COX8A-Related COX Deficiency

Mendelian MONDO:0033650 Pathograph 15 Show in embeddings browser Mitochondrial Disease Inborn Error of Metabolism

COX8A-related mitochondrial complex IV deficiency is an autosomal recessive structural-subunit disorder reported with Leigh syndrome spectrum, leukodystrophy, severe epilepsy, developmental abnormalities and pulmonary hypertension. A homozygous intronic splice-acceptor variant produces abnormal RNA and loss of normal COX8A function. Patient cells and engineered cell models show reduced stable complex IV and enzyme activity, with residual enzyme preferentially retained in respiratory supercomplexes. ClinGen classified the broader COX8A–mitochondrial disease relationship as Limited in March 2024 because only one clinical case supported the assertion.

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1
Inheritance
6
Pathophys.
1
Histopath.
12
Phenotypes
15
Pathograph
1
Genes
1
Variants
7
Medical Actions
2
Models
7
References
👪

Inheritance

1
Autosomal recessive HP:0000007
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:26685157 SUPPORT Human Clinical
"we identified a homozygous splice site mutation in COX8A, which codes for the ubiquitously expressed isoform of subunit VIII, the smallest nuclear-encoded subunit of complex IV."
The clinical report identifies a homozygous structural-subunit variant.
⚙

Pathophysiology

6
Homozygous COX8A splice-acceptor variant
The reported NM_004074.3:c.115-1G>C variant affects the final nucleotide of intron 1. The physical alteration is a single nucleotide substitution; the subsequent 49-nucleotide deletion occurs in RNA.
COX8A hgnc:2294 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves COX8A (hgnc:2294). hgnc:2294 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context COX8A hgnc:2294 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns COX8A (hgnc:2294). hgnc:2294 is a gene from the HUGO Gene Nomenclature Committee. Variant type: single nucleotide variant Genomic context: intron variant_origin: GERMLINE zygosity: HOMOZYGOUS
Downstream
Aberrant COX8A splicing The splice-acceptor substitution alters processing of the COX8A transcript.
Show evidence (2 references)
PMID:26685157 SUPPORT Human Clinical
"we identified a homozygous splice site mutation in COX8A, which codes for the ubiquitously expressed isoform of subunit VIII, the smallest nuclear-encoded subunit of complex IV."
The clinical report identifies a homozygous structural-subunit variant.
url:https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a1671723-9b23-4f70-b64d-dd1829b926bc-2024-03-18T040000.000Z SUPPORT In Vitro
"this 49 nt deletion results in a shift of the reading frame for the entire exon 2"
The aberrant transcript removes 49 nucleotides; this is an RNA consequence of an intronic SNV, not a genomic deletion.
Aberrant COX8A splicing
Patient fibroblast RNA uses abnormal splicing and loses 49 nucleotides, shifting the reading frame of exon 2. This changes most of the mature subunit sequence.
COX8A hgnc:2294 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves COX8A (hgnc:2294). hgnc:2294 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
Reduced COX8A transcript abundance The abnormal transcript is less abundant; the decay mechanism is not directly resolved.
Loss of normal COX8A function The frameshift disrupts the sequence of the mature structural subunit.
Show evidence (4 references)
PMID:26685157 SUPPORT In Vitro
"The mutation, affecting the last nucleotide of intron 1, leads to aberrant splicing, a frame-shift in the highly conserved exon 2, and decreased amount of the COX8A transcript."
Patient-cell RNA analysis links the intronic variant to abnormal splicing and reduced transcript abundance; it does not directly measure a decay pathway.
url:https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a1671723-9b23-4f70-b64d-dd1829b926bc-2024-03-18T040000.000Z SUPPORT In Vitro
"A shorter COX8A-specific PCR product was present in fibroblasts of the COX8A patient (Fig. 3B, asterisk), indicating aberrant splicing"
ClinGen reproduces the patient-cell RNA evidence from Hallmann 2016.
url:https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a1671723-9b23-4f70-b64d-dd1829b926bc-2024-03-18T040000.000Z SUPPORT In Vitro
"this 49 nt deletion results in a shift of the reading frame for the entire exon 2"
The aberrant transcript removes 49 nucleotides; this is an RNA consequence of an intronic SNV, not a genomic deletion.
+ 1 more reference
Reduced COX8A transcript abundance
COX8A RNA abundance is reduced in patient fibroblasts. Reduced abundance does not by itself identify altered transcription or prove a particular RNA-decay pathway.
COX8A hgnc:2294 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves COX8A (hgnc:2294). hgnc:2294 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
Loss of normal COX8A function Lower transcript availability compounds the abnormal coding sequence.
Show evidence (1 reference)
PMID:26685157 SUPPORT In Vitro
"The mutation, affecting the last nucleotide of intron 1, leads to aberrant splicing, a frame-shift in the highly conserved exon 2, and decreased amount of the COX8A transcript."
Patient-cell RNA analysis links the intronic variant to abnormal splicing and reduced transcript abundance; it does not directly measure a decay pathway.
Loss of normal COX8A function
The aberrantly spliced transcript cannot produce the normal structural subunit. Sequence disruption and lower RNA abundance together impair normal COX8A function; residual respiratory activity does not imply normal subunit restoration.
COX8A hgnc:2294 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves COX8A (hgnc:2294). hgnc:2294 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
Reduced stable free complex IV Loss of normal subunit function impairs holoenzyme stability, supported by wild-type complementation.
Show evidence (3 references)
PMID:26685157 SUPPORT Human Clinical
"The loss of the wild-type COX8A protein severely impairs the stability of the entire cytochrome c oxidase enzyme complex and manifests in isolated complex IV deficiency in skeletal muscle and fibroblasts"
The report links loss of the normal subunit to deficient complex IV; complete loss of every respiratory complex is not established.
url:https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a1671723-9b23-4f70-b64d-dd1829b926bc-2024-03-18T040000.000Z SUPPORT In Vitro
"As exon 2 encodes the 31 C-terminal amino acids of the 44 amino acid-long mature peptide, the translated mutant protein is very likely not functional."
The source predicts a severe effect on the mature protein; it does not directly demonstrate nonsense-mediated decay.
PMID:26685157 SUPPORT In Vitro
"Stability and activity of complex IV could be rescued in the patient's fibroblasts by lentiviral expression of wild-type COX8A."
Wild-type complementation supports a causal relationship between COX8A dysfunction and the cellular enzyme defect.
Reduced stable free complex IV
Patient cells and engineered COX8A-deficient cells have markedly reduced free complex IV monomers and dimers. Some residual enzyme remains in respiratory supercomplexes, suggesting structural stabilization there. The results do not establish a universal block of every complex IV assembly intermediate.
COX8A hgnc:2294 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves COX8A (hgnc:2294). hgnc:2294 is a gene from the HUGO Gene Nomenclature Committee.
Experimental models
Patient-derived COX8A-deficient fibroblasts CELL LINE
Engineered COX8A-deficient HEK293T clones CELL LINE
Downstream
Reduced complex IV activity Reduced stable enzyme abundance accompanies reduced measured complex IV activity.
Show evidence (3 references)
PMID:33705280 SUPPORT In Vitro
"In immunoblots of BN-PAGE separated mitochondria from both cellular models almost no monomers and dimers of the fully assembled COX could be visualized."
Patient fibroblasts and engineered HEK293T cells lose most free complex IV; residual supercomplex-associated enzyme must be distinguished.
PMID:33705280 SUPPORT In Vitro
"Interestingly, supercomplexes of COX formed with complex III and also with complexes I and III retained considerable immunoreactivity, while nearly no immunoreactivity attributable to subassemblies was found."
Supports the distinction in the description between depleted free enzyme and retained supercomplex-associated enzyme; the adjacent BN-PAGE evidence establishes free-monomer and dimer depletion.
PMID:26685157 SUPPORT In Vitro
"Stability and activity of complex IV could be rescued in the patient's fibroblasts by lentiviral expression of wild-type COX8A."
Wild-type complementation supports a causal relationship between COX8A dysfunction and the cellular enzyme defect.
Reduced complex IV activity
Complex IV enzyme activity is severely reduced in patient muscle and cultured fibroblasts, with residual activity in later cellular assays. COX8A supports holoenzyme stability; it is not an autonomous catalytic subunit. No direct measurement in these sources establishes universal ATP depletion or oxidative stress in patients.
COX8A hgnc:2294 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves COX8A (hgnc:2294). hgnc:2294 is a gene from the HUGO Gene Nomenclature Committee.
cytochrome-c oxidase activity GO:0004129 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased cytochrome-c oxidase activity (GO:0004129). GO:0004129 is a molecular function from the Gene Ontology.
Experimental models
Patient-derived COX8A-deficient fibroblasts CELL LINE
Engineered COX8A-deficient HEK293T clones CELL LINE
Downstream
Seizures The biochemical lesion is associated with the reported neurological disease; the intervening neural mechanism has not been established.
Leukodystrophy White-matter injury accompanies the inherited enzyme defect; a specific ROS-mediated pathway is not demonstrated.
Lactic acidosis The reported mitochondrial disease includes lactic acidosis; the tissue-specific metabolic intermediates remain unresolved.
Show evidence (3 references)
PMID:26685157 SUPPORT Human Clinical
"The loss of the wild-type COX8A protein severely impairs the stability of the entire cytochrome c oxidase enzyme complex and manifests in isolated complex IV deficiency in skeletal muscle and fibroblasts"
The report links loss of the normal subunit to deficient complex IV; complete loss of every respiratory complex is not established.
PMID:33705280 SUPPORT In Vitro
"In both cellular model systems, between 20 to 30% of the residual enzymatic activity of cytochrome c oxidase (COX) was detectable."
The later study reports residual cellular activity, so neither universal zero activity nor complete ATP collapse follows.
PMID:26685157 SUPPORT In Vitro
"Stability and activity of complex IV could be rescued in the patient's fibroblasts by lentiviral expression of wild-type COX8A."
Wild-type complementation supports a causal relationship between COX8A dysfunction and the cellular enzyme defect.
✶

Histopathology

1
Reduced muscle cytochrome c oxidase staining
The original muscle sample showed weak COX staining in the ClinGen case abstraction.
Show evidence (1 reference)
url:https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a1671723-9b23-4f70-b64d-dd1829b926bc-2024-03-18T040000.000Z SUPPORT Human Clinical
"uniformly weak COX staining + COX deficiency in muscle 10% of control"
ClinGen summarizes weak muscle COX histochemistry and reduced enzyme activity in the original case.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for COX8A-Related COX Deficiency Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

12
Cardiovascular 1
Elevated pulmonary artery pressure HP:0004890 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Elevated pulmonary artery pressure (HP:0004890). HP:0004890 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a1671723-9b23-4f70-b64d-dd1829b926bc-2024-03-18T040000.000Z SUPPORT Human Clinical
"Microcephaly ... Pulmonary arterial hypertension ... Seizure"
ClinGen case-level phenotype abstraction of Hallmann 2016; this is a single patient, not a cohort frequency.
Head and Neck 1
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)
url:https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a1671723-9b23-4f70-b64d-dd1829b926bc-2024-03-18T040000.000Z SUPPORT Human Clinical
"Lactic acidosis ... Microcephaly ... Pulmonary arterial hypertension"
ClinGen case-level phenotype abstraction of Hallmann 2016; this is a single patient, not a cohort frequency.
Metabolism 2
Elevated 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://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a1671723-9b23-4f70-b64d-dd1829b926bc-2024-03-18T040000.000Z SUPPORT Human Clinical
"Increased circulating lactate concentration ... Lactic acidosis"
ClinGen case-level phenotype abstraction of Hallmann 2016; this is a single patient, not a cohort frequency.
Lactic acidosis HP:0003128 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Lactic acidosis (HP:0003128). HP:0003128 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a1671723-9b23-4f70-b64d-dd1829b926bc-2024-03-18T040000.000Z SUPPORT Human Clinical
"Increased circulating lactate concentration ... Lactic acidosis"
ClinGen case-level phenotype abstraction of Hallmann 2016; this is a single patient, not a cohort frequency.
Musculoskeletal 3
Congenital kyphoscoliosis HP:0008453 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Congenital kyphoscoliosis (HP:0008453). HP:0008453 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a1671723-9b23-4f70-b64d-dd1829b926bc-2024-03-18T040000.000Z SUPPORT Human Clinical
"Congenital kyphoscoliosis ... Global developmental delay"
ClinGen case-level phenotype abstraction of Hallmann 2016; this is a single patient, not a cohort frequency.
Appendicular spasticity HP:0034353 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Appendicular spasticity (HP:0034353). HP:0034353 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
url:https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a1671723-9b23-4f70-b64d-dd1829b926bc-2024-03-18T040000.000Z SUPPORT Human Clinical
"Appendicular spasticity ... Bilateral basal ganglia lesions"
ClinGen case-level phenotype abstraction of Hallmann 2016; this is a single patient, not a cohort frequency.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/ SUPPORT Human Clinical
"COX8A ... 1 person ... Seizures; hypotonia; spasticity; leukodystrophy"
The gene-specific row of the broader GeneReviews chapter lists these features for one reported person; no frequency estimate is inferred.
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 (2 references)
url:https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a1671723-9b23-4f70-b64d-dd1829b926bc-2024-03-18T040000.000Z SUPPORT Human Clinical
"Global developmental delay ... Hypotonia ... Increased circulating lactate concentration"
ClinGen case-level phenotype abstraction of Hallmann 2016; this is a single patient, not a cohort frequency.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/ SUPPORT Human Clinical
"COX8A ... 1 person ... Seizures; hypotonia; spasticity; leukodystrophy"
The gene-specific row of the broader GeneReviews chapter lists these features for one reported person; no frequency estimate is inferred.
Nervous System 4
Seizures HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizure (HP:0001250), qualified as severity severe. HP:0001250 is a phenotype from the Human Phenotype Ontology.
Severity: SEVERE
Show evidence (2 references)
PMID:26685157 SUPPORT Human Clinical
"In a patient with Leigh-like syndrome presenting with leukodystrophy and severe epilepsy"
The original patient has both findings; the report does not establish population frequencies.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/ SUPPORT Human Clinical
"COX8A ... 1 person ... Seizures; hypotonia; spasticity; leukodystrophy"
The gene-specific row of the broader GeneReviews chapter lists these features for one reported person; no frequency estimate is inferred.
Leukodystrophy HP:0002415 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Leukodystrophy (HP:0002415). HP:0002415 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:26685157 SUPPORT Human Clinical
"In a patient with Leigh-like syndrome presenting with leukodystrophy and severe epilepsy"
The original patient has both findings; the report does not establish population frequencies.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/ SUPPORT Human Clinical
"COX8A ... 1 person ... Seizures; hypotonia; spasticity; leukodystrophy"
The gene-specific row of the broader GeneReviews chapter lists these features for one reported person; no frequency estimate is inferred.
Global developmental delay HP:0001263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a1671723-9b23-4f70-b64d-dd1829b926bc-2024-03-18T040000.000Z SUPPORT Human Clinical
"Congenital kyphoscoliosis ... Global developmental delay"
ClinGen case-level phenotype abstraction of Hallmann 2016; this is a single patient, not a cohort frequency.
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://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a1671723-9b23-4f70-b64d-dd1829b926bc-2024-03-18T040000.000Z SUPPORT Human Clinical
"Appendicular spasticity ... Bilateral basal ganglia lesions"
ClinGen case-level phenotype abstraction of Hallmann 2016; this is a single patient, not a cohort frequency.
Growth 1
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)
url:https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a1671723-9b23-4f70-b64d-dd1829b926bc-2024-03-18T040000.000Z SUPPORT Human Clinical
"Pulmonary arterial hypertension ... Seizure ... Short stature"
ClinGen case-level phenotype abstraction of Hallmann 2016; this is a single patient, not a cohort frequency.
🧬

Genetic Associations

1
COX8A
Gene: COX8A hgnc:2294 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is COX8A (hgnc:2294). hgnc:2294 is a gene from the HUGO Gene Nomenclature Committee.
Autosomal recessive
Show evidence (2 references)
PMID:26685157 SUPPORT Human Clinical
"we identified a homozygous splice site mutation in COX8A, which codes for the ubiquitously expressed isoform of subunit VIII, the smallest nuclear-encoded subunit of complex IV."
The clinical report identifies a homozygous structural-subunit variant.
PMID:26685157 SUPPORT In Vitro
"Stability and activity of complex IV could be rescued in the patient's fibroblasts by lentiviral expression of wild-type COX8A."
Wild-type complementation supports a causal relationship between COX8A dysfunction and the cellular enzyme defect.
Variants (1)
NM_004074.3:c.115-1G>C Pathogenic
Gene: COX8A hgnc:2294 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in COX8A (hgnc:2294). hgnc:2294 is a gene from the HUGO Gene Nomenclature Committee. single nucleotide variant
Variant detail: splice acceptor variant
Genomic context: intron
Homozygous intron-1 splice-acceptor SNV in the reported patient. Aberrant splicing removes 49 RNA nucleotides and changes the exon-2 reading frame. This is not a 49-base genomic deletion.
Show evidence (4 references)
PMID:26685157 SUPPORT Human Clinical
"we identified a homozygous splice site mutation in COX8A, which codes for the ubiquitously expressed isoform of subunit VIII, the smallest nuclear-encoded subunit of complex IV."
The clinical report identifies a homozygous structural-subunit variant.
PMID:26685157 SUPPORT In Vitro
"The mutation, affecting the last nucleotide of intron 1, leads to aberrant splicing, a frame-shift in the highly conserved exon 2, and decreased amount of the COX8A transcript."
Patient-cell RNA analysis links the intronic variant to abnormal splicing and reduced transcript abundance; it does not directly measure a decay pathway.
url:https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a1671723-9b23-4f70-b64d-dd1829b926bc-2024-03-18T040000.000Z SUPPORT In Vitro
"this 49 nt deletion results in a shift of the reading frame for the entire exon 2"
The aberrant transcript removes 49 nucleotides; this is an RNA consequence of an intronic SNV, not a genomic deletion.
+ 1 more reference
💊

Medical Actions

7
Multidisciplinary supportive care
Action: Supportive CareNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. NCIT:C15747
General Leigh syndrome spectrum guidance; no COX8A-specific therapeutic trial is demonstrated. Coordinate neurological, nutritional, respiratory and rehabilitation care according to manifestations.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/ SUPPORT Human Clinical
"Supportive care to improve quality of life, maximize function, and reduce complications is recommended."
The chapter provides a general supportive-care framework.
Antiseizure treatment
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
General Leigh syndrome spectrum guidance; no COX8A-specific therapeutic trial is demonstrated. An experienced neurologist should individualize antiseizure medication. The available sources do not establish a preferred COX8A-specific drug.
Mechanism Target:
MODULATES Seizures — Symptom-directed management from general LSS guidance; COX8A-specific efficacy has not been established.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/ SUPPORT Human Clinical
"Treatment w/ASM by experienced neurologist"
LSS guidance supports specialist antiseizure treatment.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/ SUPPORT Human Clinical
"Treatment w/ASM by experienced neurologist"
LSS guidance supports specialist antiseizure treatment.
Acidosis correction
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: sodium hydrogencarbonate CHEBI:32139 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses sodium hydrogencarbonate (CHEBI:32139). CHEBI:32139 is a therapeutic agent from Chemical Entities of Biological Interest.
General Leigh syndrome spectrum guidance; no COX8A-specific therapeutic trial is demonstrated. Clinically significant acidosis may require sodium bicarbonate or sodium citrate, selected and monitored by the treating team.
Mechanism Target:
MODULATES Lactic acidosis — Symptom-directed management from general LSS guidance; COX8A-specific efficacy has not been established.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/ SUPPORT Human Clinical
"Sodium bicarbonate or sodium citrate for significant acidosis"
This recommendation treats significant acidosis in LSS, rather than repairing COX8A.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/ SUPPORT Human Clinical
"Sodium bicarbonate or sodium citrate for significant acidosis"
This recommendation treats significant acidosis in LSS, rather than repairing COX8A.
Nutritional 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
General Leigh syndrome spectrum guidance; no COX8A-specific therapeutic trial is demonstrated. Assess growth, nutritional intake and swallowing safety; provide supplementation and feeding support when indicated.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/ SUPPORT Human Clinical
"nutritional supplementation as needed (incl micronutrients)"
The general LSS care table recommends nutritional support when needed.
Clinical 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
General Leigh syndrome spectrum guidance; no COX8A-specific therapeutic trial is demonstrated. Regular neurological, ophthalmological, hearing and cardiac assessment should be tailored to manifestations.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/ SUPPORT Human Clinical
"Neurologic, ophthalmologic, audiologic, and cardiologic evaluations are recommended"
The chapter recommends multisystem surveillance for LSS.
Medication and perioperative precautions
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 Leigh syndrome spectrum guidance; no COX8A-specific therapeutic trial is demonstrated. Avoid sodium valproate if possible; the absolute POLG contraindication should not be relabeled as a COX8A-specific rule. Plan anesthesia and monitoring, minimize prolonged fasting, and avoid lactate-containing solutions in those at risk of lactic acidosis.
Show evidence (3 references)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/ SUPPORT Human Clinical
"Sodium valproate should be avoided if possible, because of its inhibitory effect on respiratory chain enzymes."
This is the general mitochondrial-disease precaution, with the separate absolute contraindication applying to POLG-related disease.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/ SUPPORT Human Clinical
"Catabolism should be prevented by minimizing preoperative fasting and considering intravenous glucose perioperatively during prolonged anesthesia"
General perioperative LSS guidance; the chapter qualifies glucose use for people on ketogenic diets.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/ SUPPORT Human Clinical
"Avoid lactate-containing agents (e.g., Ringer's lactate) in those at risk of lactic acidosis"
General LSS guidance on fluids in people at risk of lactic acidosis.
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
General Leigh syndrome spectrum guidance; no COX8A-specific therapeutic trial is demonstrated. Confirm parental carrier status. With two heterozygous parents, recurrence risks per conception are 25% affected, 50% carrier and 25% unaffected noncarrier. Family variant identification enables prenatal and preimplantation testing.
Show evidence (2 references)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/ SUPPORT Human Clinical
"each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic ... carrier ... and a 25% chance of being unaffected and not a carrier."
These are conditional autosomal recessive recurrence risks, not measured COX8A penetrance.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/ SUPPORT Human Clinical
"Once the LSS-related ... pathogenic variant ... (s) have been identified in an affected family member, prenatal and ... preimplantation genetic testing ... are possible."
General LSS counseling guidance supports family-specific reproductive testing.
🔬

Biochemical Markers

2
Reduced tissue and cellular cytochrome c oxidase activity (Decreased)
Show evidence (2 references)
PMID:26685157 SUPPORT Human Clinical
"The loss of the wild-type COX8A protein severely impairs the stability of the entire cytochrome c oxidase enzyme complex and manifests in isolated complex IV deficiency in skeletal muscle and fibroblasts"
The report links loss of the normal subunit to deficient complex IV; complete loss of every respiratory complex is not established.
PMID:33705280 SUPPORT In Vitro
"In both cellular model systems, between 20 to 30% of the residual enzymatic activity of cytochrome c oxidase (COX) was detectable."
The later study reports residual cellular activity, so neither universal zero activity nor complete ATP collapse follows.
Elevated lactate with acidosis (Increased lactate; lactic acidosis reported)
Show evidence (1 reference)
CGGV:assertion_a1671723-9b23-4f70-b64d-dd1829b926bc-2024-03-18T040000.000Z SUPPORT Human Clinical
"in an individual from a consanguineous family with Leigh syndrome spectrum (LSS) disorder, congenital scoliosis, developmental delay, pulmonary hypertension, epilepsy, and lactic acidosis."
ClinGen summarizes the single published proband at its March 2024 assessment.
🔬

Diagnosis

4
Molecular diagnosis and segregation
Identify biallelic COX8A variants within a broader mitochondrial diagnostic evaluation. The reported patient was diagnosed by exome sequencing; family testing and RNA or functional analysis can clarify splice variants.
Genetic Testing NCIT:C15709 NCI Thesaurus (NCIT)
Show evidence (3 references)
PMID:26685157 SUPPORT Human Clinical
"we identified a homozygous splice site mutation in COX8A, which codes for the ubiquitously expressed isoform of subunit VIII, the smallest nuclear-encoded subunit of complex IV."
The clinical report identifies a homozygous structural-subunit variant.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/ SUPPORT Human Clinical
"Genome sequencing is preferred (if available), as it allows analysis of the mitochondrial and nuclear genome, and typically has the highest diagnostic rate."
General LSS diagnostic guidance; COX8A is one of many candidate nuclear genes.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/ SUPPORT Human Clinical
"molecular genetic testing ... is recommended for the parents of the proband to confirm that both parents are ... heterozygous"
General autosomal recessive LSS guidance supports parental testing and recurrence-risk assessment.
COX8A RNA analysis
Patient fibroblast RT-PCR and transcript analysis identify the shorter aberrantly spliced product and the exon-2 frameshift.
Show evidence (2 references)
url:https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a1671723-9b23-4f70-b64d-dd1829b926bc-2024-03-18T040000.000Z SUPPORT In Vitro
"A shorter COX8A-specific PCR product was present in fibroblasts of the COX8A patient (Fig. 3B, asterisk), indicating aberrant splicing"
ClinGen reproduces the patient-cell RNA evidence from Hallmann 2016.
url:https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a1671723-9b23-4f70-b64d-dd1829b926bc-2024-03-18T040000.000Z SUPPORT In Vitro
"this 49 nt deletion results in a shift of the reading frame for the entire exon 2"
The aberrant transcript removes 49 nucleotides; this is an RNA consequence of an intronic SNV, not a genomic deletion.
Respiratory-chain enzymology
Complex IV activity in patient muscle and fibroblasts supports the biochemical diagnosis. Residual activity depends on the assay and cellular model; research cell percentages should not be assigned to every patient tissue.
Show evidence (2 references)
PMID:26685157 SUPPORT Human Clinical
"The loss of the wild-type COX8A protein severely impairs the stability of the entire cytochrome c oxidase enzyme complex and manifests in isolated complex IV deficiency in skeletal muscle and fibroblasts"
The report links loss of the normal subunit to deficient complex IV; complete loss of every respiratory complex is not established.
PMID:33705280 SUPPORT In Vitro
"In both cellular model systems, between 20 to 30% of the residual enzymatic activity of cytochrome c oxidase (COX) was detectable."
The later study reports residual cellular activity, so neither universal zero activity nor complete ATP collapse follows.
Brain MRI
Assess white-matter disease and basal-ganglia involvement in the clinical context of Leigh syndrome spectrum.
Magnetic Resonance Imaging NCIT:C16809 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:26685157 SUPPORT Human Clinical
"In a patient with Leigh-like syndrome presenting with leukodystrophy and severe epilepsy"
The original patient has both findings; the report does not establish population frequencies.
url:https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a1671723-9b23-4f70-b64d-dd1829b926bc-2024-03-18T040000.000Z SUPPORT Human Clinical
"Appendicular spasticity ... Bilateral basal ganglia lesions"
ClinGen case-level phenotype abstraction of Hallmann 2016; this is a single patient, not a cohort frequency.
🧫

Experimental Models

2
Patient-derived COX8A-deficient fibroblasts CELL_LINE
The original patient line shows abnormal splicing, reduced stable complex IV and enzyme activity. Wild-type lentiviral COX8A restores enzyme stability and activity. Later work reuses this line and finds residual complex IV in supercomplexes with no mtUPR/ISR transcriptional induction. Daria Rotko's doctoral thesis also reports lower mitochondrial BK-alpha protein without a statistically significant KCNMA1 RNA decrease; its clinical significance is unresolved.
Publication
PMID:26685157
Pathograph links
Reduced stable free complex IV partially recapitulates observes: cellular
Limitations: Cellular biochemical findings do not reproduce the entire neurological or pulmonary phenotype.
Reduced complex IV activity partially recapitulates observes: cellular
Limitations: Cellular biochemical findings do not reproduce the entire neurological or pulmonary phenotype.
Show evidence (7 references)
PMID:26685157 SUPPORT In Vitro
"The mutation, affecting the last nucleotide of intron 1, leads to aberrant splicing, a frame-shift in the highly conserved exon 2, and decreased amount of the COX8A transcript."
Patient-cell RNA analysis links the intronic variant to abnormal splicing and reduced transcript abundance; it does not directly measure a decay pathway.
PMID:26685157 SUPPORT In Vitro
"Stability and activity of complex IV could be rescued in the patient's fibroblasts by lentiviral expression of wild-type COX8A."
Wild-type complementation supports a causal relationship between COX8A dysfunction and the cellular enzyme defect.
PMID:33705280 SUPPORT In Vitro
"In immunoblots of BN-PAGE separated mitochondria from both cellular models almost no monomers and dimers of the fully assembled COX could be visualized."
Patient fibroblasts and engineered HEK293T cells lose most free complex IV; residual supercomplex-associated enzyme must be distinguished.
+ 4 more references
Engineered COX8A-deficient HEK293T clones CELL_LINE
CRISPR/Cas9 targeting of exon 1 produced two viable clones with compound frameshift and in-frame mitochondrial-targeting-sequence lesions. Neither clone was a complete knockout. They reproduce reduced complex IV abundance and activity with variable retention of supercomplex-associated enzyme; they are not additional clinical genotypes. Transcriptome analysis did not detect induction of mtUPR/ISR genes in the assayed models.
Publication
PMID:33705280
Pathograph links
Reduced stable free complex IV partially recapitulates observes: cellular
Limitations: Cellular biochemical findings do not reproduce the entire neurological or pulmonary phenotype.
Reduced complex IV activity partially recapitulates observes: cellular
Limitations: Cellular biochemical findings do not reproduce the entire neurological or pulmonary phenotype.
Show evidence (6 references)
PMID:33705280 SUPPORT In Vitro
"in CRISPR/Cas9 genome-edited HEK293T cells"
The peer-reviewed study identifies the engineered cell system.
url:https://rcin.org.pl/Content/236269/PhD%20thesis%20Daria%20Rotko%20FINAL.pdf SUPPORT In Vitro
"While no viable mutant cell line was characterized as a full COX8A knockout"
The author thesis explicitly identifies incomplete engineered lesions; these are not complete knockout models.
PMID:33705280 SUPPORT In Vitro
"In immunoblots of BN-PAGE separated mitochondria from both cellular models almost no monomers and dimers of the fully assembled COX could be visualized."
Patient fibroblasts and engineered HEK293T cells lose most free complex IV; residual supercomplex-associated enzyme must be distinguished.
+ 3 more references
{ }

Source YAML

click to show 
name: COX8A-Related COX Deficiency
category: Mendelian
creation_date: '2026-06-20T00:00:00Z'
synonyms:
- COX8A deficiency
- Mitochondrial complex IV deficiency, nuclear type 15
- MC4DN15
- COX8A-related cytochrome c oxidase deficiency
- COX8A-related Leigh-like syndrome
disease_term:
  preferred_term: COX8A-related COX deficiency (MC4DN15)
  term:
    id: MONDO:0033650
    label: mitochondrial complex IV deficiency, nuclear type 15
parents:
- Mitochondrial Disease
- Inborn Error of Metabolism
description: COX8A-related mitochondrial complex IV deficiency is an autosomal recessive structural-subunit disorder reported with Leigh syndrome spectrum, leukodystrophy, severe epilepsy, developmental abnormalities and pulmonary hypertension. A homozygous intronic splice-acceptor variant produces abnormal RNA and loss of normal COX8A function. Patient cells and engineered cell models show reduced stable complex IV and enzyme activity, with residual enzyme preferentially retained in respiratory supercomplexes. ClinGen classified the broader COX8A–mitochondrial disease relationship as Limited in March 2024 because only one clinical case supported the assertion.
inheritance:
- &id011
  name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - &id001
    reference: PMID:26685157
    reference_title: Loss of the smallest subunit of cytochrome c oxidase, COX8A, causes Leigh-like syndrome and epilepsy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: we identified a homozygous splice site mutation in COX8A, which codes for the ubiquitously expressed isoform of subunit VIII, the smallest nuclear-encoded subunit of complex IV.
    explanation: The clinical report identifies a homozygous structural-subunit variant.
notes: The small clinical evidence base does not establish phenotype frequencies, penetrance, or severity subtypes. Clinical findings below refer to the reported proband or ClinGen's case-level abstraction. General Leigh syndrome spectrum care recommendations are distinguished from COX8A-specific treatment evidence. The 2021 cellular study reuses the previously reported patient fibroblasts and does not add an independent family.
pathophysiology:
- name: Homozygous COX8A splice-acceptor variant
  description: The reported NM_004074.3:c.115-1G>C variant affects the final nucleotide of intron 1. The physical alteration is a single nucleotide substitution; the subsequent 49-nucleotide deletion occurs in RNA.
  evidence:
  - *id001
  - &id004
    reference: url:https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a1671723-9b23-4f70-b64d-dd1829b926bc-2024-03-18T040000.000Z
    reference_title: curation results for Gene-Disease Validity
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: this 49 nt deletion results in a shift of the reading frame for the entire exon 2
    explanation: The aberrant transcript removes 49 nucleotides; this is an RNA consequence of an intronic SNV, not a genomic deletion.
  genes:
  - &id002
    preferred_term: COX8A
    term:
      id: hgnc:2294
      label: COX8A
  role: trigger
  genetic_context:
    gene: *id002
    variant_type: single nucleotide variant
    genomic_contexts:
    - intron
    variant_origin: GERMLINE
    zygosity: HOMOZYGOUS
  downstream:
  - target: Aberrant COX8A splicing
    causal_link_type: DIRECT
    description: The splice-acceptor substitution alters processing of the COX8A transcript.
    evidence:
    - &id003
      reference: PMID:26685157
      reference_title: Loss of the smallest subunit of cytochrome c oxidase, COX8A, causes Leigh-like syndrome and epilepsy.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: The mutation, affecting the last nucleotide of intron 1, leads to aberrant splicing, a frame-shift in the highly conserved exon 2, and decreased amount of the COX8A transcript.
      explanation: Patient-cell RNA analysis links the intronic variant to abnormal splicing and reduced transcript abundance; it does not directly measure a decay pathway.
- name: Aberrant COX8A splicing
  description: Patient fibroblast RNA uses abnormal splicing and loses 49 nucleotides, shifting the reading frame of exon 2. This changes most of the mature subunit sequence.
  evidence:
  - *id003
  - &id012
    reference: url:https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a1671723-9b23-4f70-b64d-dd1829b926bc-2024-03-18T040000.000Z
    reference_title: curation results for Gene-Disease Validity
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: A shorter COX8A-specific PCR product was present in fibroblasts of the COX8A patient (Fig. 3B, asterisk), indicating aberrant splicing
    explanation: ClinGen reproduces the patient-cell RNA evidence from Hallmann 2016.
  - *id004
  - &id005
    reference: url:https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a1671723-9b23-4f70-b64d-dd1829b926bc-2024-03-18T040000.000Z
    reference_title: curation results for Gene-Disease Validity
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: As exon 2 encodes the 31 C-terminal amino acids of the 44 amino acid-long mature peptide, the translated mutant protein is very likely not functional.
    explanation: The source predicts a severe effect on the mature protein; it does not directly demonstrate nonsense-mediated decay.
  genes:
  - *id002
  downstream:
  - target: Reduced COX8A transcript abundance
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: The abnormal transcript is less abundant; the decay mechanism is not directly resolved.
    evidence:
    - *id003
  - target: Loss of normal COX8A function
    causal_link_type: DIRECT
    description: The frameshift disrupts the sequence of the mature structural subunit.
    evidence:
    - *id005
- name: Reduced COX8A transcript abundance
  description: COX8A RNA abundance is reduced in patient fibroblasts. Reduced abundance does not by itself identify altered transcription or prove a particular RNA-decay pathway.
  evidence:
  - *id003
  genes:
  - *id002
  downstream:
  - target: Loss of normal COX8A function
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Lower transcript availability compounds the abnormal coding sequence.
    evidence:
    - *id003
    - *id005
- name: Loss of normal COX8A function
  description: The aberrantly spliced transcript cannot produce the normal structural subunit. Sequence disruption and lower RNA abundance together impair normal COX8A function; residual respiratory activity does not imply normal subunit restoration.
  evidence:
  - &id008
    reference: PMID:26685157
    reference_title: Loss of the smallest subunit of cytochrome c oxidase, COX8A, causes Leigh-like syndrome and epilepsy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The loss of the wild-type COX8A protein severely impairs the stability of the entire cytochrome c oxidase enzyme complex and manifests in isolated complex IV deficiency in skeletal muscle and fibroblasts
    explanation: The report links loss of the normal subunit to deficient complex IV; complete loss of every respiratory complex is not established.
  - *id005
  - &id006
    reference: PMID:26685157
    reference_title: Loss of the smallest subunit of cytochrome c oxidase, COX8A, causes Leigh-like syndrome and epilepsy.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Stability and activity of complex IV could be rescued in the patient's fibroblasts by lentiviral expression of wild-type COX8A.
    explanation: Wild-type complementation supports a causal relationship between COX8A dysfunction and the cellular enzyme defect.
  genes:
  - *id002
  downstream:
  - target: Reduced stable free complex IV
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Loss of normal subunit function impairs holoenzyme stability, supported by wild-type complementation.
    evidence:
    - &id007
      reference: PMID:33705280
      reference_title: Molecular and Functional Effects of Loss of Cytochrome c Oxidase Subunit 8A.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: In immunoblots of BN-PAGE separated mitochondria from both cellular models almost no monomers and dimers of the fully assembled COX could be visualized.
      explanation: Patient fibroblasts and engineered HEK293T cells lose most free complex IV; residual supercomplex-associated enzyme must be distinguished.
    - *id006
- name: Reduced stable free complex IV
  description: Patient cells and engineered COX8A-deficient cells have markedly reduced free complex IV monomers and dimers. Some residual enzyme remains in respiratory supercomplexes, suggesting structural stabilization there. The results do not establish a universal block of every complex IV assembly intermediate.
  evidence:
  - *id007
  - &id017
    reference: PMID:33705280
    reference_title: Molecular and Functional Effects of Loss of Cytochrome c Oxidase Subunit 8A.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Interestingly, supercomplexes of COX formed with complex III and also with complexes I and III retained considerable immunoreactivity, while nearly no immunoreactivity attributable to subassemblies was found.
    explanation: Supports the distinction in the description between depleted free enzyme and retained supercomplex-associated enzyme; the adjacent BN-PAGE evidence establishes free-monomer and dimer depletion.
  - *id006
  genes:
  - *id002
  conforms_to: complex_iv_assembly_deficiency#Complex IV Biogenesis Failure
  downstream:
  - target: Reduced complex IV activity
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Reduced stable enzyme abundance accompanies reduced measured complex IV activity.
    evidence:
    - *id007
    - &id009
      reference: PMID:33705280
      reference_title: Molecular and Functional Effects of Loss of Cytochrome c Oxidase Subunit 8A.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: In both cellular model systems, between 20 to 30% of the residual enzymatic activity of cytochrome c oxidase (COX) was detectable.
      explanation: The later study reports residual cellular activity, so neither universal zero activity nor complete ATP collapse follows.
    - *id006
- name: Reduced complex IV activity
  description: Complex IV enzyme activity is severely reduced in patient muscle and cultured fibroblasts, with residual activity in later cellular assays. COX8A supports holoenzyme stability; it is not an autonomous catalytic subunit. No direct measurement in these sources establishes universal ATP depletion or oxidative stress in patients.
  evidence:
  - *id008
  - *id009
  - *id006
  genes:
  - *id002
  molecular_functions:
  - preferred_term: cytochrome-c oxidase activity
    term:
      id: GO:0004129
      label: cytochrome-c oxidase activity
    modifier: DECREASED
  downstream:
  - target: Seizures
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: The biochemical lesion is associated with the reported neurological disease; the intervening neural mechanism has not been established.
    evidence:
    - &id010
      reference: PMID:26685157
      reference_title: Loss of the smallest subunit of cytochrome c oxidase, COX8A, causes Leigh-like syndrome and epilepsy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: In a patient with Leigh-like syndrome presenting with leukodystrophy and severe epilepsy
      explanation: The original patient has both findings; the report does not establish population frequencies.
    - *id008
  - target: Leukodystrophy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: White-matter injury accompanies the inherited enzyme defect; a specific ROS-mediated pathway is not demonstrated.
    evidence:
    - *id010
    - *id008
  - target: Lactic acidosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: The reported mitochondrial disease includes lactic acidosis; the tissue-specific metabolic intermediates remain unresolved.
    evidence:
    - &id014
      reference: CGGV:assertion_a1671723-9b23-4f70-b64d-dd1829b926bc-2024-03-18T040000.000Z
      reference_title: COX8A / mitochondrial disease (Limited)
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: in an individual from a consanguineous family with Leigh syndrome spectrum (LSS) disorder, congenital scoliosis, developmental delay, pulmonary hypertension, epilepsy, and lactic acidosis.
      explanation: ClinGen summarizes the single published proband at its March 2024 assessment.
phenotypes:
- name: Seizures
  description: Severe epilepsy was reported in the original patient.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
    severity: SEVERE
  evidence:
  - *id010
  - 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: HUMAN_CLINICAL
    snippet: COX8A ... 1 person ... Seizures; hypotonia; spasticity; leukodystrophy
    explanation: The gene-specific row of the broader GeneReviews chapter lists these features for one reported person; no frequency estimate is inferred.
- name: Leukodystrophy
  description: White-matter disease was a central feature of the reported Leigh-like presentation.
  phenotype_term:
    preferred_term: Leukodystrophy
    term:
      id: HP:0002415
      label: Leukodystrophy
  evidence:
  - *id010
  - 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: HUMAN_CLINICAL
    snippet: COX8A ... 1 person ... Seizures; hypotonia; spasticity; leukodystrophy
    explanation: The gene-specific row of the broader GeneReviews chapter lists these features for one reported person; no frequency estimate is inferred.
- name: Congenital kyphoscoliosis
  description: Congenital spinal curvature was recorded in the ClinGen abstraction of the proband.
  phenotype_term:
    preferred_term: Congenital kyphoscoliosis
    term:
      id: HP:0008453
      label: Congenital kyphoscoliosis
  evidence:
  - reference: url:https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a1671723-9b23-4f70-b64d-dd1829b926bc-2024-03-18T040000.000Z
    reference_title: curation results for Gene-Disease Validity
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Congenital kyphoscoliosis ... Global developmental delay
    explanation: ClinGen case-level phenotype abstraction of Hallmann 2016; this is a single patient, not a cohort frequency.
- name: Global developmental delay
  description: Developmental delay was reported in the proband.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: url:https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a1671723-9b23-4f70-b64d-dd1829b926bc-2024-03-18T040000.000Z
    reference_title: curation results for Gene-Disease Validity
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Congenital kyphoscoliosis ... Global developmental delay
    explanation: ClinGen case-level phenotype abstraction of Hallmann 2016; this is a single patient, not a cohort frequency.
- name: Appendicular spasticity
  description: ClinGen records limb spasticity in the reported patient.
  phenotype_term:
    preferred_term: Appendicular spasticity
    term:
      id: HP:0034353
      label: Appendicular spasticity
  evidence:
  - reference: url:https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a1671723-9b23-4f70-b64d-dd1829b926bc-2024-03-18T040000.000Z
    reference_title: curation results for Gene-Disease Validity
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Appendicular spasticity ... Bilateral basal ganglia lesions
    explanation: ClinGen case-level phenotype abstraction of Hallmann 2016; this is a single patient, not a cohort frequency.
  - 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: HUMAN_CLINICAL
    snippet: COX8A ... 1 person ... Seizures; hypotonia; spasticity; leukodystrophy
    explanation: The gene-specific row of the broader GeneReviews chapter lists these features for one reported person; no frequency estimate is inferred.
- name: Hypotonia
  description: Hypotonia was recorded in the reported patient.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: url:https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a1671723-9b23-4f70-b64d-dd1829b926bc-2024-03-18T040000.000Z
    reference_title: curation results for Gene-Disease Validity
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Global developmental delay ... Hypotonia ... Increased circulating lactate concentration
    explanation: ClinGen case-level phenotype abstraction of Hallmann 2016; this is a single patient, not a cohort frequency.
  - 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: HUMAN_CLINICAL
    snippet: COX8A ... 1 person ... Seizures; hypotonia; spasticity; leukodystrophy
    explanation: The gene-specific row of the broader GeneReviews chapter lists these features for one reported person; no frequency estimate is inferred.
- name: Microcephaly
  description: Microcephaly appears in the case-level ClinGen phenotype record.
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  evidence:
  - reference: url:https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a1671723-9b23-4f70-b64d-dd1829b926bc-2024-03-18T040000.000Z
    reference_title: curation results for Gene-Disease Validity
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Lactic acidosis ... Microcephaly ... Pulmonary arterial hypertension
    explanation: ClinGen case-level phenotype abstraction of Hallmann 2016; this is a single patient, not a cohort frequency.
- name: Short stature
  description: Short stature was recorded for the proband; no frequency estimate is available.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: url:https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a1671723-9b23-4f70-b64d-dd1829b926bc-2024-03-18T040000.000Z
    reference_title: curation results for Gene-Disease Validity
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Pulmonary arterial hypertension ... Seizure ... Short stature
    explanation: ClinGen case-level phenotype abstraction of Hallmann 2016; this is a single patient, not a cohort frequency.
- name: Bilateral basal ganglia lesions
  description: Basal-ganglia lesions were recorded in addition to leukodystrophy.
  phenotype_term:
    preferred_term: Bilateral basal ganglia lesions
    term:
      id: HP:0007146
      label: Bilateral basal ganglia lesions
  evidence:
  - &id013
    reference: url:https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a1671723-9b23-4f70-b64d-dd1829b926bc-2024-03-18T040000.000Z
    reference_title: curation results for Gene-Disease Validity
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Appendicular spasticity ... Bilateral basal ganglia lesions
    explanation: ClinGen case-level phenotype abstraction of Hallmann 2016; this is a single patient, not a cohort frequency.
- name: Elevated pulmonary artery pressure
  description: Pulmonary hypertension was reported. The broader pressure phenotype is used because the available case summary does not document invasive hemodynamic subclassification.
  phenotype_term:
    preferred_term: Elevated pulmonary artery pressure
    term:
      id: HP:0004890
      label: Elevated pulmonary artery pressure
  evidence:
  - reference: url:https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a1671723-9b23-4f70-b64d-dd1829b926bc-2024-03-18T040000.000Z
    reference_title: curation results for Gene-Disease Validity
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Microcephaly ... Pulmonary arterial hypertension ... Seizure
    explanation: ClinGen case-level phenotype abstraction of Hallmann 2016; this is a single patient, not a cohort frequency.
- name: Elevated circulating lactate
  description: The ClinGen patient record includes elevated circulating lactate.
  phenotype_term:
    preferred_term: Increased circulating lactate concentration
    term:
      id: HP:0002151
      label: Increased circulating lactate concentration
  evidence:
  - reference: url:https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a1671723-9b23-4f70-b64d-dd1829b926bc-2024-03-18T040000.000Z
    reference_title: curation results for Gene-Disease Validity
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Increased circulating lactate concentration ... Lactic acidosis
    explanation: ClinGen case-level phenotype abstraction of Hallmann 2016; this is a single patient, not a cohort frequency.
- name: Lactic acidosis
  description: Lactic acidosis accompanied the reported mitochondrial disease.
  phenotype_term:
    preferred_term: Lactic acidosis
    term:
      id: HP:0003128
      label: Lactic acidosis
  evidence:
  - reference: url:https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a1671723-9b23-4f70-b64d-dd1829b926bc-2024-03-18T040000.000Z
    reference_title: curation results for Gene-Disease Validity
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Increased circulating lactate concentration ... Lactic acidosis
    explanation: ClinGen case-level phenotype abstraction of Hallmann 2016; this is a single patient, not a cohort frequency.
genetic:
- name: COX8A
  gene_term: *id002
  inheritance:
  - *id011
  features: The clinical evidence centers on a homozygous splice-acceptor variant and functional complementation in patient fibroblasts. Experimental MTS deletions in HEK293T cells are models, not additional human disease alleles.
  variants:
  - name: NM_004074.3:c.115-1G>C
    description: Homozygous intron-1 splice-acceptor SNV in the reported patient. Aberrant splicing removes 49 RNA nucleotides and changes the exon-2 reading frame. This is not a 49-base genomic deletion.
    gene: *id002
    type: splice_acceptor_variant
    variant_type: single nucleotide variant
    genomic_contexts:
    - intron
    clinical_significance: PATHOGENIC
    evidence:
    - *id001
    - *id003
    - *id004
    - reference: url:https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a1671723-9b23-4f70-b64d-dd1829b926bc-2024-03-18T040000.000Z
      reference_title: curation results for Gene-Disease Validity
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: COX8A homoyzgous for c.115-1G>C Absent in gnomADv4.0.0
      explanation: The ClinGen case record supplies the exact allele notation and its population-database assessment at curation time.
  evidence:
  - *id001
  - *id006
  gene_disease_validity:
  - validity_classification: LIMITED
    classified_by: CLINGEN
    external_id: CGGV:assertion_a1671723-9b23-4f70-b64d-dd1829b926bc-2024-03-18T040000.000Z
    notes: The March 2024 assertion concerns COX8A–primary mitochondrial disease (MONDO:0044970), a broader entity that includes MC4DN15. Only one clinical case was included; strong cellular support does not change the panel classification.
    evidence:
    - reference: CGGV:assertion_a1671723-9b23-4f70-b64d-dd1829b926bc-2024-03-18T040000.000Z
      reference_title: COX8A / mitochondrial disease (Limited)
      supports: SUPPORT
      evidence_source: OTHER
      snippet: In summary, there is limited evidence to support this gene-disease relationship given that only one case has been reported to date.
      explanation: The expert-panel classification reflects limited clinical replication as of March 2024 despite functional evidence.
diagnosis:
- name: Molecular diagnosis and segregation
  description: Identify biallelic COX8A variants within a broader mitochondrial diagnostic evaluation. The reported patient was diagnosed by exome sequencing; family testing and RNA or functional analysis can clarify splice variants.
  diagnosis_term:
    preferred_term: Genetic Testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - *id001
  - 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: HUMAN_CLINICAL
    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: General LSS diagnostic guidance; COX8A is one of many candidate nuclear genes.
  - 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: HUMAN_CLINICAL
    snippet: molecular genetic testing ... is recommended for the parents of the proband to confirm that both parents are ... heterozygous
    explanation: General autosomal recessive LSS guidance supports parental testing and recurrence-risk assessment.
- name: COX8A RNA analysis
  description: Patient fibroblast RT-PCR and transcript analysis identify the shorter aberrantly spliced product and the exon-2 frameshift.
  evidence:
  - *id012
  - *id004
- name: Respiratory-chain enzymology
  description: Complex IV activity in patient muscle and fibroblasts supports the biochemical diagnosis. Residual activity depends on the assay and cellular model; research cell percentages should not be assigned to every patient tissue.
  evidence:
  - *id008
  - *id009
- name: Brain MRI
  description: Assess white-matter disease and basal-ganglia involvement in the clinical context of Leigh syndrome spectrum.
  diagnosis_term:
    preferred_term: Magnetic Resonance Imaging
    term:
      id: NCIT:C16809
      label: Magnetic Resonance Imaging
  evidence:
  - *id010
  - *id013
biochemical:
- name: Reduced tissue and cellular cytochrome c oxidase activity
  presence: Decreased
  evidence:
  - *id008
  - *id009
- name: Elevated lactate with acidosis
  presence: Increased lactate; lactic acidosis reported
  evidence:
  - *id014
treatments:
- name: Multidisciplinary supportive care
  description: General Leigh syndrome spectrum guidance; no COX8A-specific therapeutic trial is demonstrated. Coordinate neurological, nutritional, respiratory and rehabilitation care according to manifestations.
  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: HUMAN_CLINICAL
    snippet: Supportive care to improve quality of life, maximize function, and reduce complications is recommended.
    explanation: The chapter provides a general supportive-care framework.
- name: Antiseizure treatment
  description: General Leigh syndrome spectrum guidance; no COX8A-specific therapeutic trial is demonstrated. An experienced neurologist should individualize antiseizure medication. The available sources do not establish a preferred COX8A-specific drug.
  treatment_term:
    preferred_term: Anticonvulsant Therapy
    term:
      id: NCIT:C64172
      label: Anticonvulsant Therapy
  evidence:
  - &id015
    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: HUMAN_CLINICAL
    snippet: Treatment w/ASM by experienced neurologist
    explanation: LSS guidance supports specialist antiseizure treatment.
  target_mechanisms:
  - target: Seizures
    treatment_effect: MODULATES
    description: Symptom-directed management from general LSS guidance; COX8A-specific efficacy has not been established.
    evidence:
    - *id015
- name: Acidosis correction
  description: General Leigh syndrome spectrum guidance; no COX8A-specific therapeutic trial is demonstrated. Clinically significant acidosis may require sodium bicarbonate or sodium citrate, selected and monitored by the treating team.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: sodium hydrogencarbonate
      term:
        id: CHEBI:32139
        label: sodium hydrogencarbonate
  evidence:
  - &id016
    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: HUMAN_CLINICAL
    snippet: Sodium bicarbonate or sodium citrate for significant acidosis
    explanation: This recommendation treats significant acidosis in LSS, rather than repairing COX8A.
  target_mechanisms:
  - target: Lactic acidosis
    treatment_effect: MODULATES
    description: Symptom-directed management from general LSS guidance; COX8A-specific efficacy has not been established.
    evidence:
    - *id016
- name: Nutritional support
  description: General Leigh syndrome spectrum guidance; no COX8A-specific therapeutic trial is demonstrated. Assess growth, nutritional intake and swallowing safety; provide supplementation and feeding support when indicated.
  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: HUMAN_CLINICAL
    snippet: nutritional supplementation as needed (incl micronutrients)
    explanation: The general LSS care table recommends nutritional support when needed.
- name: Clinical surveillance
  description: General Leigh syndrome spectrum guidance; no COX8A-specific therapeutic trial is demonstrated. Regular neurological, ophthalmological, hearing and cardiac assessment should be tailored to manifestations.
  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: HUMAN_CLINICAL
    snippet: Neurologic, ophthalmologic, audiologic, and cardiologic evaluations are recommended
    explanation: The chapter recommends multisystem surveillance for LSS.
- name: Medication and perioperative precautions
  description: General Leigh syndrome spectrum guidance; no COX8A-specific therapeutic trial is demonstrated. Avoid sodium valproate if possible; the absolute POLG contraindication should not be relabeled as a COX8A-specific rule. Plan anesthesia and monitoring, minimize prolonged fasting, and avoid lactate-containing solutions in those at risk of lactic 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: HUMAN_CLINICAL
    snippet: Sodium valproate should be avoided if possible, because of its inhibitory effect on respiratory chain enzymes.
    explanation: This is the general mitochondrial-disease precaution, with the separate absolute contraindication applying to POLG-related disease.
  - 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: HUMAN_CLINICAL
    snippet: Catabolism should be prevented by minimizing preoperative fasting and considering intravenous glucose perioperatively during prolonged anesthesia
    explanation: General perioperative LSS guidance; the chapter qualifies glucose use for people on ketogenic diets.
  - 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: HUMAN_CLINICAL
    snippet: Avoid lactate-containing agents (e.g., Ringer's lactate) in those at risk of lactic acidosis
    explanation: General LSS guidance on fluids in people at risk of lactic acidosis.
- name: Genetic counseling
  description: General Leigh syndrome spectrum guidance; no COX8A-specific therapeutic trial is demonstrated. Confirm parental carrier status. With two heterozygous parents, recurrence risks per conception are 25% affected, 50% carrier and 25% unaffected noncarrier. Family variant identification enables prenatal and preimplantation testing.
  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: HUMAN_CLINICAL
    snippet: each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic ... carrier ... and a 25% chance of being unaffected and not a carrier.
    explanation: These are conditional autosomal recessive recurrence risks, not measured COX8A penetrance.
  - 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: HUMAN_CLINICAL
    snippet: Once the LSS-related ... pathogenic variant ... (s) have been identified in an affected family member, prenatal and ... preimplantation genetic testing ... are possible.
    explanation: General LSS counseling guidance supports family-specific reproductive testing.
experimental_models:
- name: Patient-derived COX8A-deficient fibroblasts
  experimental_model_type: CELL_LINE
  description: The original patient line shows abnormal splicing, reduced stable complex IV and enzyme activity. Wild-type lentiviral COX8A restores enzyme stability and activity. Later work reuses this line and finds residual complex IV in supercomplexes with no mtUPR/ISR transcriptional induction. Daria Rotko's doctoral thesis also reports lower mitochondrial BK-alpha protein without a statistically significant KCNMA1 RNA decrease; its clinical significance is unresolved.
  publication: PMID:26685157
  evidence:
  - *id003
  - *id006
  - *id007
  - *id017
  - &id018
    reference: PMID:33705280
    reference_title: Molecular and Functional Effects of Loss of Cytochrome c Oxidase Subunit 8A.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: With transcriptome analysis by 3'-RNA sequencing we failed to detect in our cellular models of COX8A deficiency transcriptional changes of genes involved in the mitochondrial unfolded protein response (mtUPR) and the integrated stress response (ISR).
    explanation: This is a negative transcriptional result in the assayed models, not proof that all stress signaling is absent.
  - reference: url:https://rcin.org.pl/Content/236269/PhD%20thesis%20Daria%20Rotko%20FINAL.pdf
    reference_title: https://rcin.org.pl/Content/236269/PhD%20thesis%20Daria%20Rotko%20FINAL.pdf
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: The results of the study confirmed the decrease in the total amount of the total full-sized BK-α protein in cell lysate, and in particular mitoBK-α protein in the mitochondria of COX8A-deficient fibroblasts
    explanation: The thesis reports a patient-cell protein finding without establishing a causal link to the neurological phenotype.
  - reference: url:https://rcin.org.pl/Content/236269/PhD%20thesis%20Daria%20Rotko%20FINAL.pdf
    reference_title: https://rcin.org.pl/Content/236269/PhD%20thesis%20Daria%20Rotko%20FINAL.pdf
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: No statistically significant decrease in the expression of KCNMA1 was detected in a qRT-PCR assay with GAPDH as a reference gene
    explanation: Patient-cell BK-alpha protein reduction is not accompanied by demonstrated KCNMA1 transcriptional downregulation.
  modeled_mechanisms:
  - target: Reduced stable free complex IV
    relationship: PARTIALLY_RECAPITULATES
    model_scale: CELLULAR
    limitations: Cellular biochemical findings do not reproduce the entire neurological or pulmonary phenotype.
  - target: Reduced complex IV activity
    relationship: PARTIALLY_RECAPITULATES
    model_scale: CELLULAR
    limitations: Cellular biochemical findings do not reproduce the entire neurological or pulmonary phenotype.
- name: Engineered COX8A-deficient HEK293T clones
  experimental_model_type: CELL_LINE
  description: CRISPR/Cas9 targeting of exon 1 produced two viable clones with compound frameshift and in-frame mitochondrial-targeting-sequence lesions. Neither clone was a complete knockout. They reproduce reduced complex IV abundance and activity with variable retention of supercomplex-associated enzyme; they are not additional clinical genotypes. Transcriptome analysis did not detect induction of mtUPR/ISR genes in the assayed models.
  publication: PMID:33705280
  evidence:
  - reference: PMID:33705280
    reference_title: Molecular and Functional Effects of Loss of Cytochrome c Oxidase Subunit 8A.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: in CRISPR/Cas9 genome-edited HEK293T cells
    explanation: The peer-reviewed study identifies the engineered cell system.
  - reference: url:https://rcin.org.pl/Content/236269/PhD%20thesis%20Daria%20Rotko%20FINAL.pdf
    reference_title: https://rcin.org.pl/Content/236269/PhD%20thesis%20Daria%20Rotko%20FINAL.pdf
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: While no viable mutant cell line was characterized as a full COX8A knockout
    explanation: The author thesis explicitly identifies incomplete engineered lesions; these are not complete knockout models.
  - *id007
  - *id017
  - *id009
  - *id018
  modeled_mechanisms:
  - target: Reduced stable free complex IV
    relationship: PARTIALLY_RECAPITULATES
    model_scale: CELLULAR
    limitations: Cellular biochemical findings do not reproduce the entire neurological or pulmonary phenotype.
  - target: Reduced complex IV activity
    relationship: PARTIALLY_RECAPITULATES
    model_scale: CELLULAR
    limitations: Cellular biochemical findings do not reproduce the entire neurological or pulmonary phenotype.
references:
- reference: PMID:26685157
  title: Loss of the smallest subunit of cytochrome c oxidase, COX8A, causes Leigh-like syndrome and epilepsy.
- reference: PMID:33705280
  title: Molecular and Functional Effects of Loss of Cytochrome c Oxidase Subunit 8A.
- reference: CGGV:assertion_a1671723-9b23-4f70-b64d-dd1829b926bc-2024-03-18T040000.000Z
  title: COX8A / mitochondrial disease (Limited)
- reference: url:https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a1671723-9b23-4f70-b64d-dd1829b926bc-2024-03-18T040000.000Z
  title: curation results for Gene-Disease Validity
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/
  title: Nuclear Gene-Encoded Leigh Syndrome Spectrum Overview - GeneReviews® - NCBI Bookshelf
  tags:
  - GeneReviews
- reference: url:https://rcin.org.pl/Content/236269/PhD%20thesis%20Daria%20Rotko%20FINAL.pdf
  title: https://rcin.org.pl/Content/236269/PhD%20thesis%20Daria%20Rotko%20FINAL.pdf
- reference: PMID:26425749
  title: Nuclear Gene-Encoded Leigh Syndrome Spectrum Overview.
  tags:
  - GeneReviews
histopathology:
- name: Reduced muscle cytochrome c oxidase staining
  description: The original muscle sample showed weak COX staining in the ClinGen case abstraction.
  evidence:
  - reference: url:https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a1671723-9b23-4f70-b64d-dd1829b926bc-2024-03-18T040000.000Z
    reference_title: curation results for Gene-Disease Validity
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: uniformly weak COX staining + COX deficiency in muscle 10% of control
    explanation: ClinGen summarizes weak muscle COX histochemistry and reduced enzyme activity in the original case.
📚

References & Deep Research

References

7
PMID:26685157
Loss of the smallest subunit of cytochrome c oxidase, COX8A, causes Leigh-like syndrome and epilepsy.
No top-level findings curated for this source.
PMID:33705280
Molecular and Functional Effects of Loss of Cytochrome c Oxidase Subunit 8A.
No top-level findings curated for this source.
No top-level findings curated for this source.
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.
url:https://rcin.org.pl/Content/236269/PhD%20thesis%20Daria%20Rotko%20FINAL.pdf
https://rcin.org.pl/Content/236269/PhD%20thesis%20Daria%20Rotko%20FINAL.pdf
No top-level findings curated for this source.
PMID:26425749
Nuclear Gene-Encoded Leigh Syndrome Spectrum Overview.
No top-level findings curated for this source.