COX10-Related COX Deficiency

Mendelian MONDO:0033635 Pathograph 28 Show in embeddings browser Mitochondrial Disease Inborn Error of Metabolism

COX10-related cytochrome c oxidase deficiency is an autosomal recessive mitochondrial disorder caused by biallelic pathogenic COX10 variants. COX10 is heme O synthase, an enzyme required for heme A biosynthesis and complex IV biogenesis, rather than a structural subunit of mature complex IV. Reported disease ranges from infantile Leigh syndrome or cardiomyopathy with anemia to childhood white-matter disease and a multisystem phenotype compatible with survival into adulthood. The severity of biochemical deficiency does not reliably predict clinical severity.

Ask OpenScientist

Ask a research question about COX10-Related COX Deficiency. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).

Submitting...

Do not include personal health information in your question. Questions and results are cached in your browser's local storage.

1
Inheritance
6
Pathophys.
23
Phenotypes
2
Gaps
28
Pathograph
1
Genes
12
Medical Actions
2
Models
10
References
👪

Inheritance

1
Autosomal recessive
Biallelic pathogenic COX10 variants cause disease. For a couple confirmed to carry one disease-causing allele each, the recurrence risk follows autosomal recessive inheritance. A contiguous deletion involving PMP22 adds a separate dominant neuropathy risk.
Show evidence (2 references)
PMID:36176336 SUPPORT Human Clinical
"caused by biallelic COX10 mutations coexisting with HNPP caused by heterozygous PMP22 deletion"
Separates recessive COX10 disease from dominant PMP22-associated HNPP.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/ SUPPORT BACKGROUND Other
"each sib of an ... has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic ... and a 25% chance of being unaffected and not a"
GeneReviews gives 25% affected, 50% carrier and 25% noncarrier risks when both parents carry a pathogenic allele in the same recessive LSS gene.
?

Discussions and Knowledge Gaps

2
Does severe biochemical deficiency determine clinical severity?
INTERPRETATION cox10_clinical_variability
Severe biochemical or yeast respiratory defects do not imply an inevitable infantile outcome. The adult Asp336Val/Arg339Trp case and the yeast follow-up leave the determinants of organ involvement and survival unresolved; proposed modifier genes remain hypotheses.
Show evidence (2 references)
PMID:24100867 SUPPORT Human Clinical
"These findings establish that COX10 mutations cause adult mitochondrial disease."
Clinical outcome extends beyond the early lethal presentations.
PMID:39152498 SUPPORT Model Organism
"We thought that using more sensitive enzyme assays might reveal partial activity from one or both proteins but found that both are fully nonfunctional"
The follow-up did not find residual activity for these alleles in yeast.
Do the reported toddler variants establish COX10 deficiency?
INTERPRETATION cox10_uncertain_toddler_variants
The Thr377Ile and Thr14Ile substitutions were reported as VUS, not proven pathogenic alleles. The later yeast paper tested Thr380Ile and discussed Thr377Ile by positional analogy; that is not direct functional testing of Thr377Ile. Clinical observations and supplement exposure from the toddler report therefore remain provisional disease-association evidence.
Show evidence (2 references)
PMID:38846886 SUPPORT Human Clinical
"Functional studies might elucidate the impact of these variants on the produced protein by the COX10 gene."
The case report calls for functional studies rather than reporting them.
PMID:39152498 SUPPORT BACKGROUND Other
"The second variant is highly similar to the T380I variant that we found to be nonfunctional"
Thr377Ile is discussed by analogy to a different tested variant.
⚙

Pathophysiology

6
COX10 Dysfunction
Biallelic pathogenic missense, initiation-codon or partial-deletion alleles impair COX10 function. Different variants require individual evaluation; sequence prediction alone does not establish loss of function.
COX10 hgnc:2260 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves COX10 (hgnc:2260). hgnc:2260 is a gene from the HUGO Gene Nomenclature Committee.
protoheme IX farnesyltransferase activity GO:0008495 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased protoheme IX farnesyltransferase activity (GO:0008495). GO:0008495 is a molecular function from the Gene Ontology.
Downstream
Deficient Heme A Biosynthesis Impaired heme O synthase reduces production of the precursor required for heme A.
Show evidence (3 references)
PMID:10767350 SUPPORT Model Organism
"complementation study in yeast permitted us to ascribe the COX deficiency to a homozygous missense mutation in the COX10 gene."
Yeast complementation supports the functional consequence of the familial mutation.
PMID:15455402 SUPPORT Human Clinical
"We report a cytochrome c oxidase (COX)-deficient patient, clinically affected with Leigh-like disease, with a homozygous mutation in the COX10 start codon."
Initiation-codon disruption is another established allelic class.
PMID:10767350 SUPPORT Human Clinical
"We report here a genetic linkage study of a consanguineous family with an isolated COX defect and subsequent identification of a mutation in a third nuclear gene causing a deficiency of the enzyme."
The human linkage component identified the familial COX10 disorder; functional complementation is cited separately.
Deficient Heme A Biosynthesis
Deficient conversion of heme B to heme O limits heme A availability. Reduced heme A was measured in patient muscle and fibroblast mitochondria.
heme A biosynthetic process GO:0006784 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased heme A biosynthetic process (GO:0006784). GO:0006784 is a biological process from the Gene Ontology.
Downstream
Reduced Complex IV Assembly Limited heme A availability impairs maturation of the heme-containing COX complex.
Show evidence (1 reference)
PMID:12928484 SUPPORT In Vitro
"Heme A content was reduced in mitochondria from patient muscle and fibroblasts in proportion to the reduction in COX enzyme activity and the amount of fully assembled enzyme."
Heme A depletion tracks the biochemical COX defect in patient tissue and cultures.
Reduced Complex IV Assembly
Patients have reduced fully assembled cytochrome c oxidase and reduced core subunits. The start-codon case and the adult missense case lacked accumulation of the partially assembled intermediates seen with some other COX assembly defects.
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
Patient Fibroblast COX10 Complementation PRIMARY CELL CULTURE The patient-derived cellular system has reduced mature COX without accumulating assembly intermediates.
Downstream
Reduced Terminal Electron Transfer Reduced functional COX lowers capacity for electron transfer from cytochrome c to oxygen.
Show evidence (2 references)
PMID:15455402 SUPPORT In Vitro
"Two-dimensional gel electrophoresis showed a decrease of fully assembled COX without the accumulation of partially assembled COX subcomplexes."
The assembly defect is demonstrated directly.
PMID:24100867 SUPPORT In Vitro
"Muscle COX holoenzyme and subassemblies were undetectable on immunoblots of blue-native gels, whereas denaturing gels and immunocytochemistry showed reduced core subunit MTCO1."
The adult phenotype also has an early COX assembly defect.
Reduced Terminal Electron Transfer
Reduced complex IV activity limits terminal respiratory-chain capacity. This is a reduction in respiratory reserve, not evidence that electron transfer or ATP generation is completely absent in every patient.
mitochondrial electron transport, cytochrome c to oxygen GO:0006123 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased mitochondrial electron transport, cytochrome c to oxygen (GO:0006123). GO:0006123 is a biological process from the Gene Ontology.
Experimental models
Human COX10 Alleles in Yeast OTHER Variant-dependent COX enzyme activity and respiratory growth measure the consequences of COX10 dysfunction.
Downstream
Impaired Oxidative Energy Production Reduced COX-dependent proton translocation can restrict oxidative ATP production.
Show evidence (2 references)
PMID:36176336 SUPPORT In Vitro
"The enzyme activity in fibroblast revealed a selective decrease in complex IV"
Patient fibroblasts show an isolated complex IV defect.
PMID:39152498 SUPPORT Model Organism
"Cells expressing the other variants showed low cytochrome c oxidase activity and failed to grow on nonfermentable media."
Human COX10 variants can reduce COX activity and respiratory growth in yeast.
Impaired Oxidative Energy Production
Reduced respiratory capacity can limit oxidative energy generation and increase vulnerability to metabolic stress. The clinical expression is variable; neither uniform ATP collapse nor an invariant sequence of organ injury has been established.
mitochondrial ATP synthesis coupled electron transport GO:0042775 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased mitochondrial ATP synthesis coupled electron transport (GO:0042775). GO:0042775 is a biological process from the Gene Ontology.
Downstream
White Matter Injury Mitochondrial dysfunction is associated with destructive white-matter lesions in COX10-associated Leigh disease; the intervening cellular sequence is unresolved.
Myopathy Respiratory-chain dysfunction contributes to muscle disease.
Hypertrophic cardiomyopathy Cardiac involvement can accompany COX10 deficiency.
Renal tubular dysfunction Mitochondrial dysfunction can affect renal tubular function.
Lactic acidosis Impaired oxidative metabolism can favor lactate accumulation; lactic acidosis is not demonstrated in every genotype-confirmed case.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/ SUPPORT BACKGROUND Other
"a continuum of progressive neurodegenerative disorders caused by abnormalities of mitochondrial energy generation"
General Leigh-spectrum mechanism applicable to the COX10-associated encephalopathic presentation.
White Matter Injury
COX10-associated Leigh disease can involve diffuse white-matter degeneration with myelin and axonal loss, neuropil vacuolation and gliosis. These tissue findings do not establish a specific primary oligodendrocyte defect.
Downstream
Leukodystrophy White-matter degeneration underlies the leukodystrophic presentation.
Encephalopathy Diffuse CNS injury contributes to progressive neurologic dysfunction.
Spastic paraplegia White-matter tract injury can contribute to pyramidal motor dysfunction.
Intellectual disability CNS involvement can impair cognition and development.
Cerebellar ataxia Cerebellar and connecting white-matter injury can contribute to ataxia.
Show evidence (2 references)
PMID:36176336 SUPPORT Human Clinical
"The brain showed diffuse and severe white matter degeneration"
Postmortem pathology in an affected member of the COX10/PMP22 family.
PMID:36176336 SUPPORT Human Clinical
"The loss of myelin and axons appeared to be similar in extent in the degenerated white matter"
Both myelin and axons were affected; this does not prove that one lesion initiates the other.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for COX10-Related COX Deficiency Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

23
Blood 1
Anemia HP:0001903 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Anemia (HP:0001903). HP:0001903 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:12928484 SUPPORT Human Clinical
"in a patient with anemia and Leigh Syndrome, and in a patient with anemia, sensorineural deafness and fatal infantile hypertrophic cardiomyopathy."
Both newly described COX10 patients had anemia.
PMID:30588737 SUPPORT Human Clinical
"In addition, anemia without ring sideroblasts was found in three other patients with mitochondrial disorders, including two children with later onset of PS and one child with failure to thrive, microcephaly, developmental delay, hypertrophic cardiomyopathy, and renal tubular acidosis due to the..."
This is evidence for anemia without ring sideroblasts, not sideroblastic anemia.
Cardiovascular 1
Hypertrophic cardiomyopathy HP:0001639 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypertrophic cardiomyopathy (HP:0001639). HP:0001639 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:12928484 SUPPORT Human Clinical
"in a patient with anemia and Leigh Syndrome, and in a patient with anemia, sensorineural deafness and fatal infantile hypertrophic cardiomyopathy."
One of the functionally complemented patients had fatal infantile hypertrophic cardiomyopathy.
PMID:30588737 SUPPORT Human Clinical
"In addition, anemia without ring sideroblasts was found in three other patients with mitochondrial disorders, including two children with later onset of PS and one child with failure to thrive, microcephaly, developmental delay, hypertrophic cardiomyopathy, and renal tubular acidosis due to the..."
A separate COX10 patient had hypertrophic cardiomyopathy.
Ear 1
Sensorineural hearing impairment HP:0000407 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sensorineural hearing impairment (HP:0000407). HP:0000407 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:12928484 SUPPORT Human Clinical
"in a patient with anemia and Leigh Syndrome, and in a patient with anemia, sensorineural deafness and fatal infantile hypertrophic cardiomyopathy."
The infant with cardiomyopathy had sensorineural deafness.
PMID:24100867 SUPPORT Human Clinical
"We describe an adult patient with isolated COX deficiency associated with a relatively mild clinical phenotype comprising myopathy; demyelinating neuropathy; premature ovarian failure; short stature; hearing loss; pigmentary maculopathy; and renal tubular dysfunction."
Hearing loss was part of the adult phenotype.
Eye 1
Pigmentary maculopathy Abnormal macular pigmentation HP:0008002 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pigmentary maculopathy, annotated with Abnormal macular pigmentation (HP:0008002). HP:0008002 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:24100867 SUPPORT Human Clinical
"We describe an adult patient with isolated COX deficiency associated with a relatively mild clinical phenotype comprising myopathy; demyelinating neuropathy; premature ovarian failure; short stature; hearing loss; pigmentary maculopathy; and renal tubular dysfunction."
The adult report describes macular pigmentary disease.
Genitourinary 3
Renal tubular dysfunction HP:0000124 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Renal tubular dysfunction (HP:0000124). HP:0000124 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:24100867 SUPPORT Human Clinical
"We describe an adult patient with isolated COX deficiency associated with a relatively mild clinical phenotype comprising myopathy; demyelinating neuropathy; premature ovarian failure; short stature; hearing loss; pigmentary maculopathy; and renal tubular dysfunction."
The adult case had renal tubular dysfunction.
PMID:12928484 SUPPORT BACKGROUND Other
"Mutations in COX10 have previously been reported in a single family with tubulopathy and leukodystrophy."
Earlier COX10-associated tubulopathy.
Renal tubular acidosis HP:0001947 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Renal tubular acidosis (HP:0001947). HP:0001947 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30588737 SUPPORT Human Clinical
"In addition, anemia without ring sideroblasts was found in three other patients with mitochondrial disorders, including two children with later onset of PS and one child with failure to thrive, microcephaly, developmental delay, hypertrophic cardiomyopathy, and renal tubular acidosis due to the..."
The finding is specifically assigned to the COX10 patient.
Premature ovarian insufficiency HP:0008209 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Premature ovarian insufficiency (HP:0008209). HP:0008209 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:24100867 SUPPORT Human Clinical
"We describe an adult patient with isolated COX deficiency associated with a relatively mild clinical phenotype comprising myopathy; demyelinating neuropathy; premature ovarian failure; short stature; hearing loss; pigmentary maculopathy; and renal tubular dysfunction."
One adult case establishes occurrence, not a general frequency.
Head and Neck 1
Microcephaly HP:0000252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Microcephaly (HP:0000252). HP:0000252 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30588737 SUPPORT Human Clinical
"In addition, anemia without ring sideroblasts was found in three other patients with mitochondrial disorders, including two children with later onset of PS and one child with failure to thrive, microcephaly, developmental delay, hypertrophic cardiomyopathy, and renal tubular acidosis due to the..."
The primary abstract explicitly reports microcephaly.
Metabolism 1
Lactic acidosis HP:0003128 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Lactic acidosis (HP:0003128). HP:0003128 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38846886 SUPPORT INDIRECT Human Clinical
"Her laboratory data revealed lactic acidosis and her brain MRI manifested diffuse leukodystrophy"
The report documents the metabolic finding but leaves two COX10 variants classified as VUS.
Musculoskeletal 3
Spastic paraplegia HP:0001258 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Spastic paraplegia (HP:0001258). HP:0001258 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36176336 SUPPORT Human Clinical
"The proband and her 2 siblings developed spastic paraplegia and mental retardation during childhood."
The sibling observation supports childhood pyramidal and cognitive involvement, not a population frequency.
Myopathy HP:0003198 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Myopathy (HP:0003198). HP:0003198 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:24100867 SUPPORT Human Clinical
"We describe an adult patient with isolated COX deficiency associated with a relatively mild clinical phenotype comprising myopathy; demyelinating neuropathy; premature ovarian failure; short stature; hearing loss; pigmentary maculopathy; and renal tubular dysfunction."
The adult report demonstrates muscle involvement without requiring Leigh encephalopathy.
Muscle weakness HP:0001324 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Muscle weakness (HP:0001324). HP:0001324 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38846886 SUPPORT INDIRECT Human Clinical
"A 3-year-old girl was admitted due to muscle weakness and a decline in developmental milestones 7 days after a significant stressor."
The clinical observation is direct; its attribution to COX10 remains uncertain.
Nervous System 8
Encephalopathy HP:0001298 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Encephalopathy (HP:0001298). HP:0001298 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:36176336 SUPPORT Human Clinical
"Leigh encephalopathy was diagnosed neuropathologically. Brain MRI revealed changes in cerebral white matter as well as multiple lesions in the brainstem and cerebellum."
Neuropathology and neuroimaging establish CNS involvement in this family.
PMID:12928484 SUPPORT Human Clinical
"in a patient with anemia and Leigh Syndrome, and in a patient with anemia, sensorineural deafness and fatal infantile hypertrophic cardiomyopathy."
An independent infant had anemia and Leigh syndrome.
Leukodystrophy HP:0002415 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Leukodystrophy (HP:0002415). HP:0002415 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:12928484 SUPPORT BACKGROUND Other
"Mutations in COX10 have previously been reported in a single family with tubulopathy and leukodystrophy."
The founding COX10 family had leukodystrophy.
PMID:36176336 SUPPORT Human Clinical
"The brain showed diffuse and severe white matter degeneration"
Primary pathology supports white-matter involvement.
Intellectual disability HP:0001249 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intellectual disability (HP:0001249). HP:0001249 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36176336 SUPPORT Human Clinical
"Patients 1 (III-1, eFigure 1, links.lww.com/NXG/A545) and 3 (III-3) presented with spastic paraplegia, intellectual disability, cerebellar ataxia, and respiratory failure."
Intellectual disability is explicitly reported.
Cerebellar ataxia HP:0001251 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cerebellar ataxia, annotated with Ataxia (HP:0001251). HP:0001251 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36176336 SUPPORT Human Clinical
"Patients 1 (III-1, eFigure 1, links.lww.com/NXG/A545) and 3 (III-3) presented with spastic paraplegia, intellectual disability, cerebellar ataxia, and respiratory failure."
The primary clinical description reports cerebellar ataxia.
Developmental regression HP:0002376 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Developmental regression (HP:0002376). HP:0002376 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:38846886 SUPPORT INDIRECT Human Clinical
"Seven days after the infection, she lost the ability to walk and speak."
Reported loss of skills in the candidate case.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/ SUPPORT BACKGROUND Other
"typically in infancy or early childhood with sudden neurodevelopmental regression"
Clinical-characteristics background for nuclear Leigh spectrum; not a COX10-specific onset estimate.
Global developmental delay HP:0001263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30588737 SUPPORT Human Clinical
"In addition, anemia without ring sideroblasts was found in three other patients with mitochondrial disorders, including two children with later onset of PS and one child with failure to thrive, microcephaly, developmental delay, hypertrophic cardiomyopathy, and renal tubular acidosis due to the..."
Developmental delay is reported without an individual-domain breakdown.
Demyelinating peripheral neuropathy HP:0007108 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Demyelinating peripheral neuropathy (HP:0007108). HP:0007108 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:24100867 SUPPORT Human Clinical
"We describe an adult patient with isolated COX deficiency associated with a relatively mild clinical phenotype comprising myopathy; demyelinating neuropathy; premature ovarian failure; short stature; hearing loss; pigmentary maculopathy; and renal tubular dysfunction."
The adult case supports this association independently of the later contiguous-deletion family.
Focal seizures Focal-onset seizure HP:0007359 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Focal seizures, annotated with Focal-onset seizure (HP:0007359). HP:0007359 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38846886 SUPPORT INDIRECT Human Clinical
"Additionally, she had experienced focal convulsions that were managed with 150 mg of levetiracetam and 10 mg of clobazam."
The seizure observation is reported, while COX10 causality remains unconfirmed.
Respiratory 1
Respiratory insufficiency HP:0002093 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Respiratory insufficiency (HP:0002093). HP:0002093 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36176336 SUPPORT Human Clinical
"Patients 1 (III-1, eFigure 1, links.lww.com/NXG/A545) and 3 (III-3) presented with spastic paraplegia, intellectual disability, cerebellar ataxia, and respiratory failure."
Respiratory failure occurred in two affected family members.
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 (1 reference)
PMID:30588737 SUPPORT Human Clinical
"In addition, anemia without ring sideroblasts was found in three other patients with mitochondrial disorders, including two children with later onset of PS and one child with failure to thrive, microcephaly, developmental delay, hypertrophic cardiomyopathy, and renal tubular acidosis due to the..."
The primary abstract reports impaired growth.
Short stature HP:0004322 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short stature (HP:0004322). HP:0004322 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:24100867 SUPPORT Human Clinical
"We describe an adult patient with isolated COX deficiency associated with a relatively mild clinical phenotype comprising myopathy; demyelinating neuropathy; premature ovarian failure; short stature; hearing loss; pigmentary maculopathy; and renal tubular dysfunction."
The adult case had short stature.
🧬

Genetic Associations

1
COX10 pathogenic alleles and uncertain variants
Gene: COX10 hgnc:2260 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is COX10 (hgnc:2260). hgnc:2260 is a gene from the HUGO Gene Nomenclature Committee.
Autosomal recessive
Show evidence (6 references)
PMID:12928484 SUPPORT Human Clinical
"Mutation analysis of COX10 identified four different missense alleles, predicting amino acid substitutions at evolutionarily conserved residues."
The founding functional series included missense alleles.
PMID:15455402 SUPPORT Human Clinical
"We report a cytochrome c oxidase (COX)-deficient patient, clinically affected with Leigh-like disease, with a homozygous mutation in the COX10 start codon."
Start-codon alteration is supported by complementation.
PMID:36176336 SUPPORT Human Clinical
"most likely caused by biallelic COX10 mutations composed of novel missense mutation and partial deletion"
The deletion affects part of COX10, not necessarily the entire gene.
+ 3 more references
💊

Medical Actions

12
Multidisciplinary Supportive Care
Action: Supportive CareNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. NCIT:C15747
Platform: Other
Care is directed to the manifestations present. GeneReviews recommendations for nuclear Leigh syndrome provide a clinical framework for COX10-associated encephalopathy; they are not evidence of a COX10-specific disease-modifying treatment.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/ SUPPORT BACKGROUND Other
"Supportive care to improve quality of life, maximize function, and reduce complications is recommended."
General LSS management recommendation.
Nutritional and Feeding Support
Action: Nutritional SupportNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Nutritional Support (NCIT:C15433). NCIT:C15433 is a clinical intervention from the NCI Thesaurus. NCIT:C15433
Platform: Other
Assess swallowing and nutrition; feeding therapy, supplementation and enteral support may be needed according to clinical impairment.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/ SUPPORT BACKGROUND Other
"gastrostomy tube placement may improve nutritional intake for those w/persistent feeding issues, choking, or aspiration risk due to dysphagia"
General LSS feeding guidance, individualized to clinical need.
Motor Rehabilitation
Action: RehabilitationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Rehabilitation (NCIT:C15315). NCIT:C15315 is a clinical intervention from the NCI Thesaurus. NCIT:C15315
Platform: Other
Physical and occupational therapy and mobility equipment can support function in patients with myopathy, ataxia or spasticity.
Target Phenotypes: Myopathy HP:0003198 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Myopathy (HP:0003198). HP:0003198 is a phenotype from the Human Phenotype Ontology. Cerebellar ataxia HP:0001251 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Cerebellar ataxia, annotated with Ataxia (HP:0001251). HP:0001251 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/ SUPPORT BACKGROUND Other
"Equipment to prevent falling, maintain independent mobility as appropriate"
GeneReviews supports mobility interventions for LSS-associated myopathy or ataxia.
Hearing Rehabilitation
Action: Hearing amplification or cochlear implantation with audiological rehabilitationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Hearing amplification or cochlear implantation with audiological rehabilitation, annotated with Rehabilitation (NCIT:C15315), qualified as Medical Device Hearing Aid; Medical Device Cochlear Implant. NCIT:C15315 is a clinical intervention from the NCI Thesaurus. Ontology label: Rehabilitation NCIT:C15315
Platform: Device
Hearing aids or cochlear implantation may be considered according to hearing impairment and specialist assessment; this is general LSS care guidance rather than demonstrated COX10-specific implant outcomes.
Target Phenotypes: Sensorineural hearing impairment HP:0000407 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Sensorineural hearing impairment (HP:0000407). HP:0000407 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/ SUPPORT BACKGROUND Other
"Hearing aids or cochlear implants for SNHL"
GeneReviews recommends hearing rehabilitation for sensorineural impairment.
Renal Electrolyte Support
Action: Supportive CareNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. NCIT:C15747
Platform: Other
Renal tubular losses require nephrology-directed electrolyte monitoring and replacement when present.
Target Phenotypes: Renal tubular dysfunction HP:0000124 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Renal tubular dysfunction (HP:0000124). HP:0000124 is a phenotype from the Human Phenotype Ontology. Renal tubular acidosis HP:0001947 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Renal tubular acidosis (HP:0001947). HP:0001947 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/ SUPPORT BACKGROUND Other
"Electrolyte monitoring ... replacement for renal tubular losses as advised by nephrologist"
General LSS supportive treatment for a documented COX10 manifestation.
Respiratory Support
Platform: Device
Respiratory compromise warrants specialist assessment and ventilatory support when indicated.
Target Phenotypes: Respiratory insufficiency HP:0002093 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Respiratory insufficiency (HP:0002093). HP:0002093 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/ SUPPORT BACKGROUND Other
"Ventilatory support for persons w/LSS ... respiratory compromise"
General Leigh-spectrum respiratory care.
Metabolic Stress and Medication Precautions
Action: Supportive CareNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. NCIT:C15747
Platform: Other
Minimize fasting and catabolism during illness or procedures. General LSS guidance advises caution with anesthesia, prolonged propofol, neuromuscular blockers and lactate-containing fluids in susceptible patients. Valproate should be avoided when possible; the absolute contraindication specified for POLG disease should not be attributed automatically to COX10.
Show evidence (3 references)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/ SUPPORT BACKGROUND Other
"Catabolism should be prevented by minimizing preoperative fasting and considering intravenous glucose perioperatively during prolonged anesthesia"
GeneReviews perioperative guidance; its ketogenic-diet exception requires individual assessment.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/ SUPPORT BACKGROUND Other
"Sodium valproate should be avoided if possible, because of its inhibitory effect on respiratory chain enzymes."
General mitochondrial caution, not evidence of a COX10-specific absolute contraindication.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/ SUPPORT BACKGROUND Other
"Prolonged propofol use during maintenance anesthesia may increase the risk of lactic acidosis."
General anesthetic precaution.
Reported Mitochondrial Supplement Cocktail
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: 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. biotin CHEBI:15956 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses biotin (CHEBI:15956). CHEBI:15956 is a therapeutic agent from Chemical Entities of Biological Interest. thiamine CHEBI:18385 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses thiamine, annotated with thiamine(1+) (CHEBI:18385). CHEBI:18385 is a therapeutic agent from Chemical Entities of Biological Interest. riboflavin CHEBI:17015 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses riboflavin (CHEBI:17015). CHEBI:17015 is a therapeutic agent from Chemical Entities of Biological Interest. pyridoxine CHEBI:16709 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses pyridoxine (CHEBI:16709). CHEBI:16709 is a therapeutic agent from Chemical Entities of Biological Interest. L-carnitine CHEBI:16347 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses L-carnitine, annotated with (R)-carnitine (CHEBI:16347). CHEBI:16347 is a therapeutic agent from Chemical Entities of Biological Interest. folinic acid CHEBI:15640 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses folinic acid, annotated with 5-formyltetrahydrofolic acid (CHEBI:15640). CHEBI:15640 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
A toddler with two uncertain COX10 variants received coenzyme Q10, biotin, thiamine, riboflavin, pyridoxine, L-carnitine and folinic acid. Swallowing improved but walking, sitting and speaking did not recover at six months. The uncontrolled course and uncertain molecular diagnosis do not establish efficacy or correction of heme A biosynthesis.
Show evidence (2 references)
PMID:38846886 SUPPORT Human Clinical
"the patient was administered an oral mitochondrial cocktail comprising daily doses of coenzyme-Q10, biotin, thiamine, riboflavin, pyridoxine, L-Carnitine, and folinic acid."
Records an empirical combination, not a validated COX10 therapy.
PMID:38846886 SUPPORT Human Clinical
"At the 6-month follow-up after admission, the patient’s food regurgitation had improved and she could swallow properly. However, her motor functions for walking, sitting, and speaking had not recovered."
The limited outcome does not establish treatment causality.
Seizure Management
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: levetiracetam CHEBI:6437 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses levetiracetam (CHEBI:6437). CHEBI:6437 is a therapeutic agent from Chemical Entities of Biological Interest. clobazam CHEBI:31413 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses clobazam (CHEBI:31413). CHEBI:31413 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Antiseizure treatment is individualized by a neurologist. Levetiracetam and clobazam were used for focal convulsions in the 2024 uncertain-genotype case, without evidence that these drugs modify COX10 disease.
Target Phenotypes: Focal seizures HP:0007359 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Focal seizures, annotated with Focal-onset seizure (HP:0007359). HP:0007359 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38846886 SUPPORT Human Clinical
"Additionally, she had experienced focal convulsions that were managed with 150 mg of levetiracetam and 10 mg of clobazam."
Records symptomatic seizure treatment in the candidate case.
Multisystem Surveillance
Platform: Other
Follow-up monitors neurologic, ophthalmologic, hearing, cardiac, renal, growth and hematologic involvement. GeneReviews suggests regular review, generally every 6-12 months, individualized to the manifestations and genotype.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/ SUPPORT BACKGROUND Other
"Affected individuals should be followed at regular intervals (typically every 6-12 months) to monitor progression of known manifestations and the appearance of new manifestations."
Broad nuclear LSS surveillance recommendation, not a COX10-specific natural-history estimate.
Genetic Counseling
Action: Genetic CounselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic Counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. NCIT:C15240
Platform: Other
Counsel families about autosomal recessive COX10 inheritance, carrier testing and reproductive options once familial pathogenic variants are established. When a contiguous deletion includes PMP22, counsel separately about the dominant neuropathy risk.
Show evidence (3 references)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/ SUPPORT BACKGROUND Other
"each sib of an ... has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic ... and a 25% chance of being unaffected and not a"
Autosomal recessive recurrence risks apply when both parents carry a pathogenic allele.
PMID:36176336 SUPPORT Human Clinical
"Genetic rearrangements resulting in HNPP deletion disrupted 1 copy of COX10 on the recombinant allele."
A deletion may carry different inheritance implications for the two neighboring genes.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/ SUPPORT BACKGROUND Other
"have been identified in an affected family member, prenatal and ... preimplantation genetic testing ... are possible."
Reproductive testing becomes possible after identifying the familial pathogenic variants.
Cardiac Management
Action: Supportive CareNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. NCIT:C15747
Platform: Other
Cardiomyopathy warrants cardiology-directed treatment for congestion or arrhythmia according to the individual findings. This is supportive management, not correction of COX10 or heme A synthesis.
Target Phenotypes: Hypertrophic cardiomyopathy HP:0001639 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Hypertrophic cardiomyopathy (HP:0001639). HP:0001639 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/ SUPPORT BACKGROUND Other
"Anticongestive therapy or antiarrhythmic therapy may be required ... treatment should be managed by a cardiologist."
General nuclear Leigh-spectrum guidance for cardiomyopathy applies to the cardiac phenotype, without COX10-specific efficacy data.
🔬

Diagnosis

3
Genomic sequencing with copy-number assessment
Establish biallelic pathogenic COX10 variants in a compatible phenotype, using a mitochondrial-disease panel or genomic sequencing and segregation studies. Include copy-number analysis: a COX10 partial deletion can be missed by sequence-only interpretation, particularly when PMP22-associated neuropathy coexists.
Show evidence (2 references)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/ SUPPORT BACKGROUND Other
"Molecular genetic testing approaches can include a combination of ... targeted testing ... comprehensive ... exome sequencing ... genome sequencing"
GeneReviews supports panel and genomic approaches for genetically heterogeneous LSS.
PMID:36176336 SUPPORT Human Clinical
"CNV analysis of COX10 revealed a decreased gene dosage, indicating the presence of a deletion in patients 1, 3, and 4"
Copy-number testing revealed the second COX10 lesion.
Respiratory-chain and assembly studies
Muscle or fibroblast enzymology, COX histochemistry and assembly studies can support pathogenicity, especially when variants remain uncertain. Reduced COX staining without ragged-red fibers is compatible with disease. A VUS pair alone does not confirm COX10 deficiency.
Show evidence (3 references)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/ SUPPORT BACKGROUND Other
"enzymatic testing of a muscle or skin biopsy may be necessary to confirm the pathogenicity of variants of ... uncertain significance ... identified by genomic testing"
Biochemical testing has a specific role when genomic evidence is uncertain.
PMID:36176336 SUPPORT Human Clinical
"Modified Gomori trichrome staining revealed no ragged-red fibers ... COX activity was found to be reduced in a widespread and severe manner"
Absence of ragged-red fibers does not exclude the COX defect.
PMID:15455402 SUPPORT In Vitro
"Two-dimensional gel electrophoresis showed a decrease of fully assembled COX without the accumulation of partially assembled COX subcomplexes."
Assembly studies distinguish reduced mature enzyme from intermediate accumulation.
CNS imaging and multisystem evaluation
MRI evaluates white-matter, brainstem and cerebellar involvement; clinical assessment also addresses hearing, cardiac, renal, hematologic and neuromuscular manifestations. Encephalopathy is one presentation rather than a prerequisite for all COX10 disease.
Show evidence (2 references)
PMID:36176336 SUPPORT Human Clinical
"Brain MRI revealed changes in cerebral white matter as well as multiple lesions in the brainstem and cerebellum."
Imaging documents the CNS phenotype.
PMID:24100867 SUPPORT Human Clinical
"We describe an adult patient with isolated COX deficiency associated with a relatively mild clinical phenotype comprising myopathy; demyelinating neuropathy; premature ovarian failure; short stature; hearing loss; pigmentary maculopathy; and renal tubular dysfunction."
The adult multisystem case broadens the diagnostic presentation.
🧫

Experimental Models

2
Patient Fibroblast COX10 Complementation PRIMARY_CELL_CULTURE
Patient-derived fibroblasts permit assessment of the complex IV assembly defect and rescue by wild-type COX10 expression. Complementation establishes gene causality in this model; it is not a clinical gene-therapy result.
Publication
PMID:15455402
Pathograph links
Reduced Complex IV Assembly recapitulates fidelity: high observes: molecular The patient-derived cellular system has reduced mature COX without accumulating assembly intermediates.
Limitations: Fibroblasts do not model the full brain, heart, renal or auditory phenotype.
Show evidence (1 reference)
PMID:15455402 SUPPORT In Vitro
"Two-dimensional gel electrophoresis showed a decrease of fully assembled COX without the accumulation of partially assembled COX subcomplexes."
Direct measurement of the assembly defect.
Show evidence (2 references)
PMID:15455402 SUPPORT In Vitro
"Overexpression of the COX10 protein in the patient's fibroblasts proved that the detected mutation was indeed the disease cause."
Restoration with COX10 demonstrates causality in patient cells.
PMID:12928484 SUPPORT In Vitro
"expression of COX10 from a retroviral vector complements the COX deficiency"
Earlier patient fibroblasts were also complemented with COX10.
Human COX10 Alleles in Yeast OTHER
Human reference COX10 and 25 variants were expressed in Saccharomyces cerevisiae lacking endogenous COX10. Eleven variants supported approximately half or more of reference COX activity and robust growth on a nonfermentable substrate; others had low activity and failed respiratory growth. Results inform variant function but do not by themselves classify human pathogenicity or prognosis.
Publication
PMID:39152498
Pathograph links
Reduced Terminal Electron Transfer recapitulates fidelity: moderate observes: molecular Variant-dependent COX enzyme activity and respiratory growth measure the consequences of COX10 dysfunction.
Limitations: Species context can alter activity. Asp336Val and Arg339Trp were nonfunctional in yeast despite the survival of a patient with that combination into adulthood.
Show evidence (1 reference)
PMID:39152498 SUPPORT Model Organism
"11 of these Cox10 variants supported approximately half or more the cytochrome c oxidase activity compared to the reference sequence. All of the strains containing those 11 variants also grew robustly using a nonfermentable carbon source."
The measured activity and growth outcomes.
Show evidence (1 reference)
PMID:39152498 SUPPORT Model Organism
"Despite the strong evolutionary conservation in oxidative phosphorylation mechanisms, it is possible that these variants will have a different level of activity in humans compared to yeast cells."
The authors explicitly identify the translational limitation.
{ }

Source YAML

click to show 
name: COX10-Related COX Deficiency
category: Mendelian
creation_date: '2026-05-30T00:00:00Z'
synonyms:
- COX10 deficiency
- Mitochondrial complex IV deficiency, nuclear type 3
- MC4DN3
- COX10-related cytochrome c oxidase deficiency
disease_term:
  preferred_term: COX10-related COX deficiency (MC4DN3)
  term:
    id: MONDO:0033635
    label: mitochondrial complex IV deficiency, nuclear type 3
parents:
- Mitochondrial Disease
- Inborn Error of Metabolism
description: COX10-related cytochrome c oxidase deficiency is an autosomal recessive mitochondrial disorder caused by biallelic pathogenic COX10 variants. COX10 is heme O synthase, an enzyme required for heme A biosynthesis and complex IV biogenesis, rather than a structural subunit of mature complex IV. Reported disease ranges from infantile Leigh syndrome or cardiomyopathy with anemia to childhood white-matter disease and a multisystem phenotype compatible with survival into adulthood. The severity of biochemical deficiency does not reliably predict clinical severity.
pathophysiology:
- name: COX10 Dysfunction
  biological_scale: MOLECULAR
  description: Biallelic pathogenic missense, initiation-codon or partial-deletion alleles impair COX10 function. Different variants require individual evaluation; sequence prediction alone does not establish loss of function.
  genes:
  - preferred_term: COX10
    term:
      id: hgnc:2260
      label: COX10
  evidence:
  - reference: PMID:10767350
    reference_title: A mutation in the human heme A:farnesyltransferase gene (COX10 ) causes cytochrome c oxidase deficiency.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: complementation study in yeast permitted us to ascribe the COX deficiency to a homozygous missense mutation in the COX10 gene.
    explanation: Yeast complementation supports the functional consequence of the familial mutation.
  - reference: PMID:15455402
    reference_title: Cytochrome c oxidase biogenesis in a patient with a mutation in COX10 gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We report a cytochrome c oxidase (COX)-deficient patient, clinically affected with Leigh-like disease, with a homozygous mutation in the COX10 start codon.
    explanation: Initiation-codon disruption is another established allelic class.
  - reference: PMID:10767350
    reference_title: A mutation in the human heme A:farnesyltransferase gene (COX10 ) causes cytochrome c oxidase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We report here a genetic linkage study of a consanguineous family with an isolated COX defect and subsequent identification of a mutation in a third nuclear gene causing a deficiency of the enzyme.
    explanation: The human linkage component identified the familial COX10 disorder; functional complementation is cited separately.
  downstream:
  - target: Deficient Heme A Biosynthesis
    causal_link_type: DIRECT
    description: Impaired heme O synthase reduces production of the precursor required for heme A.
    evidence:
    - reference: PMID:12928484
      reference_title: Mutations in COX10 result in a defect in mitochondrial heme A biosynthesis and account for multiple, early-onset clinical phenotypes associated with isolated COX deficiency.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: COX10 functions in the first step of the mitochondrial heme A biosynthetic pathway, catalyzing the conversion of protoheme (heme B) to heme O via the farnesylation of a vinyl group at position C2.
      explanation: COX10 catalyzes the first biosynthetic step.
      quote_role: BACKGROUND
  molecular_functions:
  - preferred_term: protoheme IX farnesyltransferase activity
    term:
      id: GO:0008495
      label: protoheme IX farnesyltransferase activity
    modifier: DECREASED
- name: Deficient Heme A Biosynthesis
  biological_scale: MOLECULAR
  description: Deficient conversion of heme B to heme O limits heme A availability. Reduced heme A was measured in patient muscle and fibroblast mitochondria.
  biological_processes:
  - preferred_term: heme A biosynthetic process
    term:
      id: GO:0006784
      label: heme A biosynthetic process
    modifier: DECREASED
  evidence:
  - reference: PMID:12928484
    reference_title: Mutations in COX10 result in a defect in mitochondrial heme A biosynthesis and account for multiple, early-onset clinical phenotypes associated with isolated COX deficiency.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Heme A content was reduced in mitochondria from patient muscle and fibroblasts in proportion to the reduction in COX enzyme activity and the amount of fully assembled enzyme.
    explanation: Heme A depletion tracks the biochemical COX defect in patient tissue and cultures.
  downstream:
  - target: Reduced Complex IV Assembly
    causal_link_type: DIRECT
    description: Limited heme A availability impairs maturation of the heme-containing COX complex.
    evidence:
    - reference: PMID:12928484
      reference_title: Mutations in COX10 result in a defect in mitochondrial heme A biosynthesis and account for multiple, early-onset clinical phenotypes associated with isolated COX deficiency.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Heme A content was reduced in mitochondria from patient muscle and fibroblasts in proportion to the reduction in COX enzyme activity and the amount of fully assembled enzyme.
      explanation: The study links lower heme A with less assembled COX.
- name: Reduced Complex IV Assembly
  biological_scale: MOLECULAR
  conforms_to: complex_iv_assembly_deficiency#Complex IV Biogenesis Failure
  description: Patients have reduced fully assembled cytochrome c oxidase and reduced core subunits. The start-codon case and the adult missense case lacked accumulation of the partially assembled intermediates seen with some other COX assembly defects.
  biological_processes:
  - preferred_term: mitochondrial respiratory chain complex IV assembly
    term:
      id: GO:0033617
      label: mitochondrial respiratory chain complex IV assembly
    modifier: DECREASED
  evidence:
  - reference: PMID:15455402
    reference_title: Cytochrome c oxidase biogenesis in a patient with a mutation in COX10 gene.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Two-dimensional gel electrophoresis showed a decrease of fully assembled COX without the accumulation of partially assembled COX subcomplexes.
    explanation: The assembly defect is demonstrated directly.
  - reference: PMID:24100867
    reference_title: COX10 mutations resulting in complex multisystem mitochondrial disease that remains stable into adulthood.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Muscle COX holoenzyme and subassemblies were undetectable on immunoblots of blue-native gels, whereas denaturing gels and immunocytochemistry showed reduced core subunit MTCO1.
    explanation: The adult phenotype also has an early COX assembly defect.
  downstream:
  - target: Reduced Terminal Electron Transfer
    causal_link_type: DIRECT
    description: Reduced functional COX lowers capacity for electron transfer from cytochrome c to oxygen.
    evidence:
    - reference: PMID:12928484
      reference_title: Mutations in COX10 result in a defect in mitochondrial heme A biosynthesis and account for multiple, early-onset clinical phenotypes associated with isolated COX deficiency.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Heme A content was reduced in mitochondria from patient muscle and fibroblasts in proportion to the reduction in COX enzyme activity and the amount of fully assembled enzyme.
      explanation: Less assembled enzyme accompanies lower enzyme activity.
- name: Reduced Terminal Electron Transfer
  biological_scale: MOLECULAR
  description: Reduced complex IV activity limits terminal respiratory-chain capacity. This is a reduction in respiratory reserve, not evidence that electron transfer or ATP generation is completely absent in every patient.
  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
  evidence:
  - reference: PMID:36176336
    reference_title: Biallelic COX10 Mutations and PMP22 Deletion in a Family With Leigh Syndrome and Hereditary Neuropathy With Liability to Pressure Palsy.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: The enzyme activity in fibroblast revealed a selective decrease in complex IV
    explanation: Patient fibroblasts show an isolated complex IV defect.
  - reference: PMID:39152498
    reference_title: Phenotypic assessment of Cox10 variants and their implications for Leigh Syndrome.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Cells expressing the other variants showed low cytochrome c oxidase activity and failed to grow on nonfermentable media.
    explanation: Human COX10 variants can reduce COX activity and respiratory growth in yeast.
  downstream:
  - target: Impaired Oxidative Energy Production
    causal_link_type: DIRECT
    description: Reduced COX-dependent proton translocation can restrict oxidative ATP production.
- name: Impaired Oxidative Energy Production
  biological_scale: CELLULAR
  description: Reduced respiratory capacity can limit oxidative energy generation and increase vulnerability to metabolic stress. The clinical expression is variable; neither uniform ATP collapse nor an invariant sequence of organ injury has been established.
  biological_processes:
  - preferred_term: mitochondrial ATP synthesis coupled electron transport
    term:
      id: GO:0042775
      label: mitochondrial ATP synthesis coupled electron transport
    modifier: DECREASED
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/
    reference_title: Nuclear Gene-Encoded Leigh Syndrome Spectrum Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: a continuum of progressive neurodegenerative disorders caused by abnormalities of mitochondrial energy generation
    explanation: General Leigh-spectrum mechanism applicable to the COX10-associated encephalopathic presentation.
    quote_role: BACKGROUND
  downstream:
  - target: White Matter Injury
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Mitochondrial dysfunction is associated with destructive white-matter lesions in COX10-associated Leigh disease; the intervening cellular sequence is unresolved.
    evidence:
    - reference: PMID:36176336
      reference_title: Biallelic COX10 Mutations and PMP22 Deletion in a Family With Leigh Syndrome and Hereditary Neuropathy With Liability to Pressure Palsy.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: An enzyme activity analysis revealed that mitochondrial respiratory chain complex IV deficiency is the cause of Leigh syndrome in this family
      explanation: The authors connect the COX defect with the Leigh syndrome that included destructive white-matter pathology. This is clinical-mechanistic inference; ATP failure and the intervening cellular injury sequence were not measured directly.
  - target: Myopathy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Respiratory-chain dysfunction contributes to muscle disease.
    evidence:
    - reference: PMID:24100867
      reference_title: COX10 mutations resulting in complex multisystem mitochondrial disease that remains stable into adulthood.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: We describe an adult patient with isolated COX deficiency associated with a relatively mild clinical phenotype comprising myopathy; demyelinating neuropathy; premature ovarian failure; short stature; hearing loss; pigmentary maculopathy; and renal tubular dysfunction.
      explanation: Myopathy accompanies confirmed COX10-associated biochemical deficiency.
  - target: Hypertrophic cardiomyopathy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Cardiac involvement can accompany COX10 deficiency.
    evidence:
    - reference: PMID:12928484
      reference_title: Mutations in COX10 result in a defect in mitochondrial heme A biosynthesis and account for multiple, early-onset clinical phenotypes associated with isolated COX deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: in a patient with anemia and Leigh Syndrome, and in a patient with anemia, sensorineural deafness and fatal infantile hypertrophic cardiomyopathy.
      explanation: The rescued patient-cell defect came from an infant with hypertrophic cardiomyopathy.
  - target: Renal tubular dysfunction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Mitochondrial dysfunction can affect renal tubular function.
    evidence:
    - reference: PMID:24100867
      reference_title: COX10 mutations resulting in complex multisystem mitochondrial disease that remains stable into adulthood.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: We describe an adult patient with isolated COX deficiency associated with a relatively mild clinical phenotype comprising myopathy; demyelinating neuropathy; premature ovarian failure; short stature; hearing loss; pigmentary maculopathy; and renal tubular dysfunction.
      explanation: Renal tubular disease is part of the adult multisystem phenotype.
  - target: Lactic acidosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Impaired oxidative metabolism can favor lactate accumulation; lactic acidosis is not demonstrated in every genotype-confirmed case.
    evidence:
    - reference: PMID:38846886
      reference_title: 'Complex mitochondrial disease caused by the mutation of COX10 in a toddler: a case-report study.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Her laboratory data revealed lactic acidosis and her brain MRI manifested diffuse leukodystrophy
      explanation: Observed in a reported COX10 candidate case with two VUS; attribution is provisional.
      directness: INDIRECT
- name: White Matter Injury
  biological_scale: TISSUE
  description: COX10-associated Leigh disease can involve diffuse white-matter degeneration with myelin and axonal loss, neuropil vacuolation and gliosis. These tissue findings do not establish a specific primary oligodendrocyte defect.
  evidence:
  - reference: PMID:36176336
    reference_title: Biallelic COX10 Mutations and PMP22 Deletion in a Family With Leigh Syndrome and Hereditary Neuropathy With Liability to Pressure Palsy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The brain showed diffuse and severe white matter degeneration
    explanation: Postmortem pathology in an affected member of the COX10/PMP22 family.
  - reference: PMID:36176336
    reference_title: Biallelic COX10 Mutations and PMP22 Deletion in a Family With Leigh Syndrome and Hereditary Neuropathy With Liability to Pressure Palsy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The loss of myelin and axons appeared to be similar in extent in the degenerated white matter
    explanation: Both myelin and axons were affected; this does not prove that one lesion initiates the other.
  downstream:
  - target: Leukodystrophy
    causal_link_type: DIRECT
    description: White-matter degeneration underlies the leukodystrophic presentation.
  - target: Encephalopathy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Diffuse CNS injury contributes to progressive neurologic dysfunction.
  - target: Spastic paraplegia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: White-matter tract injury can contribute to pyramidal motor dysfunction.
  - target: Intellectual disability
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: CNS involvement can impair cognition and development.
  - target: Cerebellar ataxia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Cerebellar and connecting white-matter injury can contribute to ataxia.
phenotypes:
- name: Encephalopathy
  description: Leigh-spectrum encephalopathy is one COX10 presentation; it is not obligatory in the adult myopathic phenotype.
  phenotype_term:
    preferred_term: Encephalopathy
    term:
      id: HP:0001298
      label: Encephalopathy
  evidence:
  - reference: PMID:36176336
    reference_title: Biallelic COX10 Mutations and PMP22 Deletion in a Family With Leigh Syndrome and Hereditary Neuropathy With Liability to Pressure Palsy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Leigh encephalopathy was diagnosed neuropathologically. Brain MRI revealed changes in cerebral white matter as well as multiple lesions in the brainstem and cerebellum.
    explanation: Neuropathology and neuroimaging establish CNS involvement in this family.
  - reference: PMID:12928484
    reference_title: Mutations in COX10 result in a defect in mitochondrial heme A biosynthesis and account for multiple, early-onset clinical phenotypes associated with isolated COX deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: in a patient with anemia and Leigh Syndrome, and in a patient with anemia, sensorineural deafness and fatal infantile hypertrophic cardiomyopathy.
    explanation: An independent infant had anemia and Leigh syndrome.
- name: Leukodystrophy
  description: Diffuse cerebral white-matter disease has been reported in COX10-associated disease.
  phenotype_term:
    preferred_term: Leukodystrophy
    term:
      id: HP:0002415
      label: Leukodystrophy
  evidence:
  - reference: PMID:12928484
    reference_title: Mutations in COX10 result in a defect in mitochondrial heme A biosynthesis and account for multiple, early-onset clinical phenotypes associated with isolated COX deficiency.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Mutations in COX10 have previously been reported in a single family with tubulopathy and leukodystrophy.
    explanation: The founding COX10 family had leukodystrophy.
    quote_role: BACKGROUND
  - reference: PMID:36176336
    reference_title: Biallelic COX10 Mutations and PMP22 Deletion in a Family With Leigh Syndrome and Hereditary Neuropathy With Liability to Pressure Palsy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The brain showed diffuse and severe white matter degeneration
    explanation: Primary pathology supports white-matter involvement.
- name: Spastic paraplegia
  description: Childhood-onset spastic paraplegia was reported in three affected siblings.
  phenotype_term:
    preferred_term: Spastic paraplegia
    term:
      id: HP:0001258
      label: Spastic paraplegia
  evidence:
  - reference: PMID:36176336
    reference_title: Biallelic COX10 Mutations and PMP22 Deletion in a Family With Leigh Syndrome and Hereditary Neuropathy With Liability to Pressure Palsy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The proband and her 2 siblings developed spastic paraplegia and mental retardation during childhood.
    explanation: The sibling observation supports childhood pyramidal and cognitive involvement, not a population frequency.
- name: Intellectual disability
  description: Intellectual disability accompanied the childhood spastic-paraplegia presentation; severity was not specified uniformly.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:36176336
    reference_title: Biallelic COX10 Mutations and PMP22 Deletion in a Family With Leigh Syndrome and Hereditary Neuropathy With Liability to Pressure Palsy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Patients 1 (III-1, eFigure 1, links.lww.com/NXG/A545) and 3 (III-3) presented with spastic paraplegia, intellectual disability, cerebellar ataxia, and respiratory failure.
    explanation: Intellectual disability is explicitly reported.
- name: Cerebellar ataxia
  description: Cerebellar ataxia was documented in two detailed affected members of the COX10/PMP22 family.
  phenotype_term:
    preferred_term: Cerebellar ataxia
    term:
      id: HP:0001251
      label: Ataxia
  evidence:
  - reference: PMID:36176336
    reference_title: Biallelic COX10 Mutations and PMP22 Deletion in a Family With Leigh Syndrome and Hereditary Neuropathy With Liability to Pressure Palsy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Patients 1 (III-1, eFigure 1, links.lww.com/NXG/A545) and 3 (III-3) presented with spastic paraplegia, intellectual disability, cerebellar ataxia, and respiratory failure.
    explanation: The primary clinical description reports cerebellar ataxia.
- name: Respiratory insufficiency
  description: Respiratory failure can complicate the encephalopathic presentation.
  phenotype_term:
    preferred_term: Respiratory insufficiency
    term:
      id: HP:0002093
      label: Respiratory insufficiency
  evidence:
  - reference: PMID:36176336
    reference_title: Biallelic COX10 Mutations and PMP22 Deletion in a Family With Leigh Syndrome and Hereditary Neuropathy With Liability to Pressure Palsy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Patients 1 (III-1, eFigure 1, links.lww.com/NXG/A545) and 3 (III-3) presented with spastic paraplegia, intellectual disability, cerebellar ataxia, and respiratory failure.
    explanation: Respiratory failure occurred in two affected family members.
- name: Myopathy
  description: Myopathy is documented in a genetically and biochemically established adult phenotype.
  phenotype_term:
    preferred_term: Myopathy
    term:
      id: HP:0003198
      label: Myopathy
  evidence:
  - reference: PMID:24100867
    reference_title: COX10 mutations resulting in complex multisystem mitochondrial disease that remains stable into adulthood.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We describe an adult patient with isolated COX deficiency associated with a relatively mild clinical phenotype comprising myopathy; demyelinating neuropathy; premature ovarian failure; short stature; hearing loss; pigmentary maculopathy; and renal tubular dysfunction.
    explanation: The adult report demonstrates muscle involvement without requiring Leigh encephalopathy.
- name: Muscle weakness
  description: Muscle weakness was a presenting symptom in a three-year-old with candidate COX10 variants. Both reported variants were VUS without direct functional confirmation, so this case is provisional evidence.
  phenotype_term:
    preferred_term: Muscle weakness
    term:
      id: HP:0001324
      label: Muscle weakness
  evidence:
  - reference: PMID:38846886
    reference_title: 'Complex mitochondrial disease caused by the mutation of COX10 in a toddler: a case-report study.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: A 3-year-old girl was admitted due to muscle weakness and a decline in developmental milestones 7 days after a significant stressor.
    explanation: The clinical observation is direct; its attribution to COX10 remains uncertain.
    directness: INDIRECT
- name: Developmental regression
  description: Acute regression after illness was reported in the toddler with uncertain COX10 variants. General nuclear Leigh-spectrum guidance describes metabolic-stress-associated regression, without establishing a COX10-specific frequency or age distribution.
  phenotype_term:
    preferred_term: Developmental regression
    term:
      id: HP:0002376
      label: Developmental regression
  evidence:
  - reference: PMID:38846886
    reference_title: 'Complex mitochondrial disease caused by the mutation of COX10 in a toddler: a case-report study.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Seven days after the infection, she lost the ability to walk and speak.
    explanation: Reported loss of skills in the candidate case.
    directness: INDIRECT
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/
    reference_title: Nuclear Gene-Encoded Leigh Syndrome Spectrum Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: typically in infancy or early childhood with sudden neurodevelopmental regression
    explanation: Clinical-characteristics background for nuclear Leigh spectrum; not a COX10-specific onset estimate.
    quote_role: BACKGROUND
- name: Lactic acidosis
  description: Lactic acidosis was recorded in the 2024 candidate case; confirmation of its COX10 attribution requires functional or stronger variant evidence.
  phenotype_term:
    preferred_term: Lactic acidosis
    term:
      id: HP:0003128
      label: Lactic acidosis
  evidence:
  - reference: PMID:38846886
    reference_title: 'Complex mitochondrial disease caused by the mutation of COX10 in a toddler: a case-report study.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Her laboratory data revealed lactic acidosis and her brain MRI manifested diffuse leukodystrophy
    explanation: The report documents the metabolic finding but leaves two COX10 variants classified as VUS.
    directness: INDIRECT
- name: Hypertrophic cardiomyopathy
  description: Infantile hypertrophic cardiomyopathy may be severe and fatal; it also occurred in the anemia and renal-tubular-acidosis case.
  phenotype_term:
    preferred_term: Hypertrophic cardiomyopathy
    term:
      id: HP:0001639
      label: Hypertrophic cardiomyopathy
  evidence:
  - reference: PMID:12928484
    reference_title: Mutations in COX10 result in a defect in mitochondrial heme A biosynthesis and account for multiple, early-onset clinical phenotypes associated with isolated COX deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: in a patient with anemia and Leigh Syndrome, and in a patient with anemia, sensorineural deafness and fatal infantile hypertrophic cardiomyopathy.
    explanation: One of the functionally complemented patients had fatal infantile hypertrophic cardiomyopathy.
  - reference: PMID:30588737
    reference_title: Sideroblastic anemia associated with multisystem mitochondrial disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In addition, anemia without ring sideroblasts was found in three other patients with mitochondrial disorders, including two children with later onset of PS and one child with failure to thrive, microcephaly, developmental delay, hypertrophic cardiomyopathy, and renal tubular acidosis due to the heterozygous mutations c.610A>G (p.Asn204Asp) and c.674C>T (p.Pro225Leu) in the COX10 gene encoding the cytochrome c oxidase assembly factor.
    explanation: A separate COX10 patient had hypertrophic cardiomyopathy.
- name: Anemia
  description: Anemia accompanies some severe multisystem presentations. The COX10 child in the 2019 mitochondrial-anemia study had no ring sideroblasts; the sideroblastic findings in that study belonged to other diagnoses.
  phenotype_term:
    preferred_term: Anemia
    term:
      id: HP:0001903
      label: Anemia
  evidence:
  - reference: PMID:12928484
    reference_title: Mutations in COX10 result in a defect in mitochondrial heme A biosynthesis and account for multiple, early-onset clinical phenotypes associated with isolated COX deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: in a patient with anemia and Leigh Syndrome, and in a patient with anemia, sensorineural deafness and fatal infantile hypertrophic cardiomyopathy.
    explanation: Both newly described COX10 patients had anemia.
  - reference: PMID:30588737
    reference_title: Sideroblastic anemia associated with multisystem mitochondrial disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In addition, anemia without ring sideroblasts was found in three other patients with mitochondrial disorders, including two children with later onset of PS and one child with failure to thrive, microcephaly, developmental delay, hypertrophic cardiomyopathy, and renal tubular acidosis due to the heterozygous mutations c.610A>G (p.Asn204Asp) and c.674C>T (p.Pro225Leu) in the COX10 gene encoding the cytochrome c oxidase assembly factor.
    explanation: This is evidence for anemia without ring sideroblasts, not sideroblastic anemia.
- name: Sensorineural hearing impairment
  description: Sensorineural deafness was reported in a functionally confirmed infant; hearing loss was also present in the adult multisystem case.
  phenotype_term:
    preferred_term: Sensorineural hearing impairment
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
  evidence:
  - reference: PMID:12928484
    reference_title: Mutations in COX10 result in a defect in mitochondrial heme A biosynthesis and account for multiple, early-onset clinical phenotypes associated with isolated COX deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: in a patient with anemia and Leigh Syndrome, and in a patient with anemia, sensorineural deafness and fatal infantile hypertrophic cardiomyopathy.
    explanation: The infant with cardiomyopathy had sensorineural deafness.
  - reference: PMID:24100867
    reference_title: COX10 mutations resulting in complex multisystem mitochondrial disease that remains stable into adulthood.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We describe an adult patient with isolated COX deficiency associated with a relatively mild clinical phenotype comprising myopathy; demyelinating neuropathy; premature ovarian failure; short stature; hearing loss; pigmentary maculopathy; and renal tubular dysfunction.
    explanation: Hearing loss was part of the adult phenotype.
- name: Renal tubular dysfunction
  description: Renal tubular dysfunction occurs in the multisystem spectrum.
  phenotype_term:
    preferred_term: Renal tubular dysfunction
    term:
      id: HP:0000124
      label: Renal tubular dysfunction
  evidence:
  - reference: PMID:24100867
    reference_title: COX10 mutations resulting in complex multisystem mitochondrial disease that remains stable into adulthood.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We describe an adult patient with isolated COX deficiency associated with a relatively mild clinical phenotype comprising myopathy; demyelinating neuropathy; premature ovarian failure; short stature; hearing loss; pigmentary maculopathy; and renal tubular dysfunction.
    explanation: The adult case had renal tubular dysfunction.
  - reference: PMID:12928484
    reference_title: Mutations in COX10 result in a defect in mitochondrial heme A biosynthesis and account for multiple, early-onset clinical phenotypes associated with isolated COX deficiency.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Mutations in COX10 have previously been reported in a single family with tubulopathy and leukodystrophy.
    explanation: Earlier COX10-associated tubulopathy.
    quote_role: BACKGROUND
- name: Renal tubular acidosis
  description: Renal tubular acidosis was reported in the COX10 patient with anemia, cardiomyopathy and growth/developmental abnormalities.
  phenotype_term:
    preferred_term: Renal tubular acidosis
    term:
      id: HP:0001947
      label: Renal tubular acidosis
  evidence:
  - reference: PMID:30588737
    reference_title: Sideroblastic anemia associated with multisystem mitochondrial disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In addition, anemia without ring sideroblasts was found in three other patients with mitochondrial disorders, including two children with later onset of PS and one child with failure to thrive, microcephaly, developmental delay, hypertrophic cardiomyopathy, and renal tubular acidosis due to the heterozygous mutations c.610A>G (p.Asn204Asp) and c.674C>T (p.Pro225Leu) in the COX10 gene encoding the cytochrome c oxidase assembly factor.
    explanation: The finding is specifically assigned to the COX10 patient.
- name: Global developmental delay
  description: Developmental delay was reported in the anemia and cardiomyopathy case; domain-specific testing was not detailed in the abstract.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:30588737
    reference_title: Sideroblastic anemia associated with multisystem mitochondrial disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In addition, anemia without ring sideroblasts was found in three other patients with mitochondrial disorders, including two children with later onset of PS and one child with failure to thrive, microcephaly, developmental delay, hypertrophic cardiomyopathy, and renal tubular acidosis due to the heterozygous mutations c.610A>G (p.Asn204Asp) and c.674C>T (p.Pro225Leu) in the COX10 gene encoding the cytochrome c oxidase assembly factor.
    explanation: Developmental delay is reported without an individual-domain breakdown.
- name: Microcephaly
  description: Microcephaly was reported in one multisystem COX10 case.
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  evidence:
  - reference: PMID:30588737
    reference_title: Sideroblastic anemia associated with multisystem mitochondrial disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In addition, anemia without ring sideroblasts was found in three other patients with mitochondrial disorders, including two children with later onset of PS and one child with failure to thrive, microcephaly, developmental delay, hypertrophic cardiomyopathy, and renal tubular acidosis due to the heterozygous mutations c.610A>G (p.Asn204Asp) and c.674C>T (p.Pro225Leu) in the COX10 gene encoding the cytochrome c oxidase assembly factor.
    explanation: The primary abstract explicitly reports microcephaly.
- name: Failure to thrive
  description: Failure to thrive accompanied one severe multisystem presentation.
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: PMID:30588737
    reference_title: Sideroblastic anemia associated with multisystem mitochondrial disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In addition, anemia without ring sideroblasts was found in three other patients with mitochondrial disorders, including two children with later onset of PS and one child with failure to thrive, microcephaly, developmental delay, hypertrophic cardiomyopathy, and renal tubular acidosis due to the heterozygous mutations c.610A>G (p.Asn204Asp) and c.674C>T (p.Pro225Leu) in the COX10 gene encoding the cytochrome c oxidase assembly factor.
    explanation: The primary abstract reports impaired growth.
- name: Demyelinating peripheral neuropathy
  description: Demyelinating neuropathy occurred in the confirmed adult COX10 case. Neuropathy in the separate 2022 family cosegregated with PMP22 deletion and is not independent evidence for this COX10 phenotype.
  phenotype_term:
    preferred_term: Demyelinating peripheral neuropathy
    term:
      id: HP:0007108
      label: Demyelinating peripheral neuropathy
  evidence:
  - reference: PMID:24100867
    reference_title: COX10 mutations resulting in complex multisystem mitochondrial disease that remains stable into adulthood.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We describe an adult patient with isolated COX deficiency associated with a relatively mild clinical phenotype comprising myopathy; demyelinating neuropathy; premature ovarian failure; short stature; hearing loss; pigmentary maculopathy; and renal tubular dysfunction.
    explanation: The adult case supports this association independently of the later contiguous-deletion family.
- name: Premature ovarian insufficiency
  description: Premature ovarian failure was reported in the adult multisystem case; penetrance is unknown.
  phenotype_term:
    preferred_term: Premature ovarian insufficiency
    term:
      id: HP:0008209
      label: Premature ovarian insufficiency
  evidence:
  - reference: PMID:24100867
    reference_title: COX10 mutations resulting in complex multisystem mitochondrial disease that remains stable into adulthood.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We describe an adult patient with isolated COX deficiency associated with a relatively mild clinical phenotype comprising myopathy; demyelinating neuropathy; premature ovarian failure; short stature; hearing loss; pigmentary maculopathy; and renal tubular dysfunction.
    explanation: One adult case establishes occurrence, not a general frequency.
- name: Short stature
  description: Short stature was reported in the adult multisystem case.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:24100867
    reference_title: COX10 mutations resulting in complex multisystem mitochondrial disease that remains stable into adulthood.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We describe an adult patient with isolated COX deficiency associated with a relatively mild clinical phenotype comprising myopathy; demyelinating neuropathy; premature ovarian failure; short stature; hearing loss; pigmentary maculopathy; and renal tubular dysfunction.
    explanation: The adult case had short stature.
- name: Pigmentary maculopathy
  description: Pigmentary maculopathy was reported in the adult COX10 case; the evidence does not establish generalized retinitis pigmentosa.
  phenotype_term:
    preferred_term: Pigmentary maculopathy
    term:
      id: HP:0008002
      label: Abnormal macular pigmentation
  evidence:
  - reference: PMID:24100867
    reference_title: COX10 mutations resulting in complex multisystem mitochondrial disease that remains stable into adulthood.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We describe an adult patient with isolated COX deficiency associated with a relatively mild clinical phenotype comprising myopathy; demyelinating neuropathy; premature ovarian failure; short stature; hearing loss; pigmentary maculopathy; and renal tubular dysfunction.
    explanation: The adult report describes macular pigmentary disease.
- name: Focal seizures
  description: Focal convulsions developed during follow-up of the toddler with two uncertain COX10 variants; this is provisional disease-association evidence.
  phenotype_term:
    preferred_term: Focal seizures
    term:
      id: HP:0007359
      label: Focal-onset seizure
  evidence:
  - reference: PMID:38846886
    reference_title: 'Complex mitochondrial disease caused by the mutation of COX10 in a toddler: a case-report study.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Additionally, she had experienced focal convulsions that were managed with 150 mg of levetiracetam and 10 mg of clobazam.
    explanation: The seizure observation is reported, while COX10 causality remains unconfirmed.
    directness: INDIRECT
inheritance:
- name: Autosomal recessive
  description: Biallelic pathogenic COX10 variants cause disease. For a couple confirmed to carry one disease-causing allele each, the recurrence risk follows autosomal recessive inheritance. A contiguous deletion involving PMP22 adds a separate dominant neuropathy risk.
  evidence:
  - reference: PMID:36176336
    reference_title: Biallelic COX10 Mutations and PMP22 Deletion in a Family With Leigh Syndrome and Hereditary Neuropathy With Liability to Pressure Palsy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: caused by biallelic COX10 mutations coexisting with HNPP caused by heterozygous PMP22 deletion
    explanation: Separates recessive COX10 disease from dominant PMP22-associated HNPP.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/
    reference_title: Nuclear Gene-Encoded Leigh Syndrome Spectrum Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: each sib of an ... has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic ... and a 25% chance of being unaffected and not a
    explanation: GeneReviews gives 25% affected, 50% carrier and 25% noncarrier risks when both parents carry a pathogenic allele in the same recessive LSS gene.
    quote_role: BACKGROUND
genetic:
- name: COX10 pathogenic alleles and uncertain variants
  gene_term:
    preferred_term: COX10
    term:
      id: hgnc:2260
      label: COX10
  inheritance:
  - name: Autosomal recessive
  features: 'Established disease-associated alleles include missense variants, a homozygous initiation-codon alteration and a partial COX10 deletion in trans with p.Pro295Leu. The adult p.Asp336Val/p.Arg339Trp combination demonstrates that severe yeast respiratory defects do not imply inevitable infantile death. The 2024 p.Thr377Ile/p.Thr14Ile report remains uncertain: both substitutions were homozygous and classified as VUS, with functional studies proposed rather than performed. No specific modifier gene is established.'
  evidence:
  - reference: PMID:12928484
    reference_title: Mutations in COX10 result in a defect in mitochondrial heme A biosynthesis and account for multiple, early-onset clinical phenotypes associated with isolated COX deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Mutation analysis of COX10 identified four different missense alleles, predicting amino acid substitutions at evolutionarily conserved residues.
    explanation: The founding functional series included missense alleles.
  - reference: PMID:15455402
    reference_title: Cytochrome c oxidase biogenesis in a patient with a mutation in COX10 gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We report a cytochrome c oxidase (COX)-deficient patient, clinically affected with Leigh-like disease, with a homozygous mutation in the COX10 start codon.
    explanation: Start-codon alteration is supported by complementation.
  - reference: PMID:36176336
    reference_title: Biallelic COX10 Mutations and PMP22 Deletion in a Family With Leigh Syndrome and Hereditary Neuropathy With Liability to Pressure Palsy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: most likely caused by biallelic COX10 mutations composed of novel missense mutation and partial deletion
    explanation: The deletion affects part of COX10, not necessarily the entire gene.
  - reference: PMID:24100867
    reference_title: COX10 mutations resulting in complex multisystem mitochondrial disease that remains stable into adulthood.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Whole-exome sequencing detected 1 known pathogenic and 1 novel COX10 mutation: c.1007A>T; p.Asp336Val, previously associated with fatal infantile COX deficiency, and c.1015C>T; p.Arg339Trp.'
    explanation: The adult case expands the genotype-phenotype spectrum.
  - reference: PMID:38846886
    reference_title: 'Complex mitochondrial disease caused by the mutation of COX10 in a toddler: a case-report study.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Based on American College of Medical Genetics (ACMG) classification, this variant is considered a variant of uncertain significance (VUS) leaning pathogenic variant.
    explanation: The authors retain VUS status for Thr377Ile.
  - reference: PMID:38846886
    reference_title: 'Complex mitochondrial disease caused by the mutation of COX10 in a toddler: a case-report study.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: another homozygous missense variant with a lower pathogenicity score was found in this patient’s data (COX10:c.41C>T; p.Thr14Ile). According to ACMG classification, this variant is a VUS.
    explanation: Thr14Ile is also a VUS; it is not an established modifier.
diagnosis:
- name: Genomic sequencing with copy-number assessment
  description: 'Establish biallelic pathogenic COX10 variants in a compatible phenotype, using a mitochondrial-disease panel or genomic sequencing and segregation studies. Include copy-number analysis: a COX10 partial deletion can be missed by sequence-only interpretation, particularly when PMP22-associated neuropathy coexists.'
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/
    reference_title: Nuclear Gene-Encoded Leigh Syndrome Spectrum Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Molecular genetic testing approaches can include a combination of ... targeted testing ... comprehensive ... exome sequencing ... genome sequencing
    explanation: GeneReviews supports panel and genomic approaches for genetically heterogeneous LSS.
    quote_role: BACKGROUND
  - reference: PMID:36176336
    reference_title: Biallelic COX10 Mutations and PMP22 Deletion in a Family With Leigh Syndrome and Hereditary Neuropathy With Liability to Pressure Palsy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: CNV analysis of COX10 revealed a decreased gene dosage, indicating the presence of a deletion in patients 1, 3, and 4
    explanation: Copy-number testing revealed the second COX10 lesion.
- name: Respiratory-chain and assembly studies
  description: Muscle or fibroblast enzymology, COX histochemistry and assembly studies can support pathogenicity, especially when variants remain uncertain. Reduced COX staining without ragged-red fibers is compatible with disease. A VUS pair alone does not confirm COX10 deficiency.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/
    reference_title: Nuclear Gene-Encoded Leigh Syndrome Spectrum Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: enzymatic testing of a muscle or skin biopsy may be necessary to confirm the pathogenicity of variants of ... uncertain significance ... identified by genomic testing
    explanation: Biochemical testing has a specific role when genomic evidence is uncertain.
    quote_role: BACKGROUND
  - reference: PMID:36176336
    reference_title: Biallelic COX10 Mutations and PMP22 Deletion in a Family With Leigh Syndrome and Hereditary Neuropathy With Liability to Pressure Palsy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Modified Gomori trichrome staining revealed no ragged-red fibers ... COX activity was found to be reduced in a widespread and severe manner
    explanation: Absence of ragged-red fibers does not exclude the COX defect.
  - reference: PMID:15455402
    reference_title: Cytochrome c oxidase biogenesis in a patient with a mutation in COX10 gene.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Two-dimensional gel electrophoresis showed a decrease of fully assembled COX without the accumulation of partially assembled COX subcomplexes.
    explanation: Assembly studies distinguish reduced mature enzyme from intermediate accumulation.
- name: CNS imaging and multisystem evaluation
  description: MRI evaluates white-matter, brainstem and cerebellar involvement; clinical assessment also addresses hearing, cardiac, renal, hematologic and neuromuscular manifestations. Encephalopathy is one presentation rather than a prerequisite for all COX10 disease.
  evidence:
  - reference: PMID:36176336
    reference_title: Biallelic COX10 Mutations and PMP22 Deletion in a Family With Leigh Syndrome and Hereditary Neuropathy With Liability to Pressure Palsy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Brain MRI revealed changes in cerebral white matter as well as multiple lesions in the brainstem and cerebellum.
    explanation: Imaging documents the CNS phenotype.
  - reference: PMID:24100867
    reference_title: COX10 mutations resulting in complex multisystem mitochondrial disease that remains stable into adulthood.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We describe an adult patient with isolated COX deficiency associated with a relatively mild clinical phenotype comprising myopathy; demyelinating neuropathy; premature ovarian failure; short stature; hearing loss; pigmentary maculopathy; and renal tubular dysfunction.
    explanation: The adult multisystem case broadens the diagnostic presentation.
treatments:
- name: Multidisciplinary Supportive Care
  description: Care is directed to the manifestations present. GeneReviews recommendations for nuclear Leigh syndrome provide a clinical framework for COX10-associated encephalopathy; they are not evidence of a COX10-specific disease-modifying treatment.
  therapeutic_modality: OTHER
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/
    reference_title: Nuclear Gene-Encoded Leigh Syndrome Spectrum Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Supportive care to improve quality of life, maximize function, and reduce complications is recommended.
    explanation: General LSS management recommendation.
    quote_role: BACKGROUND
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
- name: Nutritional and Feeding Support
  description: Assess swallowing and nutrition; feeding therapy, supplementation and enteral support may be needed according to clinical impairment.
  therapeutic_modality: OTHER
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/
    reference_title: Nuclear Gene-Encoded Leigh Syndrome Spectrum Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: gastrostomy tube placement may improve nutritional intake for those w/persistent feeding issues, choking, or aspiration risk due to dysphagia
    explanation: General LSS feeding guidance, individualized to clinical need.
    quote_role: BACKGROUND
  treatment_term:
    preferred_term: Nutritional Support
    term:
      id: NCIT:C15433
      label: Nutritional Support
- name: Motor Rehabilitation
  description: Physical and occupational therapy and mobility equipment can support function in patients with myopathy, ataxia or spasticity.
  therapeutic_modality: OTHER
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/
    reference_title: Nuclear Gene-Encoded Leigh Syndrome Spectrum Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Equipment to prevent falling, maintain independent mobility as appropriate
    explanation: GeneReviews supports mobility interventions for LSS-associated myopathy or ataxia.
    quote_role: BACKGROUND
  treatment_term:
    preferred_term: Rehabilitation
    term:
      id: NCIT:C15315
      label: Rehabilitation
  target_phenotypes:
  - preferred_term: Myopathy
    term:
      id: HP:0003198
      label: Myopathy
  - preferred_term: Cerebellar ataxia
    term:
      id: HP:0001251
      label: Ataxia
- name: Hearing Rehabilitation
  description: Hearing aids or cochlear implantation may be considered according to hearing impairment and specialist assessment; this is general LSS care guidance rather than demonstrated COX10-specific implant outcomes.
  therapeutic_modality: DEVICE
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/
    reference_title: Nuclear Gene-Encoded Leigh Syndrome Spectrum Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Hearing aids or cochlear implants for SNHL
    explanation: GeneReviews recommends hearing rehabilitation for sensorineural impairment.
    quote_role: BACKGROUND
  target_phenotypes:
  - preferred_term: Sensorineural hearing impairment
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
  treatment_term:
    preferred_term: Hearing amplification or cochlear implantation with audiological rehabilitation
    term:
      id: NCIT:C15315
      label: Rehabilitation
    qualifiers:
    - predicate:
        preferred_term: Medical Device
        term:
          id: NCIT:C16830
          label: Medical Device
      value:
        preferred_term: Hearing Aid
        term:
          id: NCIT:C183182
          label: Hearing Aid
    - predicate:
        preferred_term: Medical Device
        term:
          id: NCIT:C16830
          label: Medical Device
      value:
        preferred_term: Cochlear Implant
        term:
          id: NCIT:C157820
          label: Cochlear Implant
  notes: The devices are alternative options selected according to hearing severity and specialist assessment, not a combined regimen. The action is bound to rehabilitation because this entry cites general care guidance rather than a reported COX10-specific implantation procedure.
- name: Renal Electrolyte Support
  description: Renal tubular losses require nephrology-directed electrolyte monitoring and replacement when present.
  therapeutic_modality: OTHER
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/
    reference_title: Nuclear Gene-Encoded Leigh Syndrome Spectrum Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Electrolyte monitoring ... replacement for renal tubular losses as advised by nephrologist
    explanation: General LSS supportive treatment for a documented COX10 manifestation.
    quote_role: BACKGROUND
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_phenotypes:
  - preferred_term: Renal tubular dysfunction
    term:
      id: HP:0000124
      label: Renal tubular dysfunction
  - preferred_term: Renal tubular acidosis
    term:
      id: HP:0001947
      label: Renal tubular acidosis
- name: Respiratory Support
  description: Respiratory compromise warrants specialist assessment and ventilatory support when indicated.
  therapeutic_modality: DEVICE
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/
    reference_title: Nuclear Gene-Encoded Leigh Syndrome Spectrum Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Ventilatory support for persons w/LSS ... respiratory compromise
    explanation: General Leigh-spectrum respiratory care.
    quote_role: BACKGROUND
  target_phenotypes:
  - preferred_term: Respiratory insufficiency
    term:
      id: HP:0002093
      label: Respiratory insufficiency
- name: Metabolic Stress and Medication Precautions
  description: Minimize fasting and catabolism during illness or procedures. General LSS guidance advises caution with anesthesia, prolonged propofol, neuromuscular blockers and lactate-containing fluids in susceptible patients. Valproate should be avoided when possible; the absolute contraindication specified for POLG disease should not be attributed automatically to COX10.
  therapeutic_modality: OTHER
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/
    reference_title: Nuclear Gene-Encoded Leigh Syndrome Spectrum Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Catabolism should be prevented by minimizing preoperative fasting and considering intravenous glucose perioperatively during prolonged anesthesia
    explanation: GeneReviews perioperative guidance; its ketogenic-diet exception requires individual assessment.
    quote_role: BACKGROUND
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/
    reference_title: Nuclear Gene-Encoded Leigh Syndrome Spectrum Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Sodium valproate should be avoided if possible, because of its inhibitory effect on respiratory chain enzymes.
    explanation: General mitochondrial caution, not evidence of a COX10-specific absolute contraindication.
    quote_role: BACKGROUND
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/
    reference_title: Nuclear Gene-Encoded Leigh Syndrome Spectrum Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Prolonged propofol use during maintenance anesthesia may increase the risk of lactic acidosis.
    explanation: General anesthetic precaution.
    quote_role: BACKGROUND
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
- name: Reported Mitochondrial Supplement Cocktail
  description: A toddler with two uncertain COX10 variants received coenzyme Q10, biotin, thiamine, riboflavin, pyridoxine, L-carnitine and folinic acid. Swallowing improved but walking, sitting and speaking did not recover at six months. The uncontrolled course and uncertain molecular diagnosis do not establish efficacy or correction of heme A biosynthesis.
  therapeutic_modality: SMALL_MOLECULE
  evidence:
  - reference: PMID:38846886
    reference_title: 'Complex mitochondrial disease caused by the mutation of COX10 in a toddler: a case-report study.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: the patient was administered an oral mitochondrial cocktail comprising daily doses of coenzyme-Q10, biotin, thiamine, riboflavin, pyridoxine, L-Carnitine, and folinic acid.
    explanation: Records an empirical combination, not a validated COX10 therapy.
  - reference: PMID:38846886
    reference_title: 'Complex mitochondrial disease caused by the mutation of COX10 in a toddler: a case-report study.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: At the 6-month follow-up after admission, the patient’s food regurgitation had improved and she could swallow properly. However, her motor functions for walking, sitting, and speaking had not recovered.
    explanation: The limited outcome does not establish treatment causality.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: coenzyme Q10
      term:
        id: CHEBI:46245
        label: coenzyme Q10
    - preferred_term: biotin
      term:
        id: CHEBI:15956
        label: biotin
    - preferred_term: thiamine
      term:
        id: CHEBI:18385
        label: thiamine(1+)
    - preferred_term: riboflavin
      term:
        id: CHEBI:17015
        label: riboflavin
    - preferred_term: pyridoxine
      term:
        id: CHEBI:16709
        label: pyridoxine
    - preferred_term: L-carnitine
      term:
        id: CHEBI:16347
        label: (R)-carnitine
    - preferred_term: folinic acid
      term:
        id: CHEBI:15640
        label: 5-formyltetrahydrofolic acid
- name: Seizure Management
  description: Antiseizure treatment is individualized by a neurologist. Levetiracetam and clobazam were used for focal convulsions in the 2024 uncertain-genotype case, without evidence that these drugs modify COX10 disease.
  therapeutic_modality: SMALL_MOLECULE
  evidence:
  - reference: PMID:38846886
    reference_title: 'Complex mitochondrial disease caused by the mutation of COX10 in a toddler: a case-report study.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Additionally, she had experienced focal convulsions that were managed with 150 mg of levetiracetam and 10 mg of clobazam.
    explanation: Records symptomatic seizure treatment in the candidate case.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: levetiracetam
      term:
        id: CHEBI:6437
        label: levetiracetam
    - preferred_term: clobazam
      term:
        id: CHEBI:31413
        label: clobazam
  target_phenotypes:
  - preferred_term: Focal seizures
    term:
      id: HP:0007359
      label: Focal-onset seizure
- name: Multisystem Surveillance
  description: Follow-up monitors neurologic, ophthalmologic, hearing, cardiac, renal, growth and hematologic involvement. GeneReviews suggests regular review, generally every 6-12 months, individualized to the manifestations and genotype.
  therapeutic_modality: OTHER
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/
    reference_title: Nuclear Gene-Encoded Leigh Syndrome Spectrum Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Affected individuals should be followed at regular intervals (typically every 6-12 months) to monitor progression of known manifestations and the appearance of new manifestations.
    explanation: Broad nuclear LSS surveillance recommendation, not a COX10-specific natural-history estimate.
    quote_role: BACKGROUND
- name: Genetic Counseling
  description: Counsel families about autosomal recessive COX10 inheritance, carrier testing and reproductive options once familial pathogenic variants are established. When a contiguous deletion includes PMP22, counsel separately about the dominant neuropathy risk.
  therapeutic_modality: OTHER
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/
    reference_title: Nuclear Gene-Encoded Leigh Syndrome Spectrum Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: each sib of an ... has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic ... and a 25% chance of being unaffected and not a
    explanation: Autosomal recessive recurrence risks apply when both parents carry a pathogenic allele.
    quote_role: BACKGROUND
  - reference: PMID:36176336
    reference_title: Biallelic COX10 Mutations and PMP22 Deletion in a Family With Leigh Syndrome and Hereditary Neuropathy With Liability to Pressure Palsy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Genetic rearrangements resulting in HNPP deletion disrupted 1 copy of COX10 on the recombinant allele.
    explanation: A deletion may carry different inheritance implications for the two neighboring genes.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/
    reference_title: Nuclear Gene-Encoded Leigh Syndrome Spectrum Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: have been identified in an affected family member, prenatal and ... preimplantation genetic testing ... are possible.
    explanation: Reproductive testing becomes possible after identifying the familial pathogenic variants.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
- name: Cardiac Management
  description: Cardiomyopathy warrants cardiology-directed treatment for congestion or arrhythmia according to the individual findings. This is supportive management, not correction of COX10 or heme A synthesis.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_phenotypes:
  - preferred_term: Hypertrophic cardiomyopathy
    term:
      id: HP:0001639
      label: Hypertrophic cardiomyopathy
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/
    reference_title: Nuclear Gene-Encoded Leigh Syndrome Spectrum Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: Anticongestive therapy or antiarrhythmic therapy may be required ... treatment should be managed by a cardiologist.
    explanation: General nuclear Leigh-spectrum guidance for cardiomyopathy applies to the cardiac phenotype, without COX10-specific efficacy data.
experimental_models:
- name: Patient Fibroblast COX10 Complementation
  experimental_model_type: PRIMARY_CELL_CULTURE
  publication: PMID:15455402
  description: Patient-derived fibroblasts permit assessment of the complex IV assembly defect and rescue by wild-type COX10 expression. Complementation establishes gene causality in this model; it is not a clinical gene-therapy result.
  modeled_mechanisms:
  - target: Reduced Complex IV Assembly
    relationship: RECAPITULATES
    model_scale: MOLECULAR
    fidelity: HIGH
    description: The patient-derived cellular system has reduced mature COX without accumulating assembly intermediates.
    limitations: Fibroblasts do not model the full brain, heart, renal or auditory phenotype.
    evidence:
    - reference: PMID:15455402
      reference_title: Cytochrome c oxidase biogenesis in a patient with a mutation in COX10 gene.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Two-dimensional gel electrophoresis showed a decrease of fully assembled COX without the accumulation of partially assembled COX subcomplexes.
      explanation: Direct measurement of the assembly defect.
  evidence:
  - reference: PMID:15455402
    reference_title: Cytochrome c oxidase biogenesis in a patient with a mutation in COX10 gene.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Overexpression of the COX10 protein in the patient's fibroblasts proved that the detected mutation was indeed the disease cause.
    explanation: Restoration with COX10 demonstrates causality in patient cells.
  - reference: PMID:12928484
    reference_title: Mutations in COX10 result in a defect in mitochondrial heme A biosynthesis and account for multiple, early-onset clinical phenotypes associated with isolated COX deficiency.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: expression of COX10 from a retroviral vector complements the COX deficiency
    explanation: Earlier patient fibroblasts were also complemented with COX10.
- name: Human COX10 Alleles in Yeast
  experimental_model_type: OTHER
  publication: PMID:39152498
  description: Human reference COX10 and 25 variants were expressed in Saccharomyces cerevisiae lacking endogenous COX10. Eleven variants supported approximately half or more of reference COX activity and robust growth on a nonfermentable substrate; others had low activity and failed respiratory growth. Results inform variant function but do not by themselves classify human pathogenicity or prognosis.
  modeled_mechanisms:
  - target: Reduced Terminal Electron Transfer
    relationship: RECAPITULATES
    model_scale: MOLECULAR
    fidelity: MODERATE
    description: Variant-dependent COX enzyme activity and respiratory growth measure the consequences of COX10 dysfunction.
    limitations: Species context can alter activity. Asp336Val and Arg339Trp were nonfunctional in yeast despite the survival of a patient with that combination into adulthood.
    evidence:
    - reference: PMID:39152498
      reference_title: Phenotypic assessment of Cox10 variants and their implications for Leigh Syndrome.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: 11 of these Cox10 variants supported approximately half or more the cytochrome c oxidase activity compared to the reference sequence. All of the strains containing those 11 variants also grew robustly using a nonfermentable carbon source.
      explanation: The measured activity and growth outcomes.
  evidence:
  - reference: PMID:39152498
    reference_title: Phenotypic assessment of Cox10 variants and their implications for Leigh Syndrome.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Despite the strong evolutionary conservation in oxidative phosphorylation mechanisms, it is possible that these variants will have a different level of activity in humans compared to yeast cells.
    explanation: The authors explicitly identify the translational limitation.
discussions:
- evidence:
  - reference: PMID:24100867
    reference_title: COX10 mutations resulting in complex multisystem mitochondrial disease that remains stable into adulthood.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: These findings establish that COX10 mutations cause adult mitochondrial disease.
    explanation: Clinical outcome extends beyond the early lethal presentations.
  - reference: PMID:39152498
    reference_title: Phenotypic assessment of Cox10 variants and their implications for Leigh Syndrome.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: We thought that using more sensitive enzyme assays might reveal partial activity from one or both proteins but found that both are fully nonfunctional
    explanation: The follow-up did not find residual activity for these alleles in yeast.
  discussion_id: cox10_clinical_variability
  kind: INTERPRETATION
  prompt: Does severe biochemical deficiency determine clinical severity?
  rationale: Severe biochemical or yeast respiratory defects do not imply an inevitable infantile outcome. The adult Asp336Val/Arg339Trp case and the yeast follow-up leave the determinants of organ involvement and survival unresolved; proposed modifier genes remain hypotheses.
- evidence:
  - reference: PMID:38846886
    reference_title: 'Complex mitochondrial disease caused by the mutation of COX10 in a toddler: a case-report study.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Functional studies might elucidate the impact of these variants on the produced protein by the COX10 gene.
    explanation: The case report calls for functional studies rather than reporting them.
  - reference: PMID:39152498
    reference_title: Phenotypic assessment of Cox10 variants and their implications for Leigh Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: The second variant is highly similar to the T380I variant that we found to be nonfunctional
    explanation: Thr377Ile is discussed by analogy to a different tested variant.
    quote_role: BACKGROUND
  discussion_id: cox10_uncertain_toddler_variants
  kind: INTERPRETATION
  prompt: Do the reported toddler variants establish COX10 deficiency?
  rationale: The Thr377Ile and Thr14Ile substitutions were reported as VUS, not proven pathogenic alleles. The later yeast paper tested Thr380Ile and discussed Thr377Ile by positional analogy; that is not direct functional testing of Thr377Ile. Clinical observations and supplement exposure from the toddler report therefore remain provisional disease-association evidence.
notes: COX10 disease is a variable heme A biosynthesis/complex IV biogenesis disorder, not primary coenzyme Q10 deficiency. Genetically confirmed myopathic adult and Leigh-spectrum presentations are retained within one entry. Phenotype frequencies and penetrance cannot be inferred from the small, selected reports. The nuclear Leigh-spectrum GeneReviews overview supplies general care and counseling context; its pooled frequencies and therapies for other genes are not COX10-specific evidence.
references:
- reference: PMID:10767350
  title: A mutation in the human heme A:farnesyltransferase gene (COX10 ) causes cytochrome c oxidase deficiency.
- reference: PMID:12928484
  title: Mutations in COX10 result in a defect in mitochondrial heme A biosynthesis and account for multiple, early-onset clinical phenotypes associated with isolated COX deficiency.
- reference: PMID:15455402
  title: Cytochrome c oxidase biogenesis in a patient with a mutation in COX10 gene.
- reference: PMID:24100867
  title: COX10 mutations resulting in complex multisystem mitochondrial disease that remains stable into adulthood.
- reference: PMID:30588737
  title: Sideroblastic anemia associated with multisystem mitochondrial disorders.
- reference: PMID:36176336
  title: Biallelic COX10 Mutations and PMP22 Deletion in a Family With Leigh Syndrome and Hereditary Neuropathy With Liability to Pressure Palsy.
- reference: PMID:38846886
  title: 'Complex mitochondrial disease caused by the mutation of COX10 in a toddler: a case-report study.'
- reference: PMID:39152498
  title: Phenotypic assessment of Cox10 variants and their implications for Leigh Syndrome.
- reference: PMID:26425749
  title: Nuclear Gene-Encoded Leigh Syndrome Spectrum Overview.
  tags:
  - GeneReviews
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/
  title: Nuclear Gene-Encoded Leigh Syndrome Spectrum Overview - GeneReviews® - NCBI Bookshelf
  tags:
  - GeneReviews
📚

References & Deep Research

References

10
PMID:10767350
A mutation in the human heme A:farnesyltransferase gene (COX10 ) causes cytochrome c oxidase deficiency.
No top-level findings curated for this source.
PMID:12928484
Mutations in COX10 result in a defect in mitochondrial heme A biosynthesis and account for multiple, early-onset clinical phenotypes associated with isolated COX deficiency.
No top-level findings curated for this source.
PMID:15455402
Cytochrome c oxidase biogenesis in a patient with a mutation in COX10 gene.
No top-level findings curated for this source.
PMID:24100867
COX10 mutations resulting in complex multisystem mitochondrial disease that remains stable into adulthood.
No top-level findings curated for this source.
PMID:30588737
Sideroblastic anemia associated with multisystem mitochondrial disorders.
No top-level findings curated for this source.
PMID:36176336
Biallelic COX10 Mutations and PMP22 Deletion in a Family With Leigh Syndrome and Hereditary Neuropathy With Liability to Pressure Palsy.
No top-level findings curated for this source.
PMID:38846886
Complex mitochondrial disease caused by the mutation of COX10 in a toddler: a case-report study.
No top-level findings curated for this source.
PMID:39152498
Phenotypic assessment of Cox10 variants and their implications for Leigh Syndrome.
No top-level findings curated for this source.
PMID:26425749
Nuclear Gene-Encoded Leigh Syndrome Spectrum Overview.
No top-level findings curated for this source.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/
Nuclear Gene-Encoded Leigh Syndrome Spectrum Overview - GeneReviews® - NCBI Bookshelf
No top-level findings curated for this source.