COXFA4-Related COX Deficiency

Mendelian MONDO:0033656 Pathograph 39 Show in embeddings browser Mitochondrial Disease Inborn Error of Metabolism

Autosomal recessive COXFA4-related mitochondrial disease (MC4DN21) is caused by biallelic loss-of-function variants in a nuclear-encoded complex IV subunit formerly called NDUFA4. Splice variants and genomic deletions cause loss of detectable subunit protein and impair late maturation, stability and activity of cytochrome c oxidase. Residual enzyme and partial COXFA4L2 compensation distinguish this from a complete block of core-complex assembly. The spectrum includes Leigh-like encephalopathy, developmental and movement disorders, lactic acidosis and variable cardiac involvement; some individuals have mild developmental disease without established Leigh syndrome. Childhood progression, adult survival and early deaths have all been reported. Cellular paralog rescue and polyamine supplementation in Xenopus remain preclinical findings.

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1
Inheritance
13
Pathophys.
1
Histopath.
35
Phenotypes
39
Pathograph
1
Genes
10
Variants
12
Medical Actions
1
Datasets
6
Models
8
References
👪

Inheritance

1
Autosomal recessive
Show evidence (1 reference)
PMID:23746447 SUPPORT Human Clinical
"all four affected individuals were homozygous for the mutation, whereas three unaffected family members (II-2, III-1, and III-2) were heterozygous"
Segregation in the founding pedigree supports recessive inheritance.
⚙

Pathophysiology

13
COXFA4 splice-site single-nucleotide variants
Biallelic intronic SNVs disrupt donor or acceptor sites. The founding c.42+1G>C variant and later donor-2 variants have distinct transcript consequences.
COXFA4 hgnc:7687 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves COXFA4, annotated with NDUFA4 (hgnc:7687). hgnc:7687 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context COXFA4 hgnc:7687 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns COXFA4, annotated with NDUFA4 (hgnc:7687). hgnc:7687 is a gene from the HUGO Gene Nomenclature Committee. Variant type: single nucleotide variant Genomic context: intron functional_impact_category: LOSS_OF_FUNCTION
Downstream
Abnormal COXFA4 splicing Disrupted splice recognition produces intron retention or exon skipping.
Show evidence (1 reference)
PMID:23746447 SUPPORT Human Clinical
"identified a homozygous splice donor site mutation (c.42+1G → C, NM_002489.3) in NDUFA4"
The founding intronic SNV is distinct from the resulting four-base RNA retention.
COXFA4 splice-donor nucleotide deletion
The homozygous c.42+1del allele reported in subject S6 is a one-base genomic deletion at the first donor site. Patient RNA was unavailable for this allele in the 2026 study.
COXFA4 hgnc:7687 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves COXFA4, annotated with NDUFA4 (hgnc:7687). hgnc:7687 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context COXFA4 hgnc:7687 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns COXFA4, annotated with NDUFA4 (hgnc:7687). hgnc:7687 is a gene from the HUGO Gene Nomenclature Committee. Variant type: deletion Genomic context: intron
Downstream
Loss of COXFA4 protein Loss of functional protein is inferred from the splice-site lesion and cohort interpretation; the specific S6 RNA and protein effects remain untested.
Show evidence (1 reference)
PMID:42218136 SUPPORT Human Clinical
"Confirmation of COXFA4 c.42+1del, c.42+2 T > C, c.42+1 G > C, c.131+1 G > C, and c.131+5 G > A variants was assessed using standard PCR-based sequencing."
The small donor deletion is a distinct physical variant class.
COXFA4 genomic deletions
Reported homozygous deletions remove all or part of COXFA4. The 2025 siblings have deletion of the coding region without another protein-coding gene; the 2026 cohort includes distinct partial and larger whole-gene deletions.
COXFA4 hgnc:7687 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves COXFA4, annotated with NDUFA4 (hgnc:7687). hgnc:7687 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context COXFA4 hgnc:7687 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns COXFA4, annotated with NDUFA4 (hgnc:7687). hgnc:7687 is a gene from the HUGO Gene Nomenclature Committee. Variant type: deletion functional_impact_category: LOSS_OF_FUNCTION
Downstream
Loss of COXFA4 protein Removal of coding sequence eliminates the normal encoded subunit.
Show evidence (2 references)
PMID:39967265 SUPPORT Human Clinical
"Exome sequencing revealed a homozygous deletion of 7p21.3 (10933348–10941418, GRCh38) in both siblings that includes the entirety of the coding region of COXFA4 and no other protein-coding genes."
A homozygous genomic deletion removes COXFA4 coding sequence in two tested siblings.
PMID:42218136 SUPPORT Human Clinical
"The first deletion spanned 8013 bp and partially overlapped the gene, whereas the second was a larger deletion of 63,856 bp on chromosome 7, which completely overlapped the COXFA4 locus"
The newer structural variants differ in their extent.
COXFA4 deletion-insertion
The 2024 homozygous allele removes the gene and inserts an Alu-rich segment from chromosome 19. Alu sequence homology suggests a rearrangement mechanism, but no single repair pathway was experimentally established.
COXFA4 hgnc:7687 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves COXFA4, annotated with NDUFA4 (hgnc:7687). hgnc:7687 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context COXFA4 hgnc:7687 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns COXFA4, annotated with NDUFA4 (hgnc:7687). hgnc:7687 is a gene from the HUGO Gene Nomenclature Committee. allele_type: gene-spanning deletion with insertion functional_impact_category: LOSS_OF_FUNCTION
Downstream
Loss of COXFA4 protein The rearrangement removes the COXFA4 gene.
Show evidence (1 reference)
PMID:38674434 SUPPORT Human Clinical
"the patient had a deletion of chr7:10969448–10982428, with 337 bp insertion from chr19:14427161–14427497."
Breakpoint sequencing refines the GRCh37 deletion and detects an inserted chromosome-19 segment.
Abnormal COXFA4 splicing
Donor-1 variants can retain four intronic RNA nucleotides; donor-2 variants can skip exon 2. Some correctly spliced RNA persists in particular samples. The RNA changes must not be confused with genomic insertion or deletion size.
COXFA4 hgnc:7687 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves COXFA4, annotated with NDUFA4 (hgnc:7687). hgnc:7687 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
Loss of COXFA4 protein Aberrant transcripts accompany loss of detectable subunit protein; a specific RNA-decay pathway is not established.
Show evidence (2 references)
PMID:23746447 SUPPORT In Vitro
"the first 4 bp of intron 1 are retained following activation of a cryptic splice site 4 bp downstream of the c.42+1G → C mutation"
RNA analysis identifies aberrant donor use; this is not a genomic four-base insertion.
PMID:42218136 SUPPORT In Vitro
"In S1 and S2 (c.131+1 G > C), exon 2 was absent, indicating complete exon skipping compared to controls"
The donor-2 alleles produce a different RNA consequence from the donor-1 variants.
Loss of COXFA4 protein
COXFA4 protein is undetectable in the assayed affected muscle and fibroblasts. This structural subunit supports complex IV maturation and activity; it is not a complex I subunit.
COXFA4 hgnc:7687 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves COXFA4, annotated with NDUFA4 (hgnc:7687). hgnc:7687 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
Reduced mature complex IV accumulation Loss of the late-incorporating subunit impairs stable holoenzyme accumulation.
Increased COXFA4L2 expression Assayed deficient fibroblasts increase paralog expression through an unresolved regulatory pathway.
Reduced ODC-pathway transcripts in experimental models COXFA4 knockout is associated with reduced ODC-pathway transcripts; the connection to respiratory-complex activity is unresolved.
Show evidence (2 references)
PMID:23746447 SUPPORT In Vitro
"NDUFA4 protein was undetectable in all affected subjects examined"
Immunoblotting and cellular staining establish loss of detectable protein in the tested muscle and fibroblasts.
PMID:42218136 SUPPORT In Vitro
"Stable expression of wild-type COXFA4 in fibroblasts of S2 (c.131+1 G > C), S4 (c.131+5 G > A), and S5 (c.42+2 T > C, Fig. 6A) significantly restored complex IV activity"
Patient-cell complementation supports a causal COXFA4 defect.
Reduced mature complex IV accumulation
Core assemblies can still form without COXFA4, but late stable holoenzyme accumulation is reduced in patient fibroblasts. Reduced respirasome abundance appears secondary to limited mature complex IV. Earlier patient muscle showed assembled enzyme without abnormal subassemblies.
COXFA4 hgnc:7687 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves COXFA4, annotated with NDUFA4 (hgnc:7687). hgnc:7687 is a gene from the HUGO Gene Nomenclature Committee.
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
COXFA4-deficient patient fibroblasts CELL LINE
Downstream
Reduced complex IV activity Impaired maturation and stable accumulation accompany reduced enzyme activity.
Show evidence (3 references)
PMID:42218136 SUPPORT In Vitro
"This analysis revealed a reduction in fully assembled complex IV in all COXFA4-deficient samples"
BN-PAGE shows reduced assembled enzyme in the assayed patient-derived fibroblasts.
PMID:42218136 SUPPORT In Vitro
"The observation that all COX-containing assemblies still form, although at lower levels, is consistent with this late-stage role."
The defect affects late maturation and stable accumulation, rather than preventing all core-complex assembly.
PMID:23746447 SUPPORT In Vitro
"the COX enzyme complex without NDUFA4 was detectable with no abnormal subassemblies in patient muscle"
Patient muscle demonstrates preserved core assembly despite subunit loss.
Reduced complex IV activity
Complex IV activity is reduced with residual activity retained. The magnitude varies with tissue and culture conditions; normal glucose-grown fibroblast measurements have been reported. COXFA4 supports holoenzyme function rather than catalyzing electron transfer independently.
COXFA4 hgnc:7687 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves COXFA4, annotated with NDUFA4 (hgnc:7687). hgnc:7687 is a gene from the HUGO Gene Nomenclature Committee.
cytochrome-c oxidase activity GO:0004129 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased cytochrome-c oxidase activity (GO:0004129). GO:0004129 is a molecular function from the Gene Ontology.
Experimental models
COXFA4-deficient patient fibroblasts CELL LINE
Downstream
Impaired mitochondrial respiration Reduced terminal respiratory enzyme function accompanies lower cellular oxygen consumption.
Show evidence (2 references)
PMID:42218136 SUPPORT In Vitro
"spectrophotometric measurements of COXFA4-deficient samples showed a 60–85% reduction complex IV enzymatic activity"
This is the range in the study fibroblast assays, not a universal tissue or patient percentage.
PMID:23746447 SUPPORT In Vitro
"current diagnostic procedures that typically use glucose as a carbon source in the culture medium may not detect a reduction in COX activity."
Normal glucose-grown fibroblast activity does not exclude the disorder.
Impaired mitochondrial respiration
Patient-derived fibroblasts show lower basal respiration and ATP-linked oxygen consumption. These assays do not establish universal ATP depletion, oxidative stress or a specific neuronal injury pathway in patients.
aerobic respiration GO:0009060 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased aerobic respiration (GO:0009060). GO:0009060 is a biological process from the Gene Ontology.
Downstream
Global developmental delay The inherited respiratory defect is associated with this clinical manifestation; intervening tissue mechanisms are incompletely defined.
Hypotonia The inherited respiratory defect is associated with this clinical manifestation; intervening tissue mechanisms are incompletely defined.
Spasticity The inherited respiratory defect is associated with this clinical manifestation; intervening tissue mechanisms are incompletely defined.
Lactic acidosis The inherited respiratory-chain defect is associated with this clinical manifestation. This link summarizes the disease-level relationship; the intervening tissue mechanisms have not been resolved.
Leukoencephalopathy The inherited respiratory-chain defect is associated with this clinical manifestation. This link summarizes the disease-level relationship; the intervening tissue mechanisms have not been resolved.
Cardiomyopathy The inherited respiratory-chain defect is associated with this clinical manifestation. This link summarizes the disease-level relationship; the intervening tissue mechanisms have not been resolved.
Show evidence (1 reference)
PMID:42218136 SUPPORT In Vitro
"showed a significant decrease in basal respiration (∼50%) and ATP-linked oxygen consumption (∼46%) in all samples"
Seahorse measurements in the specified patient fibroblasts establish impaired respiration; ATP-linked OCR is not a direct measurement of cellular ATP concentration.
Increased COXFA4L2 expression
COXFA4-deficient fibroblasts and SH-SY5Y knockdown cells upregulate the paralog. The induction mechanism is unresolved; increased HIF-1alpha was not observed. Compensation in primary neurons in vivo is unproven.
COXFA4L2 hgnc:29836 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves COXFA4L2, annotated with NDUFA4L2 (hgnc:29836). hgnc:29836 is a gene from the HUGO Gene Nomenclature Committee.
gene expression GO:0010467 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased gene expression (GO:0010467). GO:0010467 is a biological process from the Gene Ontology.
Experimental models
COXFA4-knockdown SH-SY5Y neuroblastoma cells CELL LINE
Downstream
Partial paralog compensation COXFA4L2 can partly substitute for the missing subunit in tested cells.
Show evidence (1 reference)
PMID:42218136 SUPPORT In Vitro
"COXFA4L2 mRNA expression was significantly upregulated in all cases, particularly in S3"
qPCR establishes increased paralog transcripts in the assayed fibroblasts; the induction pathway is unresolved.
Partial paralog compensation
COXFA4L2 overexpression partially restores complex IV activity, and its depletion reduces respiratory reserve in one patient line. This is cellular compensation, not a proven determinant of individual clinical severity.
COXFA4L2 hgnc:29836 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves COXFA4L2, annotated with NDUFA4L2 (hgnc:29836). hgnc:29836 is a gene from the HUGO Gene Nomenclature Committee.
cytochrome-c oxidase activity GO:0004129 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves increased cytochrome-c oxidase activity (GO:0004129). GO:0004129 is a molecular function from the Gene Ontology.
Experimental models
COXFA4-deficient patient fibroblasts CELL LINE
COXFA4-knockdown SH-SY5Y neuroblastoma cells CELL LINE
Show evidence (2 references)
PMID:42218136 SUPPORT In Vitro
"Expression of COXFA4L2 also improved complex IV activity, though less effectively, with a ∼1.7-fold increase relative to uncomplemented cells"
Paralog overexpression provides partial functional rescue in patient fibroblasts, not proven clinical benefit.
PMID:42218136 SUPPORT In Vitro
"Basal respiration was preserved, whereas maximal respiration was significantly reduced in S14 COXFA4L2-depleted cells relative to S14."
Paralog depletion in one patient line reduces respiratory reserve, supporting a compensatory role.
Reduced ODC-pathway transcripts in experimental models
COXFA4-knockout iPSC transcriptomics and Xenopus experiments show reduced ODC-pathway components. A larger reduction of odc1 and azin1 than inhibitory oaz1 is reported in embryos. The pathway has not been measured in affected human tissues.
Experimental models
COXFA4-knockout induced pluripotent stem cells IPSC DERIVED MODEL
Downstream
Reduced polyamine abundance in Xenopus Reduced biosynthetic-pathway expression accompanies lower total polyamines in the model.
Show evidence (2 references)
PMID:39967265 SUPPORT In Vitro
"We were particularly struck by the decrease in nearly all components of the ODC pathway"
Reanalysis of COXFA4-knockout iPSC RNA-seq identified reduced pathway transcripts; this is experimental rather than patient-tissue evidence.
PMID:39967265 SUPPORT Model Organism
"there was a larger decrease in integral components of the ODC pathway (odc1 and azin1) compared to inhibitory ODC pathway component oaz1."
Embryonic qPCR supports an altered balance of pathway transcripts.
Reduced polyamine abundance in Xenopus
Total polyamine abundance is reduced in mosaic coxfa4-mutant embryos. Polyamine supplementation improves cardiac function and survival without restoring complex IV activity; applicability to patient myocardium remains unproven.
Animal models
Xenopus tropicalis coxfa4 F0 mosaic crispants Xenopus tropicalis recapitulates
Show evidence (3 references)
PMID:39967265 SUPPORT Model Organism
"we observed a decrease in global polyamine levels in coxfa4 crispant embryos"
A whole-embryo assay supports reduced polyamine abundance in mosaic Xenopus mutants.
PMID:39967265 SUPPORT Model Organism
"We observed improvement in cardiomyopathy severity upon polyamine exposure (Figure 5A; Video S3) and improvement in overall survival"
Supplementation improves outcomes in Xenopus; human efficacy and dosing are not established.
PMID:39967265 SUPPORT Model Organism
"In-gel complex IV activity remained decreased despite polyamine supplementation"
The cardiac benefit in the animal model does not establish restoration of respiratory-complex activity.
✶

Histopathology

1
Variable muscle COX staining and lipid accumulation
The founding proband had normal COX histochemistry despite deficient enzymology; another affected child had reduced staining throughout the muscle fibers. Lipid droplets were reported. These findings are variable rather than universal diagnostic criteria.
Show evidence (2 references)
PMID:23746447 SUPPORT Human Clinical
"COX histochemistry was normal. Electron microscopy revealed lipid droplets in some fibers."
The founding proband demonstrates limited sensitivity of COX histochemistry.
PMID:23746447 SUPPORT Human Clinical
"Reduced COX staining in all muscle fibers was seen in III-13"
A different affected child had a positive histochemical finding.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for COXFA4-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

35
Cardiovascular 4
Cardiomyopathy HP:0001638 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cardiomyopathy (HP:0001638). HP:0001638 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39967265 SUPPORT Human Clinical
"Individual IV-6 initially presented neonatally with cardiomyopathy, microcephaly, and faltering growth"
This is a human clinical finding, not an animal-model phenotype or a population frequency.
Wolff-Parkinson-White pattern Wolff-Parkinson-White syndrome HP:0001716 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Wolff-Parkinson-White syndrome (HP:0001716). HP:0001716 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42218136 SUPPORT Human Clinical
"Cardiology | WPW pattern, mild LV hypertrophy | Biventricular hypertrophy | Persistent patent ductus arteriosus | – | Concentric LV hypertrophy"
This is a human clinical finding, not an animal-model phenotype or a population frequency.
Patent ductus arteriosus HP:0001643 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Patent ductus arteriosus (HP:0001643). HP:0001643 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42218136 SUPPORT Human Clinical
"Cardiology | WPW pattern, mild LV hypertrophy | Biventricular hypertrophy | Persistent patent ductus arteriosus | – | Concentric LV hypertrophy"
This is a human clinical finding, not an animal-model phenotype or a population frequency.
Supraventricular tachycardia HP:0004755 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Supraventricular tachycardia (HP:0004755). HP:0004755 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42218136 SUPPORT Human Clinical
"Cardiology | -- | SVT, WPW, closed PDA | -- | -- | -- | -- | -- | -- ... SVT Supraventricular tachycardia"
The clinical text or table identifies this manifestation; abbreviated table terms are expanded in the source legend.
Digestive 3
Feeding difficulties HP:0011968 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Feeding difficulties (HP:0011968). HP:0011968 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42218136 SUPPORT Human Clinical
"Initial symptom | Hypotonia, poor feeding, lethargic | Respiratory distress (birth) raised lactate | Respiratory distress (birth) | Born at 32/40, respiratory distress, NGT fed | Respiratory distress (birth) feeding difficulties"
This is a human clinical finding, not an animal-model phenotype or a population frequency.
Constipation HP:0002019 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Constipation (HP:0002019). HP:0002019 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42218136 SUPPORT Human Clinical
"Gastrointestinal | Constipation | Constipation | -- | -- | Vomiting, PEG-fed | Constipation"
This is a human clinical finding, not an animal-model phenotype or a population frequency.
Dysphagia HP:0002015 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dysphagia (HP:0002015). HP:0002015 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42218136 SUPPORT Human Clinical
"Neuromuscular | Proximal muscle weakness, non-ambulatory | Hypotonia | Muscle weakness, ptosis | Exercise intolerance, limb contractures | Myopathic face, non-ambulatory | Sensory axonal neuropathy, dysphagia"
The clinical text or table identifies this manifestation; abbreviated table terms are expanded in the source legend.
Eye 4
Nystagmus HP:0000639 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Nystagmus (HP:0000639). HP:0000639 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42218136 SUPPORT Human Clinical
"Additional neurological manifestations included cerebellar ataxia (S1, S3, S4, S7, S11), dystonia (S1, S9, S11, S12), ptosis (S3), nystagmus (S4, S7), dysarthria (S1, S7, S11), pyramidal signs (S9–S12), peripheral neuropathy (S14), developmental regression (S1, S9), and seizures (S4, S14)."
This is a human clinical finding, not an animal-model phenotype or a population frequency.
Ptosis HP:0000508 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ptosis (HP:0000508). HP:0000508 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42218136 SUPPORT Human Clinical
"Additional neurological manifestations included cerebellar ataxia (S1, S3, S4, S7, S11), dystonia (S1, S9, S11, S12), ptosis (S3), nystagmus (S4, S7), dysarthria (S1, S7, S11), pyramidal signs (S9–S12), peripheral neuropathy (S14), developmental regression (S1, S9), and seizures (S4, S14)."
The clinical text or table identifies this manifestation; abbreviated table terms are expanded in the source legend.
Optic atrophy HP:0000648 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Optic atrophy (HP:0000648). HP:0000648 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42218136 SUPPORT Human Clinical
"Ophthalmology | -- | Mild OA, nystagmus | -- | Convergent L eye squint ... OA Optic atrophy"
The clinical text or table identifies this manifestation; abbreviated table terms are expanded in the source legend.
Cataract HP:0000518 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cataract (HP:0000518). HP:0000518 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42218136 SUPPORT Human Clinical
"Ophthalmology | Nystagmus | Cataract | – | Nystagmus | – | –"
The clinical text or table identifies this manifestation; abbreviated table terms are expanded in the source legend.
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:39967265 SUPPORT Human Clinical
"Individual IV-6 initially presented neonatally with cardiomyopathy, microcephaly, and faltering growth"
This is a human clinical finding, not an animal-model phenotype or a population frequency.
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:39967265 SUPPORT Human Clinical
"Both have persistent lactic acidosis in the range of 3–7 mmol/L."
This is a human clinical finding, not an animal-model phenotype or a population frequency.
Musculoskeletal 6
Hypotonia HP:0001252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypotonia (HP:0001252). HP:0001252 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42218136 SUPPORT Human Clinical
"Common clinical features included neonatal or early infantile hypotonia, progressive motor impairment, spasticity, global developmental delay, and varying degrees of intellectual disability."
This is a human clinical finding, not an animal-model phenotype or a population frequency.
Spasticity HP:0001257 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Spasticity (HP:0001257). HP:0001257 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42218136 SUPPORT Human Clinical
"Common clinical features included neonatal or early infantile hypotonia, progressive motor impairment, spasticity, global developmental delay, and varying degrees of intellectual disability."
This is a human clinical finding, not an animal-model phenotype or a population frequency.
Scoliosis HP:0002650 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Scoliosis (HP:0002650). HP:0002650 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42218136 SUPPORT Human Clinical
"Systemic involvement was also observed, including cardiomyopathy or conduction abnormalities (S1-3, S5, S7), bulbar dysfunction (S5, S14), skeletal abnormalities such as scoliosis (S5, S9), and endocrine or metabolic features (S1, S7, S14)."
The cohort explicitly reports scoliosis; other neurological manifestations are not evidence for this skeletal finding.
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:42218136 SUPPORT Human Clinical
"progressive developmental delays, neurodegeneration, muscle weakness, and lactic acidosis."
This is a human clinical finding, not an animal-model phenotype or a population frequency.
Joint contractures HP:0034392 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Joint contracture (HP:0034392). HP:0034392 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42218136 SUPPORT Human Clinical
"Neuromuscular | Proximal muscle weakness, non-ambulatory | Hypotonia | Muscle weakness, ptosis | Exercise intolerance, limb contractures"
This is a human clinical finding, not an animal-model phenotype or a population frequency.
Muscle atrophy Skeletal muscle atrophy HP:0003202 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Skeletal muscle atrophy (HP:0003202). HP:0003202 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42218136 SUPPORT Human Clinical
"Neuromuscular | MW, hypotonia, non-ambulatory | MW, hypotonia | -- | Mild scoliosis, LC (ankle) | MW, hypotonia, LC, EI (7 y) | Mild MA | Mild MA | -- ... MA Muscle atrophy"
This is a human clinical finding, not an animal-model phenotype or a population frequency.
Nervous System 12
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:42218136 SUPPORT Human Clinical
"Common clinical features included neonatal or early infantile hypotonia, progressive motor impairment, spasticity, global developmental delay, and varying degrees of intellectual disability."
This is a human clinical finding, not an animal-model phenotype or a population frequency.
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:42218136 SUPPORT Human Clinical
"Common clinical features included neonatal or early infantile hypotonia, progressive motor impairment, spasticity, global developmental delay, and varying degrees of intellectual disability."
This is a human clinical finding, not an animal-model phenotype or a population frequency.
Ataxia HP:0001251 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ataxia (HP:0001251). HP:0001251 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42218136 SUPPORT Human Clinical
"Additional neurological manifestations included cerebellar ataxia (S1, S3, S4, S7, S11), dystonia (S1, S9, S11, S12), ptosis (S3), nystagmus (S4, S7), dysarthria (S1, S7, S11), pyramidal signs (S9–S12), peripheral neuropathy (S14), developmental regression (S1, S9), and seizures (S4, S14)."
This is a human clinical finding, not an animal-model phenotype or a population frequency.
Dystonia HP:0001332 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dystonia (HP:0001332). HP:0001332 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42218136 SUPPORT Human Clinical
"Additional neurological manifestations included cerebellar ataxia (S1, S3, S4, S7, S11), dystonia (S1, S9, S11, S12), ptosis (S3), nystagmus (S4, S7), dysarthria (S1, S7, S11), pyramidal signs (S9–S12), peripheral neuropathy (S14), developmental regression (S1, S9), and seizures (S4, S14)."
This is a human clinical finding, not an animal-model phenotype or a population frequency.
Dysarthria HP:0001260 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dysarthria (HP:0001260). HP:0001260 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42218136 SUPPORT Human Clinical
"Additional neurological manifestations included cerebellar ataxia (S1, S3, S4, S7, S11), dystonia (S1, S9, S11, S12), ptosis (S3), nystagmus (S4, S7), dysarthria (S1, S7, S11), pyramidal signs (S9–S12), peripheral neuropathy (S14), developmental regression (S1, S9), and seizures (S4, S14)."
This is a human clinical finding, not an animal-model phenotype or a population frequency.
Developmental regression HP:0002376 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Developmental regression (HP:0002376). HP:0002376 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42218136 SUPPORT Human Clinical
"Additional neurological manifestations included cerebellar ataxia (S1, S3, S4, S7, S11), dystonia (S1, S9, S11, S12), ptosis (S3), nystagmus (S4, S7), dysarthria (S1, S7, S11), pyramidal signs (S9–S12), peripheral neuropathy (S14), developmental regression (S1, S9), and seizures (S4, S14)."
This is a human clinical finding, not an animal-model phenotype or a population frequency.
Seizures HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:42218136 SUPPORT Human Clinical
"Additional neurological manifestations included cerebellar ataxia (S1, S3, S4, S7, S11), dystonia (S1, S9, S11, S12), ptosis (S3), nystagmus (S4, S7), dysarthria (S1, S7, S11), pyramidal signs (S9–S12), peripheral neuropathy (S14), developmental regression (S1, S9), and seizures (S4, S14)."
This is a human clinical finding, not an animal-model phenotype or a population frequency.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/ SUPPORT Human Clinical
"COXFA4 ... Epilepsy; sensory axonal peripheral neuropathy; leukoencephalopathy ... Slowly progressive; survival into 20s/30s"
The COXFA4-specific row supports these clinical associations and adult survival; its fraction of LSS is not phenotype frequency.
Leukoencephalopathy HP:0002352 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Leukoencephalopathy (HP:0002352). HP:0002352 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:42218136 SUPPORT Human Clinical
"revealed symmetrical white matter abnormalities, predominantly affecting the periventricular, corpus callosum, brainstem, and dentate regions"
This is a human clinical finding, not an animal-model phenotype or a population frequency.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/ SUPPORT Human Clinical
"COXFA4 ... Epilepsy; sensory axonal peripheral neuropathy; leukoencephalopathy ... Slowly progressive; survival into 20s/30s"
The COXFA4-specific row supports these clinical associations and adult survival; its fraction of LSS is not phenotype frequency.
Sensory axonal neuropathy HP:0003390 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sensory axonal neuropathy (HP:0003390). HP:0003390 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:23746447 SUPPORT Human Clinical
"Nerve conduction studies indicated there was a sensory axonal peripheral neuropathy."
This is a human clinical finding, not an animal-model phenotype or a population frequency.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/ SUPPORT Human Clinical
"COXFA4 ... Epilepsy; sensory axonal peripheral neuropathy; leukoencephalopathy ... Slowly progressive; survival into 20s/30s"
The COXFA4-specific row supports these clinical associations and adult survival; its fraction of LSS is not phenotype frequency.
Thin corpus callosum HP:0033725 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Thin corpus callosum (HP:0033725). HP:0033725 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39967265 SUPPORT Human Clinical
"she was found to have a thin corpus callosum and scattered T2-weighted hyperintensities near the gray-white matter junction"
This is a human clinical finding, not an animal-model phenotype or a population frequency.
Delayed speech and language development HP:0000750 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Delayed speech and language development (HP:0000750). HP:0000750 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42218136 SUPPORT Human Clinical
"Speech | No speech | 1st word (2 y), speaks in short sentences | Delayed | No speech | 1 word (1.5 y), sentence (8.5 y)"
This is a human clinical finding, not an animal-model phenotype or a population frequency.
Pyramidal signs Abnormal pyramidal sign HP:0007256 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal pyramidal sign (HP:0007256). HP:0007256 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42218136 SUPPORT Human Clinical
"Additional neurological manifestations included cerebellar ataxia (S1, S3, S4, S7, S11), dystonia (S1, S9, S11, S12), ptosis (S3), nystagmus (S4, S7), dysarthria (S1, S7, S11), pyramidal signs (S9–S12), peripheral neuropathy (S14), developmental regression (S1, S9), and seizures (S4, S14)."
The clinical text or table identifies this manifestation; abbreviated table terms are expanded in the source legend.
Respiratory 1
Respiratory distress HP:0002098 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Respiratory distress (HP:0002098). HP:0002098 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42218136 SUPPORT Human Clinical
"Initial symptom | Hypotonia, poor feeding, lethargic | Respiratory distress (birth) raised lactate | Respiratory distress (birth) | Born at 32/40, respiratory distress, NGT fed"
This is a human clinical finding, not an animal-model phenotype or a population frequency.
Constitutional 1
Exercise intolerance HP:0003546 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Exercise intolerance (HP:0003546). HP:0003546 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42218136 SUPPORT Human Clinical
"Neuromuscular | Proximal muscle weakness, non-ambulatory | Hypotonia | Muscle weakness, ptosis | Exercise intolerance, limb contractures"
This is a human clinical finding, not an animal-model phenotype or a population frequency.
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:39967265 SUPPORT Human Clinical
"Individual IV-6 initially presented neonatally with cardiomyopathy, microcephaly, and faltering growth"
This is a human clinical finding, not an animal-model phenotype or a population frequency.
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:39967265 SUPPORT Human Clinical
"He has remained small for age and at last evaluation had a height Z score of −3.2"
This is a human clinical finding, not an animal-model phenotype or a population frequency.
🧬

Genetic Associations

1
COXFA4
Gene: COXFA4 hgnc:7687 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is COXFA4, annotated with NDUFA4 (hgnc:7687). hgnc:7687 is a gene from the HUGO Gene Nomenclature Committee.
Autosomal recessive
Show evidence (3 references)
PMID:23746447 SUPPORT Human Clinical
"identified a homozygous splice donor site mutation (c.42+1G → C, NM_002489.3) in NDUFA4"
The founding intronic SNV is distinct from the resulting four-base RNA retention.
PMID:39967265 SUPPORT Human Clinical
"Exome sequencing revealed a homozygous deletion of 7p21.3 (10933348–10941418, GRCh38) in both siblings that includes the entirety of the coding region of COXFA4 and no other protein-coding genes."
A homozygous genomic deletion removes COXFA4 coding sequence in two tested siblings.
PMID:42218136 SUPPORT In Vitro
"Stable expression of wild-type COXFA4 in fibroblasts of S2 (c.131+1 G > C), S4 (c.131+5 G > A), and S5 (c.42+2 T > C, Fig. 6A) significantly restored complex IV activity"
Patient-cell complementation supports a causal COXFA4 defect.
Variants (10)
NM_002489.3:c.42+1G>C Pathogenic
Gene: COXFA4 hgnc:7687 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in COXFA4, annotated with NDUFA4 (hgnc:7687). hgnc:7687 is a gene from the HUGO Gene Nomenclature Committee. single nucleotide variant
Genomic context: intron
Founding homozygous donor-1 SNV; four-base intron retention in RNA predicts a frameshift. Some wild-type RNA remains in blood.
Show evidence (2 references)
PMID:23746447 SUPPORT Human Clinical
"identified a homozygous splice donor site mutation (c.42+1G → C, NM_002489.3) in NDUFA4"
The founding intronic SNV is distinct from the resulting four-base RNA retention.
PMID:23746447 SUPPORT In Vitro
"the first 4 bp of intron 1 are retained following activation of a cryptic splice site 4 bp downstream of the c.42+1G → C mutation"
RNA analysis identifies aberrant donor use; this is not a genomic four-base insertion.
NM_002489.4:c.131+1G>C Pathogenic
Gene: COXFA4 hgnc:7687 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in COXFA4, annotated with NDUFA4 (hgnc:7687). hgnc:7687 is a gene from the HUGO Gene Nomenclature Committee. single nucleotide variant
Genomic context: intron
Homozygous intronic splice-site variant reported in the 2026 cohort. Functional RNA experiments were performed only in available fibroblast lines.
Show evidence (1 reference)
PMID:42218136 SUPPORT Human Clinical
"Variant | c.131+1 G > C | c.131+1 G > C | c.131+1 G > C | c.131+5 G > A | c.42+2 T > C | c.42+1 G > C"
The relevant clinical table identifies the allele; RNA conclusions are restricted to tested samples.
NM_002489.4:c.131+5G>A Pathogenic
Gene: COXFA4 hgnc:7687 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in COXFA4, annotated with NDUFA4 (hgnc:7687). hgnc:7687 is a gene from the HUGO Gene Nomenclature Committee. single nucleotide variant
Genomic context: intron
Homozygous intronic splice-site variant reported in the 2026 cohort. Functional RNA experiments were performed only in available fibroblast lines.
Show evidence (1 reference)
PMID:42218136 SUPPORT Human Clinical
"Variant | c.131+1 G > C | c.131+1 G > C | c.131+1 G > C | c.131+5 G > A | c.42+2 T > C | c.42+1 G > C"
The relevant clinical table identifies the allele; RNA conclusions are restricted to tested samples.
NM_002489.4:c.42+2T>C Pathogenic
Gene: COXFA4 hgnc:7687 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in COXFA4, annotated with NDUFA4 (hgnc:7687). hgnc:7687 is a gene from the HUGO Gene Nomenclature Committee. single nucleotide variant
Genomic context: intron
Homozygous intronic splice-site variant reported in the 2026 cohort. Functional RNA experiments were performed only in available fibroblast lines.
Show evidence (1 reference)
PMID:42218136 SUPPORT Human Clinical
"Variant | c.131+1 G > C | c.131+1 G > C | c.131+1 G > C | c.131+5 G > A | c.42+2 T > C | c.42+1 G > C"
The relevant clinical table identifies the allele; RNA conclusions are restricted to tested samples.
NM_002489.4:c.43-1G>A Pathogenic
Gene: COXFA4 hgnc:7687 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in COXFA4, annotated with NDUFA4 (hgnc:7687). hgnc:7687 is a gene from the HUGO Gene Nomenclature Committee. single nucleotide variant
Genomic context: intron
Homozygous intronic splice-site variant reported in the 2026 cohort. Functional RNA experiments were performed only in available fibroblast lines.
Show evidence (1 reference)
PMID:42218136 SUPPORT Human Clinical
"Variant | c.42+1del | c.43-1 G > A | c.131+5 G > A | c.131+5 G > A | c.131+1 G > C"
The relevant clinical table identifies the allele; RNA conclusions are restricted to tested samples.
NM_002489.4:c.42+1del Pathogenic
Gene: COXFA4 hgnc:7687 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in COXFA4, annotated with NDUFA4 (hgnc:7687). hgnc:7687 is a gene from the HUGO Gene Nomenclature Committee. deletion
Genomic context: intron
One-base genomic deletion at the donor site in S6; the exact RNA effect was not directly assayed.
Show evidence (1 reference)
PMID:42218136 SUPPORT Human Clinical
"Confirmation of COXFA4 c.42+1del, c.42+2 T > C, c.42+1 G > C, c.131+1 G > C, and c.131+5 G > A variants was assessed using standard PCR-based sequencing."
The small donor deletion is a distinct physical variant class.
GRCh38 chr7:10933348–10941418 deletion Pathogenic
Gene: COXFA4 hgnc:7687 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in COXFA4, annotated with NDUFA4 (hgnc:7687). hgnc:7687 is a gene from the HUGO Gene Nomenclature Committee. deletion
Homozygous deletion of the complete COXFA4 coding region without another protein-coding gene in two genotyped siblings.
Show evidence (1 reference)
PMID:39967265 SUPPORT Human Clinical
"Exome sequencing revealed a homozygous deletion of 7p21.3 (10933348–10941418, GRCh38) in both siblings that includes the entirety of the coding region of COXFA4 and no other protein-coding genes."
A homozygous genomic deletion removes COXFA4 coding sequence in two tested siblings.
GRCh37 chr7:10969448–10982428 deletion-insertion Pathogenic
Gene: COXFA4 hgnc:7687 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in COXFA4, annotated with NDUFA4 (hgnc:7687). hgnc:7687 is a gene from the HUGO Gene Nomenclature Committee. complex deletion-insertion
Deletion of COXFA4 with a 337-bp insertion from chr19:14427161–14427497, supported by breakpoint sequencing; Alu homology suggests a rearrangement mechanism.
Show evidence (1 reference)
PMID:38674434 SUPPORT Human Clinical
"the patient had a deletion of chr7:10969448–10982428, with 337 bp insertion from chr19:14427161–14427497."
Breakpoint sequencing refines the GRCh37 deletion and detects an inserted chromosome-19 segment.
GRCh38 chr7:10932820–10940833 deletion Pathogenic
Gene: COXFA4 hgnc:7687 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in COXFA4, annotated with NDUFA4 (hgnc:7687). hgnc:7687 is a gene from the HUGO Gene Nomenclature Committee. deletion
Reported partial-gene deletion in siblings S11 and S12; preserve the paper interval without substituting the separate 2025-family deletion.
Show evidence (1 reference)
PMID:42218136 SUPPORT Human Clinical
"chr7:10,932,820–10,940,833 (top panel, identified in S11 and S12)"
Figure legend supplies the GRCh38 interval.
GRCh38 chr7:10890006–10953862 deletion Pathogenic
Gene: COXFA4 hgnc:7687 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in COXFA4, annotated with NDUFA4 (hgnc:7687). hgnc:7687 is a gene from the HUGO Gene Nomenclature Committee. deletion
Reported larger genomic deletion encompassing COXFA4 in S13; the source does not establish that all effects of this wider interval are exclusively attributable to COXFA4.
Show evidence (1 reference)
PMID:42218136 SUPPORT Human Clinical
"chr7:10,890,006–10,953,862 (bottom panel, identified in S13)"
Figure legend supplies the GRCh38 interval.
💊

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
General Leigh syndrome spectrum guidance; no COXFA4-specific therapeutic trial is demonstrated. Coordinate neurological, nutritional, respiratory and rehabilitation care according to manifestations.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/ SUPPORT Human Clinical
"Supportive care to improve quality of life, maximize function, and reduce complications is recommended."
The chapter provides a general supportive-care framework.
Antiseizure treatment
Action: Anticonvulsant TherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Anticonvulsant Therapy (NCIT:C64172). NCIT:C64172 is a clinical intervention from the NCI Thesaurus. NCIT:C64172
General Leigh syndrome spectrum guidance; no COXFA4-specific therapeutic trial is demonstrated. An experienced neurologist should individualize antiseizure medication. The available sources do not establish a preferred COXFA4-specific drug.
Mechanism Target:
MODULATES Seizures — Symptom-directed management from general LSS guidance; COXFA4-specific efficacy has not been established.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/ SUPPORT Human Clinical
"Treatment w/ASM by experienced neurologist"
LSS guidance supports specialist antiseizure treatment.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/ SUPPORT Human Clinical
"Treatment w/ASM by experienced neurologist"
LSS guidance supports specialist antiseizure treatment.
Acidosis correction
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: sodium hydrogencarbonate CHEBI:32139 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses sodium hydrogencarbonate (CHEBI:32139). CHEBI:32139 is a therapeutic agent from Chemical Entities of Biological Interest.
General Leigh syndrome spectrum guidance; no COXFA4-specific therapeutic trial is demonstrated. Clinically significant acidosis may require sodium bicarbonate or sodium citrate, selected and monitored by the treating team.
Mechanism Target:
MODULATES Lactic acidosis — Symptom-directed management from general LSS guidance; COXFA4-specific efficacy has not been established.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/ SUPPORT Human Clinical
"Sodium bicarbonate or sodium citrate for significant acidosis"
This recommendation treats significant acidosis in LSS, rather than repairing COXFA4.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/ SUPPORT Human Clinical
"Sodium bicarbonate or sodium citrate for significant acidosis"
This recommendation treats significant acidosis in LSS, rather than repairing COXFA4.
Nutritional support
Action: Nutritional SupportNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Nutritional Support (NCIT:C15433). NCIT:C15433 is a clinical intervention from the NCI Thesaurus. NCIT:C15433
General Leigh syndrome spectrum guidance; no COXFA4-specific therapeutic trial is demonstrated. Assess growth, nutritional intake and swallowing safety; provide supplementation and feeding support when indicated.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/ SUPPORT Human Clinical
"nutritional supplementation as needed (incl micronutrients)"
The general LSS care table recommends nutritional support when needed.
Clinical surveillance
Action: Supportive CareNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. NCIT:C15747
General Leigh syndrome spectrum guidance; no COXFA4-specific therapeutic trial is demonstrated. Regular neurological, ophthalmological, hearing and cardiac assessment should be tailored to manifestations.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/ SUPPORT Human Clinical
"Neurologic, ophthalmologic, audiologic, and cardiologic evaluations are recommended"
The chapter recommends multisystem surveillance for LSS.
Medication and perioperative precautions
Action: Supportive CareNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. NCIT:C15747
General Leigh syndrome spectrum guidance; no COXFA4-specific therapeutic trial is demonstrated. Avoid sodium valproate if possible; the absolute POLG contraindication should not be relabeled as a COXFA4-specific rule. Plan anesthesia and monitoring, minimize prolonged fasting, and avoid lactate-containing solutions in those at risk of lactic acidosis.
Show evidence (3 references)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/ SUPPORT Human Clinical
"Sodium valproate should be avoided if possible, because of its inhibitory effect on respiratory chain enzymes."
This is the general mitochondrial-disease precaution, with the separate absolute contraindication applying to POLG-related disease.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/ SUPPORT Human Clinical
"Catabolism should be prevented by minimizing preoperative fasting and considering intravenous glucose perioperatively during prolonged anesthesia"
General perioperative LSS guidance; the chapter qualifies glucose use for people on ketogenic diets.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/ SUPPORT Human Clinical
"Avoid lactate-containing agents (e.g., Ringer's lactate) in those at risk of lactic acidosis"
General LSS guidance on fluids in people at risk of lactic acidosis.
Genetic counseling
Action: Genetic CounselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic Counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. NCIT:C15240
General Leigh syndrome spectrum guidance; no COXFA4-specific therapeutic trial is demonstrated. Confirm parental carrier status. With two heterozygous parents, recurrence risks per conception are 25% affected, 50% carrier and 25% unaffected noncarrier. Family variant identification enables prenatal and preimplantation testing.
Show evidence (2 references)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/ SUPPORT Human Clinical
"each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic ... carrier ... and a 25% chance of being unaffected and not a carrier."
These are conditional autosomal recessive recurrence risks, not measured COXFA4 penetrance.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/ SUPPORT Human Clinical
"Once the LSS-related ... pathogenic variant ... (s) have been identified in an affected family member, prenatal and ... preimplantation genetic testing ... are possible."
General LSS counseling guidance supports family-specific reproductive testing.
Dystonia 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: baclofen CHEBI:2972 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses baclofen (CHEBI:2972). CHEBI:2972 is a therapeutic agent from Chemical Entities of Biological Interest.
General Leigh syndrome guidance: specialist-directed medication may help dystonia; response and adverse effects require individual assessment. Baclofen is one of the listed options, alongside benzhexol, tetrabenazine and gabapentin.
Mechanism Target:
MODULATES Dystonia — Symptomatic treatment according to general LSS guidance.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/ SUPPORT Human Clinical
"Benzhexol, baclofen, tetrabenazine, ... gabapentin may be useful, alone or in various combinations."
General LSS supportive-care guidance, applied according to manifestations.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/ SUPPORT Human Clinical
"Benzhexol, baclofen, tetrabenazine, ... gabapentin may be useful, alone or in various combinations."
General LSS supportive-care guidance, applied according to manifestations.
Cardiac care
Action: Supportive CareNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. NCIT:C15747
General Leigh syndrome guidance: manage cardiomyopathy and conduction abnormalities with a cardiologist; no COXFA4-specific drug efficacy is established. General LSS surveillance recommends an electrocardiogram and echocardiogram annually or as advised by the cardiologist.
Show evidence (2 references)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/ SUPPORT Human Clinical
"Anticongestive therapy or antiarrhythmic therapy may be required ... treatment should be managed by a cardiologist."
General LSS supportive-care guidance, applied according to manifestations.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/ SUPPORT Human Clinical
"Electrocardiogram ... Echocardiogram ... Annually or as advised by cardiologist"
General LSS cardiac surveillance interval.
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
General Leigh syndrome guidance supports physical and occupational therapy for myopathy or ataxia, with equipment to maintain mobility and prevent falls.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/ SUPPORT Human Clinical
"PT ... OT ... Equipment to prevent falling, maintain independent mobility as appropriate"
General LSS supportive-care guidance, applied according to manifestations.
Experimental polyamine supplementation
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: putrescine CHEBI:17148 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses putrescine (CHEBI:17148). CHEBI:17148 is a therapeutic agent from Chemical Entities of Biological Interest. spermidine CHEBI:16610 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses spermidine (CHEBI:16610). CHEBI:16610 is a therapeutic agent from Chemical Entities of Biological Interest. spermine CHEBI:15746 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses spermine (CHEBI:15746). CHEBI:15746 is a therapeutic agent from Chemical Entities of Biological Interest.
Preclinical only. A putrescine/spermidine/spermine mixture improved cardiac function and survival in Xenopus coxfa4 crispants without restoring complex IV activity. Human efficacy, safety and dosing in COXFA4 deficiency have not been established by this study.
Show evidence (2 references)
PMID:39967265 SUPPORT Model Organism
"We observed improvement in cardiomyopathy severity upon polyamine exposure (Figure 5A; Video S3) and improvement in overall survival"
Supplementation improves outcomes in Xenopus; human efficacy and dosing are not established.
PMID:39967265 SUPPORT Model Organism
"In-gel complex IV activity remained decreased despite polyamine supplementation"
The cardiac benefit in the animal model does not establish restoration of respiratory-complex activity.
Experimental COXFA4 or COXFA4L2 complementation
Preclinical genetic complementation restored or partly improved enzyme activity in patient cells; human mRNA injection also rescued aspects of the Xenopus phenotype. AAV delivery is proposed in discussion, not a tested patient treatment.
Show evidence (2 references)
PMID:42218136 SUPPORT In Vitro
"Stable expression of wild-type COXFA4 in fibroblasts of S2 (c.131+1 G > C), S4 (c.131+5 G > A), and S5 (c.42+2 T > C, Fig. 6A) significantly restored complex IV activity"
Patient-cell complementation supports a causal COXFA4 defect.
PMID:42218136 SUPPORT In Vitro
"Expression of COXFA4L2 also improved complex IV activity, though less effectively, with a ∼1.7-fold increase relative to uncomplemented cells"
Paralog overexpression provides partial functional rescue in patient fibroblasts, not proven clinical benefit.
🔬

Biochemical Markers

2
Tissue-dependent cytochrome c oxidase deficiency (Reduced in tested affected tissues; some fibroblast assays normal)
Show evidence (3 references)
PMID:42218136 SUPPORT In Vitro
"spectrophotometric measurements of COXFA4-deficient samples showed a 60–85% reduction complex IV enzymatic activity"
This is the range in the study fibroblast assays, not a universal tissue or patient percentage.
PMID:23746447 SUPPORT In Vitro
"current diagnostic procedures that typically use glucose as a carbon source in the culture medium may not detect a reduction in COX activity."
Normal glucose-grown fibroblast activity does not exclude the disorder.
PMID:42218136 SUPPORT Human Clinical
"Respiratory chain enzyme analyses of muscle tissues (S1, S4, S7, S10 and S14) showed a profound reduction in COX activity."
Human muscle enzymology supports tissue complex IV deficiency; the cohort also includes a case with additional respiratory-chain abnormalities.
Persistent circulating lactate elevation (Increased)
Show evidence (1 reference)
PMID:39967265 SUPPORT Human Clinical
"Both have persistent lactic acidosis in the range of 3–7 mmol/L."
Persistent lactate elevation in two genotyped siblings.
🔬

Diagnosis

4
Molecular diagnosis including copy-number analysis
Identify biallelic COXFA4 variants through a mitochondrial-disease workup including sequence and deletion analysis. Family segregation and RNA studies can clarify splice variants. Genome sequencing is preferred when available in general LSS guidance.
Genetic Testing NCIT:C15709 NCI Thesaurus (NCIT)
Show evidence (4 references)
PMID:23746447 SUPPORT Human Clinical
"identified a homozygous splice donor site mutation (c.42+1G → C, NM_002489.3) in NDUFA4"
The founding intronic SNV is distinct from the resulting four-base RNA retention.
PMID:39967265 SUPPORT Human Clinical
"Exome sequencing revealed a homozygous deletion of 7p21.3 (10933348–10941418, GRCh38) in both siblings that includes the entirety of the coding region of COXFA4 and no other protein-coding genes."
A homozygous genomic deletion removes COXFA4 coding sequence in two tested siblings.
PMID:38674434 SUPPORT Human Clinical
"the patient had a deletion of chr7:10969448–10982428, with 337 bp insertion from chr19:14427161–14427497."
Breakpoint sequencing refines the GRCh37 deletion and detects an inserted chromosome-19 segment.
+ 1 more reference
Respiratory-chain enzymology with culture-context interpretation
Reduced complex IV activity supports diagnosis, but a normal glucose-grown fibroblast assay does not exclude COXFA4 deficiency. Galactose culture revealed the defect in a founding patient; biochemical findings vary by tissue.
Show evidence (3 references)
PMID:42218136 SUPPORT In Vitro
"spectrophotometric measurements of COXFA4-deficient samples showed a 60–85% reduction complex IV enzymatic activity"
This is the range in the study fibroblast assays, not a universal tissue or patient percentage.
PMID:23746447 SUPPORT In Vitro
"current diagnostic procedures that typically use glucose as a carbon source in the culture medium may not detect a reduction in COX activity."
Normal glucose-grown fibroblast activity does not exclude the disorder.
PMID:42218136 SUPPORT Human Clinical
"Respiratory chain enzyme analyses of muscle tissues (S1, S4, S7, S10 and S14) showed a profound reduction in COX activity."
Human muscle enzymology supports tissue complex IV deficiency; the cohort also includes a case with additional respiratory-chain abnormalities.
RNA analysis of splice variants
RT-PCR or RNA sequencing can identify donor-site intron retention, exon skipping and residual correctly spliced transcripts; effects must be assigned to the tested allele and tissue.
Show evidence (2 references)
PMID:23746447 SUPPORT In Vitro
"the first 4 bp of intron 1 are retained following activation of a cryptic splice site 4 bp downstream of the c.42+1G → C mutation"
RNA analysis identifies aberrant donor use; this is not a genomic four-base insertion.
PMID:42218136 SUPPORT In Vitro
"In S1 and S2 (c.131+1 G > C), exon 2 was absent, indicating complete exon skipping compared to controls"
The donor-2 alleles produce a different RNA consequence from the donor-1 variants.
Brain MRI
Evaluate white-matter, callosal and brainstem abnormalities. Imaging can initially be normal, and some affected individuals do not have established Leigh syndrome.
Magnetic Resonance Imaging NCIT:C16809 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:23746447 SUPPORT Human Clinical
"Brain CT (13 years) and MRI (17 years) were both normal. However, a brain MRI at age 25 years demonstrated T2 hyperintensities in the deep white matter."
Normal early imaging does not exclude genetically established disease.
📊

Related Datasets

1
A Human Induced Pluripotent Stem Cell Array-Based Genome Wide Association Study Identifies Virus Susceptibility Locus and Variants geo:GSE182376
The COXFA4/NDUFA4 knockout versus wild-type iPSC RNA-seq subset was reanalyzed for polyamine-pathway biology in the 2025 disease study. The broader original virus-susceptibility project is not a cohort of patients with COXFA4 deficiency.
PMID:39967265
Show evidence (2 references)
GEO:GSE182376 SUPPORT Other
"RNA-sequencing was used to compare the global gene expression profiles in WT and NDUFA4-/- iPSCs"
The repository record verifies the relevant experimental contrast.
PMID:39967265 SUPPORT Computational
"This dataset was accessed via the NCBI Gene Expression Omnibus: GSE182376."
The disease-mechanism paper identifies the reused dataset.
🧫

Experimental Models

4
COXFA4-deficient patient fibroblasts CELL_LINE
Patient primary and immortalized fibroblasts reveal allele-specific splicing, low mature complex IV, reduced respiration and partial COXFA4L2 compensation. Glucose culture can mask deficiency. Complementation with wild-type COXFA4 or its paralog tests causality and residual function.
Publication
PMID:42218136
Pathograph links
Reduced mature complex IV accumulation partially recapitulates observes: cellular
Limitations: Experimental findings do not establish the complete clinical phenotype.
Reduced complex IV activity partially recapitulates observes: cellular
Limitations: Experimental findings do not establish the complete clinical phenotype.
Partial paralog compensation partially recapitulates observes: cellular
Limitations: Experimental findings do not establish the complete clinical phenotype.
Show evidence (8 references)
PMID:23746447 SUPPORT In Vitro
"the first 4 bp of intron 1 are retained following activation of a cryptic splice site 4 bp downstream of the c.42+1G → C mutation"
RNA analysis identifies aberrant donor use; this is not a genomic four-base insertion.
PMID:42218136 SUPPORT In Vitro
"In S1 and S2 (c.131+1 G > C), exon 2 was absent, indicating complete exon skipping compared to controls"
The donor-2 alleles produce a different RNA consequence from the donor-1 variants.
PMID:42218136 SUPPORT In Vitro
"spectrophotometric measurements of COXFA4-deficient samples showed a 60–85% reduction complex IV enzymatic activity"
This is the range in the study fibroblast assays, not a universal tissue or patient percentage.
+ 5 more references
COXFA4-knockdown SH-SY5Y neuroblastoma cells CELL_LINE
Stable COXFA4 knockdown induces COXFA4L2, and double depletion worsens respiration. SH-SY5Y is a transformed neuronal-like system; compensation in primary neurons in vivo remains unproven.
Publication
PMID:42218136
Pathograph links
Increased COXFA4L2 expression partially recapitulates observes: cellular
Limitations: Experimental findings do not establish the complete clinical phenotype.
Partial paralog compensation partially recapitulates observes: cellular
Limitations: Experimental findings do not establish the complete clinical phenotype.
Show evidence (1 reference)
PMID:42218136 SUPPORT In Vitro
"the double KD resulted in a more pronounced reduction in basal respiration compared to COXFA4 KD alone"
Double depletion provides functional evidence for paralog compensation in this cell line.
COXFA4-knockout induced pluripotent stem cells IPSC_DERIVED_MODEL
The 2025 study reanalyzed public RNA-seq from engineered knockout and control iPSCs to identify reduced ODC-pathway transcripts. These are not patient-derived cardiomyocytes.
Publication
PMID:39967265
Pathograph links
Reduced ODC-pathway transcripts in experimental models partially recapitulates observes: cellular
Limitations: Experimental findings do not establish the complete clinical phenotype.
Show evidence (1 reference)
PMID:39967265 SUPPORT In Vitro
"We were particularly struck by the decrease in nearly all components of the ODC pathway"
Reanalysis of COXFA4-knockout iPSC RNA-seq identified reduced pathway transcripts; this is experimental rather than patient-tissue evidence.
Ndufa4-manipulated P19-derived neural cells CELL_LINE
Retinoic-acid-differentiated mouse embryonal carcinoma cells were used to study Ndufa4 RNA, miR-145a-5p, Homer1/Ccnd2 expression and apoptosis. This Dandy-Walker-oriented experiment does not establish a human MC4DN21 neuronal mechanism; oxygen consumption and ATP generation were not measured.
Publication
PMID:36763283
Show evidence (1 reference)
PMID:36763283 SUPPORT In Vitro
"Ndufa4 overexpression promoted the proliferation of neurons and inhibited their apoptosis in vitro, which underwent reverse regulation by the Ndufa4 short hairpin RNAs."
The experiment concerns manipulated neural-like cells, not patient neurons.
🐁

Animal Models

2
Xenopus tropicalis coxfa4 F0 mosaic crispants
Early embryos show reduced cardiac contractility, craniofacial cartilage defects, brain/heart complex IV deficiency and lower polyamines. Polyamines improve cardiac function and survival without correcting complex IV activity; human COXFA4 or COXFA4L2 mRNA provides rescue. Early-stage neurological behavior does not reproduce the full human disease.
Species
Xenopus tropicalis
Genotype
CRISPR/Cas9 mosaic loss of coxfa4
Publication
PMID:39967265
Pathograph links
Reduced polyamine abundance in Xenopus recapitulates observes: organism
Limitations: Mosaic embryonic model with unproven human treatment translation.
Show evidence (3 references)
PMID:39967265 SUPPORT Model Organism
"we observed a decrease in global polyamine levels in coxfa4 crispant embryos"
A whole-embryo assay supports reduced polyamine abundance in mosaic Xenopus mutants.
PMID:39967265 SUPPORT Model Organism
"We observed improvement in cardiomyopathy severity upon polyamine exposure (Figure 5A; Video S3) and improvement in overall survival"
Supplementation improves outcomes in Xenopus; human efficacy and dosing are not established.
PMID:39967265 SUPPORT Model Organism
"In-gel complex IV activity remained decreased despite polyamine supplementation"
The cardiac benefit in the animal model does not establish restoration of respiratory-complex activity.
Whole-body Ndufa4-knockout mouse
The 2023 model shows neuronal injury, increased brain apoptosis and altered behavioral assays. The primary methods specify whole-body knockout, which can confound behavior through systemic respiratory-chain dysfunction. The proposed miR-145a-5p/Homer1/Ccnd2 pathway is not validated in affected humans.
Species
Mus musculus
Genotype
Constitutive Ndufa4 exon 3–4 deletion generated with Cre/LoxP
Publication
PMID:36763283
Show evidence (2 references)
PMID:36763283 SUPPORT Model Organism
"the whole body knockout of Ndufa4 cannot completely avoid its influence on the behavioral phenotype of mice as a component of the respiratory chain."
The authors explicitly acknowledge the systemic-model limitation.
PMID:36763283 SUPPORT Model Organism
"TUNEL staining showed increased apoptosis in the brain tissues of Ndufa4-KO mice compared with WT mice"
The animal model supports neuronal injury, not a corresponding established human histopathology.
{ }

Source YAML

click to show 
name: COXFA4-Related COX Deficiency
category: Mendelian
creation_date: '2026-06-24T00:00:00Z'
synonyms:
- COXFA4 deficiency
- NDUFA4 deficiency
- Mitochondrial complex IV deficiency, nuclear type 21
- MC4DN21
- COXFA4-related cytochrome c oxidase deficiency
- NDUFA4-related Leigh syndrome
- COXFA4-related primary mitochondrial disease
description: Autosomal recessive COXFA4-related mitochondrial disease (MC4DN21) is caused by biallelic loss-of-function variants in a nuclear-encoded complex IV subunit formerly called NDUFA4. Splice variants and genomic deletions cause loss of detectable subunit protein and impair late maturation, stability and activity of cytochrome c oxidase. Residual enzyme and partial COXFA4L2 compensation distinguish this from a complete block of core-complex assembly. The spectrum includes Leigh-like encephalopathy, developmental and movement disorders, lactic acidosis and variable cardiac involvement; some individuals have mild developmental disease without established Leigh syndrome. Childhood progression, adult survival and early deaths have all been reported. Cellular paralog rescue and polyamine supplementation in Xenopus remain preclinical findings.
disease_term:
  preferred_term: COXFA4-related COX deficiency (MC4DN21)
  term:
    id: MONDO:0033656
    label: mitochondrial complex IV deficiency, nuclear type 21
parents:
- Mitochondrial Disease
- Inborn Error of Metabolism
pathophysiology:
- name: COXFA4 splice-site single-nucleotide variants
  description: Biallelic intronic SNVs disrupt donor or acceptor sites. The founding c.42+1G>C variant and later donor-2 variants have distinct transcript consequences.
  evidence:
  - &id018
    reference: PMID:23746447
    reference_title: NDUFA4 mutations underlie dysfunction of a cytochrome c oxidase subunit linked to human neurological disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: identified a homozygous splice donor site mutation (c.42+1G → C, NM_002489.3) in NDUFA4
    explanation: The founding intronic SNV is distinct from the resulting four-base RNA retention.
  genes:
  - &id001
    preferred_term: COXFA4
    term:
      id: hgnc:7687
      label: NDUFA4
  genetic_context:
    gene: *id001
    variant_type: single nucleotide variant
    genomic_contexts:
    - intron
    functional_impact_category: LOSS_OF_FUNCTION
  downstream:
  - target: Abnormal COXFA4 splicing
    causal_link_type: DIRECT
    description: Disrupted splice recognition produces intron retention or exon skipping.
    evidence:
    - &id004
      reference: PMID:23746447
      reference_title: NDUFA4 mutations underlie dysfunction of a cytochrome c oxidase subunit linked to human neurological disease.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: the first 4 bp of intron 1 are retained following activation of a cryptic splice site 4 bp downstream of the c.42+1G → C mutation
      explanation: RNA analysis identifies aberrant donor use; this is not a genomic four-base insertion.
    - &id005
      reference: PMID:42218136
      reference_title: COXFA4L2 upregulation preserves residual cytochrome c oxidase activity in COXFA4-related Leigh-like encephalopathy.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: In S1 and S2 (c.131+1 G > C), exon 2 was absent, indicating complete exon skipping compared to controls
      explanation: The donor-2 alleles produce a different RNA consequence from the donor-1 variants.
- name: COXFA4 splice-donor nucleotide deletion
  description: The homozygous c.42+1del allele reported in subject S6 is a one-base genomic deletion at the first donor site. Patient RNA was unavailable for this allele in the 2026 study.
  evidence: &id019
  - reference: PMID:42218136
    reference_title: COXFA4L2 upregulation preserves residual cytochrome c oxidase activity in COXFA4-related Leigh-like encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Confirmation of COXFA4 c.42+1del, c.42+2 T > C, c.42+1 G > C, c.131+1 G > C, and c.131+5 G > A variants was assessed using standard PCR-based sequencing.
    explanation: The small donor deletion is a distinct physical variant class.
  genes:
  - *id001
  genetic_context:
    gene: *id001
    variant_type: deletion
    genomic_contexts:
    - intron
  downstream:
  - target: Loss of COXFA4 protein
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Loss of functional protein is inferred from the splice-site lesion and cohort interpretation; the specific S6 RNA and protein effects remain untested.
    evidence:
    - reference: PMID:42218136
      reference_title: COXFA4L2 upregulation preserves residual cytochrome c oxidase activity in COXFA4-related Leigh-like encephalopathy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: We identified seven novel biallelic COXFA4 variants, including five that disrupt mRNA splicing and two that result in partial or complete gene deletions, all leading to complete loss of COXFA4 protein.
      explanation: The authors classify the donor deletion with loss-of-function alleles; S6 RNA and protein were not directly assayed.
- name: COXFA4 genomic deletions
  description: Reported homozygous deletions remove all or part of COXFA4. The 2025 siblings have deletion of the coding region without another protein-coding gene; the 2026 cohort includes distinct partial and larger whole-gene deletions.
  evidence:
  - &id002
    reference: PMID:39967265
    reference_title: Polyamine metabolism is dysregulated in COXFA4-related mitochondrial disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Exome sequencing revealed a homozygous deletion of 7p21.3 (10933348–10941418, GRCh38) in both siblings that includes the entirety of the coding region of COXFA4 and no other protein-coding genes.
    explanation: A homozygous genomic deletion removes COXFA4 coding sequence in two tested siblings.
  - reference: PMID:42218136
    reference_title: COXFA4L2 upregulation preserves residual cytochrome c oxidase activity in COXFA4-related Leigh-like encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The first deletion spanned 8013 bp and partially overlapped the gene, whereas the second was a larger deletion of 63,856 bp on chromosome 7, which completely overlapped the COXFA4 locus
    explanation: The newer structural variants differ in their extent.
  genes:
  - *id001
  genetic_context:
    gene: *id001
    variant_type: deletion
    functional_impact_category: LOSS_OF_FUNCTION
  downstream:
  - target: Loss of COXFA4 protein
    causal_link_type: DIRECT
    description: Removal of coding sequence eliminates the normal encoded subunit.
    evidence:
    - *id002
- name: COXFA4 deletion-insertion
  description: The 2024 homozygous allele removes the gene and inserts an Alu-rich segment from chromosome 19. Alu sequence homology suggests a rearrangement mechanism, but no single repair pathway was experimentally established.
  evidence:
  - &id003
    reference: PMID:38674434
    reference_title: Biallelic NDUFA4 Deletion Causes Mitochondrial Complex IV Deficiency in a Patient with Leigh Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: the patient had a deletion of chr7:10969448–10982428, with 337 bp insertion from chr19:14427161–14427497.
    explanation: Breakpoint sequencing refines the GRCh37 deletion and detects an inserted chromosome-19 segment.
  genes:
  - *id001
  genetic_context:
    gene: *id001
    allele_type: gene-spanning deletion with insertion
    functional_impact_category: LOSS_OF_FUNCTION
  downstream:
  - target: Loss of COXFA4 protein
    causal_link_type: DIRECT
    description: The rearrangement removes the COXFA4 gene.
    evidence:
    - *id003
- name: Abnormal COXFA4 splicing
  description: Donor-1 variants can retain four intronic RNA nucleotides; donor-2 variants can skip exon 2. Some correctly spliced RNA persists in particular samples. The RNA changes must not be confused with genomic insertion or deletion size.
  evidence:
  - *id004
  - *id005
  genes:
  - *id001
  downstream:
  - target: Loss of COXFA4 protein
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Aberrant transcripts accompany loss of detectable subunit protein; a specific RNA-decay pathway is not established.
    evidence:
    - &id006
      reference: PMID:23746447
      reference_title: NDUFA4 mutations underlie dysfunction of a cytochrome c oxidase subunit linked to human neurological disease.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: NDUFA4 protein was undetectable in all affected subjects examined
      explanation: Immunoblotting and cellular staining establish loss of detectable protein in the tested muscle and fibroblasts.
- name: Loss of COXFA4 protein
  description: COXFA4 protein is undetectable in the assayed affected muscle and fibroblasts. This structural subunit supports complex IV maturation and activity; it is not a complex I subunit.
  evidence:
  - *id006
  - &id009
    reference: PMID:42218136
    reference_title: COXFA4L2 upregulation preserves residual cytochrome c oxidase activity in COXFA4-related Leigh-like encephalopathy.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Stable expression of wild-type COXFA4 in fibroblasts of S2 (c.131+1 G > C), S4 (c.131+5 G > A), and S5 (c.42+2 T > C, Fig. 6A) significantly restored complex IV activity
    explanation: Patient-cell complementation supports a causal COXFA4 defect.
  genes:
  - *id001
  downstream:
  - target: Reduced mature complex IV accumulation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Loss of the late-incorporating subunit impairs stable holoenzyme accumulation.
    evidence:
    - &id007
      reference: PMID:42218136
      reference_title: COXFA4L2 upregulation preserves residual cytochrome c oxidase activity in COXFA4-related Leigh-like encephalopathy.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: This analysis revealed a reduction in fully assembled complex IV in all COXFA4-deficient samples
      explanation: BN-PAGE shows reduced assembled enzyme in the assayed patient-derived fibroblasts.
    - &id008
      reference: PMID:42218136
      reference_title: COXFA4L2 upregulation preserves residual cytochrome c oxidase activity in COXFA4-related Leigh-like encephalopathy.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: The observation that all COX-containing assemblies still form, although at lower levels, is consistent with this late-stage role.
      explanation: The defect affects late maturation and stable accumulation, rather than preventing all core-complex assembly.
  - target: Increased COXFA4L2 expression
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Assayed deficient fibroblasts increase paralog expression through an unresolved regulatory pathway.
    evidence:
    - &id012
      reference: PMID:42218136
      reference_title: COXFA4L2 upregulation preserves residual cytochrome c oxidase activity in COXFA4-related Leigh-like encephalopathy.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: COXFA4L2 mRNA expression was significantly upregulated in all cases, particularly in S3
      explanation: qPCR establishes increased paralog transcripts in the assayed fibroblasts; the induction pathway is unresolved.
  - target: Reduced ODC-pathway transcripts in experimental models
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: COXFA4 knockout is associated with reduced ODC-pathway transcripts; the connection to respiratory-complex activity is unresolved.
    evidence:
    - &id016
      reference: PMID:39967265
      reference_title: Polyamine metabolism is dysregulated in COXFA4-related mitochondrial disease.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: We were particularly struck by the decrease in nearly all components of the ODC pathway
      explanation: Reanalysis of COXFA4-knockout iPSC RNA-seq identified reduced pathway transcripts; this is experimental rather than patient-tissue evidence.
- name: Reduced mature complex IV accumulation
  description: Core assemblies can still form without COXFA4, but late stable holoenzyme accumulation is reduced in patient fibroblasts. Reduced respirasome abundance appears secondary to limited mature complex IV. Earlier patient muscle showed assembled enzyme without abnormal subassemblies.
  evidence:
  - *id007
  - *id008
  - reference: PMID:23746447
    reference_title: NDUFA4 mutations underlie dysfunction of a cytochrome c oxidase subunit linked to human neurological disease.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: the COX enzyme complex without NDUFA4 was detectable with no abnormal subassemblies in patient muscle
    explanation: Patient muscle demonstrates preserved core assembly despite subunit loss.
  genes:
  - *id001
  conforms_to: complex_iv_assembly_deficiency#Complex IV Biogenesis Failure
  biological_processes:
  - preferred_term: mitochondrial respiratory chain complex IV assembly
    term:
      id: GO:0033617
      label: mitochondrial respiratory chain complex IV assembly
    modifier: DECREASED
  downstream:
  - target: Reduced complex IV activity
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Impaired maturation and stable accumulation accompany reduced enzyme activity.
    evidence:
    - &id010
      reference: PMID:42218136
      reference_title: COXFA4L2 upregulation preserves residual cytochrome c oxidase activity in COXFA4-related Leigh-like encephalopathy.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: spectrophotometric measurements of COXFA4-deficient samples showed a 60–85% reduction complex IV enzymatic activity
      explanation: This is the range in the study fibroblast assays, not a universal tissue or patient percentage.
    - *id009
- name: Reduced complex IV activity
  description: Complex IV activity is reduced with residual activity retained. The magnitude varies with tissue and culture conditions; normal glucose-grown fibroblast measurements have been reported. COXFA4 supports holoenzyme function rather than catalyzing electron transfer independently.
  evidence:
  - *id010
  - &id026
    reference: PMID:23746447
    reference_title: NDUFA4 mutations underlie dysfunction of a cytochrome c oxidase subunit linked to human neurological disease.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: current diagnostic procedures that typically use glucose as a carbon source in the culture medium may not detect a reduction in COX activity.
    explanation: Normal glucose-grown fibroblast activity does not exclude the disorder.
  genes:
  - *id001
  molecular_functions:
  - preferred_term: cytochrome-c oxidase activity
    term:
      id: GO:0004129
      label: cytochrome-c oxidase activity
    modifier: DECREASED
  downstream:
  - target: Impaired mitochondrial respiration
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Reduced terminal respiratory enzyme function accompanies lower cellular oxygen consumption.
    evidence:
    - &id011
      reference: PMID:42218136
      reference_title: COXFA4L2 upregulation preserves residual cytochrome c oxidase activity in COXFA4-related Leigh-like encephalopathy.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: showed a significant decrease in basal respiration (∼50%) and ATP-linked oxygen consumption (∼46%) in all samples
      explanation: Seahorse measurements in the specified patient fibroblasts establish impaired respiration; ATP-linked OCR is not a direct measurement of cellular ATP concentration.
- name: Impaired mitochondrial respiration
  description: Patient-derived fibroblasts show lower basal respiration and ATP-linked oxygen consumption. These assays do not establish universal ATP depletion, oxidative stress or a specific neuronal injury pathway in patients.
  evidence:
  - *id011
  biological_processes:
  - preferred_term: aerobic respiration
    term:
      id: GO:0009060
      label: aerobic respiration
    modifier: DECREASED
  downstream:
  - target: Global developmental delay
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: The inherited respiratory defect is associated with this clinical manifestation; intervening tissue mechanisms are incompletely defined.
    evidence:
    - reference: PMID:42218136
      reference_title: COXFA4L2 upregulation preserves residual cytochrome c oxidase activity in COXFA4-related Leigh-like encephalopathy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Common clinical features included neonatal or early infantile hypotonia, progressive motor impairment, spasticity, global developmental delay, and varying degrees of intellectual disability.
      explanation: The cohort establishes these human manifestations without a population penetrance estimate.
  - target: Hypotonia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: The inherited respiratory defect is associated with this clinical manifestation; intervening tissue mechanisms are incompletely defined.
    evidence:
    - reference: PMID:42218136
      reference_title: COXFA4L2 upregulation preserves residual cytochrome c oxidase activity in COXFA4-related Leigh-like encephalopathy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Common clinical features included neonatal or early infantile hypotonia, progressive motor impairment, spasticity, global developmental delay, and varying degrees of intellectual disability.
      explanation: The cohort establishes these human manifestations without a population penetrance estimate.
  - target: Spasticity
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: The inherited respiratory defect is associated with this clinical manifestation; intervening tissue mechanisms are incompletely defined.
    evidence:
    - reference: PMID:42218136
      reference_title: COXFA4L2 upregulation preserves residual cytochrome c oxidase activity in COXFA4-related Leigh-like encephalopathy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Common clinical features included neonatal or early infantile hypotonia, progressive motor impairment, spasticity, global developmental delay, and varying degrees of intellectual disability.
      explanation: The cohort establishes these human manifestations without a population penetrance estimate.
  - target: Lactic acidosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: The inherited respiratory-chain defect is associated with this clinical manifestation. This link summarizes the disease-level relationship; the intervening tissue mechanisms have not been resolved.
    evidence:
    - reference: PMID:42218136
      reference_title: COXFA4L2 upregulation preserves residual cytochrome c oxidase activity in COXFA4-related Leigh-like encephalopathy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: All individuals presented with a Leigh-like neurodevelopmental disorder, characterised by progressive developmental delays, neurodegeneration, muscle weakness, and lactic acidosis.
      explanation: Human observations support the clinical association with COXFA4 deficiency, without identifying each intervening mechanism.
  - target: Leukoencephalopathy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: The inherited respiratory-chain defect is associated with this clinical manifestation. This link summarizes the disease-level relationship; the intervening tissue mechanisms have not been resolved.
    evidence:
    - reference: PMID:42218136
      reference_title: COXFA4L2 upregulation preserves residual cytochrome c oxidase activity in COXFA4-related Leigh-like encephalopathy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: revealed symmetrical white matter abnormalities, predominantly affecting the periventricular, corpus callosum, brainstem, and dentate regions
      explanation: Human observations support the clinical association with COXFA4 deficiency, without identifying each intervening mechanism.
  - target: Cardiomyopathy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: The inherited respiratory-chain defect is associated with this clinical manifestation. This link summarizes the disease-level relationship; the intervening tissue mechanisms have not been resolved.
    evidence:
    - reference: PMID:42218136
      reference_title: COXFA4L2 upregulation preserves residual cytochrome c oxidase activity in COXFA4-related Leigh-like encephalopathy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Systemic involvement was also observed, including cardiomyopathy or conduction abnormalities (S1-3, S5, S7), bulbar dysfunction (S5, S14), skeletal abnormalities such as scoliosis (S5, S9), and endocrine or metabolic features (S1, S7, S14).
      explanation: Human observations support the clinical association with COXFA4 deficiency, without identifying each intervening mechanism.
- name: Increased COXFA4L2 expression
  description: COXFA4-deficient fibroblasts and SH-SY5Y knockdown cells upregulate the paralog. The induction mechanism is unresolved; increased HIF-1alpha was not observed. Compensation in primary neurons in vivo is unproven.
  evidence:
  - *id012
  genes:
  - &id015
    preferred_term: COXFA4L2
    term:
      id: hgnc:29836
      label: NDUFA4L2
  biological_processes:
  - preferred_term: gene expression
    term:
      id: GO:0010467
      label: gene expression
    modifier: INCREASED
  downstream:
  - target: Partial paralog compensation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: COXFA4L2 can partly substitute for the missing subunit in tested cells.
    evidence:
    - &id013
      reference: PMID:42218136
      reference_title: COXFA4L2 upregulation preserves residual cytochrome c oxidase activity in COXFA4-related Leigh-like encephalopathy.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Expression of COXFA4L2 also improved complex IV activity, though less effectively, with a ∼1.7-fold increase relative to uncomplemented cells
      explanation: Paralog overexpression provides partial functional rescue in patient fibroblasts, not proven clinical benefit.
    - &id014
      reference: PMID:42218136
      reference_title: COXFA4L2 upregulation preserves residual cytochrome c oxidase activity in COXFA4-related Leigh-like encephalopathy.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Basal respiration was preserved, whereas maximal respiration was significantly reduced in S14 COXFA4L2-depleted cells relative to S14.
      explanation: Paralog depletion in one patient line reduces respiratory reserve, supporting a compensatory role.
- name: Partial paralog compensation
  description: COXFA4L2 overexpression partially restores complex IV activity, and its depletion reduces respiratory reserve in one patient line. This is cellular compensation, not a proven determinant of individual clinical severity.
  evidence:
  - *id013
  - *id014
  genes:
  - *id015
  molecular_functions:
  - preferred_term: cytochrome-c oxidase activity
    term:
      id: GO:0004129
      label: cytochrome-c oxidase activity
    modifier: INCREASED
- name: Reduced ODC-pathway transcripts in experimental models
  description: COXFA4-knockout iPSC transcriptomics and Xenopus experiments show reduced ODC-pathway components. A larger reduction of odc1 and azin1 than inhibitory oaz1 is reported in embryos. The pathway has not been measured in affected human tissues.
  evidence:
  - *id016
  - reference: PMID:39967265
    reference_title: Polyamine metabolism is dysregulated in COXFA4-related mitochondrial disease.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: there was a larger decrease in integral components of the ODC pathway (odc1 and azin1) compared to inhibitory ODC pathway component oaz1.
    explanation: Embryonic qPCR supports an altered balance of pathway transcripts.
  downstream:
  - target: Reduced polyamine abundance in Xenopus
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Reduced biosynthetic-pathway expression accompanies lower total polyamines in the model.
    evidence:
    - &id017
      reference: PMID:39967265
      reference_title: Polyamine metabolism is dysregulated in COXFA4-related mitochondrial disease.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: we observed a decrease in global polyamine levels in coxfa4 crispant embryos
      explanation: A whole-embryo assay supports reduced polyamine abundance in mosaic Xenopus mutants.
- name: Reduced polyamine abundance in Xenopus
  description: Total polyamine abundance is reduced in mosaic coxfa4-mutant embryos. Polyamine supplementation improves cardiac function and survival without restoring complex IV activity; applicability to patient myocardium remains unproven.
  evidence:
  - *id017
  - &id023
    reference: PMID:39967265
    reference_title: Polyamine metabolism is dysregulated in COXFA4-related mitochondrial disease.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: We observed improvement in cardiomyopathy severity upon polyamine exposure (Figure 5A; Video S3) and improvement in overall survival
    explanation: Supplementation improves outcomes in Xenopus; human efficacy and dosing are not established.
  - &id024
    reference: PMID:39967265
    reference_title: Polyamine metabolism is dysregulated in COXFA4-related mitochondrial disease.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: In-gel complex IV activity remained decreased despite polyamine supplementation
    explanation: The cardiac benefit in the animal model does not establish restoration of respiratory-complex activity.
phenotypes:
- name: Global developmental delay
  description: Reported in affected individuals with COXFA4-related mitochondrial disease; expression varies between individuals.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:42218136
    reference_title: COXFA4L2 upregulation preserves residual cytochrome c oxidase activity in COXFA4-related Leigh-like encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Common clinical features included neonatal or early infantile hypotonia, progressive motor impairment, spasticity, global developmental delay, and varying degrees of intellectual disability.
    explanation: This is a human clinical finding, not an animal-model phenotype or a population frequency.
- name: Hypotonia
  description: Reported in affected individuals with COXFA4-related mitochondrial disease; expression varies between individuals.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:42218136
    reference_title: COXFA4L2 upregulation preserves residual cytochrome c oxidase activity in COXFA4-related Leigh-like encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Common clinical features included neonatal or early infantile hypotonia, progressive motor impairment, spasticity, global developmental delay, and varying degrees of intellectual disability.
    explanation: This is a human clinical finding, not an animal-model phenotype or a population frequency.
- name: Spasticity
  description: Reported in affected individuals with COXFA4-related mitochondrial disease; expression varies between individuals.
  phenotype_term:
    preferred_term: Spasticity
    term:
      id: HP:0001257
      label: Spasticity
  evidence:
  - reference: PMID:42218136
    reference_title: COXFA4L2 upregulation preserves residual cytochrome c oxidase activity in COXFA4-related Leigh-like encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Common clinical features included neonatal or early infantile hypotonia, progressive motor impairment, spasticity, global developmental delay, and varying degrees of intellectual disability.
    explanation: This is a human clinical finding, not an animal-model phenotype or a population frequency.
- name: Intellectual disability
  description: Reported in affected individuals with COXFA4-related mitochondrial disease; expression varies between individuals.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:42218136
    reference_title: COXFA4L2 upregulation preserves residual cytochrome c oxidase activity in COXFA4-related Leigh-like encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Common clinical features included neonatal or early infantile hypotonia, progressive motor impairment, spasticity, global developmental delay, and varying degrees of intellectual disability.
    explanation: This is a human clinical finding, not an animal-model phenotype or a population frequency.
- name: Ataxia
  description: Ataxia, described as cerebellar in several affected individuals, is part of the reported movement-disorder spectrum. Progression varies between individuals.
  phenotype_term:
    preferred_term: Ataxia
    term:
      id: HP:0001251
      label: Ataxia
  evidence:
  - reference: PMID:42218136
    reference_title: COXFA4L2 upregulation preserves residual cytochrome c oxidase activity in COXFA4-related Leigh-like encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Additional neurological manifestations included cerebellar ataxia (S1, S3, S4, S7, S11), dystonia (S1, S9, S11, S12), ptosis (S3), nystagmus (S4, S7), dysarthria (S1, S7, S11), pyramidal signs (S9–S12), peripheral neuropathy (S14), developmental regression (S1, S9), and seizures (S4, S14).
    explanation: This is a human clinical finding, not an animal-model phenotype or a population frequency.
- name: Dystonia
  description: Reported in affected individuals with COXFA4-related mitochondrial disease; expression varies between individuals.
  phenotype_term:
    preferred_term: Dystonia
    term:
      id: HP:0001332
      label: Dystonia
  evidence:
  - reference: PMID:42218136
    reference_title: COXFA4L2 upregulation preserves residual cytochrome c oxidase activity in COXFA4-related Leigh-like encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Additional neurological manifestations included cerebellar ataxia (S1, S3, S4, S7, S11), dystonia (S1, S9, S11, S12), ptosis (S3), nystagmus (S4, S7), dysarthria (S1, S7, S11), pyramidal signs (S9–S12), peripheral neuropathy (S14), developmental regression (S1, S9), and seizures (S4, S14).
    explanation: This is a human clinical finding, not an animal-model phenotype or a population frequency.
- name: Nystagmus
  description: Reported in affected individuals with COXFA4-related mitochondrial disease; expression varies between individuals.
  phenotype_term:
    preferred_term: Nystagmus
    term:
      id: HP:0000639
      label: Nystagmus
  evidence:
  - reference: PMID:42218136
    reference_title: COXFA4L2 upregulation preserves residual cytochrome c oxidase activity in COXFA4-related Leigh-like encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Additional neurological manifestations included cerebellar ataxia (S1, S3, S4, S7, S11), dystonia (S1, S9, S11, S12), ptosis (S3), nystagmus (S4, S7), dysarthria (S1, S7, S11), pyramidal signs (S9–S12), peripheral neuropathy (S14), developmental regression (S1, S9), and seizures (S4, S14).
    explanation: This is a human clinical finding, not an animal-model phenotype or a population frequency.
- name: Dysarthria
  description: Reported in affected individuals with COXFA4-related mitochondrial disease; expression varies between individuals.
  phenotype_term:
    preferred_term: Dysarthria
    term:
      id: HP:0001260
      label: Dysarthria
  evidence:
  - reference: PMID:42218136
    reference_title: COXFA4L2 upregulation preserves residual cytochrome c oxidase activity in COXFA4-related Leigh-like encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Additional neurological manifestations included cerebellar ataxia (S1, S3, S4, S7, S11), dystonia (S1, S9, S11, S12), ptosis (S3), nystagmus (S4, S7), dysarthria (S1, S7, S11), pyramidal signs (S9–S12), peripheral neuropathy (S14), developmental regression (S1, S9), and seizures (S4, S14).
    explanation: This is a human clinical finding, not an animal-model phenotype or a population frequency.
- name: Developmental regression
  description: Reported in affected individuals with COXFA4-related mitochondrial disease; expression varies between individuals.
  phenotype_term:
    preferred_term: Developmental regression
    term:
      id: HP:0002376
      label: Developmental regression
  evidence:
  - reference: PMID:42218136
    reference_title: COXFA4L2 upregulation preserves residual cytochrome c oxidase activity in COXFA4-related Leigh-like encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Additional neurological manifestations included cerebellar ataxia (S1, S3, S4, S7, S11), dystonia (S1, S9, S11, S12), ptosis (S3), nystagmus (S4, S7), dysarthria (S1, S7, S11), pyramidal signs (S9–S12), peripheral neuropathy (S14), developmental regression (S1, S9), and seizures (S4, S14).
    explanation: This is a human clinical finding, not an animal-model phenotype or a population frequency.
- name: Seizures
  description: Reported in affected individuals with COXFA4-related mitochondrial disease; expression varies between individuals.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:42218136
    reference_title: COXFA4L2 upregulation preserves residual cytochrome c oxidase activity in COXFA4-related Leigh-like encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Additional neurological manifestations included cerebellar ataxia (S1, S3, S4, S7, S11), dystonia (S1, S9, S11, S12), ptosis (S3), nystagmus (S4, S7), dysarthria (S1, S7, S11), pyramidal signs (S9–S12), peripheral neuropathy (S14), developmental regression (S1, S9), and seizures (S4, S14).
    explanation: This is a human clinical finding, not an animal-model phenotype or a population frequency.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/
    reference_title: Nuclear Gene-Encoded Leigh Syndrome Spectrum Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: COXFA4 ... Epilepsy; sensory axonal peripheral neuropathy; leukoencephalopathy ... Slowly progressive; survival into 20s/30s
    explanation: The COXFA4-specific row supports these clinical associations and adult survival; its fraction of LSS is not phenotype frequency.
- name: Scoliosis
  description: Reported in affected individuals with COXFA4-related mitochondrial disease; expression varies between individuals.
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  evidence:
  - reference: PMID:42218136
    reference_title: COXFA4L2 upregulation preserves residual cytochrome c oxidase activity in COXFA4-related Leigh-like encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Systemic involvement was also observed, including cardiomyopathy or conduction abnormalities (S1-3, S5, S7), bulbar dysfunction (S5, S14), skeletal abnormalities such as scoliosis (S5, S9), and endocrine or metabolic features (S1, S7, S14).
    explanation: The cohort explicitly reports scoliosis; other neurological manifestations are not evidence for this skeletal finding.
- name: Leukoencephalopathy
  description: Reported in affected individuals with COXFA4-related mitochondrial disease; expression varies between individuals.
  phenotype_term:
    preferred_term: Leukoencephalopathy
    term:
      id: HP:0002352
      label: Leukoencephalopathy
  evidence:
  - reference: PMID:42218136
    reference_title: COXFA4L2 upregulation preserves residual cytochrome c oxidase activity in COXFA4-related Leigh-like encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: revealed symmetrical white matter abnormalities, predominantly affecting the periventricular, corpus callosum, brainstem, and dentate regions
    explanation: This is a human clinical finding, not an animal-model phenotype or a population frequency.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/
    reference_title: Nuclear Gene-Encoded Leigh Syndrome Spectrum Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: COXFA4 ... Epilepsy; sensory axonal peripheral neuropathy; leukoencephalopathy ... Slowly progressive; survival into 20s/30s
    explanation: The COXFA4-specific row supports these clinical associations and adult survival; its fraction of LSS is not phenotype frequency.
- name: Muscle weakness
  description: Reported in affected individuals with COXFA4-related mitochondrial disease; expression varies between individuals.
  phenotype_term:
    preferred_term: Muscle weakness
    term:
      id: HP:0001324
      label: Muscle weakness
  evidence:
  - reference: PMID:42218136
    reference_title: COXFA4L2 upregulation preserves residual cytochrome c oxidase activity in COXFA4-related Leigh-like encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: progressive developmental delays, neurodegeneration, muscle weakness, and lactic acidosis.
    explanation: This is a human clinical finding, not an animal-model phenotype or a population frequency.
- name: Sensory axonal neuropathy
  description: Reported in affected individuals with COXFA4-related mitochondrial disease; expression varies between individuals.
  phenotype_term:
    preferred_term: Sensory axonal neuropathy
    term:
      id: HP:0003390
      label: Sensory axonal neuropathy
  evidence:
  - reference: PMID:23746447
    reference_title: NDUFA4 mutations underlie dysfunction of a cytochrome c oxidase subunit linked to human neurological disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Nerve conduction studies indicated there was a sensory axonal peripheral neuropathy.
    explanation: This is a human clinical finding, not an animal-model phenotype or a population frequency.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/
    reference_title: Nuclear Gene-Encoded Leigh Syndrome Spectrum Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: COXFA4 ... Epilepsy; sensory axonal peripheral neuropathy; leukoencephalopathy ... Slowly progressive; survival into 20s/30s
    explanation: The COXFA4-specific row supports these clinical associations and adult survival; its fraction of LSS is not phenotype frequency.
- name: Lactic acidosis
  description: Reported in affected individuals with COXFA4-related mitochondrial disease; expression varies between individuals.
  phenotype_term:
    preferred_term: Lactic acidosis
    term:
      id: HP:0003128
      label: Lactic acidosis
  evidence:
  - reference: PMID:39967265
    reference_title: Polyamine metabolism is dysregulated in COXFA4-related mitochondrial disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Both have persistent lactic acidosis in the range of 3–7 mmol/L.
    explanation: This is a human clinical finding, not an animal-model phenotype or a population frequency.
- name: Microcephaly
  description: Reported in affected individuals with COXFA4-related mitochondrial disease; expression varies between individuals.
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  evidence:
  - reference: PMID:39967265
    reference_title: Polyamine metabolism is dysregulated in COXFA4-related mitochondrial disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Individual IV-6 initially presented neonatally with cardiomyopathy, microcephaly, and faltering growth
    explanation: This is a human clinical finding, not an animal-model phenotype or a population frequency.
- name: Failure to thrive
  description: Reported in affected individuals with COXFA4-related mitochondrial disease; expression varies between individuals.
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: PMID:39967265
    reference_title: Polyamine metabolism is dysregulated in COXFA4-related mitochondrial disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Individual IV-6 initially presented neonatally with cardiomyopathy, microcephaly, and faltering growth
    explanation: This is a human clinical finding, not an animal-model phenotype or a population frequency.
- name: Short stature
  description: Reported in affected individuals with COXFA4-related mitochondrial disease; expression varies between individuals.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:39967265
    reference_title: Polyamine metabolism is dysregulated in COXFA4-related mitochondrial disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: He has remained small for age and at last evaluation had a height Z score of −3.2
    explanation: This is a human clinical finding, not an animal-model phenotype or a population frequency.
- name: Cardiomyopathy
  description: Cardiomyopathy occurs in some affected individuals. Reported cardiac findings include ventricular hypertrophy and, in the genetically confirmed 2025 infant, structural outflow abnormalities; not all reports establish primary hypertrophic cardiomyopathy. An untested deceased sibling is not counted as genetically confirmed.
  phenotype_term:
    preferred_term: Cardiomyopathy
    term:
      id: HP:0001638
      label: Cardiomyopathy
  evidence:
  - reference: PMID:39967265
    reference_title: Polyamine metabolism is dysregulated in COXFA4-related mitochondrial disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Individual IV-6 initially presented neonatally with cardiomyopathy, microcephaly, and faltering growth
    explanation: This is a human clinical finding, not an animal-model phenotype or a population frequency.
- name: Thin corpus callosum
  description: Reported in affected individuals with COXFA4-related mitochondrial disease; expression varies between individuals.
  phenotype_term:
    preferred_term: Thin corpus callosum
    term:
      id: HP:0033725
      label: Thin corpus callosum
  evidence:
  - reference: PMID:39967265
    reference_title: Polyamine metabolism is dysregulated in COXFA4-related mitochondrial disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: she was found to have a thin corpus callosum and scattered T2-weighted hyperintensities near the gray-white matter junction
    explanation: This is a human clinical finding, not an animal-model phenotype or a population frequency.
- name: Feeding difficulties
  description: Reported in affected individuals with COXFA4-related mitochondrial disease; expression varies between individuals.
  phenotype_term:
    preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  evidence:
  - reference: PMID:42218136
    reference_title: COXFA4L2 upregulation preserves residual cytochrome c oxidase activity in COXFA4-related Leigh-like encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Initial symptom | Hypotonia, poor feeding, lethargic | Respiratory distress (birth) raised lactate | Respiratory distress (birth) | Born at 32/40, respiratory distress, NGT fed | Respiratory distress (birth) feeding difficulties
    explanation: This is a human clinical finding, not an animal-model phenotype or a population frequency.
- name: Constipation
  description: Reported in affected individuals with COXFA4-related mitochondrial disease; expression varies between individuals.
  phenotype_term:
    preferred_term: Constipation
    term:
      id: HP:0002019
      label: Constipation
  evidence:
  - reference: PMID:42218136
    reference_title: COXFA4L2 upregulation preserves residual cytochrome c oxidase activity in COXFA4-related Leigh-like encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Gastrointestinal | Constipation | Constipation | -- | -- | Vomiting, PEG-fed | Constipation
    explanation: This is a human clinical finding, not an animal-model phenotype or a population frequency.
- name: Wolff-Parkinson-White pattern
  description: Reported in affected individuals with COXFA4-related mitochondrial disease; expression varies between individuals.
  phenotype_term:
    preferred_term: Wolff-Parkinson-White syndrome
    term:
      id: HP:0001716
      label: Wolff-Parkinson-White syndrome
  evidence:
  - reference: PMID:42218136
    reference_title: COXFA4L2 upregulation preserves residual cytochrome c oxidase activity in COXFA4-related Leigh-like encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Cardiology | WPW pattern, mild LV hypertrophy | Biventricular hypertrophy | Persistent patent ductus arteriosus | – | Concentric LV hypertrophy
    explanation: This is a human clinical finding, not an animal-model phenotype or a population frequency.
- name: Respiratory distress
  description: Neonatal respiratory distress was reported in several individuals; the premature birth and other perinatal circumstances of individual cases must also be considered.
  phenotype_term:
    preferred_term: Respiratory distress
    term:
      id: HP:0002098
      label: Respiratory distress
  evidence:
  - reference: PMID:42218136
    reference_title: COXFA4L2 upregulation preserves residual cytochrome c oxidase activity in COXFA4-related Leigh-like encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Initial symptom | Hypotonia, poor feeding, lethargic | Respiratory distress (birth) raised lactate | Respiratory distress (birth) | Born at 32/40, respiratory distress, NGT fed
    explanation: This is a human clinical finding, not an animal-model phenotype or a population frequency.
- name: Joint contractures
  description: Reported in affected individuals with COXFA4-related mitochondrial disease; expression varies between individuals.
  phenotype_term:
    preferred_term: Joint contracture
    term:
      id: HP:0034392
      label: Joint contracture
  evidence:
  - reference: PMID:42218136
    reference_title: COXFA4L2 upregulation preserves residual cytochrome c oxidase activity in COXFA4-related Leigh-like encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Neuromuscular | Proximal muscle weakness, non-ambulatory | Hypotonia | Muscle weakness, ptosis | Exercise intolerance, limb contractures
    explanation: This is a human clinical finding, not an animal-model phenotype or a population frequency.
- name: Delayed speech and language development
  description: Reported in affected individuals with COXFA4-related mitochondrial disease; expression varies between individuals.
  phenotype_term:
    preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  evidence:
  - reference: PMID:42218136
    reference_title: COXFA4L2 upregulation preserves residual cytochrome c oxidase activity in COXFA4-related Leigh-like encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Speech | No speech | 1st word (2 y), speaks in short sentences | Delayed | No speech | 1 word (1.5 y), sentence (8.5 y)
    explanation: This is a human clinical finding, not an animal-model phenotype or a population frequency.
- name: Exercise intolerance
  description: Reported in affected individuals with COXFA4-related mitochondrial disease; expression varies between individuals.
  phenotype_term:
    preferred_term: Exercise intolerance
    term:
      id: HP:0003546
      label: Exercise intolerance
  evidence:
  - reference: PMID:42218136
    reference_title: COXFA4L2 upregulation preserves residual cytochrome c oxidase activity in COXFA4-related Leigh-like encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Neuromuscular | Proximal muscle weakness, non-ambulatory | Hypotonia | Muscle weakness, ptosis | Exercise intolerance, limb contractures
    explanation: This is a human clinical finding, not an animal-model phenotype or a population frequency.
- name: Patent ductus arteriosus
  description: Reported in affected individuals with COXFA4-related mitochondrial disease; expression varies between individuals.
  phenotype_term:
    preferred_term: Patent ductus arteriosus
    term:
      id: HP:0001643
      label: Patent ductus arteriosus
  evidence:
  - reference: PMID:42218136
    reference_title: COXFA4L2 upregulation preserves residual cytochrome c oxidase activity in COXFA4-related Leigh-like encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Cardiology | WPW pattern, mild LV hypertrophy | Biventricular hypertrophy | Persistent patent ductus arteriosus | – | Concentric LV hypertrophy
    explanation: This is a human clinical finding, not an animal-model phenotype or a population frequency.
- name: Muscle atrophy
  description: Reported in affected individuals with COXFA4-related mitochondrial disease; expression varies between individuals.
  phenotype_term:
    preferred_term: Skeletal muscle atrophy
    term:
      id: HP:0003202
      label: Skeletal muscle atrophy
  evidence:
  - reference: PMID:42218136
    reference_title: COXFA4L2 upregulation preserves residual cytochrome c oxidase activity in COXFA4-related Leigh-like encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Neuromuscular | MW, hypotonia, non-ambulatory | MW, hypotonia | -- | Mild scoliosis, LC (ankle) | MW, hypotonia, LC, EI (7 y) | Mild MA | Mild MA | -- ... MA Muscle atrophy
    explanation: This is a human clinical finding, not an animal-model phenotype or a population frequency.
- name: Pyramidal signs
  description: Reported in the COXFA4 clinical cohort; the small case series does not establish a population frequency.
  phenotype_term:
    preferred_term: Abnormal pyramidal sign
    term:
      id: HP:0007256
      label: Abnormal pyramidal sign
  evidence:
  - reference: PMID:42218136
    reference_title: COXFA4L2 upregulation preserves residual cytochrome c oxidase activity in COXFA4-related Leigh-like encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Additional neurological manifestations included cerebellar ataxia (S1, S3, S4, S7, S11), dystonia (S1, S9, S11, S12), ptosis (S3), nystagmus (S4, S7), dysarthria (S1, S7, S11), pyramidal signs (S9–S12), peripheral neuropathy (S14), developmental regression (S1, S9), and seizures (S4, S14).
    explanation: The clinical text or table identifies this manifestation; abbreviated table terms are expanded in the source legend.
- name: Dysphagia
  description: Reported in the COXFA4 clinical cohort; the small case series does not establish a population frequency.
  phenotype_term:
    preferred_term: Dysphagia
    term:
      id: HP:0002015
      label: Dysphagia
  evidence:
  - reference: PMID:42218136
    reference_title: COXFA4L2 upregulation preserves residual cytochrome c oxidase activity in COXFA4-related Leigh-like encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Neuromuscular | Proximal muscle weakness, non-ambulatory | Hypotonia | Muscle weakness, ptosis | Exercise intolerance, limb contractures | Myopathic face, non-ambulatory | Sensory axonal neuropathy, dysphagia
    explanation: The clinical text or table identifies this manifestation; abbreviated table terms are expanded in the source legend.
- name: Ptosis
  description: Reported in the COXFA4 clinical cohort; the small case series does not establish a population frequency.
  phenotype_term:
    preferred_term: Ptosis
    term:
      id: HP:0000508
      label: Ptosis
  evidence:
  - reference: PMID:42218136
    reference_title: COXFA4L2 upregulation preserves residual cytochrome c oxidase activity in COXFA4-related Leigh-like encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Additional neurological manifestations included cerebellar ataxia (S1, S3, S4, S7, S11), dystonia (S1, S9, S11, S12), ptosis (S3), nystagmus (S4, S7), dysarthria (S1, S7, S11), pyramidal signs (S9–S12), peripheral neuropathy (S14), developmental regression (S1, S9), and seizures (S4, S14).
    explanation: The clinical text or table identifies this manifestation; abbreviated table terms are expanded in the source legend.
- name: Optic atrophy
  description: Reported in the COXFA4 clinical cohort; the small case series does not establish a population frequency.
  phenotype_term:
    preferred_term: Optic atrophy
    term:
      id: HP:0000648
      label: Optic atrophy
  evidence:
  - reference: PMID:42218136
    reference_title: COXFA4L2 upregulation preserves residual cytochrome c oxidase activity in COXFA4-related Leigh-like encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Ophthalmology | -- | Mild OA, nystagmus | -- | Convergent L eye squint ... OA Optic atrophy
    explanation: The clinical text or table identifies this manifestation; abbreviated table terms are expanded in the source legend.
- name: Cataract
  description: Reported in the COXFA4 clinical cohort; the small case series does not establish a population frequency.
  phenotype_term:
    preferred_term: Cataract
    term:
      id: HP:0000518
      label: Cataract
  evidence:
  - reference: PMID:42218136
    reference_title: COXFA4L2 upregulation preserves residual cytochrome c oxidase activity in COXFA4-related Leigh-like encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Ophthalmology | Nystagmus | Cataract | – | Nystagmus | – | –
    explanation: The clinical text or table identifies this manifestation; abbreviated table terms are expanded in the source legend.
- name: Supraventricular tachycardia
  description: Reported in the COXFA4 clinical cohort; the small case series does not establish a population frequency.
  phenotype_term:
    preferred_term: Supraventricular tachycardia
    term:
      id: HP:0004755
      label: Supraventricular tachycardia
  evidence:
  - reference: PMID:42218136
    reference_title: COXFA4L2 upregulation preserves residual cytochrome c oxidase activity in COXFA4-related Leigh-like encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Cardiology | -- | SVT, WPW, closed PDA | -- | -- | -- | -- | -- | -- ... SVT Supraventricular tachycardia
    explanation: The clinical text or table identifies this manifestation; abbreviated table terms are expanded in the source legend.
genetic:
- name: COXFA4
  gene_term: *id001
  inheritance:
  - &id025
    name: Autosomal recessive
    evidence:
    - reference: PMID:23746447
      reference_title: NDUFA4 mutations underlie dysfunction of a cytochrome c oxidase subunit linked to human neurological disease.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: all four affected individuals were homozygous for the mutation, whereas three unaffected family members (II-2, III-1, and III-2) were heterozygous
      explanation: Segregation in the founding pedigree supports recessive inheritance.
  features: Biallelic splice-altering variants and gene-overlapping structural variants cause loss of function. Clinical severity is variable, and neither variant class nor measured fibroblast paralog expression alone establishes prognosis.
  variants:
  - name: NM_002489.3:c.42+1G>C
    description: Founding homozygous donor-1 SNV; four-base intron retention in RNA predicts a frameshift. Some wild-type RNA remains in blood.
    gene: *id001
    variant_type: single nucleotide variant
    clinical_significance: PATHOGENIC
    evidence:
    - *id018
    - *id004
    genomic_contexts:
    - intron
  - name: NM_002489.4:c.131+1G>C
    description: Homozygous intronic splice-site variant reported in the 2026 cohort. Functional RNA experiments were performed only in available fibroblast lines.
    gene: *id001
    variant_type: single nucleotide variant
    genomic_contexts:
    - intron
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:42218136
      reference_title: COXFA4L2 upregulation preserves residual cytochrome c oxidase activity in COXFA4-related Leigh-like encephalopathy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Variant | c.131+1 G > C | c.131+1 G > C | c.131+1 G > C | c.131+5 G > A | c.42+2 T > C | c.42+1 G > C
      explanation: The relevant clinical table identifies the allele; RNA conclusions are restricted to tested samples.
  - name: NM_002489.4:c.131+5G>A
    description: Homozygous intronic splice-site variant reported in the 2026 cohort. Functional RNA experiments were performed only in available fibroblast lines.
    gene: *id001
    variant_type: single nucleotide variant
    genomic_contexts:
    - intron
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:42218136
      reference_title: COXFA4L2 upregulation preserves residual cytochrome c oxidase activity in COXFA4-related Leigh-like encephalopathy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Variant | c.131+1 G > C | c.131+1 G > C | c.131+1 G > C | c.131+5 G > A | c.42+2 T > C | c.42+1 G > C
      explanation: The relevant clinical table identifies the allele; RNA conclusions are restricted to tested samples.
  - name: NM_002489.4:c.42+2T>C
    description: Homozygous intronic splice-site variant reported in the 2026 cohort. Functional RNA experiments were performed only in available fibroblast lines.
    gene: *id001
    variant_type: single nucleotide variant
    genomic_contexts:
    - intron
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:42218136
      reference_title: COXFA4L2 upregulation preserves residual cytochrome c oxidase activity in COXFA4-related Leigh-like encephalopathy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Variant | c.131+1 G > C | c.131+1 G > C | c.131+1 G > C | c.131+5 G > A | c.42+2 T > C | c.42+1 G > C
      explanation: The relevant clinical table identifies the allele; RNA conclusions are restricted to tested samples.
  - name: NM_002489.4:c.43-1G>A
    description: Homozygous intronic splice-site variant reported in the 2026 cohort. Functional RNA experiments were performed only in available fibroblast lines.
    gene: *id001
    variant_type: single nucleotide variant
    genomic_contexts:
    - intron
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:42218136
      reference_title: COXFA4L2 upregulation preserves residual cytochrome c oxidase activity in COXFA4-related Leigh-like encephalopathy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Variant | c.42+1del | c.43-1 G > A | c.131+5 G > A | c.131+5 G > A | c.131+1 G > C
      explanation: The relevant clinical table identifies the allele; RNA conclusions are restricted to tested samples.
  - name: NM_002489.4:c.42+1del
    description: One-base genomic deletion at the donor site in S6; the exact RNA effect was not directly assayed.
    gene: *id001
    variant_type: deletion
    clinical_significance: PATHOGENIC
    evidence: *id019
    genomic_contexts:
    - intron
  - name: GRCh38 chr7:10933348–10941418 deletion
    description: Homozygous deletion of the complete COXFA4 coding region without another protein-coding gene in two genotyped siblings.
    gene: *id001
    variant_type: deletion
    clinical_significance: PATHOGENIC
    evidence:
    - *id002
  - name: GRCh37 chr7:10969448–10982428 deletion-insertion
    description: Deletion of COXFA4 with a 337-bp insertion from chr19:14427161–14427497, supported by breakpoint sequencing; Alu homology suggests a rearrangement mechanism.
    gene: *id001
    type: complex deletion-insertion
    clinical_significance: PATHOGENIC
    evidence:
    - *id003
  - name: GRCh38 chr7:10932820–10940833 deletion
    description: Reported partial-gene deletion in siblings S11 and S12; preserve the paper interval without substituting the separate 2025-family deletion.
    gene: *id001
    variant_type: deletion
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:42218136
      reference_title: COXFA4L2 upregulation preserves residual cytochrome c oxidase activity in COXFA4-related Leigh-like encephalopathy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: chr7:10,932,820–10,940,833 (top panel, identified in S11 and S12)
      explanation: Figure legend supplies the GRCh38 interval.
  - name: GRCh38 chr7:10890006–10953862 deletion
    description: Reported larger genomic deletion encompassing COXFA4 in S13; the source does not establish that all effects of this wider interval are exclusively attributable to COXFA4.
    gene: *id001
    variant_type: deletion
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:42218136
      reference_title: COXFA4L2 upregulation preserves residual cytochrome c oxidase activity in COXFA4-related Leigh-like encephalopathy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: chr7:10,890,006–10,953,862 (bottom panel, identified in S13)
      explanation: Figure legend supplies the GRCh38 interval.
  evidence:
  - *id018
  - *id002
  - *id009
  gene_disease_validity:
  - validity_classification: DEFINITIVE
    classified_by: CLINGEN
    external_id: CGGV:assertion_4f142835-c031-4885-9ed4-897b96913558-2025-03-24T040000.000Z
    notes: The March 24, 2025 ClinGen assessment uses mitochondrial disease (MONDO:0044970) and explicitly includes MC4DN21 and Leigh presentations within COXFA4-related primary mitochondrial disease. This supersedes the earlier limited Leigh-only assessment.
    evidence:
    - reference: url:https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_4f142835-c031-4885-9ed4-897b96913558-2025-03-24T040000.000Z
      reference_title: curation results for Gene-Disease Validity
      supports: SUPPORT
      evidence_source: OTHER
      snippet: there is definitive evidence to support the relationship between ... and autosomal recessive ... -related primary mitochondrial disease.
      explanation: The expert panel recognizes the broader COXFA4 disease entity.
treatments:
- description: General Leigh syndrome spectrum guidance; no COXFA4-specific therapeutic trial is demonstrated. Coordinate neurological, nutritional, respiratory and rehabilitation care according to manifestations.
  evidence:
  - evidence_source: HUMAN_CLINICAL
    explanation: The chapter provides a general supportive-care framework.
    reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/
    reference_title: Nuclear Gene-Encoded Leigh Syndrome Spectrum Overview - GeneReviews® - NCBI Bookshelf
    snippet: Supportive care to improve quality of life, maximize function, and reduce complications is recommended.
    supports: SUPPORT
  name: Multidisciplinary supportive care
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
- description: General Leigh syndrome spectrum guidance; no COXFA4-specific therapeutic trial is demonstrated. An experienced neurologist should individualize antiseizure medication. The available sources do not establish a preferred COXFA4-specific drug.
  evidence:
  - &id020
    evidence_source: HUMAN_CLINICAL
    explanation: LSS guidance supports specialist antiseizure treatment.
    reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/
    reference_title: Nuclear Gene-Encoded Leigh Syndrome Spectrum Overview - GeneReviews® - NCBI Bookshelf
    snippet: Treatment w/ASM by experienced neurologist
    supports: SUPPORT
  name: Antiseizure treatment
  target_mechanisms:
  - description: Symptom-directed management from general LSS guidance; COXFA4-specific efficacy has not been established.
    evidence:
    - *id020
    target: Seizures
    treatment_effect: MODULATES
  treatment_term:
    preferred_term: Anticonvulsant Therapy
    term:
      id: NCIT:C64172
      label: Anticonvulsant Therapy
- description: General Leigh syndrome spectrum guidance; no COXFA4-specific therapeutic trial is demonstrated. Clinically significant acidosis may require sodium bicarbonate or sodium citrate, selected and monitored by the treating team.
  evidence:
  - &id021
    evidence_source: HUMAN_CLINICAL
    explanation: This recommendation treats significant acidosis in LSS, rather than repairing COXFA4.
    reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/
    reference_title: Nuclear Gene-Encoded Leigh Syndrome Spectrum Overview - GeneReviews® - NCBI Bookshelf
    snippet: Sodium bicarbonate or sodium citrate for significant acidosis
    supports: SUPPORT
  name: Acidosis correction
  target_mechanisms:
  - description: Symptom-directed management from general LSS guidance; COXFA4-specific efficacy has not been established.
    evidence:
    - *id021
    target: Lactic acidosis
    treatment_effect: MODULATES
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: sodium hydrogencarbonate
      term:
        id: CHEBI:32139
        label: sodium hydrogencarbonate
- description: General Leigh syndrome spectrum guidance; no COXFA4-specific therapeutic trial is demonstrated. Assess growth, nutritional intake and swallowing safety; provide supplementation and feeding support when indicated.
  evidence:
  - evidence_source: HUMAN_CLINICAL
    explanation: The general LSS care table recommends nutritional support when needed.
    reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/
    reference_title: Nuclear Gene-Encoded Leigh Syndrome Spectrum Overview - GeneReviews® - NCBI Bookshelf
    snippet: nutritional supplementation as needed (incl micronutrients)
    supports: SUPPORT
  name: Nutritional support
  treatment_term:
    preferred_term: Nutritional Support
    term:
      id: NCIT:C15433
      label: Nutritional Support
- description: General Leigh syndrome spectrum guidance; no COXFA4-specific therapeutic trial is demonstrated. Regular neurological, ophthalmological, hearing and cardiac assessment should be tailored to manifestations.
  evidence:
  - evidence_source: HUMAN_CLINICAL
    explanation: The chapter recommends multisystem surveillance for LSS.
    reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/
    reference_title: Nuclear Gene-Encoded Leigh Syndrome Spectrum Overview - GeneReviews® - NCBI Bookshelf
    snippet: Neurologic, ophthalmologic, audiologic, and cardiologic evaluations are recommended
    supports: SUPPORT
  name: Clinical surveillance
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
- description: General Leigh syndrome spectrum guidance; no COXFA4-specific therapeutic trial is demonstrated. Avoid sodium valproate if possible; the absolute POLG contraindication should not be relabeled as a COXFA4-specific rule. Plan anesthesia and monitoring, minimize prolonged fasting, and avoid lactate-containing solutions in those at risk of lactic acidosis.
  evidence:
  - evidence_source: HUMAN_CLINICAL
    explanation: This is the general mitochondrial-disease precaution, with the separate absolute contraindication applying to POLG-related disease.
    reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/
    reference_title: Nuclear Gene-Encoded Leigh Syndrome Spectrum Overview - GeneReviews® - NCBI Bookshelf
    snippet: Sodium valproate should be avoided if possible, because of its inhibitory effect on respiratory chain enzymes.
    supports: SUPPORT
  - evidence_source: HUMAN_CLINICAL
    explanation: General perioperative LSS guidance; the chapter qualifies glucose use for people on ketogenic diets.
    reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/
    reference_title: Nuclear Gene-Encoded Leigh Syndrome Spectrum Overview - GeneReviews® - NCBI Bookshelf
    snippet: Catabolism should be prevented by minimizing preoperative fasting and considering intravenous glucose perioperatively during prolonged anesthesia
    supports: SUPPORT
  - evidence_source: HUMAN_CLINICAL
    explanation: General LSS guidance on fluids in people at risk of lactic acidosis.
    reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/
    reference_title: Nuclear Gene-Encoded Leigh Syndrome Spectrum Overview - GeneReviews® - NCBI Bookshelf
    snippet: Avoid lactate-containing agents (e.g., Ringer's lactate) in those at risk of lactic acidosis
    supports: SUPPORT
  name: Medication and perioperative precautions
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
- description: General Leigh syndrome spectrum guidance; no COXFA4-specific therapeutic trial is demonstrated. Confirm parental carrier status. With two heterozygous parents, recurrence risks per conception are 25% affected, 50% carrier and 25% unaffected noncarrier. Family variant identification enables prenatal and preimplantation testing.
  evidence:
  - evidence_source: HUMAN_CLINICAL
    explanation: These are conditional autosomal recessive recurrence risks, not measured COXFA4 penetrance.
    reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/
    reference_title: Nuclear Gene-Encoded Leigh Syndrome Spectrum Overview - GeneReviews® - NCBI Bookshelf
    snippet: each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic ... carrier ... and a 25% chance of being unaffected and not a carrier.
    supports: SUPPORT
  - evidence_source: HUMAN_CLINICAL
    explanation: General LSS counseling guidance supports family-specific reproductive testing.
    reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/
    reference_title: Nuclear Gene-Encoded Leigh Syndrome Spectrum Overview - GeneReviews® - NCBI Bookshelf
    snippet: Once the LSS-related ... pathogenic variant ... (s) have been identified in an affected family member, prenatal and ... preimplantation genetic testing ... are possible.
    supports: SUPPORT
  name: Genetic counseling
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
- name: Dystonia management
  description: 'General Leigh syndrome guidance: specialist-directed medication may help dystonia; response and adverse effects require individual assessment. Baclofen is one of the listed options, alongside benzhexol, tetrabenazine and gabapentin.'
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: baclofen
      term:
        id: CHEBI:2972
        label: baclofen
  evidence: &id022
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/
    reference_title: Nuclear Gene-Encoded Leigh Syndrome Spectrum Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Benzhexol, baclofen, tetrabenazine, ... gabapentin may be useful, alone or in various combinations.
    explanation: General LSS supportive-care guidance, applied according to manifestations.
  target_mechanisms:
  - target: Dystonia
    treatment_effect: MODULATES
    description: Symptomatic treatment according to general LSS guidance.
    evidence: *id022
- name: Cardiac care
  description: 'General Leigh syndrome guidance: manage cardiomyopathy and conduction abnormalities with a cardiologist; no COXFA4-specific drug efficacy is established. General LSS surveillance recommends an electrocardiogram and echocardiogram annually or as advised by the cardiologist.'
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/
    reference_title: Nuclear Gene-Encoded Leigh Syndrome Spectrum Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Anticongestive therapy or antiarrhythmic therapy may be required ... treatment should be managed by a cardiologist.
    explanation: General LSS supportive-care guidance, applied according to manifestations.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/
    reference_title: Nuclear Gene-Encoded Leigh Syndrome Spectrum Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Electrocardiogram ... Echocardiogram ... Annually or as advised by cardiologist
    explanation: General LSS cardiac surveillance interval.
- name: Rehabilitation
  description: General Leigh syndrome guidance supports physical and occupational therapy for myopathy or ataxia, with equipment to maintain mobility and prevent falls.
  treatment_term:
    preferred_term: Rehabilitation
    term:
      id: NCIT:C15315
      label: Rehabilitation
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/
    reference_title: Nuclear Gene-Encoded Leigh Syndrome Spectrum Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: PT ... OT ... Equipment to prevent falling, maintain independent mobility as appropriate
    explanation: General LSS supportive-care guidance, applied according to manifestations.
- name: Experimental polyamine supplementation
  description: Preclinical only. A putrescine/spermidine/spermine mixture improved cardiac function and survival in Xenopus coxfa4 crispants without restoring complex IV activity. Human efficacy, safety and dosing in COXFA4 deficiency have not been established by this study.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: putrescine
      term:
        id: CHEBI:17148
        label: putrescine
    - preferred_term: spermidine
      term:
        id: CHEBI:16610
        label: spermidine
    - preferred_term: spermine
      term:
        id: CHEBI:15746
        label: spermine
  evidence:
  - *id023
  - *id024
- name: Experimental COXFA4 or COXFA4L2 complementation
  description: Preclinical genetic complementation restored or partly improved enzyme activity in patient cells; human mRNA injection also rescued aspects of the Xenopus phenotype. AAV delivery is proposed in discussion, not a tested patient treatment.
  evidence:
  - *id009
  - *id013
inheritance:
- *id025
diagnosis:
- name: Molecular diagnosis including copy-number analysis
  description: Identify biallelic COXFA4 variants through a mitochondrial-disease workup including sequence and deletion analysis. Family segregation and RNA studies can clarify splice variants. Genome sequencing is preferred when available in general LSS guidance.
  diagnosis_term:
    preferred_term: Genetic Testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - *id018
  - *id002
  - *id003
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/
    reference_title: Nuclear Gene-Encoded Leigh Syndrome Spectrum Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Genome sequencing is preferred (if available), as it allows analysis of the mitochondrial and nuclear genome, and typically has the highest diagnostic rate.
    explanation: General LSS guidance covers a genetically heterogeneous differential.
- name: Respiratory-chain enzymology with culture-context interpretation
  description: Reduced complex IV activity supports diagnosis, but a normal glucose-grown fibroblast assay does not exclude COXFA4 deficiency. Galactose culture revealed the defect in a founding patient; biochemical findings vary by tissue.
  evidence:
  - *id010
  - *id026
  - reference: PMID:42218136
    reference_title: COXFA4L2 upregulation preserves residual cytochrome c oxidase activity in COXFA4-related Leigh-like encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Respiratory chain enzyme analyses of muscle tissues (S1, S4, S7, S10 and S14) showed a profound reduction in COX activity.
    explanation: Human muscle enzymology supports tissue complex IV deficiency; the cohort also includes a case with additional respiratory-chain abnormalities.
- name: RNA analysis of splice variants
  description: RT-PCR or RNA sequencing can identify donor-site intron retention, exon skipping and residual correctly spliced transcripts; effects must be assigned to the tested allele and tissue.
  evidence:
  - *id004
  - *id005
- name: Brain MRI
  description: Evaluate white-matter, callosal and brainstem abnormalities. Imaging can initially be normal, and some affected individuals do not have established Leigh syndrome.
  diagnosis_term:
    preferred_term: Magnetic Resonance Imaging
    term:
      id: NCIT:C16809
      label: Magnetic Resonance Imaging
  evidence:
  - reference: PMID:23746447
    reference_title: NDUFA4 mutations underlie dysfunction of a cytochrome c oxidase subunit linked to human neurological disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Brain CT (13 years) and MRI (17 years) were both normal. However, a brain MRI at age 25 years demonstrated T2 hyperintensities in the deep white matter.
    explanation: Normal early imaging does not exclude genetically established disease.
biochemical:
- name: Tissue-dependent cytochrome c oxidase deficiency
  presence: Reduced in tested affected tissues; some fibroblast assays normal
  evidence:
  - *id010
  - *id026
  - reference: PMID:42218136
    reference_title: COXFA4L2 upregulation preserves residual cytochrome c oxidase activity in COXFA4-related Leigh-like encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Respiratory chain enzyme analyses of muscle tissues (S1, S4, S7, S10 and S14) showed a profound reduction in COX activity.
    explanation: Human muscle enzymology supports tissue complex IV deficiency; the cohort also includes a case with additional respiratory-chain abnormalities.
- name: Persistent circulating lactate elevation
  presence: Increased
  evidence:
  - reference: PMID:39967265
    reference_title: Polyamine metabolism is dysregulated in COXFA4-related mitochondrial disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Both have persistent lactic acidosis in the range of 3–7 mmol/L.
    explanation: Persistent lactate elevation in two genotyped siblings.
histopathology:
- name: Variable muscle COX staining and lipid accumulation
  description: The founding proband had normal COX histochemistry despite deficient enzymology; another affected child had reduced staining throughout the muscle fibers. Lipid droplets were reported. These findings are variable rather than universal diagnostic criteria.
  evidence:
  - reference: PMID:23746447
    reference_title: NDUFA4 mutations underlie dysfunction of a cytochrome c oxidase subunit linked to human neurological disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: COX histochemistry was normal. Electron microscopy revealed lipid droplets in some fibers.
    explanation: The founding proband demonstrates limited sensitivity of COX histochemistry.
  - reference: PMID:23746447
    reference_title: NDUFA4 mutations underlie dysfunction of a cytochrome c oxidase subunit linked to human neurological disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Reduced COX staining in all muscle fibers was seen in III-13
    explanation: A different affected child had a positive histochemical finding.
experimental_models:
- name: COXFA4-deficient patient fibroblasts
  experimental_model_type: CELL_LINE
  description: Patient primary and immortalized fibroblasts reveal allele-specific splicing, low mature complex IV, reduced respiration and partial COXFA4L2 compensation. Glucose culture can mask deficiency. Complementation with wild-type COXFA4 or its paralog tests causality and residual function.
  publication: PMID:42218136
  evidence:
  - *id004
  - *id005
  - *id010
  - *id011
  - *id009
  - *id013
  - *id014
  - *id026
  modeled_mechanisms:
  - target: Reduced mature complex IV accumulation
    relationship: PARTIALLY_RECAPITULATES
    model_scale: CELLULAR
    limitations: Experimental findings do not establish the complete clinical phenotype.
  - target: Reduced complex IV activity
    relationship: PARTIALLY_RECAPITULATES
    model_scale: CELLULAR
    limitations: Experimental findings do not establish the complete clinical phenotype.
  - target: Partial paralog compensation
    relationship: PARTIALLY_RECAPITULATES
    model_scale: CELLULAR
    limitations: Experimental findings do not establish the complete clinical phenotype.
- name: COXFA4-knockdown SH-SY5Y neuroblastoma cells
  experimental_model_type: CELL_LINE
  description: Stable COXFA4 knockdown induces COXFA4L2, and double depletion worsens respiration. SH-SY5Y is a transformed neuronal-like system; compensation in primary neurons in vivo remains unproven.
  publication: PMID:42218136
  evidence:
  - reference: PMID:42218136
    reference_title: COXFA4L2 upregulation preserves residual cytochrome c oxidase activity in COXFA4-related Leigh-like encephalopathy.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: the double KD resulted in a more pronounced reduction in basal respiration compared to COXFA4 KD alone
    explanation: Double depletion provides functional evidence for paralog compensation in this cell line.
  modeled_mechanisms:
  - target: Increased COXFA4L2 expression
    relationship: PARTIALLY_RECAPITULATES
    model_scale: CELLULAR
    limitations: Experimental findings do not establish the complete clinical phenotype.
  - target: Partial paralog compensation
    relationship: PARTIALLY_RECAPITULATES
    model_scale: CELLULAR
    limitations: Experimental findings do not establish the complete clinical phenotype.
- name: COXFA4-knockout induced pluripotent stem cells
  experimental_model_type: IPSC_DERIVED_MODEL
  description: The 2025 study reanalyzed public RNA-seq from engineered knockout and control iPSCs to identify reduced ODC-pathway transcripts. These are not patient-derived cardiomyocytes.
  publication: PMID:39967265
  evidence:
  - *id016
  modeled_mechanisms:
  - target: Reduced ODC-pathway transcripts in experimental models
    relationship: PARTIALLY_RECAPITULATES
    model_scale: CELLULAR
    limitations: Experimental findings do not establish the complete clinical phenotype.
- name: Ndufa4-manipulated P19-derived neural cells
  experimental_model_type: CELL_LINE
  description: Retinoic-acid-differentiated mouse embryonal carcinoma cells were used to study Ndufa4 RNA, miR-145a-5p, Homer1/Ccnd2 expression and apoptosis. This Dandy-Walker-oriented experiment does not establish a human MC4DN21 neuronal mechanism; oxygen consumption and ATP generation were not measured.
  publication: PMID:36763283
  evidence:
  - reference: PMID:36763283
    reference_title: Ndufa4 Regulates the Proliferation and Apoptosis of Neurons via miR-145a-5p/Homer1/Ccnd2.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Ndufa4 overexpression promoted the proliferation of neurons and inhibited their apoptosis in vitro, which underwent reverse regulation by the Ndufa4 short hairpin RNAs.
    explanation: The experiment concerns manipulated neural-like cells, not patient neurons.
animal_models:
- name: Xenopus tropicalis coxfa4 F0 mosaic crispants
  species: Xenopus tropicalis
  genotype: CRISPR/Cas9 mosaic loss of coxfa4
  description: Early embryos show reduced cardiac contractility, craniofacial cartilage defects, brain/heart complex IV deficiency and lower polyamines. Polyamines improve cardiac function and survival without correcting complex IV activity; human COXFA4 or COXFA4L2 mRNA provides rescue. Early-stage neurological behavior does not reproduce the full human disease.
  publication: PMID:39967265
  evidence:
  - *id017
  - *id023
  - *id024
  modeled_mechanisms:
  - target: Reduced polyamine abundance in Xenopus
    relationship: RECAPITULATES
    model_scale: ORGANISM
    limitations: Mosaic embryonic model with unproven human treatment translation.
- name: Whole-body Ndufa4-knockout mouse
  species: Mus musculus
  genotype: Constitutive Ndufa4 exon 3–4 deletion generated with Cre/LoxP
  description: The 2023 model shows neuronal injury, increased brain apoptosis and altered behavioral assays. The primary methods specify whole-body knockout, which can confound behavior through systemic respiratory-chain dysfunction. The proposed miR-145a-5p/Homer1/Ccnd2 pathway is not validated in affected humans.
  publication: PMID:36763283
  evidence:
  - reference: PMID:36763283
    reference_title: Ndufa4 Regulates the Proliferation and Apoptosis of Neurons via miR-145a-5p/Homer1/Ccnd2.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: the whole body knockout of Ndufa4 cannot completely avoid its influence on the behavioral phenotype of mice as a component of the respiratory chain.
    explanation: The authors explicitly acknowledge the systemic-model limitation.
  - reference: PMID:36763283
    reference_title: Ndufa4 Regulates the Proliferation and Apoptosis of Neurons via miR-145a-5p/Homer1/Ccnd2.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: TUNEL staining showed increased apoptosis in the brain tissues of Ndufa4-KO mice compared with WT mice
    explanation: The animal model supports neuronal injury, not a corresponding established human histopathology.
datasets:
- accession: geo:GSE182376
  title: A Human Induced Pluripotent Stem Cell Array-Based Genome Wide Association Study Identifies Virus Susceptibility Locus and Variants
  description: The COXFA4/NDUFA4 knockout versus wild-type iPSC RNA-seq subset was reanalyzed for polyamine-pathway biology in the 2025 disease study. The broader original virus-susceptibility project is not a cohort of patients with COXFA4 deficiency.
  publication: PMID:39967265
  evidence:
  - reference: GEO:GSE182376
    reference_title: A Human Induced Pluripotent Stem Cell Array-Based Genome Wide Association Study Identifies Virus Susceptibility Locus and Variants
    supports: SUPPORT
    evidence_source: OTHER
    snippet: RNA-sequencing was used to compare the global gene expression profiles in WT and NDUFA4-/- iPSCs
    explanation: The repository record verifies the relevant experimental contrast.
  - reference: PMID:39967265
    reference_title: Polyamine metabolism is dysregulated in COXFA4-related mitochondrial disease.
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: 'This dataset was accessed via the NCBI Gene Expression Omnibus: GSE182376.'
    explanation: The disease-mechanism paper identifies the reused dataset.
references:
- reference: GEO:GSE182376
  title: A Human Induced Pluripotent Stem Cell Array-Based Genome Wide Association Study Identifies Virus Susceptibility Locus and Variants
- reference: PMID:23746447
  title: NDUFA4 mutations underlie dysfunction of a cytochrome c oxidase subunit linked to human neurological disease.
- reference: PMID:36763283
  title: Ndufa4 Regulates the Proliferation and Apoptosis of Neurons via miR-145a-5p/Homer1/Ccnd2.
- reference: PMID:38674434
  title: Biallelic NDUFA4 Deletion Causes Mitochondrial Complex IV Deficiency in a Patient with Leigh Syndrome.
- reference: PMID:39967265
  title: Polyamine metabolism is dysregulated in COXFA4-related mitochondrial disease.
- reference: PMID:42218136
  title: COXFA4L2 upregulation preserves residual cytochrome c oxidase activity in COXFA4-related Leigh-like encephalopathy.
- reference: url:https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_4f142835-c031-4885-9ed4-897b96913558-2025-03-24T040000.000Z
  title: curation results for Gene-Disease Validity
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/
  title: Nuclear Gene-Encoded Leigh Syndrome Spectrum Overview - GeneReviews® - NCBI Bookshelf
  tags:
  - GeneReviews
📚

References & Deep Research

References

8
GEO:GSE182376
A Human Induced Pluripotent Stem Cell Array-Based Genome Wide Association Study Identifies Virus Susceptibility Locus and Variants
No top-level findings curated for this source.
PMID:23746447
NDUFA4 mutations underlie dysfunction of a cytochrome c oxidase subunit linked to human neurological disease.
No top-level findings curated for this source.
PMID:36763283
Ndufa4 Regulates the Proliferation and Apoptosis of Neurons via miR-145a-5p/Homer1/Ccnd2.
No top-level findings curated for this source.
PMID:38674434
Biallelic NDUFA4 Deletion Causes Mitochondrial Complex IV Deficiency in a Patient with Leigh Syndrome.
No top-level findings curated for this source.
PMID:39967265
Polyamine metabolism is dysregulated in COXFA4-related mitochondrial disease.
No top-level findings curated for this source.
PMID:42218136
COXFA4L2 upregulation preserves residual cytochrome c oxidase activity in COXFA4-related Leigh-like encephalopathy.
No top-level findings curated for this source.
No top-level findings curated for this source.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/
Nuclear Gene-Encoded Leigh Syndrome Spectrum Overview - GeneReviews® - NCBI Bookshelf
No top-level findings curated for this source.