather than a patient outcome cohort.
BULK RNA SEQ
PMID:33672589
Show evidence (1 reference)
GEO:GSE166429 SUPPORT In Vitro
"COX4-1 was downregulated using a stable expression of COX4I1-targeting shRNAs in human foreskin fibroblasts (HFF), to mirror and compare it to the primary patient's cells."
The repository summary identifies the perturbation and culture model.
Loss of COX4i1 leads to combined respiratory chain deficiency and impaired mitochondrial protein synthesis PRIDE:PXD023367
Label-free mass-spectrometry proteomics of wild-type HEK293 cells and COX4I1, COX4I2 or double-knockout clones. A mechanistic perturbation resource, not a patient cohort.
PROTEOMICS
PMID:33578848
Show evidence (1 reference)
PMID:33578848 SUPPORT In Vitro
"LFQ dataset is publicly available in the PRIDE repository (https://www.ebi.ac.uk/pride), accession number PXD023367"
The primary publication identifies the deposited knockout proteome.
🧫

Experimental Models

5
Patient-derived COX4I1 fibroblasts PRIMARY_CELL_CULTURE
Patient cultures support transcript, protein, respiration, oxidative-stress and DNA-damage assays. Findings depend on genotype, medium and tissue; they do not directly measure neurologic injury.
fibroblast CL:0000057 Cell Ontology (CL) Relation: this experimental model uses this cell type This experimental model uses fibroblast (CL:0000057). CL:0000057 is a cell type from the Cell Ontology.
Cell source
Primary fibroblasts from affected individuals
Pathograph links
COX4I1 Protein Deficiency recapitulates observes: molecular
Reduced Complex IV Activity recapitulates observes: molecular
Impaired Oxidative ATP Production rescues observes: molecular
Limitations: Lentiviral wild-type complementation is a culture experiment, not a clinical gene therapy.
Findings
Wild-type COX4I1 rescued complex IV activity and ATP production in founding patient cells.
Ascorbate and N-acetylcysteine normalized ROS in galactose medium; only N-acetylcysteine improved growth in the 2018 comparison.
Nicotinamide riboside ameliorated DNA breaks in vitro; clinical efficacy is unproven.
Fibroblast assays do not directly model brain dysfunction, marrow physiology, or whole-organ growth. Genetic background and culture conditions can affect comparison between patient lines.
Show evidence (4 references)
PMID:28766551 SUPPORT In Vitro
"Western blot analysis revealed undetectable COX 4 protein while complexes I and II were comparable to controls"
Patient fibroblast immunoblotting demonstrates loss of detectable COX4 protein.
PMID:28766551 SUPPORT In Vitro
"COX activity and ATP production were restored by lentiviral transfection with the wild-type gene."
Restoration in patient fibroblasts supports a causal bioenergetic effect of COX4I1 deficiency.
url:https://pmc.ncbi.nlm.nih.gov/articles/PMC5891488/ SUPPORT In Vitro
"Only NAC had a significant positive effect on the growth ratio."
The comparison found a growth benefit only for NAC.
+ 1 more reference
COX4I1 knockdown in human foreskin fibroblasts PRIMARY_CELL_CULTURE
Knockdown cultures model HIF-1α accumulation, COX4I2 upregulation, altered metabolism and impaired recovery from DNA damage.
fibroblast CL:0000057 Cell Ontology (CL) Relation: this experimental model uses this cell type This experimental model uses fibroblast (CL:0000057). CL:0000057 is a cell type from the Cell Ontology.
Cell source
Human foreskin fibroblasts with stable COX4I1-targeting shRNA
Publication
PMID:35456968
Pathograph links
Impaired Nuclear DNA Repair recapitulates observes: molecular
COX4I2 Upregulation recapitulates observes: molecular
Show evidence (3 references)
PMID:35456968 SUPPORT In Vitro
"both HFF-shCOX4I1 and the patient’s cells displayed a significant prolongation of the γH2AX foci signal"
Persistent damage after etoposide recovery supports impaired nuclear DNA-damage repair.
PMID:33672589 SUPPORT In Vitro
"the COX4-1-deficient cells displayed increased levels of HIF-1α localized in their nuclei"
Patient and knockdown fibroblasts showed nuclear HIF-1α accumulation under normoxia.
PMID:33672589 SUPPORT INDIRECT In Vitro
"we conclude that COX4-2 is upregulated and partially rescues COX4-1 deficiency through HIF-1α activation induced by a yet-to-be-characterized, noncanonical pathway."
The authors propose a compensatory pathway from their fibroblast assays; its upstream signal and clinical impact remain uncertain.
COX4I1 knockdown HEK293 homologous-recombination reporter CELL_LINE
A plasmid reporter measured a 28% reduction in homologous-recombination efficiency. Primary fibroblast transfection limitations prompted use of this transformed cell line.
Cell source
HEK293 cells carrying COX4I1 shRNA and a recombination reporter
Publication
PMID:35456968
Pathograph links
Impaired Nuclear DNA Repair partially recapitulates observes: molecular
Limitations: Reporter repair in transformed HEK293 cells is not equivalent to repair in patient tissues.
Show evidence (1 reference)
PMID:35456968 SUPPORT In Vitro
"detecting a 28% significant decrease in the HR efficiency compared to the control."
The homologous-recombination reporter was measured in COX4I1-silenced HEK293 cells, not directly in patient fibroblasts.
COX4 isoform knockout and rescue in HEK293 CELL_LINE
Complete knockout causes complex IV loss, reduced mitochondrial translation and secondary complex I assembly defects. Forced expression of either isoform restores respiratory function; endogenous COX4I2 is not automatically induced.
Cell source
CRISPR-edited HEK293 cells lacking COX4I1 or both COX4 isoforms
Publication
PMID:33578848
Pathograph links
Reduced Mitochondrial Translation recapitulates observes: molecular
Secondary Complex I Assembly Defect recapitulates observes: molecular
Impaired Complex IV Assembly rescues observes: molecular
Limitations: Forced isoform expression rescues complete-knockout cultures, not a proven patient treatment.
Show evidence (3 references)
PMID:33578848 SUPPORT In Vitro
"Pulse-chase metabolic labeling of mitochondrial DNA (mtDNA)-encoded proteins uncovered a decrease in the translation of cIV and cI subunits."
Direct pulse-chase measurements were made in complete-knockout HEK293 models.
PMID:33578848 SUPPORT In Vitro
"complexome profiling revealed accumulation of cI assembly intermediates, indicating that cI biogenesis, rather than stability, was affected."
The complete-knockout model had a secondary complex I assembly defect.
PMID:33578848 SUPPORT In Vitro
"Expression of either isoform on the COX4I1/4I2 KO background fully restored the respiratory pattern to match control cells"
Genetic rescue establishes functional interchangeability under forced expression.
HAP1 COX4I1 intronic-variant minigene CELL_LINE
The mutant minigene reproduces leaky intronic retention seen in patient fibroblasts.
Cell source
HAP1 cells transfected with wild-type or c.73+1511A>G minigenes
Publication
PMID:41203052
Pathograph links
Aberrant COX4I1 Splicing recapitulates observes: molecular
Show evidence (1 reference)
url:https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download SUPPORT In Vitro
"the c.73 + 1511A > G variant promotes the aberrant incorporation of an intronic sequence into COX4I1 mRNA."
Patient RNA and a HAP1 minigene assay support cryptic splice activation.
{ }

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 mitochondrial complex IV deficiency is an autosomal recessive disorder caused by biallelic
  COX4I1 variants. Reduced abundance or function of the COX4-1 structural and regulatory subunit impairs complex
  IV assembly and respiratory-chain function. Presentations range from severe growth failure with chromosome
  breakage and mild hematologic abnormalities to infantile encephalopathy with regression and epilepsy, or
  later progressive spastic-dystonic motor and cognitive impairment with Leigh-like basal ganglia lesions.
  Normal lactate, normal chromosome-breakage studies, or initially normal development do not exclude the disorder.
  Nuclear DNA-repair defects and replication-associated DNA damage have been demonstrated in cell models; excess
  reactive oxygen species alone does not explain this branch of the disease mechanism.
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
- reference: PMID:29396562
  title: Cytochrome c oxidase deficiency, oxidative stress, possible antioxidant therapy and link to nuclear DNA damage.
- reference: PMID:41203052
  title: >-
    Complex IV deficiency due to COX4I1 deep intronic and de novo variants results in progressive motor impairment
    and Leigh syndrome.
- reference: GEO:GSE166429
  title: Upregulation of COX4-2 via HIF-1α stabilization in COX4-1 deficiency
- reference: PMID:28766551
  title: >-
    Mutation in the COX4I1 gene is associated with short stature, poor weight gain and increased chromosomal
    breaks, simulating Fanconi anemia.
- reference: PMID:29886046
  title: The pathomechanism of cytochrome c oxidase deficiency includes nuclear DNA damage.
- reference: PMID:31290619
  title: >-
    Biallelic variants in COX4I1 associated with a novel phenotype resembling Leigh syndrome with developmental
    regression, intellectual disability, and seizures.
- reference: PMID:33578848
  title: Loss of COX4I1 Leads to Combined Respiratory Chain Deficiency and Impaired Mitochondrial Protein Synthesis.
- reference: PMID:33672589
  title: Upregulation of COX4-2 via HIF-1α in Mitochondrial COX4-1 Deficiency.
- reference: PMID:35456968
  title: Replicative Stress Coincides with Impaired Nuclear DNA Damage Response in COX4-1 Deficiency.
- reference: PMID:40095452
  title: >-
    Compound heterozygosity of a De novo 16q24.1 deletion and missense mutation in COX4I1 leads to developmental
    regression, intellectual disability, and seizures.
- reference: url:https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download
  title: https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download
- reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC5891488/
  title: >-
    Cytochrome c oxidase deficiency, oxidative stress, possible antioxidant therapy and link to nuclear DNA
    damage - PMC
- reference: url:https://scholarworks.indianapolis.iu.edu/bitstreams/b9b37f63-6e5e-4563-b086-880db5d3d66b/download
  title: https://scholarworks.indianapolis.iu.edu/bitstreams/b9b37f63-6e5e-4563-b086-880db5d3d66b/download
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/
  title: Nuclear Gene-Encoded Leigh Syndrome Spectrum Overview - GeneReviews® - NCBI Bookshelf
genetic:
- name: COX4I1
  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
      explanation: The founding family supports recessive inheritance.
    - reference: url:https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download
      reference_title: https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Phasing analysis of long sequencing data showed that the two variants were in trans
      explanation: Targeted long-read sequencing placed the nonsense and intronic variants on opposite alleles.
  features: >-
    Causal alleles include a complex coding substitution, missense and nonsense variants, an intronic splice-altering
    variant, and a multigene deletion encompassing COX4I1. De novo occurrence of one allele does not change
    the biallelic disease mechanism. Genotype-phenotype predictions remain limited.
  variants:
  - name: NM_001861.3:c.303_304delinsTT (p.Lys101_Thr102delinsAsnSer)
    gene:
      preferred_term: COX4I1
      term:
        id: hgnc:2265
        label: COX4I1
    type: Complex coding substitution
    genomic_contexts:
    - coding sequence
    description: >-
      Founding homozygous allele, often abbreviated K101N. The measured transcript reduction does not by itself
      establish a splicing defect.
    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 focused on chr16: g.85839400_85839401delinsTT, NM_001861.3:c.303_304delinsTT, p.(Lys101_Thr102delinsAsnSer)
        in the COX4I1 gene.
      explanation: The founding allele is a complex substitution, although the paper uses K101N as shorthand.
    - 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: Western blot analysis revealed undetectable COX 4 protein while complexes I and II were comparable to controls
      explanation: Patient fibroblast immunoblotting demonstrates loss of detectable COX4 protein.
  - name: c.454C>A (p.Pro152Thr)
    gene:
      preferred_term: COX4I1
      term:
        id: hgnc:2265
        label: COX4I1
    variant_type: single nucleotide variant
    genomic_contexts:
    - coding sequence
    description: Homozygous in two siblings with neurologic disease and in trans with a COX4I1-containing deletion in a later child.
    evidence:
    - reference: url:https://scholarworks.indianapolis.iu.edu/bitstreams/b9b37f63-6e5e-4563-b086-880db5d3d66b/download
      reference_title: https://scholarworks.indianapolis.iu.edu/bitstreams/b9b37f63-6e5e-4563-b086-880db5d3d66b/download
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        A homozygous c.454C>A (p.P152T) variant in COX4I1 was detected by trio exome sequencing in Patient
        1 and confirmed by familial mutation testing in Patient 2.
      explanation: The two siblings carried the same homozygous missense allele.
    - reference: PMID:40095452
      reference_title: >-
        Compound heterozygosity of a De novo 16q24.1 deletion and missense mutation in COX4I1 leads to developmental
        regression, intellectual disability, and seizures.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Compound heterozygosity for a de novo 16q24.1 deletion and a P152T missense mutation in the COX4I1 was detected.
      explanation: The later child carried the recurrent missense allele opposite a deletion.
  - name: 16q24.1 deletion encompassing COX4I1
    gene:
      preferred_term: COX4I1
      term:
        id: hgnc:2265
        label: COX4I1
    variant_type: deletion
    genomic_contexts:
    - coding sequence
    - intron
    description: >-
      Reported de novo approximately 0.13-Mb deletion, GRCh37 chr16:85706011-85840495, in trans with paternal
      p.Pro152Thr. Eight genes are encompassed; contributions from other deleted genes cannot be excluded.
    affected_regions:
    - name: 16q24.1 multigene interval
      chromosomal_region: 16q24.1
      overlaps_genes:
      - preferred_term: COX4I1
        term:
          id: hgnc:2265
          label: COX4I1
    evidence:
    - reference: PMID:40095452
      reference_title: >-
        Compound heterozygosity of a De novo 16q24.1 deletion and missense mutation in COX4I1 leads to developmental
        regression, intellectual disability, and seizures.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The analysis revealed that the patient harbors a heterozygous deletion of approximately 0.13 Mb (chr16:85706011–85 840 495)
        in the 16q24.1 region, encompassing eight genes, including COX4I1
      explanation: The deletion includes COX4I1 and additional genes; it is not a demonstrated isolated regulatory lesion.
  - name: c.64C>T (p.Arg22Ter)
    gene:
      preferred_term: COX4I1
      term:
        id: hgnc:2265
        label: COX4I1
    variant_type: single nucleotide variant
    genomic_contexts:
    - coding sequence
    description: >-
      De novo early nonsense variant phased in trans with paternal c.73+1511A>G. Detection in multiple tissues
      did not establish parental origin or an exact developmental time of occurrence.
    evidence:
    - reference: url:https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download
      reference_title: https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: identified a heterozygous nonsense variant (c.64C > T, p.Arg22Ter) in COX4I1 gene
      explanation: Exome sequencing identified the nonsense allele.
    - reference: url:https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download
      reference_title: https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Phasing analysis of long sequencing data showed that the two variants were in trans
      explanation: Targeted long-read sequencing placed the nonsense and intronic variants on opposite alleles.
  - name: c.73+1511A>G
    gene:
      preferred_term: COX4I1
      term:
        id: hgnc:2265
        label: COX4I1
    variant_type: single nucleotide variant
    genomic_contexts:
    - intron
    description: >-
      Paternally inherited intron-2 variant causing leaky cryptic splicing, an 82-base intronic insertion with
      loss of the first two exon-3 bases, and predicted p.Glu25ValfsTer9. Patient RNA and a minigene assay
      establish the splice effect.
    functional_effects:
    - function: Aberrant splicing
      description: Cryptic splice activation reduces productive COX4I1 transcripts; residual normally spliced transcript remains.
    evidence:
    - reference: url:https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download
      reference_title: https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: the c.73 + 1511A > G variant promotes the aberrant incorporation of an intronic sequence into COX4I1 mRNA.
      explanation: Patient RNA and a HAP1 minigene assay support cryptic splice activation.
    - reference: url:https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download
      reference_title: https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Phasing analysis of long sequencing data showed that the two variants were in trans
      explanation: Targeted long-read sequencing placed the nonsense and intronic variants on opposite alleles.
  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 focused on chr16: g.85839400_85839401delinsTT, NM_001861.3:c.303_304delinsTT, p.(Lys101_Thr102delinsAsnSer)
      in the COX4I1 gene.
    explanation: The founding allele is a complex substitution, although the paper uses K101N as shorthand.
  - reference: url:https://scholarworks.indianapolis.iu.edu/bitstreams/b9b37f63-6e5e-4563-b086-880db5d3d66b/download
    reference_title: https://scholarworks.indianapolis.iu.edu/bitstreams/b9b37f63-6e5e-4563-b086-880db5d3d66b/download
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A homozygous c.454C>A (p.P152T) variant in COX4I1 was detected by trio exome sequencing in Patient 1
      and confirmed by familial mutation testing in Patient 2.
    explanation: The two siblings carried the same homozygous missense allele.
  - reference: PMID:40095452
    reference_title: >-
      Compound heterozygosity of a De novo 16q24.1 deletion and missense mutation in COX4I1 leads to developmental
      regression, intellectual disability, and seizures.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The analysis revealed that the patient harbors a heterozygous deletion of approximately 0.13 Mb (chr16:85706011–85 840 495)
      in the 16q24.1 region, encompassing eight genes, including COX4I1
    explanation: The deletion includes COX4I1 and additional genes; it is not a demonstrated isolated regulatory lesion.
  - reference: url:https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download
    reference_title: https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Phasing analysis of long sequencing data showed that the two variants were in trans
    explanation: Targeted long-read sequencing placed the nonsense and intronic variants on opposite alleles.
pathophysiology:
- name: Aberrant COX4I1 Splicing
  description: >-
    The deep-intronic c.73+1511A>G variant activates cryptic splicing. Patient transcripts retain 82 intronic
    bases while losing the first two bases of exon 3, predicting p.Glu25ValfsTer9. Residual correctly processed
    transcripts indicate leaky splicing. Splicing was only hypothesized, not demonstrated, for the founding
    complex substitution.
  evidence:
  - reference: url:https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download
    reference_title: https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: the c.73 + 1511A > G variant promotes the aberrant incorporation of an intronic sequence into COX4I1 mRNA.
    explanation: Patient RNA and a HAP1 minigene assay support cryptic splice activation.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: COX4I1
    term:
      id: hgnc:2265
      label: COX4I1
  genetic_context:
    gene:
      preferred_term: COX4I1
      term:
        id: hgnc:2265
        label: COX4I1
    variant_type: single nucleotide variant
    genomic_contexts:
    - intron
    description: c.73+1511A>G in intron 2, in trans with c.64C>T (p.Arg22Ter).
  downstream:
  - target: COX4I1 Protein Deficiency
    description: Aberrant transcripts reduce the pool of functional COX4I1.
    causal_link_type: DIRECT
    evidence:
    - reference: url:https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download
      reference_title: https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: the c.73 + 1511A > G variant promotes the aberrant incorporation of an intronic sequence into COX4I1 mRNA.
      explanation: Patient RNA and a HAP1 minigene assay support cryptic splice activation.
- name: COX4I1 Protein Deficiency
  description: >-
    Biallelic variants reduce functional COX4-1. Protein was undetectable in the founding fibroblasts and substantially
    reduced, with residual protein, in the later nonsense/intronic case. A deletion of one COX4I1 allele can
    contribute when a pathogenic variant affects the other allele.
  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: Western blot analysis revealed undetectable COX 4 protein while complexes I and II were comparable to controls
    explanation: Patient fibroblast immunoblotting demonstrates loss of detectable COX4 protein.
  - reference: url:https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download
    reference_title: https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Western blot analysis in patients ’ fibroblasts showed a marked reduction of COX4I1 protein.
    explanation: The later genotype leaves reduced rather than universally absent protein.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: COX4I1
    term:
      id: hgnc:2265
      label: COX4I1
  downstream:
  - target: Impaired Complex IV Assembly
    description: Loss of a core structural subunit impairs complex IV biogenesis.
    causal_link_type: DIRECT
    evidence:
    - reference: url:https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download
      reference_title: https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: showed a strong complex IV assembly defect as it was almost undetectable by BN-PAGE
      explanation: Muscle extracts showed a much greater assembly defect than cultured fibroblasts.
  - target: Impaired Nuclear DNA Repair
    description: >-
      COX4I1 deficiency is associated with impaired repair, but the mitochondrion-to-nucleus intermediates
      remain unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:35456968
      reference_title: Replicative Stress Coincides with Impaired Nuclear DNA Damage Response in COX4-1 Deficiency.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: both HFF-shCOX4I1 and the patient’s cells displayed a significant prolongation of the γH2AX foci signal
      explanation: Persistent damage after etoposide recovery supports impaired nuclear DNA-damage repair.
  - target: Conditional Oxidative Stress
    description: Deficient fibroblasts accumulate ROS under oxidative-phosphorylation-dependent culture conditions.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC5891488/
      reference_title: >-
        Cytochrome c oxidase deficiency, oxidative stress, possible antioxidant therapy and link to nuclear
        DNA damage - PMC
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: both ascorbate and NAC normalized the ROS production on GAL.
      explanation: Oxidative stress was conditional on galactose medium and responsive to antioxidants in culture.
  - target: HIF1A Stabilization
    description: Normoxic deficient fibroblasts accumulate nuclear HIF-1α through an unresolved signal.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:33672589
      reference_title: Upregulation of COX4-2 via HIF-1α in Mitochondrial COX4-1 Deficiency.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: the COX4-1-deficient cells displayed increased levels of HIF-1α localized in their nuclei
      explanation: Patient and knockdown fibroblasts showed nuclear HIF-1α accumulation under normoxia.
  molecular_functions:
  - preferred_term: COX4-1 contribution to cytochrome-c oxidase activity
    term:
      id: GO:0004129
      label: cytochrome-c oxidase activity
    modifier: DECREASED
    description: >-
      Activity of the assembled holoenzyme supported by its structural/regulatory COX4-1 subunit; COX4-1 is
      not the isolated oxygen-reducing catalytic center.
- name: Impaired Complex IV Assembly
  description: >-
    Reduced COX4-1 impairs assembly of the cytochrome c oxidase holoenzyme. In the 2026 case, assembly was
    modestly reduced in fibroblasts but nearly undetectable in muscle; other respiratory complexes remained
    assembled.
  evidence:
  - reference: url:https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download
    reference_title: https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: showed a strong complex IV assembly defect as it was almost undetectable by BN-PAGE
    explanation: Muscle extracts showed a much greater assembly defect than cultured fibroblasts.
  biological_scale: MOLECULAR
  conforms_to: complex_iv_assembly_deficiency#Complex IV Biogenesis Failure
  biological_processes:
  - preferred_term: mitochondrial respiratory chain complex IV assembly
    term:
      id: GO:0033617
      label: mitochondrial respiratory chain complex IV assembly
    modifier: DECREASED
  downstream:
  - target: Reduced Complex IV Activity
    description: Fewer assembled complexes reduce cytochrome c oxidase activity.
    causal_link_type: DIRECT
    evidence:
    - reference: url:https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download
      reference_title: https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        in-gel activity analysis displayed a significant reduction of complex IV activity in patient cells
        compared to controls
      explanation: Fibroblast activity assays demonstrate impaired complex IV function.
  - target: Reduced Mitochondrial Translation
    description: >-
      Complete COX4 loss in HEK293 cells disrupts mitochondrial translation; the exact assembly-to-translation
      signal is unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:33578848
      reference_title: Loss of COX4I1 Leads to Combined Respiratory Chain Deficiency and Impaired Mitochondrial Protein Synthesis.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Pulse-chase metabolic labeling of mitochondrial DNA (mtDNA)-encoded proteins uncovered a decrease in
        the translation of cIV and cI subunits.
      explanation: Direct pulse-chase measurements were made in complete-knockout HEK293 models.
- name: Reduced Complex IV Activity
  description: >-
    Complex IV electron transfer is reduced in patient fibroblasts and muscle. One P152T sibling had muscle
    complex IV activity at 16% of control. The biochemical defect and its detectability depend on tissue and
    assay.
  evidence:
  - reference: url:https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download
    reference_title: https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      in-gel activity analysis displayed a significant reduction of complex IV activity in patient cells compared
      to controls
    explanation: Fibroblast activity assays demonstrate impaired complex IV function.
  - reference: url:https://scholarworks.indianapolis.iu.edu/bitstreams/b9b37f63-6e5e-4563-b086-880db5d3d66b/download
    reference_title: https://scholarworks.indianapolis.iu.edu/bitstreams/b9b37f63-6e5e-4563-b086-880db5d3d66b/download
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: cytochrome c oxidase activity was reduced to 16% residual activity compared to control values
    explanation: Muscle respiratory-chain enzymology quantified reduced activity in the older sibling.
  biological_scale: MOLECULAR
  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
  downstream:
  - target: Impaired Oxidative ATP Production
    description: Deficient terminal electron transfer can limit oxidative ATP production.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    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: COX activity and ATP production were restored by lentiviral transfection with the wild-type gene.
      explanation: Restoration in patient fibroblasts supports a causal bioenergetic effect of COX4I1 deficiency.
- name: Impaired Oxidative ATP Production
  description: >-
    The founding patient fibroblasts had reduced ATP production that was rescued by wild-type COX4I1. Later
    assays found relatively preserved ATP-linked respiration in the same patient line, and glycolysis can compensate
    in culture. Complete cellular ATP collapse is not a uniform finding.
  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: COX activity and ATP production were restored by lentiviral transfection with the wild-type gene.
    explanation: Restoration in patient fibroblasts supports a causal bioenergetic effect of COX4I1 deficiency.
  - reference: PMID:33672589
    reference_title: Upregulation of COX4-2 via HIF-1α in Mitochondrial COX4-1 Deficiency.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: the comparable ATP-linked OCRs in the patient’s and control fibroblasts
    explanation: Later respirometry demonstrates that impairment depends on the assay and metabolic context.
  biological_scale: MOLECULAR
  biological_processes:
  - preferred_term: mitochondrial ATP synthesis coupled electron transport
    term:
      id: GO:0042775
      label: mitochondrial ATP synthesis coupled electron transport
    modifier: DECREASED
  downstream:
  - target: Neurologic Dysfunction
    description: >-
      Respiratory dysfunction is a plausible contributor to brain injury, although neural vulnerability was
      not directly tested in patient neurons.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Increased circulating lactate
    description: Altered oxidative metabolism can favor lactate accumulation; normal lactate also occurs.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download
      reference_title: https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Biochemical studies showed high levels of plasma lactate, with normal pyruvate
      explanation: The later-onset patient had increased plasma lactate; this does not alone demonstrate acidosis.
  - target: Increased Glycolysis
    description: Cultures adapt to respiratory impairment by favoring glycolysis; the upstream signaling is not fully resolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:33672589
      reference_title: Upregulation of COX4-2 via HIF-1α in Mitochondrial COX4-1 Deficiency.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        The energy maps, combining decreased basal OCRs with increased ECARs, clearly showed a tendency towards
        favoring glycolysis over OXPHOS
      explanation: Extracellular flux measurements support a glycolytic shift in patient and knockdown fibroblasts.
- name: Neurologic Dysfunction
  description: >-
    The neurologic spectrum includes infantile regression and epileptic encephalopathy, or later progressive
    motor and cognitive dysfunction with Leigh-like basal ganglia lesions. The growth-predominant founding
    case had adequate development and no seizures at follow-up.
  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: The sibling report establishes the neurologic presentation.
  - reference: url:https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download
    reference_title: https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: he experienced a progressive deterioration of motor skills, with increasing spasticity of the lower limbs
    explanation: The later-onset case expands the motor phenotype.
  biological_scale: TISSUE
  downstream:
  - target: Encephalopathy
    description: The P152T siblings had encephalopathy as part of their central nervous system presentation.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    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: >-
        The sibling report establishes the neurologic presentation. This supports the clinical manifestation
        of neurologic involvement; the intervening cellular mechanism is not established.
  - target: Developmental regression
    description: Neurologic deterioration can cause loss of previously acquired developmental abilities; age and tempo vary.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    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: >-
        The sibling report establishes the neurologic presentation. This supports the clinical manifestation
        of neurologic involvement; the intervening cellular mechanism is not established.
  - target: Intellectual disability
    description: Cognitive impairment accompanies severe neurodevelopmental involvement in some patients.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:40095452
      reference_title: >-
        Compound heterozygosity of a De novo 16q24.1 deletion and missense mutation in COX4I1 leads to developmental
        regression, intellectual disability, and seizures.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The patient presents with developmental regression, intellectual disability, epileptic seizures, microcephaly,
        and progressive cerebral atrophy
      explanation: >-
        The case discussion summarizes the directly observed neurodevelopmental phenotype. This supports the
        clinical manifestation of neurologic involvement; the intervening cellular mechanism is not established.
  - target: Seizures
    description: >-
      Cerebral involvement can manifest as epilepsy, with infantile seizure onset documented in the deletion/missense
      case.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:40095452
      reference_title: >-
        Compound heterozygosity of a De novo 16q24.1 deletion and missense mutation in COX4I1 leads to developmental
        regression, intellectual disability, and seizures.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        By the eleventh month, the child began experiencing epileptic seizures characterized by upward eye
        deviation, spasm‐like nodding, and embracing motions.
      explanation: >-
        Seizures began during infancy in this child. This supports the clinical manifestation of neurologic
        involvement; the intervening cellular mechanism is not established.
  - target: Infantile spasms
    description: The older P152T sibling developed infantile spasms with hypsarrhythmia at 12 months.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://scholarworks.indianapolis.iu.edu/bitstreams/b9b37f63-6e5e-4563-b086-880db5d3d66b/download
      reference_title: https://scholarworks.indianapolis.iu.edu/bitstreams/b9b37f63-6e5e-4563-b086-880db5d3d66b/download
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Infantile spasms associated with hypsarrhythmia on EEG started at 12 months
      explanation: >-
        The older sibling had infantile spasms with hypsarrhythmia. This supports the clinical manifestation
        of neurologic involvement; the intervening cellular mechanism is not established.
  - target: Hypotonia
    description: >-
      Central neurologic disease can contribute to hypotonia, although a peripheral or muscle contribution
      has not been excluded.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    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: >-
        The sibling report establishes the neurologic presentation. This supports the clinical manifestation
        of neurologic involvement; the intervening cellular mechanism is not established.
  - target: Bilateral basal ganglia lesions
    description: MRI demonstrates bilateral caudate and lenticular signal abnormalities in the later-onset neurologic presentation.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download
      reference_title: https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Brain MRI revealed T2 hyperintensities in both caudate and lenticular nuclei
      explanation: >-
        MRI directly establishes bilateral basal ganglia involvement. This supports the clinical manifestation
        of neurologic involvement; the intervening cellular mechanism is not established.
  - target: Cerebral atrophy
    description: Progressive cerebral volume loss documents structural brain involvement in the deletion/missense case.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:40095452
      reference_title: >-
        Compound heterozygosity of a De novo 16q24.1 deletion and missense mutation in COX4I1 leads to developmental
        regression, intellectual disability, and seizures.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        MRI reveals significant enlargement of the ventricles and marked deepening and widening of the cerebral
        sulci, suggesting progressive cerebral atrophy
      explanation: >-
        Serial imaging supports cerebral volume loss. This supports the clinical manifestation of neurologic
        involvement; the intervening cellular mechanism is not established.
  - target: Spasticity
    description: The later-onset motor disorder includes progressive lower-limb spasticity.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download
      reference_title: https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: progressive deterioration of motor skills, with increasing spasticity of the lower limbs
      explanation: >-
        Spasticity accompanied progressive motor impairment. This supports the clinical manifestation of neurologic
        involvement; the intervening cellular mechanism is not established.
  - target: Dystonia
    description: The later-onset case has a mixed spastic-dystonic movement disorder.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download
      reference_title: https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: He also showed spastic-dystonic triparesis, mainly affecting right extremities
      explanation: >-
        The later-onset patient had dystonic as well as spastic motor signs. This supports the clinical manifestation
        of neurologic involvement; the intervening cellular mechanism is not established.
  - target: Orofacial dyskinesia
    description: Involuntary orofacial movements occur in the later-onset neurologic presentation.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download
      reference_title: https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: he showed orofacial invol - untary movements, including blinking and dyskinesias
      explanation: >-
        The report specifies the anatomic distribution of dyskinesia. This supports the clinical manifestation
        of neurologic involvement; the intervening cellular mechanism is not established.
  - target: Dysarthria
    description: Orofacial motor dysfunction is associated with impaired pronunciation in the later-onset case.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download
      reference_title: https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: associated with pronunciation difficulties, tongue movement and swal - lowing
      explanation: >-
        The source links speech difficulty to orofacial motor dysfunction. This supports the clinical manifestation
        of neurologic involvement; the intervening cellular mechanism is not established.
  - target: Dysphagia
    description: Orofacial motor dysfunction is associated with swallowing difficulty in the later-onset case.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download
      reference_title: https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: associated with pronunciation difficulties, tongue movement and swal - lowing
      explanation: >-
        The same clinical description includes swallowing difficulty. This supports the clinical manifestation
        of neurologic involvement; the intervening cellular mechanism is not established.
- name: Impaired Nuclear DNA Repair
  description: >-
    Patient fibroblasts and COX4I1-knockdown HFF cells recover poorly from etoposide-induced DNA damage and
    have reduced expression of DNA-repair genes. A separate HEK293 knockdown reporter showed reduced homologous
    recombination. The molecular link between COX4-1 and nuclear repair is unresolved.
  evidence:
  - reference: PMID:35456968
    reference_title: Replicative Stress Coincides with Impaired Nuclear DNA Damage Response in COX4-1 Deficiency.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: both HFF-shCOX4I1 and the patient’s cells displayed a significant prolongation of the γH2AX foci signal
    explanation: Persistent damage after etoposide recovery supports impaired nuclear DNA-damage repair.
  - reference: PMID:35456968
    reference_title: Replicative Stress Coincides with Impaired Nuclear DNA Damage Response in COX4-1 Deficiency.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: detecting a 28% significant decrease in the HR efficiency compared to the control.
    explanation: >-
      The homologous-recombination reporter was measured in COX4I1-silenced HEK293 cells, not directly in patient
      fibroblasts.
  biological_scale: MOLECULAR
  biological_processes:
  - preferred_term: DNA repair
    term:
      id: GO:0006281
      label: DNA repair
    modifier: DECREASED
  mechanism_confidence: PROVISIONAL
  downstream:
  - target: Replication-Associated DNA Damage
    description: Impaired repair provides a candidate explanation for damage accumulating in proliferating deficient cells.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:35456968
      reference_title: Replicative Stress Coincides with Impaired Nuclear DNA Damage Response in COX4-1 Deficiency.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: We demonstrated that COX4-1 deficiency coincides with accumulative DNA damage, primarily in Ki-67-positive cells
      explanation: Damage was enriched in proliferating cells, consistent with replication stress.
- name: Replication-Associated DNA Damage
  description: >-
    Double-stranded DNA breaks occur in COX4I1-deficient cultures and are enriched in proliferating cells.
    Experiments in COX-inhibited control fibroblasts found damage despite normal ROS and ATP, arguing against
    a solely oxidative-stress explanation. An NAD+ deficit is proposed, not established as the intermediate.
  evidence:
  - reference: PMID:35456968
    reference_title: Replicative Stress Coincides with Impaired Nuclear DNA Damage Response in COX4-1 Deficiency.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: We demonstrated that COX4-1 deficiency coincides with accumulative DNA damage, primarily in Ki-67-positive cells
    explanation: Damage was enriched in proliferating cells, consistent with replication stress.
  - reference: PMID:29886046
    reference_title: The pathomechanism of cytochrome c oxidase deficiency includes nuclear DNA damage.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We now quantified the DSB by phospho histone H2AX Ser139 staining of COX4-1 and COX6B1 deficient fibroblasts
      (225% and 215% of normal, respectively) and confirmed their occurrence by neutral comet assay.
    explanation: The cultured-cell study confirmed double-stranded DNA breaks with an orthogonal assay.
  - reference: PMID:29886046
    reference_title: The pathomechanism of cytochrome c oxidase deficiency includes nuclear DNA damage.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Present results demonstrate elevated nuclear DSB in cells treated with 50 μM KCN for 24 h (170% of normal)
      in high-glucose medium conditions where ROS and ATP remain normal
    explanation: Pharmacologic complex IV inhibition separates nuclear damage from elevated ROS or ATP depletion in this model.
  biological_scale: CELLULAR
  downstream:
  - target: Increased chromosomal breakage
    description: >-
      Cellular DNA damage provides a plausible link to the founding clinical breakage phenotype; the intermediate
      steps are not established.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Reduced Cell Proliferation
    description: Persistent DNA damage may contribute to reduced proliferation; alternative causes remain possible.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:35456968
      reference_title: Replicative Stress Coincides with Impaired Nuclear DNA Damage Response in COX4-1 Deficiency.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: We demonstrated that COX4-1 deficiency coincides with accumulative DNA damage, primarily in Ki-67-positive cells
      explanation: Damage was enriched in proliferating cells, consistent with replication stress.
- name: Reduced Cell Proliferation
  description: >-
    COX4I1-knockdown fibroblasts grow poorly and show telomere shortening and increased senescence-associated
    beta-galactosidase. Other senescence markers did not confirm a complete senescence program. A contribution
    to clinical growth failure remains provisional.
  evidence:
  - reference: PMID:35456968
    reference_title: Replicative Stress Coincides with Impaired Nuclear DNA Damage Response in COX4-1 Deficiency.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: The reduced proliferation observed in COX4-1-deficient cells could be related to premature senescence
    explanation: The authors present senescence as a possible explanation rather than a proven exclusive mechanism.
  - reference: PMID:35456968
    reference_title: Replicative Stress Coincides with Impaired Nuclear DNA Damage Response in COX4-1 Deficiency.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: we failed to confirm premature senescence by other means
    explanation: The authors explicitly qualify their senescence interpretation.
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  downstream:
  - target: Short stature
    description: >-
      Reduced cellular proliferation may contribute to growth failure; this extrapolation has not been demonstrated
      in vivo.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Conditional Oxidative Stress
  description: >-
    ROS accumulation was evident when deficient fibroblasts were grown in glucose-free galactose medium, and
    was reduced by ascorbate or N-acetylcysteine. This culture-dependent result does not establish ROS as the
    cause of nuclear DNA breaks.
  evidence:
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC5891488/
    reference_title: >-
      Cytochrome c oxidase deficiency, oxidative stress, possible antioxidant therapy and link to nuclear DNA
      damage - PMC
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: both ascorbate and NAC normalized the ROS production on GAL.
    explanation: Oxidative stress was conditional on galactose medium and responsive to antioxidants in culture.
  biological_scale: CELLULAR
  biological_processes:
  - preferred_term: reactive oxygen species metabolic process
    term:
      id: GO:0072593
      label: reactive oxygen species metabolic process
    modifier: INCREASED
- name: HIF1A Stabilization
  description: >-
    Nuclear HIF-1α accumulation occurs in the founding patient fibroblasts and HFF knockdown cells under normoxia.
    The upstream signal is unknown.
  evidence:
  - reference: PMID:33672589
    reference_title: Upregulation of COX4-2 via HIF-1α in Mitochondrial COX4-1 Deficiency.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: the COX4-1-deficient cells displayed increased levels of HIF-1α localized in their nuclei
    explanation: Patient and knockdown fibroblasts showed nuclear HIF-1α accumulation under normoxia.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: HIF1A
    term:
      id: hgnc:4910
      label: HIF1A
  downstream:
  - target: COX4I2 Upregulation
    description: HIF-1α-associated transcription is proposed to drive the compensatory isoform response.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:33672589
      reference_title: Upregulation of COX4-2 via HIF-1α in Mitochondrial COX4-1 Deficiency.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        we conclude that COX4-2 is upregulated and partially rescues COX4-1 deficiency through HIF-1α activation
        induced by a yet-to-be-characterized, noncanonical pathway.
      explanation: >-
        The authors propose a compensatory pathway from their fibroblast assays; its upstream signal and clinical
        impact remain uncertain.
      directness: INDIRECT
  molecular_functions:
  - preferred_term: DNA-binding transcription factor activity, RNA polymerase II-specific
    term:
      id: GO:0000981
      label: DNA-binding transcription factor activity, RNA polymerase II-specific
    modifier: INCREASED
- name: COX4I2 Upregulation
  description: >-
    COX4-2 expression increases in the founding patient fibroblasts and HFF knockdown models and may partially
    preserve complex IV function. It was not induced spontaneously in complete-knockout HEK293 cells and could
    not be reliably detected in the 2026 patient fibroblasts. It is not a demonstrated universal clinical modifier.
  evidence:
  - reference: PMID:33672589
    reference_title: Upregulation of COX4-2 via HIF-1α in Mitochondrial COX4-1 Deficiency.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      we conclude that COX4-2 is upregulated and partially rescues COX4-1 deficiency through HIF-1α activation
      induced by a yet-to-be-characterized, noncanonical pathway.
    explanation: >-
      The authors propose a compensatory pathway from their fibroblast assays; its upstream signal and clinical
      impact remain uncertain.
    directness: INDIRECT
  - reference: PMID:33578848
    reference_title: Loss of COX4I1 Leads to Combined Respiratory Chain Deficiency and Impaired Mitochondrial Protein Synthesis.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: COX4I1 KO in HEK293 cells did not trigger expression of the alternative isoform COX4I2
    explanation: The compensation is model-dependent.
  - reference: url:https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download
    reference_title: https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: COX4I2 mRNA could not be reliably detected by quantitative PCR
    explanation: The later patient did not reproduce a detectable isoform switch.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: COX4I2
    term:
      id: hgnc:16232
      label: COX4I2
  mechanism_confidence: PROVISIONAL
  molecular_functions:
  - preferred_term: COX4-2 contribution to cytochrome-c oxidase activity
    term:
      id: GO:0004129
      label: cytochrome-c oxidase activity
    description: >-
      The alternative subunit supports holoenzyme function in the fibroblast and forced-expression models;
      clinical compensation remains provisional.
- name: Reduced Mitochondrial Translation
  description: >-
    Complete COX4 knockout in HEK293 cells reduces synthesis of mitochondrial-encoded complex I and IV subunits
    and mitoribosomal protein abundance. The 2026 patient proteome also showed reduced mitoribosomal components,
    but did not directly measure mitochondrial translation.
  evidence:
  - reference: PMID:33578848
    reference_title: Loss of COX4I1 Leads to Combined Respiratory Chain Deficiency and Impaired Mitochondrial Protein Synthesis.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Pulse-chase metabolic labeling of mitochondrial DNA (mtDNA)-encoded proteins uncovered a decrease in
      the translation of cIV and cI subunits.
    explanation: Direct pulse-chase measurements were made in complete-knockout HEK293 models.
  - reference: PMID:33578848
    reference_title: Loss of COX4I1 Leads to Combined Respiratory Chain Deficiency and Impaired Mitochondrial Protein Synthesis.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      partial impairment of mitochondrial protein synthesis correlated with decreased content of mitochondrial
      ribosomal proteins.
    explanation: Protein synthesis and ribosomal abundance covary in the knockout model.
  biological_scale: MOLECULAR
  biological_processes:
  - preferred_term: mitochondrial translation
    term:
      id: GO:0032543
      label: mitochondrial translation
    modifier: DECREASED
  downstream:
  - target: Secondary Complex I Assembly Defect
    description: >-
      Attenuated mitochondrial protein synthesis is a proposed contributor to complex I biogenesis failure
      in complete-knockout cells.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:33578848
      reference_title: Loss of COX4I1 Leads to Combined Respiratory Chain Deficiency and Impaired Mitochondrial Protein Synthesis.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        complexome profiling revealed accumulation of cI assembly intermediates, indicating that cI biogenesis,
        rather than stability, was affected.
      explanation: The complete-knockout model had a secondary complex I assembly defect.
- name: Secondary Complex I Assembly Defect
  description: >-
    Complex I assembly intermediates accumulate in complete COX4-knockout HEK293 cells. This model finding
    is not a universal patient biochemical phenotype; the founding fibroblasts and 2026 muscle/fibroblast studies
    retained other respiratory complexes.
  evidence:
  - reference: PMID:33578848
    reference_title: Loss of COX4I1 Leads to Combined Respiratory Chain Deficiency and Impaired Mitochondrial Protein Synthesis.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      complexome profiling revealed accumulation of cI assembly intermediates, indicating that cI biogenesis,
      rather than stability, was affected.
    explanation: The complete-knockout model had a secondary complex I assembly defect.
  biological_scale: MOLECULAR
  biological_processes:
  - preferred_term: mitochondrial respiratory chain complex I assembly
    term:
      id: GO:0032981
      label: mitochondrial respiratory chain complex I assembly
    modifier: DECREASED
  mechanism_confidence: PROVISIONAL
- name: Increased Glycolysis
  description: >-
    The founding patient fibroblasts and COX4I1-knockdown HFF cells shift toward glycolysis, with increased
    extracellular acidification. This metabolic adaptation can preserve ATP despite impaired respiration, but
    does not establish clinical protection.
  evidence:
  - reference: PMID:33672589
    reference_title: Upregulation of COX4-2 via HIF-1α in Mitochondrial COX4-1 Deficiency.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The energy maps, combining decreased basal OCRs with increased ECARs, clearly showed a tendency towards
      favoring glycolysis over OXPHOS
    explanation: Extracellular flux measurements support a glycolytic shift in patient and knockdown fibroblasts.
  biological_scale: CELLULAR
  biological_processes:
  - preferred_term: glycolytic process
    term:
      id: GO:0006096
      label: glycolytic process
    modifier: INCREASED
phenotypes:
- name: Short stature
  category: Growth
  description: Prominent in the founding growth-predominant case and older P152T sibling; normal stature occurs in other patients.
  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: The founding patient had growth failure.
- name: Failure to thrive
  category: Growth
  description: Poor weight gain is variable and can persist despite adequate neurodevelopment in the founding case.
  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: The founding patient had growth failure.
- name: Prominent nasal bridge
  category: Craniofacial
  description: Reported in the founding child.
  phenotype_term:
    preferred_term: Prominent nasal bridge
    term:
      id: HP:0000426
      label: Prominent nasal bridge
  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: minor dysmorphic features including prominent nasal bridge, frontal bossing, and short 5th fingers bilaterally
    explanation: The founding examination specifies these features rather than a generic facial-shape abnormality.
- name: Frontal bossing
  category: Craniofacial
  description: Reported in the founding child.
  phenotype_term:
    preferred_term: Frontal bossing
    term:
      id: HP:0002007
      label: Frontal bossing
  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: minor dysmorphic features including prominent nasal bridge, frontal bossing, and short 5th fingers bilaterally
    explanation: The founding examination specifies these features rather than a generic facial-shape abnormality.
- name: Short fifth fingers
  category: Musculoskeletal
  description: Bilateral short fifth fingers were reported in the founding child.
  phenotype_term:
    preferred_term: Short 5th finger
    term:
      id: HP:0009237
      label: Short 5th finger
  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: minor dysmorphic features including prominent nasal bridge, frontal bossing, and short 5th fingers bilaterally
    explanation: The founding examination specifies these features rather than a generic facial-shape abnormality.
- name: Delayed skeletal maturation
  category: Musculoskeletal
  description: Delayed bone age was reported in the founding child.
  phenotype_term:
    preferred_term: Delayed skeletal maturation
    term:
      id: HP:0002750
      label: Delayed skeletal maturation
  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: Investigations were positive only for RBC macrocytosis and delayed bone age.
    explanation: The founding investigation documented macrocytosis and delayed skeletal maturation.
- name: Increased mean corpuscular volume
  category: Hematologic
  description: Macrocytosis occurred initially in the founding case; later follow-up reported normocytic anemia.
  phenotype_term:
    preferred_term: Increased mean corpuscular volume
    term:
      id: HP:0005518
      label: Increased mean corpuscular volume
  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: Investigations were positive only for RBC macrocytosis and delayed bone age.
    explanation: The founding investigation documented macrocytosis and delayed skeletal maturation.
- name: Normocytic anemia
  category: Hematologic
  description: >-
    Mild normocytic anemia occurred at age nine in the founding child, with normal white-cell and platelet
    counts. Generalized marrow failure is not established by that examination.
  phenotype_term:
    preferred_term: Normocytic anemia
    term:
      id: HP:0001897
      label: Normocytic anemia
  evidence:
  - reference: PMID:35456968
    reference_title: Replicative Stress Coincides with Impaired Nuclear DNA Damage Response in COX4-1 Deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Her last blood counts showed mild normocytic anemia, with normal WBC and platelet counts
    explanation: The follow-up clinical results distinguish anemia from pancytopenia.
- name: Increased chromosomal breakage
  category: Laboratory
  description: >-
    DEB-induced chromosome breakage occurred in the founding child. Both P152T siblings had normal chromosome-breakage
    studies.
  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: The result showed normal female karyotype and 29% of the cells showed ≥1 break/cell.
    explanation: The diagnostic chromosome-breakage assay was abnormal.
  phenotype_contexts:
  - genetic_context:
      gene:
        preferred_term: COX4I1
        term:
          id: hgnc:2265
          label: COX4I1
      description: Homozygous p.Pro152Thr in the two reported siblings
    notes: >-
      Neither sibling had abnormal chromosome-breakage studies; this observation does not exclude breakage
      in other genotypes.
    evidence:
    - reference: url:https://scholarworks.indianapolis.iu.edu/bitstreams/b9b37f63-6e5e-4563-b086-880db5d3d66b/download
      reference_title: https://scholarworks.indianapolis.iu.edu/bitstreams/b9b37f63-6e5e-4563-b086-880db5d3d66b/download
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        both siblings described here did not have hematological features and abnormal chromosome breakage studies
        consistent with Fanconi anemia
      explanation: The primary report documents normal breakage studies in these two siblings.
- name: Encephalopathy
  category: Neurologic
  description: Occurs in the severe neurologic presentation; it is not universal.
  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: The sibling report establishes the neurologic presentation.
- name: Developmental regression
  category: Neurologic
  description: >-
    Infantile regression followed initially normal development in the P152T siblings; motor and cognitive decline
    began later in the nonsense/intronic case.
  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: The sibling report establishes the neurologic presentation.
- name: Intellectual disability
  category: Neurologic
  description: Variable cognitive impairment, including profound developmental limitations in the deletion/missense case.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:40095452
    reference_title: >-
      Compound heterozygosity of a De novo 16q24.1 deletion and missense mutation in COX4I1 leads to developmental
      regression, intellectual disability, and seizures.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient presents with developmental regression, intellectual disability, epileptic seizures, microcephaly,
      and progressive cerebral atrophy
    explanation: The case discussion summarizes the directly observed neurodevelopmental phenotype.
- name: Seizures
  category: Neurologic
  description: Epilepsy is prominent in several neurologic cases, but absent in the founding and later-onset cases.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:40095452
    reference_title: >-
      Compound heterozygosity of a De novo 16q24.1 deletion and missense mutation in COX4I1 leads to developmental
      regression, intellectual disability, and seizures.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      By the eleventh month, the child began experiencing epileptic seizures characterized by upward eye deviation,
      spasm‐like nodding, and embracing motions.
    explanation: Seizures began during infancy in this child.
- name: Infantile spasms
  category: Neurologic
  description: >-
    Infantile spasms were reported in the older P152T sibling and the deletion/missense case. The younger P152T
    sibling had epileptic spasms at age two without hypsarrhythmia.
  phenotype_term:
    preferred_term: Infantile spasms
    term:
      id: HP:0012469
      label: Infantile spasms
  evidence:
  - reference: url:https://scholarworks.indianapolis.iu.edu/bitstreams/b9b37f63-6e5e-4563-b086-880db5d3d66b/download
    reference_title: https://scholarworks.indianapolis.iu.edu/bitstreams/b9b37f63-6e5e-4563-b086-880db5d3d66b/download
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Infantile spasms associated with hypsarrhythmia on EEG started at 12 months
    explanation: The older sibling had infantile spasms with hypsarrhythmia.
- name: Hypotonia
  category: Neurologic
  description: Axial and appendicular hypotonia can cause severe motor impairment.
  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: The sibling report establishes the neurologic presentation.
- name: Hyperreflexia
  category: Neurologic
  description: Patellar hyperreflexia was reported in the younger P152T sibling.
  phenotype_term:
    preferred_term: Hyperreflexia
    term:
      id: HP:0001347
      label: Hyperreflexia
  evidence:
  - reference: url:https://scholarworks.indianapolis.iu.edu/bitstreams/b9b37f63-6e5e-4563-b086-880db5d3d66b/download
    reference_title: https://scholarworks.indianapolis.iu.edu/bitstreams/b9b37f63-6e5e-4563-b086-880db5d3d66b/download
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: He also had axial and appendicular hypotonia and patellar hyperreflexia.
    explanation: The examination directly documents hyperreflexia.
- name: Bilateral basal ganglia lesions
  category: Neurologic
  description: >-
    Symmetric basal ganglia abnormalities can resemble Leigh syndrome. In the later-onset case lesions remained
    stable despite clinical progression.
  phenotype_term:
    preferred_term: Bilateral basal ganglia lesions
    term:
      id: HP:0007146
      label: Bilateral basal ganglia lesions
  evidence:
  - reference: url:https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download
    reference_title: https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Brain MRI revealed T2 hyperintensities in both caudate and lenticular nuclei
    explanation: MRI directly establishes bilateral basal ganglia involvement.
- name: Cerebral atrophy
  category: Neurologic
  description: Reported in P152T siblings and progressively in the deletion/missense case.
  phenotype_term:
    preferred_term: Cerebral atrophy
    term:
      id: HP:0002059
      label: Cerebral atrophy
  evidence:
  - reference: PMID:40095452
    reference_title: >-
      Compound heterozygosity of a De novo 16q24.1 deletion and missense mutation in COX4I1 leads to developmental
      regression, intellectual disability, and seizures.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      MRI reveals significant enlargement of the ventricles and marked deepening and widening of the cerebral
      sulci, suggesting progressive cerebral atrophy
    explanation: Serial imaging supports cerebral volume loss.
- name: Cerebellar atrophy
  category: Neurologic
  description: Cerebellar volume loss was reported in both P152T siblings.
  phenotype_term:
    preferred_term: Cerebellar atrophy
    term:
      id: HP:0001272
      label: Cerebellar atrophy
  evidence:
  - reference: url:https://scholarworks.indianapolis.iu.edu/bitstreams/b9b37f63-6e5e-4563-b086-880db5d3d66b/download
    reference_title: https://scholarworks.indianapolis.iu.edu/bitstreams/b9b37f63-6e5e-4563-b086-880db5d3d66b/download
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Brain MRI showed mild to moderate generalized cerebral/cerebellar atrophy and evidence of bilateral hypertrophic
      olivary degeneration
    explanation: The younger sibling had both cerebral and cerebellar atrophy.
- name: Olivary degeneration
  category: Neurologic
  description: Bilateral hypertrophic olivary degeneration was observed in the younger P152T sibling.
  phenotype_term:
    preferred_term: Olivary degeneration
    term:
      id: HP:0008303
      label: Olivary degeneration
  evidence:
  - reference: url:https://scholarworks.indianapolis.iu.edu/bitstreams/b9b37f63-6e5e-4563-b086-880db5d3d66b/download
    reference_title: https://scholarworks.indianapolis.iu.edu/bitstreams/b9b37f63-6e5e-4563-b086-880db5d3d66b/download
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Brain MRI showed mild to moderate generalized cerebral/cerebellar atrophy and evidence of bilateral hypertrophic
      olivary degeneration
    explanation: The MRI documents the specific olivary finding.
- name: Inferior cerebellar vermis hypoplasia
  category: Neurologic
  description: The older P152T sibling had congenital inferior vermis hypoplasia.
  phenotype_term:
    preferred_term: Inferior cerebellar vermis hypoplasia
    term:
      id: HP:0007068
      label: Inferior cerebellar vermis hypoplasia
  evidence:
  - reference: url:https://scholarworks.indianapolis.iu.edu/bitstreams/b9b37f63-6e5e-4563-b086-880db5d3d66b/download
    reference_title: https://scholarworks.indianapolis.iu.edu/bitstreams/b9b37f63-6e5e-4563-b086-880db5d3d66b/download
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: diffuse cerebral and cerebellar volume loss, and congenital hypoplasia of the inferior vermis
    explanation: The report distinguishes inferior vermis hypoplasia from diffuse atrophy.
- name: Microcephaly
  category: Growth
  description: Microcephaly occurs in some severe neurologic presentations.
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  evidence:
  - reference: PMID:40095452
    reference_title: >-
      Compound heterozygosity of a De novo 16q24.1 deletion and missense mutation in COX4I1 leads to developmental
      regression, intellectual disability, and seizures.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the patient presents with normal stature (height of 117 cm, 50th percentile), microcephaly (head circumference
      of 45 cm, −3 SD)
    explanation: The clinical head circumference establishes microcephaly.
- name: Distal toe phalanx hypoplasia
  category: Musculoskeletal
  description: Bilateral distal phalangeal hypoplasia of toes two through five was reported in the younger P152T sibling.
  phenotype_term:
    preferred_term: Aplasia/Hypoplasia of the distal phalanges of the toes
    term:
      id: HP:0010185
      label: Aplasia/Hypoplasia of the distal phalanges of the toes
  evidence:
  - reference: url:https://scholarworks.indianapolis.iu.edu/bitstreams/b9b37f63-6e5e-4563-b086-880db5d3d66b/download
    reference_title: https://scholarworks.indianapolis.iu.edu/bitstreams/b9b37f63-6e5e-4563-b086-880db5d3d66b/download
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Physical examination did not show any dysmorphic features except bilateral hypoplasia of the distal phalanges
      of the 2nd-5th toes
    explanation: The finding is anatomically localized to the distal toe phalanges.
- name: Spasticity
  category: Neurologic
  description: Progressive lower-limb spasticity occurred in the later-onset case.
  phenotype_term:
    preferred_term: Spasticity
    term:
      id: HP:0001257
      label: Spasticity
  evidence:
  - reference: url:https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download
    reference_title: https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: progressive deterioration of motor skills, with increasing spasticity of the lower limbs
    explanation: Spasticity accompanied progressive motor impairment.
- name: Dystonia
  category: Neurologic
  description: Spastic-dystonic triparesis was reported in the later-onset case.
  phenotype_term:
    preferred_term: Dystonia
    term:
      id: HP:0001332
      label: Dystonia
  evidence:
  - reference: url:https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download
    reference_title: https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: He also showed spastic-dystonic triparesis, mainly affecting right extremities
    explanation: The later-onset patient had dystonic as well as spastic motor signs.
- name: Orofacial dyskinesia
  category: Neurologic
  description: Orofacial involuntary movements and blinking accompanied bulbar motor difficulties.
  phenotype_term:
    preferred_term: Orofacial dyskinesia
    term:
      id: HP:0002310
      label: Orofacial dyskinesia
  evidence:
  - reference: url:https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download
    reference_title: https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: he showed orofacial invol - untary movements, including blinking and dyskinesias
    explanation: The report specifies the anatomic distribution of dyskinesia.
- name: Dysarthria
  category: Neurologic
  description: Motor speech difficulty accompanied involuntary orofacial movements in the later-onset case.
  phenotype_term:
    preferred_term: Dysarthria
    term:
      id: HP:0001260
      label: Dysarthria
  evidence:
  - reference: url:https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download
    reference_title: https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: associated with pronunciation difficulties, tongue movement and swal - lowing
    explanation: The source links speech difficulty to orofacial motor dysfunction.
- name: Dysphagia
  category: Gastrointestinal
  description: Swallowing difficulty accompanied orofacial motor dysfunction in the later-onset case.
  phenotype_term:
    preferred_term: Dysphagia
    term:
      id: HP:0002015
      label: Dysphagia
  evidence:
  - reference: url:https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download
    reference_title: https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: associated with pronunciation difficulties, tongue movement and swal - lowing
    explanation: The same clinical description includes swallowing difficulty.
  sequelae:
  - target: Feeding difficulties
    description: Swallowing dysfunction can compromise safe and adequate feeding.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Feeding difficulties
  category: Gastrointestinal
  description: Severe neurologic disease can impair chewing and require gastrostomy feeding.
  phenotype_term:
    preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  evidence:
  - reference: PMID:40095452
    reference_title: >-
      Compound heterozygosity of a De novo 16q24.1 deletion and missense mutation in COX4I1 leads to developmental
      regression, intellectual disability, and seizures.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He exhibits global developmental delays and generalized hypotonia, with an inability to sit unassisted,
      speak, recognize family members, maintain visual tracking, or chew solid food.
    explanation: The deletion/missense case could not chew solid food.
  - reference: url:https://scholarworks.indianapolis.iu.edu/bitstreams/b9b37f63-6e5e-4563-b086-880db5d3d66b/download
    reference_title: https://scholarworks.indianapolis.iu.edu/bitstreams/b9b37f63-6e5e-4563-b086-880db5d3d66b/download
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: He had profound hypotonia and required gastrostomy tube placement for feedings.
    explanation: The younger sibling required tube feeding.
  sequelae:
  - target: Failure to thrive
    description: Inadequate oral intake can contribute to poor weight gain.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:40095452
      reference_title: >-
        Compound heterozygosity of a De novo 16q24.1 deletion and missense mutation in COX4I1 leads to developmental
        regression, intellectual disability, and seizures.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The patient's low body weight and BMI may be attributed to the lack of chewing ability, necessitating
        a liquid diet, which can lead to inadequate nutritional intake.
      explanation: The authors propose a nutritional contribution to poor weight gain.
      directness: INDIRECT
- name: Increased circulating lactate
  category: Laboratory
  description: >-
    Plasma lactate can be increased, but was normal in the founding child and older P152T sibling. Hyperlactatemia
    alone does not establish lactic acidosis.
  phenotype_term:
    preferred_term: Increased circulating lactate concentration
    term:
      id: HP:0002151
      label: Increased circulating lactate concentration
  evidence:
  - reference: url:https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download
    reference_title: https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Biochemical studies showed high levels of plasma lactate, with normal pyruvate
    explanation: The later-onset patient had increased plasma lactate; this does not alone demonstrate acidosis.
- name: Hypermetropia
  category: Ophthalmologic
  description: >-
    Moderate hyperopia in one P152T sibling is summarized in the later clinical comparison; its frequency and
    causal relation are uncertain.
  phenotype_term:
    preferred_term: Hypermetropia
    term:
      id: HP:0000540
      label: Hypermetropia
  evidence:
  - reference: url:https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download
    reference_title: https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Moderate hyperopia but no evidence of retinopathy or optic nerve atrophy
    explanation: The 2026 table summarizes an ocular finding from the earlier sibling report.
    quote_role: BACKGROUND
- name: Exotropia
  category: Ophthalmologic
  description: Intermittent alternating exotropia in the other P152T sibling is summarized in the later clinical comparison.
  phenotype_term:
    preferred_term: Exotropia
    term:
      id: HP:0000577
      label: Exotropia
  evidence:
  - reference: url:https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download
    reference_title: https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Intermittent alternating exotropia with no evidence of retinopathy or optic nerve atrophy
    explanation: The 2026 comparison table describes the earlier sibling phenotype.
    quote_role: BACKGROUND
- name: Aortic coarctation
  category: Cardiovascular
  description: >-
    Neonatal aortic coarctation was repaired in the later-onset patient. Its relationship to COX4I1 deficiency
    is uncertain and it may be coincidental; subsequent cardiac assessment was normal.
  phenotype_term:
    preferred_term: Coarctation of aorta
    term:
      id: HP:0001680
      label: Coarctation of aorta
  evidence:
  - reference: url:https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download
    reference_title: https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In the neonatal period he underwent surgery for aortic coarctation without remarkable complications.
    explanation: The case documents co-occurring congenital heart disease without demonstrating COX4I1 causation.
treatments:
- name: Nutritional and feeding support
  description: >-
    Assess growth, oral intake and swallowing safety; use feeding therapy, caloric support and gastrostomy
    when needed. Both P152T siblings required gastrostomy. General Leigh syndrome guidance supports individualized
    nutritional care.
  treatment_term:
    preferred_term: Nutritional Support
    term:
      id: NCIT:C15433
      label: Nutritional Support
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/
    reference_title: Nuclear Gene-Encoded Leigh Syndrome Spectrum Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Feeding therapy as needed; gastrostomy tube placement may improve nutritional intake for those w/persistent
      feeding issues, choking, or aspiration risk due to dysphagia
    explanation: GeneReviews supports tube feeding according to feeding safety and nutritional need.
    quote_role: REVIEW_SYNTHESIS
  - reference: url:https://scholarworks.indianapolis.iu.edu/bitstreams/b9b37f63-6e5e-4563-b086-880db5d3d66b/download
    reference_title: https://scholarworks.indianapolis.iu.edu/bitstreams/b9b37f63-6e5e-4563-b086-880db5d3d66b/download
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Like his brother, he also required gastrostomy tube for feedings.
    explanation: Both siblings required gastrostomy feeding.
  target_phenotypes:
  - preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  - preferred_term: Dysphagia
    term:
      id: HP:0002015
      label: Dysphagia
  - preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
- name: Seizure management
  description: >-
    An experienced neurologist should individualize antiseizure treatment. ACTH, topiramate, valproate, zonisamide,
    levetiracetam and clonazepam have been used in reported cases, with refractory seizures in the deletion/missense
    case. Historical valproate use is not a recommendation: general mitochondrial guidance advises avoiding
    it if possible; the absolute POLG contraindication should not be misattributed to COX4I1.
  treatment_term:
    preferred_term: Anticonvulsant Therapy
    term:
      id: NCIT:C64172
      label: Anticonvulsant Therapy
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/
    reference_title: Nuclear Gene-Encoded Leigh Syndrome Spectrum Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Treatment w/ASM by experienced neurologist ... Sodium valproate should be avoided because of its inhibitory
      effects on the mitochondrial respiratory chain.
    explanation: GeneReviews recommends specialist seizure management.
    quote_role: REVIEW_SYNTHESIS
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/
    reference_title: Nuclear Gene-Encoded Leigh Syndrome Spectrum Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Sodium valproate should be avoided if possible, because of its inhibitory effect on respiratory chain enzymes.
    explanation: GeneReviews distinguishes preferred avoidance from the separate POLG-specific absolute contraindication.
    quote_role: REVIEW_SYNTHESIS
  - reference: url:https://scholarworks.indianapolis.iu.edu/bitstreams/b9b37f63-6e5e-4563-b086-880db5d3d66b/download
    reference_title: https://scholarworks.indianapolis.iu.edu/bitstreams/b9b37f63-6e5e-4563-b086-880db5d3d66b/download
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Currently, his antiepileptic treatment includes zonisamide and levetiracetam.
    explanation: The younger sibling received these agents; this sentence does not establish efficacy.
  target_phenotypes:
  - preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  - preferred_term: Infantile spasms
    term:
      id: HP:0012469
      label: Infantile spasms
- name: Rehabilitation and communication support
  description: >-
    Physical, occupational and communication therapies and mobility aids address functional needs. An eye-tracking
    communication system had a positive reported effect in the later-onset case. Motor progression continued
    despite botulinum toxin treatment; this is not evidence of a disease-modifying benefit.
  treatment_term:
    preferred_term: Rehabilitation
    term:
      id: NCIT:C15315
      label: Rehabilitation
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/
    reference_title: Nuclear Gene-Encoded Leigh Syndrome Spectrum Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Equipment to prevent falling, maintain independent mobility as appropriate
    explanation: GeneReviews describes supportive mobility equipment.
    quote_role: REVIEW_SYNTHESIS
  - reference: url:https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download
    reference_title: https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: use of an eye-tracking system to facilitate communication, with very positive results.
    explanation: The later-onset patient benefited from assisted communication.
  - reference: url:https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download
    reference_title: https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: increasing spasticity of the lower limbs despite botulinum toxin treatment
    explanation: Motor progression occurred despite symptomatic botulinum treatment.
  target_phenotypes:
  - preferred_term: Spasticity
    term:
      id: HP:0001257
      label: Spasticity
  - preferred_term: Dystonia
    term:
      id: HP:0001332
      label: Dystonia
  - preferred_term: Dysarthria
    term:
      id: HP:0001260
      label: Dysarthria
  - preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
- name: Empirical ubiquinol supplementation
  description: >-
    Parents of the P152T siblings reported modest improvement in head control/tone or visual focus after four
    months of coenzyme Q10 treatment. These uncontrolled observations do not establish sustained or disease-modifying
    efficacy.
  treatment_term:
    preferred_term: Nutritional Support
    term:
      id: NCIT:C15433
      label: Nutritional Support
    therapeutic_agent:
    - preferred_term: ubiquinol-10
      term:
        id: CHEBI:64183
        label: ubiquinol-10
  evidence:
  - reference: url:https://scholarworks.indianapolis.iu.edu/bitstreams/b9b37f63-6e5e-4563-b086-880db5d3d66b/download
    reference_title: https://scholarworks.indianapolis.iu.edu/bitstreams/b9b37f63-6e5e-4563-b086-880db5d3d66b/download
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Four months after initiation of therapy with Coenzyme Q10, parents reported improvement in head control and tone.
    explanation: The younger sibling had a parent-reported response.
  - reference: url:https://scholarworks.indianapolis.iu.edu/bitstreams/b9b37f63-6e5e-4563-b086-880db5d3d66b/download
    reference_title: https://scholarworks.indianapolis.iu.edu/bitstreams/b9b37f63-6e5e-4563-b086-880db5d3d66b/download
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Parents reported improvement in visual focus four months after initiation of Coenzyme Q10 therapy.
    explanation: The older sibling had a parent-reported response.
  therapeutic_modality: SMALL_MOLECULE
- name: Empirical vitamin C supplementation
  description: >-
    The founding patient was maintained on vitamin C after antioxidant findings in fibroblasts. The follow-up
    did not establish a clinical treatment effect. N-acetylcysteine and nicotinamide riboside results remain
    cell-culture observations.
  treatment_term:
    preferred_term: Nutritional Support
    term:
      id: NCIT:C15433
      label: Nutritional Support
    therapeutic_agent:
    - preferred_term: L-ascorbic acid
      term:
        id: CHEBI:29073
        label: L-ascorbic acid
  evidence:
  - reference: PMID:35456968
    reference_title: Replicative Stress Coincides with Impaired Nuclear DNA Damage Response in COX4-1 Deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: She is maintained only on a daily dose of 100 mg vitamin C
    explanation: Follow-up documents use, not proven efficacy.
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC5891488/
    reference_title: >-
      Cytochrome c oxidase deficiency, oxidative stress, possible antioxidant therapy and link to nuclear DNA
      damage - PMC
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: both ascorbate and NAC normalized the ROS production on GAL.
    explanation: Oxidative stress was conditional on galactose medium and responsive to antioxidants in culture.
  therapeutic_modality: SMALL_MOLECULE
- name: Perioperative metabolic support
  description: >-
    General mitochondrial guidance supports minimizing fasting, considering intravenous glucose during prolonged
    anesthesia when appropriate, and careful respiratory monitoring. Prolonged propofol and lactate-containing
    fluids require particular caution in patients at risk of acidosis.
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/
    reference_title: Nuclear Gene-Encoded Leigh Syndrome Spectrum Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Catabolism should be prevented by minimizing preoperative fasting and considering intravenous glucose
      perioperatively during prolonged anesthesia (unless the individual is on a ketogenic diet).
    explanation: The general LSS recommendation supports an individualized perioperative plan.
    quote_role: REVIEW_SYNTHESIS
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/
    reference_title: Nuclear Gene-Encoded Leigh Syndrome Spectrum Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Prolonged propofol use during maintenance anesthesia may increase the risk of lactic acidosis.
    explanation: The chapter identifies a perioperative risk; this is not a claim that all COX4I1 patients have acidosis.
    quote_role: REVIEW_SYNTHESIS
- name: Longitudinal multidisciplinary surveillance
  description: >-
    Monitor neurologic function, development, movement disorders, nutrition, swallowing and blood counts. General
    LSS guidance supports regular ophthalmologic, audiologic and cardiac assessments, adapted to the individual;
    it does not establish those complications as frequent COX4I1 phenotypes.
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/
    reference_title: Nuclear Gene-Encoded Leigh Syndrome Spectrum Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Affected individuals should be followed at regular intervals (typically every 6-12 months) to monitor
      progression of known manifestations and the appearance of new manifestations.
    explanation: GeneReviews recommends repeated assessment across the LSS spectrum.
    quote_role: REVIEW_SYNTHESIS
- name: Genetic counseling
  description: >-
    Confirm familial alleles and phase. If both parents carry a causal allele, each pregnancy has a 25% affected
    risk; families with a de novo allele require individualized recurrence assessment, including residual parental
    mosaicism risk. Prenatal and preimplantation testing become possible after causal variants are identified.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/
    reference_title: Nuclear Gene-Encoded Leigh Syndrome Spectrum Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      If both parents are known to be ... heterozygous ... for an LSS-related ... pathogenic variant ... each
      sib of an affected individual has at conception a 25% chance of being affected
    explanation: The 25% figure is conditional on both parents being carriers.
    quote_role: REVIEW_SYNTHESIS
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/
    reference_title: Nuclear Gene-Encoded Leigh Syndrome Spectrum Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Once the LSS-related ... pathogenic variant ... (s) have been identified in an affected family member,
      prenatal and ... preimplantation genetic testing ... are possible.
    explanation: GeneReviews supports reproductive testing after molecular diagnosis.
    quote_role: REVIEW_SYNTHESIS
  - reference: url:https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download
    reference_title: https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Phasing analysis of long sequencing data showed that the two variants were in trans
    explanation: Targeted long-read sequencing placed the nonsense and intronic variants on opposite alleles.
notes: >-
  Phenotypic frequencies, penetrance, and genotype-specific prognosis cannot be estimated reliably from the
  small number of reported families. Growth/hematologic and neurologic presentations overlap and are not established
  separate molecular subtypes. Chromosome breakage does not imply a confirmed Fanconi-anemia complementation
  disorder or an established malignancy predisposition. General nuclear-encoded Leigh syndrome guidance informs
  supportive care; phenotype frequencies and treatments for other Leigh syndrome genes should not be attributed
  to COX4I1. The Tecnalia full-text PDF cited in this entry is Ugarteburu et al. (2026; PMID:41203052), and
  the Indiana repository author manuscript is Pillai et al. (2019; PMID:31290619).
diagnosis:
- name: Molecular diagnosis and segregation
  diagnosis_term:
    preferred_term: DNA Sequencing
    term:
      id: NCIT:C153598
      label: DNA Sequencing
  description: >-
    Identify biallelic causative COX4I1 alleles by exome/genome or a suitable panel, and test parents. Apparent
    homozygosity inconsistent with segregation warrants deletion analysis. A single identified allele can require
    RNA studies and intronic sequencing; long reads can resolve phase. General LSS guidance favors genome sequencing
    when available and consideration of trio testing in children.
  evidence:
  - reference: url:https://scholarworks.indianapolis.iu.edu/bitstreams/b9b37f63-6e5e-4563-b086-880db5d3d66b/download
    reference_title: https://scholarworks.indianapolis.iu.edu/bitstreams/b9b37f63-6e5e-4563-b086-880db5d3d66b/download
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A homozygous c.454C>A (p.P152T) variant in COX4I1 was detected by trio exome sequencing in Patient 1
      and confirmed by familial mutation testing in Patient 2.
    explanation: The two siblings carried the same homozygous missense allele.
  - reference: PMID:40095452
    reference_title: >-
      Compound heterozygosity of a De novo 16q24.1 deletion and missense mutation in COX4I1 leads to developmental
      regression, intellectual disability, and seizures.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The analysis revealed that the patient harbors a heterozygous deletion of approximately 0.13 Mb (chr16:85706011–85 840 495)
      in the 16q24.1 region, encompassing eight genes, including COX4I1
    explanation: The deletion includes COX4I1 and additional genes; it is not a demonstrated isolated regulatory lesion.
  - reference: url:https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download
    reference_title: https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Phasing analysis of long sequencing data showed that the two variants were in trans
    explanation: Targeted long-read sequencing placed the nonsense and intronic variants on opposite alleles.
  - reference: url:https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download
    reference_title: https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: the c.73 + 1511A > G variant promotes the aberrant incorporation of an intronic sequence into COX4I1 mRNA.
    explanation: Patient RNA and a HAP1 minigene assay support cryptic splice activation.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/
    reference_title: Nuclear Gene-Encoded Leigh Syndrome Spectrum Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Genome sequencing is preferred (if available), as it allows analysis of the mitochondrial and nuclear
      genome, and typically has the highest diagnostic rate.
    explanation: >-
      GeneReviews favors genome sequencing when available for suspected LSS; this is general diagnostic guidance,
      not a COX4I1-specific comparative yield estimate.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/
    reference_title: Nuclear Gene-Encoded Leigh Syndrome Spectrum Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      When testing children, family trio ... genome sequencing ... should be considered to assist in the identification
      of either ... biallelic ... pathogenic variants that cause rare ... autosomal recessive ... disorders
      or ... de novo ... pathogenic variants.
    explanation: Trio testing supports recognition of recessive and de novo alleles, both relevant to reported COX4I1 families.
- name: Brain MRI
  diagnosis_term:
    preferred_term: Magnetic Resonance Imaging
    term:
      id: NCIT:C16809
      label: Magnetic Resonance Imaging
  description: >-
    Assess basal ganglia and brainstem lesions, cerebral/cerebellar atrophy and other neurologic abnormalities.
    Imaging can remain stable despite clinical deterioration or be normal in the growth-predominant presentation.
  evidence:
  - reference: url:https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download
    reference_title: https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Brain MRI revealed T2 hyperintensities in both caudate and lenticular nuclei
    explanation: The patient MRI localizes characteristic lesions.
  - 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: Brain MRI was performed and found normal without any indication of mitochondrial disease
    explanation: The founding case had normal brain imaging.
- name: Lactate measurement
  diagnosis_term:
    preferred_term: Lactic Acid Measurement
    term:
      id: NCIT:C79450
      label: Lactic Acid Measurement
  description: Lactate supports the metabolic assessment but normal plasma or CSF lactate does not exclude COX4I1 disease.
  evidence:
  - reference: url:https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download
    reference_title: https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Biochemical studies showed high levels of plasma lactate, with normal pyruvate
    explanation: The later-onset patient had increased plasma lactate; this does not alone demonstrate acidosis.
  - reference: url:https://scholarworks.indianapolis.iu.edu/bitstreams/b9b37f63-6e5e-4563-b086-880db5d3d66b/download
    reference_title: https://scholarworks.indianapolis.iu.edu/bitstreams/b9b37f63-6e5e-4563-b086-880db5d3d66b/download
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He had a normal comprehensive work up including CK, plasma amino acids, urine organic acid analysis,
      carbohydrate deficient transferrin, lactate and pyruvate.
    explanation: The older sibling had normal lactate and pyruvate.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/
    reference_title: Nuclear Gene-Encoded Leigh Syndrome Spectrum Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Elevated blood and/or cerebrospinal fluid (CSF) lactate concentrations may strongly support the diagnosis
      of nuclear-encoded LSS.
    explanation: General LSS guidance supports lactate as a diagnostic clue rather than a gene-specific test.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/
    reference_title: Nuclear Gene-Encoded Leigh Syndrome Spectrum Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: A normal blood and/or CSF lactate concentration does not exclude nuclear-encoded LSS.
    explanation: >-
      The diagnostic section explicitly cautions against excluding LSS on normal lactate, consistent with normal
      results in some COX4I1 cases.
- name: Respiratory-chain and RNA functional studies
  diagnosis_term:
    preferred_term: Respiratory-chain and RNA functional studies
  description: >-
    Enzymology, immunoblotting, blue-native electrophoresis and transcript/minigene analysis can support variant
    interpretation. Tissue differences are substantial; a relatively mild fibroblast assembly defect can coexist
    with a severe muscle defect. Invasive tissue enzymology is generally reserved for selected unresolved cases
    or variants, after genomic evaluation.
  evidence:
  - reference: url:https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download
    reference_title: https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: showed a strong complex IV assembly defect as it was almost undetectable by BN-PAGE
    explanation: Muscle extracts showed a much greater assembly defect than cultured fibroblasts.
  - reference: url:https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download
    reference_title: https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      in-gel activity analysis displayed a significant reduction of complex IV activity in patient cells compared
      to controls
    explanation: Fibroblast activity assays demonstrate impaired complex IV function.
  - reference: url:https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download
    reference_title: https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: the c.73 + 1511A > G variant promotes the aberrant incorporation of an intronic sequence into COX4I1 mRNA.
    explanation: Patient RNA and a HAP1 minigene assay support cryptic splice activation.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/
    reference_title: Nuclear Gene-Encoded Leigh Syndrome Spectrum Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      in a small minority of individuals, enzymatic testing of a muscle or skin biopsy may be necessary to
      confirm the pathogenicity of variants of ... uncertain significance ... identified by genomic testing.
    explanation: >-
      GeneReviews places invasive enzymology in a selective variant-interpretation role after genomic testing,
      rather than a routine first-line requirement.
- name: Chromosome-breakage and hematologic assessment
  diagnosis_term:
    preferred_term: Chromosome-breakage and hematologic assessment
  description: >-
    Chromosome-breakage testing may be abnormal in the growth-predominant presentation but normal in neurologic
    cases. Follow blood counts and growth; a breakage phenotype alone does not establish Fanconi anemia.
  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: The result showed normal female karyotype and 29% of the cells showed ≥1 break/cell.
    explanation: DEB testing detected chromosome breakage in the founding case.
  - reference: PMID:35456968
    reference_title: Replicative Stress Coincides with Impaired Nuclear DNA Damage Response in COX4-1 Deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Her last blood counts showed mild normocytic anemia, with normal WBC and platelet counts
    explanation: Follow-up blood counts specify the hematologic involvement.
experimental_models:
- name: Patient-derived COX4I1 fibroblasts
  experimental_model_type: PRIMARY_CELL_CULTURE
  cell_source: Primary fibroblasts from affected individuals
  cell_types:
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  description: >-
    Patient cultures support transcript, protein, respiration, oxidative-stress and DNA-damage assays. Findings
    depend on genotype, medium and tissue; they do not directly measure neurologic injury.
  modeled_mechanisms:
  - target: COX4I1 Protein Deficiency
    relationship: RECAPITULATES
    model_scale: MOLECULAR
  - target: Reduced Complex IV Activity
    relationship: RECAPITULATES
    model_scale: MOLECULAR
  - target: Impaired Oxidative ATP Production
    relationship: RESCUES
    model_scale: MOLECULAR
    limitations: Lentiviral wild-type complementation is a culture experiment, not a clinical gene therapy.
  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: Western blot analysis revealed undetectable COX 4 protein while complexes I and II were comparable to controls
    explanation: Patient fibroblast immunoblotting demonstrates loss of detectable COX4 protein.
  - 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: Restoration in patient fibroblasts supports a causal bioenergetic effect of COX4I1 deficiency.
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC5891488/
    reference_title: >-
      Cytochrome c oxidase deficiency, oxidative stress, possible antioxidant therapy and link to nuclear DNA
      damage - PMC
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Only NAC had a significant positive effect on the growth ratio.
    explanation: The comparison found a growth benefit only for NAC.
  - reference: PMID:29886046
    reference_title: The pathomechanism of cytochrome c oxidase deficiency includes nuclear DNA damage.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Additionally we demonstrate the benefit of nicotinamide riboside (NR) which ameliorated DSB in COX4-1,
      COX6B1 and KCN treated cells
    explanation: The NR response is limited to cell-culture DNA damage.
  findings:
  - statement: Wild-type COX4I1 rescued complex IV activity and ATP production in founding patient cells.
  - statement: >-
      Ascorbate and N-acetylcysteine normalized ROS in galactose medium; only N-acetylcysteine improved growth
      in the 2018 comparison.
  - statement: Nicotinamide riboside ameliorated DNA breaks in vitro; clinical efficacy is unproven.
  notes: >-
    Fibroblast assays do not directly model brain dysfunction, marrow physiology, or whole-organ growth. Genetic
    background and culture conditions can affect comparison between patient lines.
- name: COX4I1 knockdown in human foreskin fibroblasts
  experimental_model_type: PRIMARY_CELL_CULTURE
  cell_source: Human foreskin fibroblasts with stable COX4I1-targeting shRNA
  cell_types:
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  description: >-
    Knockdown cultures model HIF-1α accumulation, COX4I2 upregulation, altered metabolism and impaired recovery
    from DNA damage.
  publication: PMID:35456968
  modeled_mechanisms:
  - target: Impaired Nuclear DNA Repair
    relationship: RECAPITULATES
    model_scale: MOLECULAR
  - target: COX4I2 Upregulation
    relationship: RECAPITULATES
    model_scale: MOLECULAR
  evidence:
  - reference: PMID:35456968
    reference_title: Replicative Stress Coincides with Impaired Nuclear DNA Damage Response in COX4-1 Deficiency.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: both HFF-shCOX4I1 and the patient’s cells displayed a significant prolongation of the γH2AX foci signal
    explanation: Persistent damage after etoposide recovery supports impaired nuclear DNA-damage repair.
  - reference: PMID:33672589
    reference_title: Upregulation of COX4-2 via HIF-1α in Mitochondrial COX4-1 Deficiency.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: the COX4-1-deficient cells displayed increased levels of HIF-1α localized in their nuclei
    explanation: Patient and knockdown fibroblasts showed nuclear HIF-1α accumulation under normoxia.
  - reference: PMID:33672589
    reference_title: Upregulation of COX4-2 via HIF-1α in Mitochondrial COX4-1 Deficiency.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      we conclude that COX4-2 is upregulated and partially rescues COX4-1 deficiency through HIF-1α activation
      induced by a yet-to-be-characterized, noncanonical pathway.
    explanation: >-
      The authors propose a compensatory pathway from their fibroblast assays; its upstream signal and clinical
      impact remain uncertain.
    directness: INDIRECT
- name: COX4I1 knockdown HEK293 homologous-recombination reporter
  experimental_model_type: CELL_LINE
  cell_source: HEK293 cells carrying COX4I1 shRNA and a recombination reporter
  description: >-
    A plasmid reporter measured a 28% reduction in homologous-recombination efficiency. Primary fibroblast
    transfection limitations prompted use of this transformed cell line.
  publication: PMID:35456968
  modeled_mechanisms:
  - target: Impaired Nuclear DNA Repair
    relationship: PARTIALLY_RECAPITULATES
    model_scale: MOLECULAR
    limitations: Reporter repair in transformed HEK293 cells is not equivalent to repair in patient tissues.
  evidence:
  - reference: PMID:35456968
    reference_title: Replicative Stress Coincides with Impaired Nuclear DNA Damage Response in COX4-1 Deficiency.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: detecting a 28% significant decrease in the HR efficiency compared to the control.
    explanation: >-
      The homologous-recombination reporter was measured in COX4I1-silenced HEK293 cells, not directly in patient
      fibroblasts.
- name: COX4 isoform knockout and rescue in HEK293
  experimental_model_type: CELL_LINE
  cell_source: CRISPR-edited HEK293 cells lacking COX4I1 or both COX4 isoforms
  description: >-
    Complete knockout causes complex IV loss, reduced mitochondrial translation and secondary complex I assembly
    defects. Forced expression of either isoform restores respiratory function; endogenous COX4I2 is not automatically
    induced.
  publication: PMID:33578848
  modeled_mechanisms:
  - target: Reduced Mitochondrial Translation
    relationship: RECAPITULATES
    model_scale: MOLECULAR
  - target: Secondary Complex I Assembly Defect
    relationship: RECAPITULATES
    model_scale: MOLECULAR
  - target: Impaired Complex IV Assembly
    relationship: RESCUES
    model_scale: MOLECULAR
    limitations: Forced isoform expression rescues complete-knockout cultures, not a proven patient treatment.
  evidence:
  - reference: PMID:33578848
    reference_title: Loss of COX4I1 Leads to Combined Respiratory Chain Deficiency and Impaired Mitochondrial Protein Synthesis.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Pulse-chase metabolic labeling of mitochondrial DNA (mtDNA)-encoded proteins uncovered a decrease in
      the translation of cIV and cI subunits.
    explanation: Direct pulse-chase measurements were made in complete-knockout HEK293 models.
  - reference: PMID:33578848
    reference_title: Loss of COX4I1 Leads to Combined Respiratory Chain Deficiency and Impaired Mitochondrial Protein Synthesis.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      complexome profiling revealed accumulation of cI assembly intermediates, indicating that cI biogenesis,
      rather than stability, was affected.
    explanation: The complete-knockout model had a secondary complex I assembly defect.
  - reference: PMID:33578848
    reference_title: Loss of COX4I1 Leads to Combined Respiratory Chain Deficiency and Impaired Mitochondrial Protein Synthesis.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Expression of either isoform on the COX4I1/4I2 KO background fully restored the respiratory pattern to
      match control cells
    explanation: Genetic rescue establishes functional interchangeability under forced expression.
- name: HAP1 COX4I1 intronic-variant minigene
  experimental_model_type: CELL_LINE
  cell_source: HAP1 cells transfected with wild-type or c.73+1511A>G minigenes
  description: The mutant minigene reproduces leaky intronic retention seen in patient fibroblasts.
  publication: PMID:41203052
  modeled_mechanisms:
  - target: Aberrant COX4I1 Splicing
    relationship: RECAPITULATES
    model_scale: MOLECULAR
  evidence:
  - reference: url:https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download
    reference_title: https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: the c.73 + 1511A > G variant promotes the aberrant incorporation of an intronic sequence into COX4I1 mRNA.
    explanation: Patient RNA and a HAP1 minigene assay support cryptic splice activation.
datasets:
- accession: geo:GSE166429
  title: Upregulation of COX4-2 via HIF-1α stabilization in COX4-1 deficiency
  description: >-
    CEL-Seq2 transcriptomic study of COX4I1-downregulated human foreskin fibroblasts, with metabolic/hypoxia-pathway
    analysis and later reanalysis of DNA-repair genes. This is a disease-mechanism cell model rather than a
    patient outcome cohort.
  data_type: BULK_RNA_SEQ
  publication: PMID:33672589
  evidence:
  - reference: GEO:GSE166429
    reference_title: Upregulation of COX4-2 via HIF-1α stabilization in COX4-1 deficiency
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      COX4-1 was downregulated using a stable expression of COX4I1-targeting shRNAs in human foreskin fibroblasts
      (HFF), to mirror and compare it to the primary patient's cells.
    explanation: The repository summary identifies the perturbation and culture model.
- accession: PRIDE:PXD023367
  title: Loss of COX4i1 leads to combined respiratory chain deficiency and impaired mitochondrial protein synthesis
  description: >-
    Label-free mass-spectrometry proteomics of wild-type HEK293 cells and COX4I1, COX4I2 or double-knockout
    clones. A mechanistic perturbation resource, not a patient cohort.
  data_type: PROTEOMICS
  publication: PMID:33578848
  evidence:
  - reference: PMID:33578848
    reference_title: Loss of COX4I1 Leads to Combined Respiratory Chain Deficiency and Impaired Mitochondrial Protein Synthesis.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: LFQ dataset is publicly available in the PRIDE repository (https://www.ebi.ac.uk/pride), accession number PXD023367
    explanation: The primary publication identifies the deposited knockout proteome.
biochemical:
- name: Medium- and long-chain acylcarnitine elevation
  presence: Elevated
  context: Plasma in the later-onset nonsense/intronic case
  notes: >-
    Persistent elevation occurred with high lactate. The source investigated an alternative multiple acyl-CoA
    dehydrogenase deficiency diagnosis; the reported COX4I1 case did not respond to riboflavin. This is not
    an established universal biomarker.
  evidence:
  - reference: url:https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download
    reference_title: https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: consistently increased levels of medium- and long- chain acylcarnitine species
    explanation: The case reports a persistent acylcarnitine abnormality.
📚

References & Deep Research

References

15
PMID:26425749
Nuclear Gene-Encoded Leigh Syndrome Spectrum Overview.
No top-level findings curated for this source.
PMID:29396562
Cytochrome c oxidase deficiency, oxidative stress, possible antioxidant therapy and link to nuclear DNA damage.
No top-level findings curated for this source.
PMID:41203052
Complex IV deficiency due to COX4I1 deep intronic and de novo variants results in progressive motor impairment and Leigh syndrome.
No top-level findings curated for this source.
GEO:GSE166429
Upregulation of COX4-2 via HIF-1α stabilization in COX4-1 deficiency
No top-level findings curated for this source.
PMID:28766551
Mutation in the COX4I1 gene is associated with short stature, poor weight gain and increased chromosomal breaks, simulating Fanconi anemia.
No top-level findings curated for this source.
PMID:29886046
The pathomechanism of cytochrome c oxidase deficiency includes nuclear DNA damage.
No top-level findings curated for this source.
PMID:31290619
Biallelic variants in COX4I1 associated with a novel phenotype resembling Leigh syndrome with developmental regression, intellectual disability, and seizures.
No top-level findings curated for this source.
PMID:33578848
Loss of COX4I1 Leads to Combined Respiratory Chain Deficiency and Impaired Mitochondrial Protein Synthesis.
No top-level findings curated for this source.
PMID:33672589
Upregulation of COX4-2 via HIF-1α in Mitochondrial COX4-1 Deficiency.
No top-level findings curated for this source.
PMID:35456968
Replicative Stress Coincides with Impaired Nuclear DNA Damage Response in COX4-1 Deficiency.
No top-level findings curated for this source.
PMID:40095452
Compound heterozygosity of a De novo 16q24.1 deletion and missense mutation in COX4I1 leads to developmental regression, intellectual disability, and seizures.
No top-level findings curated for this source.
url:https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download
https://dsp.tecnalia.com/bitstreams/4bea0297-ccd2-4fa4-ab62-4d8e45d99b07/download
No top-level findings curated for this source.
url:https://pmc.ncbi.nlm.nih.gov/articles/PMC5891488/
Cytochrome c oxidase deficiency, oxidative stress, possible antioxidant therapy and link to nuclear DNA damage - PMC
No top-level findings curated for this source.
url:https://scholarworks.indianapolis.iu.edu/bitstreams/b9b37f63-6e5e-4563-b086-880db5d3d66b/download
https://scholarworks.indianapolis.iu.edu/bitstreams/b9b37f63-6e5e-4563-b086-880db5d3d66b/download
No top-level findings curated for this source.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/
Nuclear Gene-Encoded Leigh Syndrome Spectrum Overview - GeneReviews® - NCBI Bookshelf
No top-level findings curated for this source.