COX5A-Related COX Deficiency

Mendelian MONDO:0033655 Pathograph 21 Show in embeddings browser Mitochondrial Disease Inborn Error of Metabolism

COX5A-related cytochrome c oxidase deficiency (MC4DN20) is an autosomal recessive mitochondrial disorder caused by biallelic COX5A variants. COX5A is a nuclear-encoded structural subunit required for normal complex IV biogenesis. Patient fibroblasts show reduced COX5A and complex IV abundance, impaired assembly and reduced enzyme activity, with residual assembled enzyme. The founding p.Arg107Cys siblings had infantile pulmonary arterial hypertension, lactic acidemia, hypotonia and severe growth failure with early death. A later p.Ile89Ser patient had a milder course with childhood ketotic hypoglycemia, severe short stature and hypergonadotropic hypogonadism, without cardiovascular or neurodevelopmental involvement. Copper rescue is a cell-culture finding; clinical benefit has not been demonstrated in these reports.

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1
Inheritance
7
Pathophys.
28
Phenotypes
21
Pathograph
1
Genes
2
Variants
3
Medical Actions
3
Models
5
References
👪

Inheritance

1
Autosomal recessive HP:0000007
Homozygous missense variants were reported in both families; both parents in the second family were heterozygous.
Autosomal recessive inheritance
Show evidence (2 references)
url:https://iris.uniroma1.it/bitstream/11573/1705503/2/Torraco_Novel_2022.pdf SUPPORT Human Clinical
"Both parents resulted heterozygous for the same variant (Figure 1C)."
Both parents of the homozygous p.Ile89Ser patient carried the variant.
PMID:28247525 SUPPORT Human Clinical
"We present patients with a homozygous pathogenic variant in the COX5A gene."
The founding family supports recessive inheritance.
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Pathophysiology

7
Predicted COX5A-COX4 Interface Disruption
Mechanism confidence: Hypothetical
The p.Arg107Cys substitution is predicted to remove contacts at the COX5A-COX4 interface. This allele-specific structural model is distinct from experimentally measured protein depletion.
Downstream
Impaired Complex IV Assembly Loss of the predicted interface contacts may impair early assembly.
Show evidence (1 reference)
PMID:28247525 SUPPORT INDIRECT Computational
"We show that the variant lies within the evolutionarily conserved COX5A/COX4 interface domain, suggesting that it alters the interaction between these two subunits during complex IV biogenesis."
Homology modeling predicts altered subunit contacts for p.Arg107Cys; a direct binding assay was not performed.
Reduced COX5A Protein Abundance
COX5A protein remains detectable at reduced abundance in patient fibroblasts. The p.Ile89Ser patient had an approximately 50% reduction; complete absence is not established.
Experimental models
p.Ile89Ser patient fibroblasts PRIMARY CELL CULTURE
Downstream
Impaired Complex IV Assembly Reduced availability of a required structural subunit impairs assembly.
Show evidence (2 references)
url:https://iris.uniroma1.it/bitstream/11573/1705503/2/Torraco_Novel_2022.pdf SUPPORT In Vitro
"found a 50% reduction of COX5A protein in the patient"
The p.Ile89Ser patient retained COX5A protein at about half the control amount.
url:https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf SUPPORT In Vitro
"COX5A protein was still detectable in low amounts in the patient cells."
Residual COX5A was detected in the younger founder sibling.
Impaired Complex IV Assembly
Early complex IV biogenesis is impaired. The p.Arg107Cys patient accumulates the monomeric COX1 S1 intermediate, while some holoenzyme still assembles. COX5A is a structural subunit with an assembly role, not a separate assembly factor.
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
p.Arg107Cys patient fibroblasts PRIMARY CELL CULTURE
COX5A knockdown in HEK293 cells CELL LINE
Downstream
Reduced Complex IV Abundance The assembly defect reduces steady-state holoenzyme abundance.
Show evidence (2 references)
PMID:28247525 SUPPORT In Vitro
"The monomeric COX1 assembly intermediate accumulates demonstrating a function of COX5A in complex IV biogenesis."
Patient-cell assembly analysis identifies accumulation of the early COX1 intermediate.
url:https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf SUPPORT In Vitro
"even though complex IV levels are clearly reduced, the complex can still be fully assembled."
The founder study explicitly found residual assembled complex IV.
Reduced Complex IV Abundance
Patient cells have reduced mature complex IV and several constituent subunits. Residual holocomplex and selected supercomplexes persist, so total absence of enzyme is not a common mechanism.
Experimental models
p.Ile89Ser patient fibroblasts PRIMARY CELL CULTURE
Downstream
Reduced Cytochrome c Oxidase Activity A smaller pool of mature complex IV lowers measured oxidase capacity.
Altered Complex IV Supercomplex Distribution The available complex IV is distributed differently among monomeric and higher-order assemblies.
Show evidence (2 references)
PMID:28247525 SUPPORT In Vitro
"In patient skin fibroblasts, the enzymatic activity and protein levels of complex IV and several of its subunits are reduced."
The biochemical deficit and subunit depletion were measured in cultured patient fibroblasts.
url:https://iris.uniroma1.it/bitstream/11573/1705503/2/Torraco_Novel_2022.pdf SUPPORT In Vitro
"confirmed the selective reduction of the holocomplex CIV (20% residual amount) as well as an almost undetectable CIV activity (Figure 2D, E)."
The p.Ile89Ser fibroblasts retained about 20% holocomplex IV, with nearly undetectable in-gel activity.
Reduced Cytochrome c Oxidase Activity
Patient fibroblasts show isolated complex IV enzymatic deficiency. COX5A supports the multimeric enzyme; it does not itself provide the redox catalytic center. The effect on ATP supply in affected organs has not been directly quantified.
COX5A hgnc:2267 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves COX5A (hgnc:2267). hgnc:2267 is a gene from the HUGO Gene Nomenclature Committee.
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.
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
p.Arg107Cys patient fibroblasts PRIMARY CELL CULTURE
COX5A knockdown in HEK293 cells CELL LINE
Downstream
Increased Circulating Lactate Respiratory-chain dysfunction is associated with lactate accumulation; the intervening flux changes were not measured in these patients.
Pulmonary arterial hypertension Complex IV dysfunction is associated with pulmonary vascular disease in the founding siblings; vascular-cell mechanisms remain unresolved.
Failure to thrive Mitochondrial dysfunction contributes to growth failure through incompletely defined systemic pathways.
Show evidence (2 references)
PMID:28247525 SUPPORT In Vitro
"In patient skin fibroblasts, the enzymatic activity and protein levels of complex IV and several of its subunits are reduced."
The biochemical deficit and subunit depletion were measured in cultured patient fibroblasts.
url:https://iris.uniroma1.it/bitstream/11573/1705503/2/Torraco_Novel_2022.pdf SUPPORT In Vitro
"selective reduction of CIV activity in the patient, whereas the activity of CI was expressed equally in the patient and control subjects (Figure 2B)."
Complex I activity was preserved in the second patient while complex IV activity was reduced.
Altered Complex IV Supercomplex Distribution
In the founder fibroblasts, monomeric complex IV was reduced while high-molecular-weight complex IV-containing assemblies were preserved. In the later patient, selected supercomplexes persisted but III2+IV was absent. Their role in the severity difference remains a hypothesis, not an established modifier.
Experimental models
p.Arg107Cys patient fibroblasts PRIMARY CELL CULTURE
p.Ile89Ser patient fibroblasts PRIMARY CELL CULTURE
Show evidence (2 references)
url:https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf SUPPORT In Vitro
"decrease of complex IV and the CuCl 2-induced increase exclusively affected monomeric complex IV , whereas the levels of the com- plex IV containing high molecular weight supercomplexes remained unaffected."
The decrease and copper response involved monomeric complex IV; higher-order supercomplex abundance was preserved.
url:https://iris.uniroma1.it/bitstream/11573/1705503/2/Torraco_Novel_2022.pdf SUPPORT In Vitro
"SC I + IV was reduced but still present in the patient, whereas SC III 2 + IV1 was totally absent (Figure 2D, E)"
The second patient showed differential preservation of CIV-containing assemblies.
Increased Circulating Lactate
Circulating lactate is elevated in the reported patients, persistently in the younger founder sibling and intermittently in the later patient. Elevated lactate alone does not establish continuously low blood pH or measured excess lactate production.
Downstream
Elevated blood lactate Elevated circulating lactate is the measured clinical manifestation.
Show evidence (1 reference)
PMID:28247525 SUPPORT Human Clinical
"Clinical details of two affected siblings suffering from early-onset pulmonary arterial hypertension, lactic acidemia, failure to thrive, and isolated complex IV deficiency are presented."
Both founding siblings had elevated circulating lactate.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for COX5A-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

28
Cardiovascular 5
Pulmonary arterial hypertension HP:0002092 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pulmonary arterial hypertension (HP:0002092). HP:0002092 is a phenotype from the Human Phenotype Ontology.
Sequelae: Tricuspid regurgitation Right atrial enlargement Right ventricular dilatation
Show evidence (4 references)
PMID:28247525 SUPPORT Human Clinical
"Clinical details of two affected siblings suffering from early-onset pulmonary arterial hypertension, lactic acidemia, failure to thrive, and isolated complex IV deficiency are presented."
Both founding siblings had early-onset pulmonary arterial hypertension.
url:https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf SUPPORT Human Clinical
"An echocar- diography performed in the first days of life revealed mild PAH"
The younger founding sibling had mild pulmonary hypertension in the neonatal period.
url:https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf SUPPORT Human Clinical
"severe suprasystemic PAH, with marked tricuspid regurgitation, a dilated right atrium, and a dilated right ventricle."
The elder founding sibling had severe pulmonary hypertension with tricuspid regurgitation and right-heart enlargement.
+ 1 more reference
Cardiomegaly HP:0001640 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cardiomegaly (HP:0001640). HP:0001640 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf SUPPORT Human Clinical
"In a chest X-ray examination, car- diomegaly was noted"
The primary report documents cardiomegaly.
Tricuspid regurgitation HP:0005180 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Tricuspid regurgitation (HP:0005180). HP:0005180 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf SUPPORT Human Clinical
"severe suprasystemic PAH, with marked tricuspid regurgitation, a dilated right atrium, and a dilated right ventricle."
Echocardiography documented pulmonary hypertension, valve regurgitation and right-heart enlargement in the elder founder sibling.
Right atrial enlargement HP:0030718 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Right atrial enlargement (HP:0030718). HP:0030718 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf SUPPORT Human Clinical
"severe suprasystemic PAH, with marked tricuspid regurgitation, a dilated right atrium, and a dilated right ventricle."
Echocardiography documented pulmonary hypertension, valve regurgitation and right-heart enlargement in the elder founder sibling.
Right ventricular dilatation HP:0005133 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Right ventricular dilatation (HP:0005133). HP:0005133 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf SUPPORT Human Clinical
"severe suprasystemic PAH, with marked tricuspid regurgitation, a dilated right atrium, and a dilated right ventricle."
Echocardiography documented pulmonary hypertension, valve regurgitation and right-heart enlargement in the elder founder sibling.
Digestive 3
Gastroesophageal reflux HP:0002020 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Gastroesophageal reflux (HP:0002020). HP:0002020 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf SUPPORT Human Clinical
"Gastroesophageal reflux disease was then diagnosed, and she was discharged on a high calorie diet applied via nasogas- tric tube feeding."
Reflux was diagnosed and high-calorie tube feeding was provided.
Vomiting HP:0002013 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Vomiting (HP:0002013). HP:0002013 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf SUPPORT Human Clinical
"progressive lethargy with reduced oral intake and vom- iting after each feeding."
The clinical account documents feeding-associated vomiting.
Hepatomegaly HP:0002240 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hepatomegaly (HP:0002240). HP:0002240 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf SUPPORT Human Clinical
"Additional symptoms and laboratory findings at this time included coughing and vomiting along with mild hepatomegaly, slightly elevated transaminases and lactate levels."
The primary clinical account includes mild hepatomegaly.
Endocrine 2
Hypergonadotropic hypogonadism HP:0000815 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypergonadotropic hypogonadism (HP:0000815). HP:0000815 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://iris.uniroma1.it/bitstream/11573/1705503/2/Torraco_Novel_2022.pdf SUPPORT Human Clinical
"A clear initial ovarian insufficiency was detected by FSH 112 mIU/ml (normal value 1.9 –7.8), LH 21.5 mIU/ml (normal value >10.1), and 17 β estradiol <5 pg/ml which documented hypergonadotropic hypogonadism."
The endocrine evaluation establishes this finding in one patient.
Pineal cyst HP:0012683 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pineal cyst (HP:0012683). HP:0012683 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://iris.uniroma1.it/bitstream/11573/1705503/2/Torraco_Novel_2022.pdf SUPPORT Human Clinical
"4 years showed pineal gland cyst with a maximum diameter of 10 mm,"
The MRI described a pineal cyst in one patient.
Eye 1
Deeply set eyes HP:0000490 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Deeply set eyes, annotated with Deeply set eye (HP:0000490). HP:0000490 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf SUPPORT Human Clinical
"a large anterior fontanel, a wide open posterior fontanel, frontal bossing, synophrys, deep-set eyes, long eyelashes, short extremities, and short hands and feet."
The elder sibling had these examination findings.
Head and Neck 4
Wide anterior fontanel HP:0000260 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Wide anterior fontanel (HP:0000260). HP:0000260 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf SUPPORT Human Clinical
"a large anterior fontanel, a wide open posterior fontanel, frontal bossing, synophrys, deep-set eyes, long eyelashes, short extremities, and short hands and feet."
The elder sibling had these examination findings.
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)
url:https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf SUPPORT Human Clinical
"a large anterior fontanel, a wide open posterior fontanel, frontal bossing, synophrys, deep-set eyes, long eyelashes, short extremities, and short hands and feet."
The elder sibling had these examination findings.
Synophrys HP:0000664 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Synophrys (HP:0000664). HP:0000664 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf SUPPORT Human Clinical
"a large anterior fontanel, a wide open posterior fontanel, frontal bossing, synophrys, deep-set eyes, long eyelashes, short extremities, and short hands and feet."
The elder sibling had these examination findings.
Long eyelashes HP:0000527 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Long eyelashes (HP:0000527). HP:0000527 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf SUPPORT Human Clinical
"a large anterior fontanel, a wide open posterior fontanel, frontal bossing, synophrys, deep-set eyes, long eyelashes, short extremities, and short hands and feet."
The elder sibling had these examination findings.
Limbs 2
Small hands HP:0200055 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Small hands, annotated with Small hand (HP:0200055). HP:0200055 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf SUPPORT Human Clinical
"a large anterior fontanel, a wide open posterior fontanel, frontal bossing, synophrys, deep-set eyes, long eyelashes, short extremities, and short hands and feet."
The elder sibling had these examination findings.
Short feet Short foot HP:0001773 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short feet, annotated with Short foot (HP:0001773). HP:0001773 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf SUPPORT Human Clinical
"a large anterior fontanel, a wide open posterior fontanel, frontal bossing, synophrys, deep-set eyes, long eyelashes, short extremities, and short hands and feet."
The elder sibling had these examination findings.
Metabolism 4
Elevated blood lactate Increased circulating lactate concentration HP:0002151 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Elevated blood lactate, annotated with Increased circulating lactate concentration (HP:0002151). HP:0002151 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:28247525 SUPPORT Human Clinical
"Clinical details of two affected siblings suffering from early-onset pulmonary arterial hypertension, lactic acidemia, failure to thrive, and isolated complex IV deficiency are presented."
The reported lactic acidemia supports elevated circulating lactate; blood pH is a separate observation.
url:https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf SUPPORT Human Clinical
"Laboratory findings included normal blood gases and mildly elevated lactate (3.8 mmol/L)."
Elevated lactate initially coexisted with normal blood gases in the elder sibling, supporting the lactate concentration binding rather than requiring acidosis.
Elevated hepatic transaminases Elevated circulating hepatic transaminase concentration HP:0002910 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Elevated hepatic transaminases, annotated with Elevated circulating hepatic transaminase concentration (HP:0002910). HP:0002910 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://iris.uniroma1.it/bitstream/11573/1705503/2/Torraco_Novel_2022.pdf SUPPORT Human Clinical
"Clinical exams at 5 months revealed mild eleva- tion of lactate dehydrogenase (738 IU/L) and aspartate aminotransfer- ase (76 IU/L)."
The later patient had elevated AST in infancy.
Metabolic acidosis HP:0001942 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Metabolic acidosis (HP:0001942). HP:0001942 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
url:https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf SUPPORT Human Clinical
"mixed metabolic and respiratory acidosis."
Mixed acidosis accompanied terminal deterioration.
url:https://iris.uniroma1.it/bitstream/11573/1705503/2/Torraco_Novel_2022.pdf SUPPORT Human Clinical
"fasting blood test revealed ketotic hypoglycemia unresponsive to glucagone and meta- bolic acidosis."
The later patient had an episodic metabolic disturbance.
Ketotic hypoglycemia HP:0012734 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ketotic hypoglycemia (HP:0012734). HP:0012734 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://iris.uniroma1.it/bitstream/11573/1705503/2/Torraco_Novel_2022.pdf SUPPORT Human Clinical
"fasting blood test revealed ketotic hypoglycemia unresponsive to glucagone and meta- bolic acidosis."
The clinical narrative documents ketotic hypoglycemia.
Musculoskeletal 1
Hypotonia HP:0001252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypotonia (HP:0001252). HP:0001252 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf SUPPORT Human Clinical
"She had central hypoto- nia with mildly reduced peripheral muscle tone and slightly brisk deep tendon reflexes."
The founder case examination documents reduced tone.
Nervous System 3
Developmental delay Neurodevelopmental delay HP:0012758 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Developmental delay, annotated with Neurodevelopmental delay (HP:0012758). HP:0012758 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf SUPPORT Human Clinical
"Furthermore, she only reached developmental mile- stones with delay."
The primary founder report documents delayed milestones.
Cerebral cortical atrophy HP:0002120 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cerebral cortical atrophy (HP:0002120). HP:0002120 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://iris.uniroma1.it/bitstream/11573/1705503/2/Torraco_Novel_2022.pdf SUPPORT Human Clinical
"moderate signs of cortical atrophy, with periventricular hyperintensities"
The MRI description supports cortical atrophy.
Periventricular white matter hyperintensities HP:0030891 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Periventricular white matter hyperintensities (HP:0030891). HP:0030891 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://iris.uniroma1.it/bitstream/11573/1705503/2/Torraco_Novel_2022.pdf SUPPORT Human Clinical
"1B is another axial T2 weighted image showing periventricular abnormal T2 hyperintensity."
The figure legend identifies periventricular T2 hyperintensity.
Respiratory 1
Respiratory distress HP:0002098 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Respiratory distress (HP:0002098). HP:0002098 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf SUPPORT Human Clinical
"the age of 15 months after being admitted to a regional hospital due to severe respiratory distress."
The younger founder sibling died during respiratory deterioration.
Growth 2
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 (2 references)
url:https://iris.uniroma1.it/bitstream/11573/1705503/2/Torraco_Novel_2022.pdf SUPPORT Human Clinical
"The patient presented failure to thrive since the 3rd month of life."
The later patient had early growth failure.
url:https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf SUPPORT Human Clinical
"growth stagnated and she was admitted to a hospital at the age of 3 months with failure to thrive:"
The elder founding sibling was admitted with growth failure at three months.
Severe short stature HP:0003510 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Severe short stature (HP:0003510). HP:0003510 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://iris.uniroma1.it/bitstream/11573/1705503/2/Torraco_Novel_2022.pdf SUPPORT Human Clinical
"At 11 year and 9 months she was 115.2 cm tall"
The report documents severe short stature in late childhood.
🧬

Genetic Associations

1
COX5A
Gene: COX5A hgnc:2267 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is COX5A (hgnc:2267). hgnc:2267 is a gene from the HUGO Gene Nomenclature Committee.
Autosomal recessive
Show evidence (3 references)
url:https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf SUPPORT Human Clinical
"chr15(GRCh37):g.75219127G>A; NM_004255.3 (GenBank reference sequence):c.319C>T; p.(Arg107Cys)."
The founder study reports the transcript and protein change for the homozygous allele.
url:https://iris.uniroma1.it/bitstream/11573/1705503/2/Torraco_Novel_2022.pdf SUPPORT Human Clinical
"NGS analysis revealed a homozygous c.266 T > G variant (Figure 1C) which is predicted to produce a p.(Ile89Ser) aminoacidic substitution in a highly conserved region (Figure S1A) of COX5A (NM_004255.4)."
The second family carried homozygous c.266T>G, p.Ile89Ser.
PMID:28247525 SUPPORT In Vitro
"Lentiviral complementation rescues complex IV deficiency."
Wild-type complementation supports the causal role of COX5A; the full text documents increased complex IV abundance.
Variants (2)
c.319C>T (p.Arg107Cys)
NM_004255.3; homozygous in the two founding siblings. Interface disruption is predicted computationally; wild-type complementation supports causality.
Show evidence (3 references)
url:https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf SUPPORT Human Clinical
"chr15(GRCh37):g.75219127G>A; NM_004255.3 (GenBank reference sequence):c.319C>T; p.(Arg107Cys)."
The founder study reports the transcript and protein change for the homozygous allele.
PMID:28247525 SUPPORT INDIRECT Computational
"We show that the variant lies within the evolutionarily conserved COX5A/COX4 interface domain, suggesting that it alters the interaction between these two subunits during complex IV biogenesis."
Homology modeling predicts altered subunit contacts for p.Arg107Cys; a direct binding assay was not performed.
PMID:28247525 SUPPORT In Vitro
"Lentiviral complementation rescues complex IV deficiency."
Wild-type complementation supports the causal role of COX5A; the full text documents increased complex IV abundance.
c.266T>G (p.Ile89Ser)
NM_004255.4; homozygous in the later patient, with heterozygous parents and a selective cellular complex IV defect.
Show evidence (4 references)
url:https://iris.uniroma1.it/bitstream/11573/1705503/2/Torraco_Novel_2022.pdf SUPPORT Human Clinical
"NGS analysis revealed a homozygous c.266 T > G variant (Figure 1C) which is predicted to produce a p.(Ile89Ser) aminoacidic substitution in a highly conserved region (Figure S1A) of COX5A (NM_004255.4)."
The second family carried homozygous c.266T>G, p.Ile89Ser.
url:https://iris.uniroma1.it/bitstream/11573/1705503/2/Torraco_Novel_2022.pdf SUPPORT Human Clinical
"Both parents resulted heterozygous for the same variant (Figure 1C)."
Both parents of the homozygous p.Ile89Ser patient carried the variant.
url:https://iris.uniroma1.it/bitstream/11573/1705503/2/Torraco_Novel_2022.pdf SUPPORT In Vitro
"found a 50% reduction of COX5A protein in the patient"
The p.Ile89Ser patient retained COX5A protein at about half the control amount.
+ 1 more reference
💊

Medical Actions

3
High-calorie enteral nutrition
Action: Enteral Tube FeedingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Enteral Tube Feeding (NCIT:C93322). NCIT:C93322 is a clinical intervention from the NCI Thesaurus. NCIT:C93322
Platform: Behavioral / lifestyle
High-calorie nasogastric feeding was used for the elder founder sibling, but weight gain remained poor. This documents supportive use, not demonstrated disease modification.
Target Phenotypes: 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 (1 reference)
url:https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf SUPPORT Human Clinical
"she was discharged on a high calorie diet applied via nasogas- tric tube feeding. However, weight gain remained poor."
The founder report documents nutritional treatment and limited response.
Thiamine, carnitine and coenzyme Q10
Action: Nutritional SupplementationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Nutritional Supplementation (NCIT:C15425). NCIT:C15425 is a clinical intervention from the NCI Thesaurus. NCIT:C15425
Agent: thiamine(1+) CHEBI:18385 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses thiamine(1+) (CHEBI:18385). CHEBI:18385 is a therapeutic agent from Chemical Entities of Biological Interest. carnitine CHEBI:17126 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses carnitine (CHEBI:17126). CHEBI:17126 is a therapeutic agent from Chemical Entities of Biological Interest. coenzyme Q10 CHEBI:46245 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses coenzyme Q10 (CHEBI:46245). CHEBI:46245 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
The younger founder sibling received this mitochondrial supplement combination without an apparent effect. Benefit for COX5A disease is not established.
Show evidence (1 reference)
url:https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf SUPPORT Human Clinical
"She received thiamine, carnitine, and coenzyme Q10 without an apparent effect."
The only described clinical supplement use had no apparent effect.
Copper chloride (preclinical)
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: copper(II) chloride CHEBI:49553 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses copper(II) chloride (CHEBI:49553). CHEBI:49553 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Copper chloride increased complex IV abundance in cultured p.Arg107Cys patient fibroblasts. The COX1 assembly intermediate persisted; a translation-inhibition experiment was consistent with stabilization of residual complexes or subassemblies. These experiments do not establish a safe or effective clinical treatment.
Mechanism Target:
Reduced Complex IV Abundance — Copper increases residual enzyme abundance in patient cells; it has not been shown to repair the interface defect.
Show evidence (1 reference)
url:https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf SUPPORT In Vitro
"decrease of complex IV and the CuCl 2-induced increase exclusively affected monomeric complex IV , whereas the levels of the com- plex IV containing high molecular weight supercomplexes remained unaffected."
The decrease and copper response involved monomeric complex IV; higher-order supercomplex abundance was preserved.
Show evidence (2 references)
PMID:28247525 SUPPORT In Vitro
"A potential therapeutic lead is demonstrated by showing that copper supplementation leads to partial rescue of complex IV deficiency in patient fibroblasts."
Copper rescue is preclinical.
url:https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf SUPPORT In Vitro
"accumulation of COX1 did not resolve in CuCl2-treated fibroblasts, suggesting another mechanism of complex IV rescue."
Copper did not normalize the accumulated assembly intermediate.
🔬

Diagnosis

3
Molecular genetic testing
Exome sequencing followed by confirmation and family segregation identified the reported homozygous COX5A variants. The varied phenotype means that pulmonary hypertension is not required for the diagnosis.
Show evidence (3 references)
url:https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf SUPPORT Human Clinical
"chr15(GRCh37):g.75219127G>A; NM_004255.3 (GenBank reference sequence):c.319C>T; p.(Arg107Cys)."
The founder study reports the transcript and protein change for the homozygous allele.
url:https://iris.uniroma1.it/bitstream/11573/1705503/2/Torraco_Novel_2022.pdf SUPPORT Human Clinical
"NGS analysis revealed a homozygous c.266 T > G variant (Figure 1C) which is predicted to produce a p.(Ile89Ser) aminoacidic substitution in a highly conserved region (Figure S1A) of COX5A (NM_004255.4)."
The second family carried homozygous c.266T>G, p.Ile89Ser.
url:https://iris.uniroma1.it/bitstream/11573/1705503/2/Torraco_Novel_2022.pdf SUPPORT Human Clinical
"Both parents resulted heterozygous for the same variant (Figure 1C)."
Both parents of the homozygous p.Ile89Ser patient carried the variant.
Respiratory-chain enzymology and assembly studies
Patient fibroblasts demonstrated isolated complex IV deficiency. Enzyme assays, immunoblotting and native electrophoresis distinguish reduced activity and abundance from complete failure to assemble the enzyme.
Show evidence (3 references)
PMID:28247525 SUPPORT In Vitro
"In patient skin fibroblasts, the enzymatic activity and protein levels of complex IV and several of its subunits are reduced."
The biochemical deficit and subunit depletion were measured in cultured patient fibroblasts.
url:https://iris.uniroma1.it/bitstream/11573/1705503/2/Torraco_Novel_2022.pdf SUPPORT In Vitro
"confirmed the selective reduction of the holocomplex CIV (20% residual amount) as well as an almost undetectable CIV activity (Figure 2D, E)."
The p.Ile89Ser fibroblasts retained about 20% holocomplex IV, with nearly undetectable in-gel activity.
url:https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf SUPPORT In Vitro
"even though complex IV levels are clearly reduced, the complex can still be fully assembled."
The founder study explicitly found residual assembled complex IV.
Cardiac, metabolic, growth and endocrine assessment
The clinical reports support evaluating lactate and acid-base status, growth, fasting hypoglycemia, cardiac involvement and pubertal endocrine function according to presentation. No disease-specific surveillance interval is established by this small literature.
Show evidence (3 references)
PMID:28247525 SUPPORT Human Clinical
"Clinical details of two affected siblings suffering from early-onset pulmonary arterial hypertension, lactic acidemia, failure to thrive, and isolated complex IV deficiency are presented."
Pulmonary hypertension, elevated lactate and growth failure in the founding siblings support cardiac, metabolic and growth assessment.
url:https://iris.uniroma1.it/bitstream/11573/1705503/2/Torraco_Novel_2022.pdf SUPPORT Human Clinical
"fasting blood test revealed ketotic hypoglycemia unresponsive to glucagone and meta- bolic acidosis."
The clinical narrative documents ketotic hypoglycemia.
url:https://iris.uniroma1.it/bitstream/11573/1705503/2/Torraco_Novel_2022.pdf SUPPORT Human Clinical
"A clear initial ovarian insufficiency was detected by FSH 112 mIU/ml (normal value 1.9 –7.8), LH 21.5 mIU/ml (normal value >10.1), and 17 β estradiol <5 pg/ml which documented hypergonadotropic hypogonadism."
The endocrine evaluation establishes this finding in one patient.
🧫

Experimental Models

3
p.Arg107Cys patient fibroblasts PRIMARY_CELL_CULTURE
Skin fibroblasts from the younger founding sibling show reduced complex IV, accumulated S1 intermediate and rescue of complex IV abundance by wild-type complementation. Copper increased residual complex IV without clearing S1.
Cell source
p.Arg107Cys patient fibroblasts
Publication
PMID:28247525
Pathograph links
Impaired Complex IV Assembly recapitulates observes: molecular
Limitations: Cultured-cell biochemistry does not establish pulmonary vascular, growth or endocrine outcomes in patients.
Reduced Cytochrome c Oxidase Activity recapitulates observes: molecular
Limitations: Cultured-cell biochemistry does not establish pulmonary vascular, growth or endocrine outcomes in patients.
Altered Complex IV Supercomplex Distribution recapitulates observes: molecular
Limitations: Cultured-cell biochemistry does not establish pulmonary vascular, growth or endocrine outcomes in patients.
Show evidence (4 references)
PMID:28247525 SUPPORT In Vitro
"In patient skin fibroblasts, the enzymatic activity and protein levels of complex IV and several of its subunits are reduced."
The biochemical deficit and subunit depletion were measured in cultured patient fibroblasts.
PMID:28247525 SUPPORT In Vitro
"The monomeric COX1 assembly intermediate accumulates demonstrating a function of COX5A in complex IV biogenesis."
Patient-cell assembly analysis identifies accumulation of the early COX1 intermediate.
PMID:28247525 SUPPORT In Vitro
"Lentiviral complementation rescues complex IV deficiency."
Wild-type complementation supports the causal role of COX5A; the full text documents increased complex IV abundance.
+ 1 more reference
p.Ile89Ser patient fibroblasts PRIMARY_CELL_CULTURE
Primary fibroblasts from the later patient demonstrate COX5A depletion, reduced assembled complex IV, selective enzymatic deficiency and differential preservation of supercomplexes.
Cell source
p.Ile89Ser patient fibroblasts
Publication
PMID:35246835
Pathograph links
Reduced COX5A Protein Abundance recapitulates observes: molecular
Limitations: Cultured-cell biochemistry does not establish pulmonary vascular, growth or endocrine outcomes in patients.
Reduced Complex IV Abundance recapitulates observes: molecular
Limitations: Cultured-cell biochemistry does not establish pulmonary vascular, growth or endocrine outcomes in patients.
Altered Complex IV Supercomplex Distribution recapitulates observes: molecular
Limitations: Cultured-cell biochemistry does not establish pulmonary vascular, growth or endocrine outcomes in patients.
Show evidence (3 references)
url:https://iris.uniroma1.it/bitstream/11573/1705503/2/Torraco_Novel_2022.pdf SUPPORT In Vitro
"found a 50% reduction of COX5A protein in the patient"
The p.Ile89Ser patient retained COX5A protein at about half the control amount.
url:https://iris.uniroma1.it/bitstream/11573/1705503/2/Torraco_Novel_2022.pdf SUPPORT In Vitro
"confirmed the selective reduction of the holocomplex CIV (20% residual amount) as well as an almost undetectable CIV activity (Figure 2D, E)."
The p.Ile89Ser fibroblasts retained about 20% holocomplex IV, with nearly undetectable in-gel activity.
url:https://iris.uniroma1.it/bitstream/11573/1705503/2/Torraco_Novel_2022.pdf SUPPORT In Vitro
"SC I + IV was reduced but still present in the patient, whereas SC III 2 + IV1 was totally absent (Figure 2D, E)"
The second patient showed differential preservation of CIV-containing assemblies.
COX5A knockdown in HEK293 cells CELL_LINE
Stable RNA interference supports a role for COX5A in enzyme assembly and oxygen affinity. This engineered model does not reproduce either patient missense allele.
Cell source
COX5A knockdown in HEK293 cells
Publication
PMID:20307258
Pathograph links
Impaired Complex IV Assembly partially recapitulates observes: molecular
Limitations: Cultured-cell biochemistry does not establish pulmonary vascular, growth or endocrine outcomes in patients.
Reduced Cytochrome c Oxidase Activity partially recapitulates observes: molecular
Limitations: Cultured-cell biochemistry does not establish pulmonary vascular, growth or endocrine outcomes in patients.
Show evidence (1 reference)
PMID:20307258 SUPPORT In Vitro
"Knockdown of Cox4, Cox5a and Cox6a resulted in reduced CcO activity, diminished affinity of the residual enzyme for oxygen, decreased holoCcO and CcO dimer levels, increased accumulation of CcO subcomplexes and gave rise to an altered pattern of respiratory supercomplexes."
The perturbation series includes COX5A knockdown in HEK293 cells.
{ }

Source YAML

click to show 
name: COX5A-Related COX Deficiency
category: Mendelian
creation_date: '2026-06-19T00:00:00Z'
synonyms:
- COX5A deficiency
- Mitochondrial complex IV deficiency, nuclear type 20
- MC4DN20
- COX5A-related cytochrome c oxidase deficiency
disease_term:
  preferred_term: COX5A-related COX deficiency (MC4DN20)
  term:
    id: MONDO:0033655
    label: mitochondrial complex IV deficiency, nuclear type 20
parents:
- Mitochondrial Disease
- Inborn Error of Metabolism
notes: >-
  The clinical evidence is a very small family series and a later single-patient report. Severity and organ
  involvement vary; these observations do not establish reliable frequencies, penetrance estimates or separate
  molecular subtypes. Preserved neurodevelopment in the later patient coexisted with structural MRI abnormalities.
  ATP depletion and the tissue-specific route from complex IV dysfunction to pulmonary hypertension or ovarian
  insufficiency were not directly measured. The 2017 primary report records the younger sibling dying at 15
  months; the 2022 comparison table lists 16 months. The primary age is retained here. Patient-level data in
  the 2022 study are available on request with privacy restrictions; no public cohort accession is given.
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Homozygous missense variants were reported in both families; both parents in the second family were heterozygous.
  evidence:
  - reference: url:https://iris.uniroma1.it/bitstream/11573/1705503/2/Torraco_Novel_2022.pdf
    reference_title: https://iris.uniroma1.it/bitstream/11573/1705503/2/Torraco_Novel_2022.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Both parents resulted heterozygous for the same variant (Figure 1C).
    explanation: Both parents of the homozygous p.Ile89Ser patient carried the variant.
  - reference: PMID:28247525
    reference_title: >-
      Mutation in mitochondrial complex IV subunit COX5A causes pulmonary arterial hypertension, lactic acidemia,
      and failure to thrive.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We present patients with a homozygous pathogenic variant in the COX5A gene.
    explanation: The founding family supports recessive inheritance.
diagnosis:
- name: Molecular genetic testing
  description: >-
    Exome sequencing followed by confirmation and family segregation identified the reported homozygous COX5A
    variants. The varied phenotype means that pulmonary hypertension is not required for the diagnosis.
  evidence:
  - reference: url:https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf
    reference_title: https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: chr15(GRCh37):g.75219127G>A; NM_004255.3 (GenBank reference sequence):c.319C>T; p.(Arg107Cys).
    explanation: The founder study reports the transcript and protein change for the homozygous allele.
  - reference: url:https://iris.uniroma1.it/bitstream/11573/1705503/2/Torraco_Novel_2022.pdf
    reference_title: https://iris.uniroma1.it/bitstream/11573/1705503/2/Torraco_Novel_2022.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      NGS analysis revealed a homozygous c.266 T > G variant (Figure 1C) which is predicted to produce a p.(Ile89Ser)
      aminoacidic substitution in a highly conserved region (Figure S1A) of COX5A (NM_004255.4).
    explanation: The second family carried homozygous c.266T>G, p.Ile89Ser.
  - reference: url:https://iris.uniroma1.it/bitstream/11573/1705503/2/Torraco_Novel_2022.pdf
    reference_title: https://iris.uniroma1.it/bitstream/11573/1705503/2/Torraco_Novel_2022.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Both parents resulted heterozygous for the same variant (Figure 1C).
    explanation: Both parents of the homozygous p.Ile89Ser patient carried the variant.
- name: Respiratory-chain enzymology and assembly studies
  description: >-
    Patient fibroblasts demonstrated isolated complex IV deficiency. Enzyme assays, immunoblotting and native
    electrophoresis distinguish reduced activity and abundance from complete failure to assemble the enzyme.
  evidence:
  - reference: PMID:28247525
    reference_title: >-
      Mutation in mitochondrial complex IV subunit COX5A causes pulmonary arterial hypertension, lactic acidemia,
      and failure to thrive.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In patient skin fibroblasts, the enzymatic activity and protein levels of complex IV and several of its
      subunits are reduced.
    explanation: The biochemical deficit and subunit depletion were measured in cultured patient fibroblasts.
  - reference: url:https://iris.uniroma1.it/bitstream/11573/1705503/2/Torraco_Novel_2022.pdf
    reference_title: https://iris.uniroma1.it/bitstream/11573/1705503/2/Torraco_Novel_2022.pdf
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      confirmed the selective reduction of the holocomplex CIV (20% residual amount) as well as an almost undetectable
      CIV activity (Figure 2D, E).
    explanation: >-
      The p.Ile89Ser fibroblasts retained about 20% holocomplex IV, with nearly undetectable in-gel activity.
  - reference: url:https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf
    reference_title: https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: even though complex IV levels are clearly reduced, the complex can still be fully assembled.
    explanation: The founder study explicitly found residual assembled complex IV.
- name: Cardiac, metabolic, growth and endocrine assessment
  description: >-
    The clinical reports support evaluating lactate and acid-base status, growth, fasting hypoglycemia, cardiac
    involvement and pubertal endocrine function according to presentation. No disease-specific surveillance
    interval is established by this small literature.
  evidence:
  - reference: PMID:28247525
    reference_title: >-
      Mutation in mitochondrial complex IV subunit COX5A causes pulmonary arterial hypertension, lactic acidemia,
      and failure to thrive.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical details of two affected siblings suffering from early-onset pulmonary arterial hypertension,
      lactic acidemia, failure to thrive, and isolated complex IV deficiency are presented.
    explanation: >-
      Pulmonary hypertension, elevated lactate and growth failure in the founding siblings support cardiac,
      metabolic and growth assessment.
  - reference: url:https://iris.uniroma1.it/bitstream/11573/1705503/2/Torraco_Novel_2022.pdf
    reference_title: https://iris.uniroma1.it/bitstream/11573/1705503/2/Torraco_Novel_2022.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      fasting blood test revealed ketotic hypoglycemia unresponsive to glucagone and meta- bolic acidosis.
    explanation: The clinical narrative documents ketotic hypoglycemia.
  - reference: url:https://iris.uniroma1.it/bitstream/11573/1705503/2/Torraco_Novel_2022.pdf
    reference_title: https://iris.uniroma1.it/bitstream/11573/1705503/2/Torraco_Novel_2022.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A clear initial ovarian insufficiency was detected by FSH 112 mIU/ml (normal value 1.9 –7.8), LH 21.5
      mIU/ml (normal value >10.1), and 17 β estradiol <5 pg/ml which documented hypergonadotropic hypogonadism.
    explanation: The endocrine evaluation establishes this finding in one patient.
experimental_models:
- name: p.Arg107Cys patient fibroblasts
  experimental_model_type: PRIMARY_CELL_CULTURE
  cell_source: p.Arg107Cys patient fibroblasts
  description: >-
    Skin fibroblasts from the younger founding sibling show reduced complex IV, accumulated S1 intermediate
    and rescue of complex IV abundance by wild-type complementation. Copper increased residual complex IV without
    clearing S1.
  publication: PMID:28247525
  evidence:
  - reference: PMID:28247525
    reference_title: >-
      Mutation in mitochondrial complex IV subunit COX5A causes pulmonary arterial hypertension, lactic acidemia,
      and failure to thrive.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In patient skin fibroblasts, the enzymatic activity and protein levels of complex IV and several of its
      subunits are reduced.
    explanation: The biochemical deficit and subunit depletion were measured in cultured patient fibroblasts.
  - reference: PMID:28247525
    reference_title: >-
      Mutation in mitochondrial complex IV subunit COX5A causes pulmonary arterial hypertension, lactic acidemia,
      and failure to thrive.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The monomeric COX1 assembly intermediate accumulates demonstrating a function of COX5A in complex IV
      biogenesis.
    explanation: Patient-cell assembly analysis identifies accumulation of the early COX1 intermediate.
  - reference: PMID:28247525
    reference_title: >-
      Mutation in mitochondrial complex IV subunit COX5A causes pulmonary arterial hypertension, lactic acidemia,
      and failure to thrive.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Lentiviral complementation rescues complex IV deficiency.
    explanation: >-
      Wild-type complementation supports the causal role of COX5A; the full text documents increased complex
      IV abundance.
  - reference: url:https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf
    reference_title: https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      decrease of complex IV and the CuCl 2-induced increase exclusively affected monomeric complex IV , whereas
      the levels of the com- plex IV containing high molecular weight supercomplexes remained unaffected.
    explanation: >-
      The decrease and copper response involved monomeric complex IV; higher-order supercomplex abundance was
      preserved.
  modeled_mechanisms:
  - target: Impaired Complex IV Assembly
    relationship: RECAPITULATES
    model_scale: MOLECULAR
    limitations: >-
      Cultured-cell biochemistry does not establish pulmonary vascular, growth or endocrine outcomes in patients.
  - target: Reduced Cytochrome c Oxidase Activity
    relationship: RECAPITULATES
    model_scale: MOLECULAR
    limitations: >-
      Cultured-cell biochemistry does not establish pulmonary vascular, growth or endocrine outcomes in patients.
  - target: Altered Complex IV Supercomplex Distribution
    relationship: RECAPITULATES
    model_scale: MOLECULAR
    limitations: >-
      Cultured-cell biochemistry does not establish pulmonary vascular, growth or endocrine outcomes in patients.
- name: p.Ile89Ser patient fibroblasts
  experimental_model_type: PRIMARY_CELL_CULTURE
  cell_source: p.Ile89Ser patient fibroblasts
  description: >-
    Primary fibroblasts from the later patient demonstrate COX5A depletion, reduced assembled complex IV, selective
    enzymatic deficiency and differential preservation of supercomplexes.
  publication: PMID:35246835
  evidence:
  - reference: url:https://iris.uniroma1.it/bitstream/11573/1705503/2/Torraco_Novel_2022.pdf
    reference_title: https://iris.uniroma1.it/bitstream/11573/1705503/2/Torraco_Novel_2022.pdf
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: found a 50% reduction of COX5A protein in the patient
    explanation: The p.Ile89Ser patient retained COX5A protein at about half the control amount.
  - reference: url:https://iris.uniroma1.it/bitstream/11573/1705503/2/Torraco_Novel_2022.pdf
    reference_title: https://iris.uniroma1.it/bitstream/11573/1705503/2/Torraco_Novel_2022.pdf
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      confirmed the selective reduction of the holocomplex CIV (20% residual amount) as well as an almost undetectable
      CIV activity (Figure 2D, E).
    explanation: >-
      The p.Ile89Ser fibroblasts retained about 20% holocomplex IV, with nearly undetectable in-gel activity.
  - reference: url:https://iris.uniroma1.it/bitstream/11573/1705503/2/Torraco_Novel_2022.pdf
    reference_title: https://iris.uniroma1.it/bitstream/11573/1705503/2/Torraco_Novel_2022.pdf
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      SC I + IV was reduced but still present in the patient, whereas SC III 2 + IV1 was totally absent (Figure
      2D, E)
    explanation: The second patient showed differential preservation of CIV-containing assemblies.
  modeled_mechanisms:
  - target: Reduced COX5A Protein Abundance
    relationship: RECAPITULATES
    model_scale: MOLECULAR
    limitations: >-
      Cultured-cell biochemistry does not establish pulmonary vascular, growth or endocrine outcomes in patients.
  - target: Reduced Complex IV Abundance
    relationship: RECAPITULATES
    model_scale: MOLECULAR
    limitations: >-
      Cultured-cell biochemistry does not establish pulmonary vascular, growth or endocrine outcomes in patients.
  - target: Altered Complex IV Supercomplex Distribution
    relationship: RECAPITULATES
    model_scale: MOLECULAR
    limitations: >-
      Cultured-cell biochemistry does not establish pulmonary vascular, growth or endocrine outcomes in patients.
- name: COX5A knockdown in HEK293 cells
  experimental_model_type: CELL_LINE
  cell_source: COX5A knockdown in HEK293 cells
  description: >-
    Stable RNA interference supports a role for COX5A in enzyme assembly and oxygen affinity. This engineered
    model does not reproduce either patient missense allele.
  publication: PMID:20307258
  evidence:
  - reference: PMID:20307258
    reference_title: >-
      Novel insights into the assembly and function of human nuclear-encoded cytochrome c oxidase subunits
      4, 5a, 6a, 7a and 7b.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Knockdown of Cox4, Cox5a and Cox6a resulted in reduced CcO activity, diminished affinity of the residual
      enzyme for oxygen, decreased holoCcO and CcO dimer levels, increased accumulation of CcO subcomplexes
      and gave rise to an altered pattern of respiratory supercomplexes.
    explanation: The perturbation series includes COX5A knockdown in HEK293 cells.
  modeled_mechanisms:
  - target: Impaired Complex IV Assembly
    relationship: PARTIALLY_RECAPITULATES
    model_scale: MOLECULAR
    limitations: >-
      Cultured-cell biochemistry does not establish pulmonary vascular, growth or endocrine outcomes in patients.
  - target: Reduced Cytochrome c Oxidase Activity
    relationship: PARTIALLY_RECAPITULATES
    model_scale: MOLECULAR
    limitations: >-
      Cultured-cell biochemistry does not establish pulmonary vascular, growth or endocrine outcomes in patients.
description: >-
  COX5A-related cytochrome c oxidase deficiency (MC4DN20) is an autosomal recessive mitochondrial disorder
  caused by biallelic COX5A variants. COX5A is a nuclear-encoded structural subunit required for normal complex
  IV biogenesis. Patient fibroblasts show reduced COX5A and complex IV abundance, impaired assembly and reduced
  enzyme activity, with residual assembled enzyme. The founding p.Arg107Cys siblings had infantile pulmonary
  arterial hypertension, lactic acidemia, hypotonia and severe growth failure with early death. A later p.Ile89Ser
  patient had a milder course with childhood ketotic hypoglycemia, severe short stature and hypergonadotropic
  hypogonadism, without cardiovascular or neurodevelopmental involvement. Copper rescue is a cell-culture finding;
  clinical benefit has not been demonstrated in these reports.
references:
- reference: PMID:28247525
  title: >-
    Mutation in mitochondrial complex IV subunit COX5A causes pulmonary arterial hypertension, lactic acidemia,
    and failure to thrive.
- reference: PMID:35246835
  title: >-
    A novel homozygous variant in COX5A causes an attenuated phenotype with failure to thrive, lactic acidosis,
    hypoglycemia, and short stature.
- reference: PMID:20307258
  title: >-
    Novel insights into the assembly and function of human nuclear-encoded cytochrome c oxidase subunits 4,
    5a, 6a, 7a and 7b.
- reference: url:https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf
  title: https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf
- reference: url:https://iris.uniroma1.it/bitstream/11573/1705503/2/Torraco_Novel_2022.pdf
  title: https://iris.uniroma1.it/bitstream/11573/1705503/2/Torraco_Novel_2022.pdf
pathophysiology:
- name: Predicted COX5A-COX4 Interface Disruption
  description: >-
    The p.Arg107Cys substitution is predicted to remove contacts at the COX5A-COX4 interface. This allele-specific
    structural model is distinct from experimentally measured protein depletion.
  biological_scale: MOLECULAR
  evidence:
  - reference: PMID:28247525
    reference_title: >-
      Mutation in mitochondrial complex IV subunit COX5A causes pulmonary arterial hypertension, lactic acidemia,
      and failure to thrive.
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      We show that the variant lies within the evolutionarily conserved COX5A/COX4 interface domain, suggesting
      that it alters the interaction between these two subunits during complex IV biogenesis.
    explanation: >-
      Homology modeling predicts altered subunit contacts for p.Arg107Cys; a direct binding assay was not performed.
    directness: INDIRECT
  mechanism_confidence: HYPOTHETICAL
  downstream:
  - target: Impaired Complex IV Assembly
    description: Loss of the predicted interface contacts may impair early assembly.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:28247525
      reference_title: >-
        Mutation in mitochondrial complex IV subunit COX5A causes pulmonary arterial hypertension, lactic acidemia,
        and failure to thrive.
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      snippet: >-
        We show that the variant lies within the evolutionarily conserved COX5A/COX4 interface domain, suggesting
        that it alters the interaction between these two subunits during complex IV biogenesis.
      explanation: >-
        Homology modeling predicts altered subunit contacts for p.Arg107Cys; a direct binding assay was not
        performed.
      directness: INDIRECT
- name: Reduced COX5A Protein Abundance
  description: >-
    COX5A protein remains detectable at reduced abundance in patient fibroblasts. The p.Ile89Ser patient had
    an approximately 50% reduction; complete absence is not established.
  biological_scale: MOLECULAR
  evidence:
  - reference: url:https://iris.uniroma1.it/bitstream/11573/1705503/2/Torraco_Novel_2022.pdf
    reference_title: https://iris.uniroma1.it/bitstream/11573/1705503/2/Torraco_Novel_2022.pdf
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: found a 50% reduction of COX5A protein in the patient
    explanation: The p.Ile89Ser patient retained COX5A protein at about half the control amount.
  - reference: url:https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf
    reference_title: https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: COX5A protein was still detectable in low amounts in the patient cells.
    explanation: Residual COX5A was detected in the younger founder sibling.
  downstream:
  - target: Impaired Complex IV Assembly
    description: Reduced availability of a required structural subunit impairs assembly.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:28247525
      reference_title: >-
        Mutation in mitochondrial complex IV subunit COX5A causes pulmonary arterial hypertension, lactic acidemia,
        and failure to thrive.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        The monomeric COX1 assembly intermediate accumulates demonstrating a function of COX5A in complex IV
        biogenesis.
      explanation: Patient-cell assembly analysis identifies accumulation of the early COX1 intermediate.
- name: Impaired Complex IV Assembly
  description: >-
    Early complex IV biogenesis is impaired. The p.Arg107Cys patient accumulates the monomeric COX1 S1 intermediate,
    while some holoenzyme still assembles. COX5A is a structural subunit with an assembly role, not a separate
    assembly factor.
  biological_scale: MOLECULAR
  evidence:
  - reference: PMID:28247525
    reference_title: >-
      Mutation in mitochondrial complex IV subunit COX5A causes pulmonary arterial hypertension, lactic acidemia,
      and failure to thrive.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The monomeric COX1 assembly intermediate accumulates demonstrating a function of COX5A in complex IV
      biogenesis.
    explanation: Patient-cell assembly analysis identifies accumulation of the early COX1 intermediate.
  - reference: url:https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf
    reference_title: https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: even though complex IV levels are clearly reduced, the complex can still be fully assembled.
    explanation: The founder study explicitly found residual assembled complex IV.
  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 Abundance
    description: The assembly defect reduces steady-state holoenzyme abundance.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://iris.uniroma1.it/bitstream/11573/1705503/2/Torraco_Novel_2022.pdf
      reference_title: https://iris.uniroma1.it/bitstream/11573/1705503/2/Torraco_Novel_2022.pdf
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        confirmed the selective reduction of the holocomplex CIV (20% residual amount) as well as an almost
        undetectable CIV activity (Figure 2D, E).
      explanation: >-
        The p.Ile89Ser fibroblasts retained about 20% holocomplex IV, with nearly undetectable in-gel activity.
- name: Reduced Complex IV Abundance
  description: >-
    Patient cells have reduced mature complex IV and several constituent subunits. Residual holocomplex and
    selected supercomplexes persist, so total absence of enzyme is not a common mechanism.
  biological_scale: MOLECULAR
  evidence:
  - reference: PMID:28247525
    reference_title: >-
      Mutation in mitochondrial complex IV subunit COX5A causes pulmonary arterial hypertension, lactic acidemia,
      and failure to thrive.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In patient skin fibroblasts, the enzymatic activity and protein levels of complex IV and several of its
      subunits are reduced.
    explanation: The biochemical deficit and subunit depletion were measured in cultured patient fibroblasts.
  - reference: url:https://iris.uniroma1.it/bitstream/11573/1705503/2/Torraco_Novel_2022.pdf
    reference_title: https://iris.uniroma1.it/bitstream/11573/1705503/2/Torraco_Novel_2022.pdf
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      confirmed the selective reduction of the holocomplex CIV (20% residual amount) as well as an almost undetectable
      CIV activity (Figure 2D, E).
    explanation: >-
      The p.Ile89Ser fibroblasts retained about 20% holocomplex IV, with nearly undetectable in-gel activity.
  downstream:
  - target: Reduced Cytochrome c Oxidase Activity
    description: A smaller pool of mature complex IV lowers measured oxidase capacity.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:28247525
      reference_title: >-
        Mutation in mitochondrial complex IV subunit COX5A causes pulmonary arterial hypertension, lactic acidemia,
        and failure to thrive.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        In patient skin fibroblasts, the enzymatic activity and protein levels of complex IV and several of
        its subunits are reduced.
      explanation: The biochemical deficit and subunit depletion were measured in cultured patient fibroblasts.
  - target: Altered Complex IV Supercomplex Distribution
    description: >-
      The available complex IV is distributed differently among monomeric and higher-order assemblies.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf
      reference_title: https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        decrease of complex IV and the CuCl 2-induced increase exclusively affected monomeric complex IV ,
        whereas the levels of the com- plex IV containing high molecular weight supercomplexes remained unaffected.
      explanation: >-
        The decrease and copper response involved monomeric complex IV; higher-order supercomplex abundance
        was preserved.
- name: Reduced Cytochrome c Oxidase Activity
  description: >-
    Patient fibroblasts show isolated complex IV enzymatic deficiency. COX5A supports the multimeric enzyme;
    it does not itself provide the redox catalytic center. The effect on ATP supply in affected organs has
    not been directly quantified.
  biological_scale: MOLECULAR
  evidence:
  - reference: PMID:28247525
    reference_title: >-
      Mutation in mitochondrial complex IV subunit COX5A causes pulmonary arterial hypertension, lactic acidemia,
      and failure to thrive.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In patient skin fibroblasts, the enzymatic activity and protein levels of complex IV and several of its
      subunits are reduced.
    explanation: The biochemical deficit and subunit depletion were measured in cultured patient fibroblasts.
  - reference: url:https://iris.uniroma1.it/bitstream/11573/1705503/2/Torraco_Novel_2022.pdf
    reference_title: https://iris.uniroma1.it/bitstream/11573/1705503/2/Torraco_Novel_2022.pdf
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      selective reduction of CIV activity in the patient, whereas the activity of CI was expressed equally
      in the patient and control subjects (Figure 2B).
    explanation: Complex I activity was preserved in the second patient while complex IV activity was reduced.
  genes:
  - preferred_term: COX5A
    term:
      id: hgnc:2267
      label: COX5A
  molecular_functions:
  - preferred_term: cytochrome-c oxidase activity
    term:
      id: GO:0004129
      label: cytochrome-c oxidase activity
    modifier: DECREASED
  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: Increased Circulating Lactate
    description: >-
      Respiratory-chain dysfunction is associated with lactate accumulation; the intervening flux changes were
      not measured in these patients.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:28247525
      reference_title: >-
        Mutation in mitochondrial complex IV subunit COX5A causes pulmonary arterial hypertension, lactic acidemia,
        and failure to thrive.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Clinical details of two affected siblings suffering from early-onset pulmonary arterial hypertension,
        lactic acidemia, failure to thrive, and isolated complex IV deficiency are presented.
      explanation: >-
        The founding cases had elevated lactate. Their association with complex IV deficiency supports this
        indirect link without directly measuring glycolytic flux.
  - target: Pulmonary arterial hypertension
    description: >-
      Complex IV dysfunction is associated with pulmonary vascular disease in the founding siblings; vascular-cell
      mechanisms remain unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:28247525
      reference_title: >-
        Mutation in mitochondrial complex IV subunit COX5A causes pulmonary arterial hypertension, lactic acidemia,
        and failure to thrive.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Clinical details of two affected siblings suffering from early-onset pulmonary arterial hypertension,
        lactic acidemia, failure to thrive, and isolated complex IV deficiency are presented.
      explanation: >-
        The two siblings had pulmonary arterial hypertension alongside complex IV deficiency; this co-occurrence
        does not establish the intervening vascular mechanism.
  - target: Failure to thrive
    description: >-
      Mitochondrial dysfunction contributes to growth failure through incompletely defined systemic pathways.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:28247525
      reference_title: >-
        Mutation in mitochondrial complex IV subunit COX5A causes pulmonary arterial hypertension, lactic acidemia,
        and failure to thrive.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Clinical details of two affected siblings suffering from early-onset pulmonary arterial hypertension,
        lactic acidemia, failure to thrive, and isolated complex IV deficiency are presented.
      explanation: >-
        Growth failure accompanied complex IV deficiency in the founding siblings; the intervening nutritional
        and metabolic mechanisms were not measured.
- name: Altered Complex IV Supercomplex Distribution
  description: >-
    In the founder fibroblasts, monomeric complex IV was reduced while high-molecular-weight complex IV-containing
    assemblies were preserved. In the later patient, selected supercomplexes persisted but III2+IV was absent.
    Their role in the severity difference remains a hypothesis, not an established modifier.
  biological_scale: MOLECULAR
  evidence:
  - reference: url:https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf
    reference_title: https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      decrease of complex IV and the CuCl 2-induced increase exclusively affected monomeric complex IV , whereas
      the levels of the com- plex IV containing high molecular weight supercomplexes remained unaffected.
    explanation: >-
      The decrease and copper response involved monomeric complex IV; higher-order supercomplex abundance was
      preserved.
  - reference: url:https://iris.uniroma1.it/bitstream/11573/1705503/2/Torraco_Novel_2022.pdf
    reference_title: https://iris.uniroma1.it/bitstream/11573/1705503/2/Torraco_Novel_2022.pdf
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      SC I + IV was reduced but still present in the patient, whereas SC III 2 + IV1 was totally absent (Figure
      2D, E)
    explanation: The second patient showed differential preservation of CIV-containing assemblies.
- name: Increased Circulating Lactate
  description: >-
    Circulating lactate is elevated in the reported patients, persistently in the younger founder sibling and
    intermittently in the later patient. Elevated lactate alone does not establish continuously low blood pH
    or measured excess lactate production.
  biological_scale: ORGANISM
  evidence:
  - reference: PMID:28247525
    reference_title: >-
      Mutation in mitochondrial complex IV subunit COX5A causes pulmonary arterial hypertension, lactic acidemia,
      and failure to thrive.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical details of two affected siblings suffering from early-onset pulmonary arterial hypertension,
      lactic acidemia, failure to thrive, and isolated complex IV deficiency are presented.
    explanation: Both founding siblings had elevated circulating lactate.
  downstream:
  - target: Elevated blood lactate
    description: Elevated circulating lactate is the measured clinical manifestation.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:28247525
      reference_title: >-
        Mutation in mitochondrial complex IV subunit COX5A causes pulmonary arterial hypertension, lactic acidemia,
        and failure to thrive.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Clinical details of two affected siblings suffering from early-onset pulmonary arterial hypertension,
        lactic acidemia, failure to thrive, and isolated complex IV deficiency are presented.
      explanation: >-
        The reported lactic acidemia supports elevated circulating lactate; blood pH is a separate observation.
phenotypes:
- name: Pulmonary arterial hypertension
  description: >-
    Mild neonatal pulmonary hypertension in the younger founder sibling and severe suprasystemic disease with
    right-heart dilation in the elder. The later p.Ile89Ser patient had normal cardiac evaluation; this is
    not universal.
  phenotype_term:
    preferred_term: Pulmonary arterial hypertension
    term:
      id: HP:0002092
      label: Pulmonary arterial hypertension
  evidence:
  - reference: PMID:28247525
    reference_title: >-
      Mutation in mitochondrial complex IV subunit COX5A causes pulmonary arterial hypertension, lactic acidemia,
      and failure to thrive.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical details of two affected siblings suffering from early-onset pulmonary arterial hypertension,
      lactic acidemia, failure to thrive, and isolated complex IV deficiency are presented.
    explanation: Both founding siblings had early-onset pulmonary arterial hypertension.
  - reference: url:https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf
    reference_title: https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: An echocar- diography performed in the first days of life revealed mild PAH
    explanation: The younger founding sibling had mild pulmonary hypertension in the neonatal period.
  - reference: url:https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf
    reference_title: https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      severe suprasystemic PAH, with marked tricuspid regurgitation, a dilated right atrium, and a dilated
      right ventricle.
    explanation: >-
      The elder founding sibling had severe pulmonary hypertension with tricuspid regurgitation and right-heart
      enlargement.
  - reference: url:https://iris.uniroma1.it/bitstream/11573/1705503/2/Torraco_Novel_2022.pdf
    reference_title: https://iris.uniroma1.it/bitstream/11573/1705503/2/Torraco_Novel_2022.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Full cardiological exam and heart Doppler ultrasound resulted normal.
    explanation: >-
      The later p.Ile89Ser patient had a normal cardiac evaluation, so pulmonary hypertension is not obligatory.
  sequelae:
  - target: Tricuspid regurgitation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Severe pulmonary hypertension can produce right-heart pressure-load consequences; the report documents
      the associated echocardiographic finding.
    evidence:
    - reference: url:https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf
      reference_title: https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        severe suprasystemic PAH, with marked tricuspid regurgitation, a dilated right atrium, and a dilated
        right ventricle.
      explanation: >-
        The elder sibling had this right-heart finding with severe suprasystemic pulmonary hypertension. The
        causal interpretation is indirect; pressure-driven remodeling was not separately measured.
      directness: INDIRECT
  - target: Right atrial enlargement
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Severe pulmonary hypertension can produce right-heart pressure-load consequences; the report documents
      the associated echocardiographic finding.
    evidence:
    - reference: url:https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf
      reference_title: https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        severe suprasystemic PAH, with marked tricuspid regurgitation, a dilated right atrium, and a dilated
        right ventricle.
      explanation: >-
        The elder sibling had this right-heart finding with severe suprasystemic pulmonary hypertension. The
        causal interpretation is indirect; pressure-driven remodeling was not separately measured.
      directness: INDIRECT
  - target: Right ventricular dilatation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Severe pulmonary hypertension can produce right-heart pressure-load consequences; the report documents
      the associated echocardiographic finding.
    evidence:
    - reference: url:https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf
      reference_title: https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        severe suprasystemic PAH, with marked tricuspid regurgitation, a dilated right atrium, and a dilated
        right ventricle.
      explanation: >-
        The elder sibling had this right-heart finding with severe suprasystemic pulmonary hypertension. The
        causal interpretation is indirect; pressure-driven remodeling was not separately measured.
      directness: INDIRECT
- name: Elevated blood lactate
  description: >-
    Elevated lactate in both founding siblings and intermittent lactic acidosis reported in the later patient.
    Blood gases were initially normal in the elder founder sibling despite elevated lactate.
  phenotype_term:
    preferred_term: Elevated blood lactate
    term:
      id: HP:0002151
      label: Increased circulating lactate concentration
  evidence:
  - reference: PMID:28247525
    reference_title: >-
      Mutation in mitochondrial complex IV subunit COX5A causes pulmonary arterial hypertension, lactic acidemia,
      and failure to thrive.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical details of two affected siblings suffering from early-onset pulmonary arterial hypertension,
      lactic acidemia, failure to thrive, and isolated complex IV deficiency are presented.
    explanation: >-
      The reported lactic acidemia supports elevated circulating lactate; blood pH is a separate observation.
  - reference: url:https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf
    reference_title: https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Laboratory findings included normal blood gases and mildly elevated lactate (3.8 mmol/L).
    explanation: >-
      Elevated lactate initially coexisted with normal blood gases in the elder sibling, supporting the lactate
      concentration binding rather than requiring acidosis.
- name: Failure to thrive
  description: >-
    Growth failure occurred in both families. The later patient presented from the third month of life.
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: url:https://iris.uniroma1.it/bitstream/11573/1705503/2/Torraco_Novel_2022.pdf
    reference_title: https://iris.uniroma1.it/bitstream/11573/1705503/2/Torraco_Novel_2022.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The patient presented failure to thrive since the 3rd month of life.
    explanation: The later patient had early growth failure.
  - reference: url:https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf
    reference_title: https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      growth stagnated and she was admitted to a hospital at the age of 3 months with failure to thrive:
    explanation: The elder founding sibling was admitted with growth failure at three months.
- name: Hypotonia
  description: Hypotonia was reported in the founding siblings, with central predominance in the elder.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: url:https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf
    reference_title: https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      She had central hypoto- nia with mildly reduced peripheral muscle tone and slightly brisk deep tendon
      reflexes.
    explanation: The founder case examination documents reduced tone.
- name: Developmental delay
  description: >-
    The elder founder sibling attained early motor and social milestones late. The later patient had preserved
    neurodevelopment; developmental delay should not be presumed in all cases.
  phenotype_term:
    preferred_term: Developmental delay
    term:
      id: HP:0012758
      label: Neurodevelopmental delay
  evidence:
  - reference: url:https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf
    reference_title: https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Furthermore, she only reached developmental mile- stones with delay.
    explanation: The primary founder report documents delayed milestones.
- name: Gastroesophageal reflux
  description: Diagnosed in the elder founder sibling during evaluation of growth failure and vomiting.
  phenotype_term:
    preferred_term: Gastroesophageal reflux
    term:
      id: HP:0002020
      label: Gastroesophageal reflux
  evidence:
  - reference: url:https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf
    reference_title: https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Gastroesophageal reflux disease was then diagnosed, and she was discharged on a high calorie diet applied
      via nasogas- tric tube feeding.
    explanation: Reflux was diagnosed and high-calorie tube feeding was provided.
- name: Vomiting
  description: The elder founder sibling vomited after feeds during clinical deterioration.
  phenotype_term:
    preferred_term: Vomiting
    term:
      id: HP:0002013
      label: Vomiting
  evidence:
  - reference: url:https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf
    reference_title: https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: progressive lethargy with reduced oral intake and vom- iting after each feeding.
    explanation: The clinical account documents feeding-associated vomiting.
- name: Hepatomegaly
  description: Mild hepatomegaly occurred in the elder founder sibling.
  phenotype_term:
    preferred_term: Hepatomegaly
    term:
      id: HP:0002240
      label: Hepatomegaly
  evidence:
  - reference: url:https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf
    reference_title: https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Additional symptoms and laboratory findings at this time included coughing and vomiting along with mild
      hepatomegaly, slightly elevated transaminases and lactate levels.
    explanation: The primary clinical account includes mild hepatomegaly.
- name: Elevated hepatic transaminases
  description: >-
    Mild transaminase elevation occurred in the founding siblings and the later patient. Synthetic liver function
    was preserved in the younger founder sibling.
  phenotype_term:
    preferred_term: Elevated hepatic transaminases
    term:
      id: HP:0002910
      label: Elevated circulating hepatic transaminase concentration
  evidence:
  - reference: url:https://iris.uniroma1.it/bitstream/11573/1705503/2/Torraco_Novel_2022.pdf
    reference_title: https://iris.uniroma1.it/bitstream/11573/1705503/2/Torraco_Novel_2022.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical exams at 5 months revealed mild eleva- tion of lactate dehydrogenase (738 IU/L) and aspartate
      aminotransfer- ase (76 IU/L).
    explanation: The later patient had elevated AST in infancy.
- name: Cardiomegaly
  description: Chest radiography in the elder founder sibling showed an enlarged cardiac silhouette.
  phenotype_term:
    preferred_term: Cardiomegaly
    term:
      id: HP:0001640
      label: Cardiomegaly
  evidence:
  - reference: url:https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf
    reference_title: https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In a chest X-ray examination, car- diomegaly was noted
    explanation: The primary report documents cardiomegaly.
- name: Tricuspid regurgitation
  description: Echocardiographic finding in the elder founder sibling with severe pulmonary hypertension.
  phenotype_term:
    preferred_term: Tricuspid regurgitation
    term:
      id: HP:0005180
      label: Tricuspid regurgitation
  evidence:
  - reference: url:https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf
    reference_title: https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      severe suprasystemic PAH, with marked tricuspid regurgitation, a dilated right atrium, and a dilated
      right ventricle.
    explanation: >-
      Echocardiography documented pulmonary hypertension, valve regurgitation and right-heart enlargement in
      the elder founder sibling.
- name: Right atrial enlargement
  description: Echocardiographic finding in the elder founder sibling with severe pulmonary hypertension.
  phenotype_term:
    preferred_term: Right atrial enlargement
    term:
      id: HP:0030718
      label: Right atrial enlargement
  evidence:
  - reference: url:https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf
    reference_title: https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      severe suprasystemic PAH, with marked tricuspid regurgitation, a dilated right atrium, and a dilated
      right ventricle.
    explanation: >-
      Echocardiography documented pulmonary hypertension, valve regurgitation and right-heart enlargement in
      the elder founder sibling.
- name: Right ventricular dilatation
  description: Echocardiographic finding in the elder founder sibling with severe pulmonary hypertension.
  phenotype_term:
    preferred_term: Right ventricular dilatation
    term:
      id: HP:0005133
      label: Right ventricular dilatation
  evidence:
  - reference: url:https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf
    reference_title: https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      severe suprasystemic PAH, with marked tricuspid regurgitation, a dilated right atrium, and a dilated
      right ventricle.
    explanation: >-
      Echocardiography documented pulmonary hypertension, valve regurgitation and right-heart enlargement in
      the elder founder sibling.
- name: Respiratory distress
  description: Severe respiratory deterioration preceded the early deaths in the founding siblings.
  phenotype_term:
    preferred_term: Respiratory distress
    term:
      id: HP:0002098
      label: Respiratory distress
  evidence:
  - reference: url:https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf
    reference_title: https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the age of 15 months after being admitted to a regional hospital due to severe respiratory distress.
    explanation: The younger founder sibling died during respiratory deterioration.
- name: Metabolic acidosis
  description: >-
    The elder founder sibling developed terminal mixed metabolic and respiratory acidosis. The later patient
    had a fasting-associated episode of metabolic acidosis despite its absence in the summary table.
  phenotype_term:
    preferred_term: Metabolic acidosis
    term:
      id: HP:0001942
      label: Metabolic acidosis
  evidence:
  - reference: url:https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf
    reference_title: https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: mixed metabolic and respiratory acidosis.
    explanation: Mixed acidosis accompanied terminal deterioration.
  - reference: url:https://iris.uniroma1.it/bitstream/11573/1705503/2/Torraco_Novel_2022.pdf
    reference_title: https://iris.uniroma1.it/bitstream/11573/1705503/2/Torraco_Novel_2022.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      fasting blood test revealed ketotic hypoglycemia unresponsive to glucagone and meta- bolic acidosis.
    explanation: The later patient had an episodic metabolic disturbance.
- name: Ketotic hypoglycemia
  description: >-
    Fasting-associated ketotic hypoglycemia unresponsive to glucagon was documented at 3 years 10 months in
    the later patient.
  phenotype_term:
    preferred_term: Ketotic hypoglycemia
    term:
      id: HP:0012734
      label: Ketotic hypoglycemia
  evidence:
  - reference: url:https://iris.uniroma1.it/bitstream/11573/1705503/2/Torraco_Novel_2022.pdf
    reference_title: https://iris.uniroma1.it/bitstream/11573/1705503/2/Torraco_Novel_2022.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      fasting blood test revealed ketotic hypoglycemia unresponsive to glucagone and meta- bolic acidosis.
    explanation: The clinical narrative documents ketotic hypoglycemia.
- name: Severe short stature
  description: >-
    Severe linear growth failure persisted in the later patient into late childhood, with height 115.2 cm at
    11 years 9 months.
  phenotype_term:
    preferred_term: Severe short stature
    term:
      id: HP:0003510
      label: Severe short stature
  evidence:
  - reference: url:https://iris.uniroma1.it/bitstream/11573/1705503/2/Torraco_Novel_2022.pdf
    reference_title: https://iris.uniroma1.it/bitstream/11573/1705503/2/Torraco_Novel_2022.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: At 11 year and 9 months she was 115.2 cm tall
    explanation: The report documents severe short stature in late childhood.
- name: Hypergonadotropic hypogonadism
  description: >-
    Elevated gonadotropins with very low estradiol indicated early ovarian insufficiency in the later patient
    at 11 years 9 months.
  phenotype_term:
    preferred_term: Hypergonadotropic hypogonadism
    term:
      id: HP:0000815
      label: Hypergonadotropic hypogonadism
  evidence:
  - reference: url:https://iris.uniroma1.it/bitstream/11573/1705503/2/Torraco_Novel_2022.pdf
    reference_title: https://iris.uniroma1.it/bitstream/11573/1705503/2/Torraco_Novel_2022.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A clear initial ovarian insufficiency was detected by FSH 112 mIU/ml (normal value 1.9 –7.8), LH 21.5
      mIU/ml (normal value >10.1), and 17 β estradiol <5 pg/ml which documented hypergonadotropic hypogonadism.
    explanation: The endocrine evaluation establishes this finding in one patient.
- name: Cerebral cortical atrophy
  description: >-
    Moderate cortical atrophy was described on MRI at age four in the later patient, despite preserved neurodevelopment.
  phenotype_term:
    preferred_term: Cerebral cortical atrophy
    term:
      id: HP:0002120
      label: Cerebral cortical atrophy
  evidence:
  - reference: url:https://iris.uniroma1.it/bitstream/11573/1705503/2/Torraco_Novel_2022.pdf
    reference_title: https://iris.uniroma1.it/bitstream/11573/1705503/2/Torraco_Novel_2022.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: moderate signs of cortical atrophy, with periventricular hyperintensities
    explanation: The MRI description supports cortical atrophy.
- name: Periventricular white matter hyperintensities
  description: MRI at age four showed periventricular signal abnormality in the later patient.
  phenotype_term:
    preferred_term: Periventricular white matter hyperintensities
    term:
      id: HP:0030891
      label: Periventricular white matter hyperintensities
  evidence:
  - reference: url:https://iris.uniroma1.it/bitstream/11573/1705503/2/Torraco_Novel_2022.pdf
    reference_title: https://iris.uniroma1.it/bitstream/11573/1705503/2/Torraco_Novel_2022.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 1B is another axial T2 weighted image showing periventricular abnormal T2 hyperintensity.
    explanation: The figure legend identifies periventricular T2 hyperintensity.
- name: Wide anterior fontanel
  description: >-
    Reported in the elder founder sibling; the younger sibling had no distinctive dysmorphic features.
  phenotype_term:
    preferred_term: Wide anterior fontanel
    term:
      id: HP:0000260
      label: Wide anterior fontanel
  evidence:
  - reference: url:https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf
    reference_title: https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a large anterior fontanel, a wide open posterior fontanel, frontal bossing, synophrys, deep-set eyes,
      long eyelashes, short extremities, and short hands and feet.
    explanation: The elder sibling had these examination findings.
- name: Frontal bossing
  description: >-
    Reported in the elder founder sibling; the younger sibling had no distinctive dysmorphic features.
  phenotype_term:
    preferred_term: Frontal bossing
    term:
      id: HP:0002007
      label: Frontal bossing
  evidence:
  - reference: url:https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf
    reference_title: https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a large anterior fontanel, a wide open posterior fontanel, frontal bossing, synophrys, deep-set eyes,
      long eyelashes, short extremities, and short hands and feet.
    explanation: The elder sibling had these examination findings.
- name: Synophrys
  description: >-
    Reported in the elder founder sibling; the younger sibling had no distinctive dysmorphic features.
  phenotype_term:
    preferred_term: Synophrys
    term:
      id: HP:0000664
      label: Synophrys
  evidence:
  - reference: url:https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf
    reference_title: https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a large anterior fontanel, a wide open posterior fontanel, frontal bossing, synophrys, deep-set eyes,
      long eyelashes, short extremities, and short hands and feet.
    explanation: The elder sibling had these examination findings.
- name: Deeply set eyes
  description: >-
    Reported in the elder founder sibling; the younger sibling had no distinctive dysmorphic features.
  phenotype_term:
    preferred_term: Deeply set eyes
    term:
      id: HP:0000490
      label: Deeply set eye
  evidence:
  - reference: url:https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf
    reference_title: https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a large anterior fontanel, a wide open posterior fontanel, frontal bossing, synophrys, deep-set eyes,
      long eyelashes, short extremities, and short hands and feet.
    explanation: The elder sibling had these examination findings.
- name: Long eyelashes
  description: >-
    Reported in the elder founder sibling; the younger sibling had no distinctive dysmorphic features.
  phenotype_term:
    preferred_term: Long eyelashes
    term:
      id: HP:0000527
      label: Long eyelashes
  evidence:
  - reference: url:https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf
    reference_title: https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a large anterior fontanel, a wide open posterior fontanel, frontal bossing, synophrys, deep-set eyes,
      long eyelashes, short extremities, and short hands and feet.
    explanation: The elder sibling had these examination findings.
- name: Small hands
  description: >-
    Reported in the elder founder sibling; the younger sibling had no distinctive dysmorphic features.
  phenotype_term:
    preferred_term: Small hands
    term:
      id: HP:0200055
      label: Small hand
  evidence:
  - reference: url:https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf
    reference_title: https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a large anterior fontanel, a wide open posterior fontanel, frontal bossing, synophrys, deep-set eyes,
      long eyelashes, short extremities, and short hands and feet.
    explanation: The elder sibling had these examination findings.
- name: Short feet
  description: >-
    Reported in the elder founder sibling; the younger sibling had no distinctive dysmorphic features.
  phenotype_term:
    preferred_term: Short feet
    term:
      id: HP:0001773
      label: Short foot
  evidence:
  - reference: url:https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf
    reference_title: https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a large anterior fontanel, a wide open posterior fontanel, frontal bossing, synophrys, deep-set eyes,
      long eyelashes, short extremities, and short hands and feet.
    explanation: The elder sibling had these examination findings.
- name: Pineal cyst
  description: >-
    A 10 mm pineal gland cyst was observed on MRI at age four in the later patient. Its causal relationship
    to COX5A deficiency is uncertain.
  phenotype_term:
    preferred_term: Pineal cyst
    term:
      id: HP:0012683
      label: Pineal cyst
  evidence:
  - reference: url:https://iris.uniroma1.it/bitstream/11573/1705503/2/Torraco_Novel_2022.pdf
    reference_title: https://iris.uniroma1.it/bitstream/11573/1705503/2/Torraco_Novel_2022.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 4 years showed pineal gland cyst with a maximum diameter of 10 mm,
    explanation: The MRI described a pineal cyst in one patient.
genetic:
- name: COX5A
  gene_term:
    preferred_term: COX5A
    term:
      id: hgnc:2267
      label: COX5A
  inheritance:
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    description: >-
      Homozygous missense variants were reported in both families; both parents in the second family were heterozygous.
    evidence:
    - reference: url:https://iris.uniroma1.it/bitstream/11573/1705503/2/Torraco_Novel_2022.pdf
      reference_title: https://iris.uniroma1.it/bitstream/11573/1705503/2/Torraco_Novel_2022.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Both parents resulted heterozygous for the same variant (Figure 1C).
      explanation: Both parents of the homozygous p.Ile89Ser patient carried the variant.
    - reference: PMID:28247525
      reference_title: >-
        Mutation in mitochondrial complex IV subunit COX5A causes pulmonary arterial hypertension, lactic acidemia,
        and failure to thrive.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: We present patients with a homozygous pathogenic variant in the COX5A gene.
      explanation: The founding family supports recessive inheritance.
  features: >-
    Two reported homozygous missense alleles expand the clinical spectrum: c.319C>T (p.Arg107Cys) in the founding
    siblings and c.266T>G (p.Ile89Ser) in the later patient. The case numbers do not establish penetrance or
    a dependable genotype-severity rule.
  variants:
  - name: c.319C>T (p.Arg107Cys)
    description: >-
      NM_004255.3; homozygous in the two founding siblings. Interface disruption is predicted computationally;
      wild-type complementation supports causality.
    evidence:
    - reference: url:https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf
      reference_title: https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: chr15(GRCh37):g.75219127G>A; NM_004255.3 (GenBank reference sequence):c.319C>T; p.(Arg107Cys).
      explanation: The founder study reports the transcript and protein change for the homozygous allele.
    - reference: PMID:28247525
      reference_title: >-
        Mutation in mitochondrial complex IV subunit COX5A causes pulmonary arterial hypertension, lactic acidemia,
        and failure to thrive.
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      snippet: >-
        We show that the variant lies within the evolutionarily conserved COX5A/COX4 interface domain, suggesting
        that it alters the interaction between these two subunits during complex IV biogenesis.
      explanation: >-
        Homology modeling predicts altered subunit contacts for p.Arg107Cys; a direct binding assay was not
        performed.
      directness: INDIRECT
    - reference: PMID:28247525
      reference_title: >-
        Mutation in mitochondrial complex IV subunit COX5A causes pulmonary arterial hypertension, lactic acidemia,
        and failure to thrive.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Lentiviral complementation rescues complex IV deficiency.
      explanation: >-
        Wild-type complementation supports the causal role of COX5A; the full text documents increased complex
        IV abundance.
  - name: c.266T>G (p.Ile89Ser)
    description: >-
      NM_004255.4; homozygous in the later patient, with heterozygous parents and a selective cellular complex
      IV defect.
    evidence:
    - reference: url:https://iris.uniroma1.it/bitstream/11573/1705503/2/Torraco_Novel_2022.pdf
      reference_title: https://iris.uniroma1.it/bitstream/11573/1705503/2/Torraco_Novel_2022.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        NGS analysis revealed a homozygous c.266 T > G variant (Figure 1C) which is predicted to produce a
        p.(Ile89Ser) aminoacidic substitution in a highly conserved region (Figure S1A) of COX5A (NM_004255.4).
      explanation: The second family carried homozygous c.266T>G, p.Ile89Ser.
    - reference: url:https://iris.uniroma1.it/bitstream/11573/1705503/2/Torraco_Novel_2022.pdf
      reference_title: https://iris.uniroma1.it/bitstream/11573/1705503/2/Torraco_Novel_2022.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Both parents resulted heterozygous for the same variant (Figure 1C).
      explanation: Both parents of the homozygous p.Ile89Ser patient carried the variant.
    - reference: url:https://iris.uniroma1.it/bitstream/11573/1705503/2/Torraco_Novel_2022.pdf
      reference_title: https://iris.uniroma1.it/bitstream/11573/1705503/2/Torraco_Novel_2022.pdf
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: found a 50% reduction of COX5A protein in the patient
      explanation: The p.Ile89Ser patient retained COX5A protein at about half the control amount.
    - reference: url:https://iris.uniroma1.it/bitstream/11573/1705503/2/Torraco_Novel_2022.pdf
      reference_title: https://iris.uniroma1.it/bitstream/11573/1705503/2/Torraco_Novel_2022.pdf
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        confirmed the selective reduction of the holocomplex CIV (20% residual amount) as well as an almost
        undetectable CIV activity (Figure 2D, E).
      explanation: >-
        The p.Ile89Ser fibroblasts retained about 20% holocomplex IV, with nearly undetectable in-gel activity.
  evidence:
  - reference: url:https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf
    reference_title: https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: chr15(GRCh37):g.75219127G>A; NM_004255.3 (GenBank reference sequence):c.319C>T; p.(Arg107Cys).
    explanation: The founder study reports the transcript and protein change for the homozygous allele.
  - reference: url:https://iris.uniroma1.it/bitstream/11573/1705503/2/Torraco_Novel_2022.pdf
    reference_title: https://iris.uniroma1.it/bitstream/11573/1705503/2/Torraco_Novel_2022.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      NGS analysis revealed a homozygous c.266 T > G variant (Figure 1C) which is predicted to produce a p.(Ile89Ser)
      aminoacidic substitution in a highly conserved region (Figure S1A) of COX5A (NM_004255.4).
    explanation: The second family carried homozygous c.266T>G, p.Ile89Ser.
  - reference: PMID:28247525
    reference_title: >-
      Mutation in mitochondrial complex IV subunit COX5A causes pulmonary arterial hypertension, lactic acidemia,
      and failure to thrive.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Lentiviral complementation rescues complex IV deficiency.
    explanation: >-
      Wild-type complementation supports the causal role of COX5A; the full text documents increased complex
      IV abundance.
treatments:
- name: High-calorie enteral nutrition
  description: >-
    High-calorie nasogastric feeding was used for the elder founder sibling, but weight gain remained poor.
    This documents supportive use, not demonstrated disease modification.
  treatment_term:
    preferred_term: Enteral Tube Feeding
    term:
      id: NCIT:C93322
      label: Enteral Tube Feeding
  evidence:
  - reference: url:https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf
    reference_title: https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      she was discharged on a high calorie diet applied via nasogas- tric tube feeding. However, weight gain
      remained poor.
    explanation: The founder report documents nutritional treatment and limited response.
  target_phenotypes:
  - preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  therapeutic_modality: BEHAVIORAL
- name: Thiamine, carnitine and coenzyme Q10
  description: >-
    The younger founder sibling received this mitochondrial supplement combination without an apparent effect.
    Benefit for COX5A disease is not established.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Nutritional Supplementation
    term:
      id: NCIT:C15425
      label: Nutritional Supplementation
    therapeutic_agent:
    - preferred_term: thiamine(1+)
      term:
        id: CHEBI:18385
        label: thiamine(1+)
    - preferred_term: carnitine
      term:
        id: CHEBI:17126
        label: carnitine
    - preferred_term: coenzyme Q10
      term:
        id: CHEBI:46245
        label: coenzyme Q10
  evidence:
  - reference: url:https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf
    reference_title: https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: She received thiamine, carnitine, and coenzyme Q10 without an apparent effect.
    explanation: The only described clinical supplement use had no apparent effect.
- name: Copper chloride (preclinical)
  description: >-
    Copper chloride increased complex IV abundance in cultured p.Arg107Cys patient fibroblasts. The COX1 assembly
    intermediate persisted; a translation-inhibition experiment was consistent with stabilization of residual
    complexes or subassemblies. These experiments do not establish a safe or effective clinical treatment.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: copper(II) chloride
      term:
        id: CHEBI:49553
        label: copper(II) chloride
  evidence:
  - reference: PMID:28247525
    reference_title: >-
      Mutation in mitochondrial complex IV subunit COX5A causes pulmonary arterial hypertension, lactic acidemia,
      and failure to thrive.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      A potential therapeutic lead is demonstrated by showing that copper supplementation leads to partial
      rescue of complex IV deficiency in patient fibroblasts.
    explanation: Copper rescue is preclinical.
  - reference: url:https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf
    reference_title: https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      accumulation of COX1 did not resolve in CuCl2-treated fibroblasts, suggesting another mechanism of complex
      IV rescue.
    explanation: Copper did not normalize the accumulated assembly intermediate.
  target_mechanisms:
  - target: Reduced Complex IV Abundance
    description: >-
      Copper increases residual enzyme abundance in patient cells; it has not been shown to repair the interface
      defect.
    evidence:
    - reference: url:https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf
      reference_title: https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        decrease of complex IV and the CuCl 2-induced increase exclusively affected monomeric complex IV ,
        whereas the levels of the com- plex IV containing high molecular weight supercomplexes remained unaffected.
      explanation: >-
        The decrease and copper response involved monomeric complex IV; higher-order supercomplex abundance
        was preserved.
📚

References & Deep Research

References

5
PMID:28247525
Mutation in mitochondrial complex IV subunit COX5A causes pulmonary arterial hypertension, lactic acidemia, and failure to thrive.
No top-level findings curated for this source.
PMID:35246835
A novel homozygous variant in COX5A causes an attenuated phenotype with failure to thrive, lactic acidosis, hypoglycemia, and short stature.
No top-level findings curated for this source.
PMID:20307258
Novel insights into the assembly and function of human nuclear-encoded cytochrome c oxidase subunits 4, 5a, 6a, 7a and 7b.
No top-level findings curated for this source.
url:https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf
https://repository.ubn.ru.nl/bitstream/handle/2066/174071/174071.pdf
No top-level findings curated for this source.
url:https://iris.uniroma1.it/bitstream/11573/1705503/2/Torraco_Novel_2022.pdf
https://iris.uniroma1.it/bitstream/11573/1705503/2/Torraco_Novel_2022.pdf
No top-level findings curated for this source.