COQ6-Related Steroid-Resistant Nephrotic Syndrome with Sensorineural Deafness

MONDO:0013836 Pathograph 19 Show in embeddings browser

Biallelic variants in COQ6, a FAD-dependent monooxygenase that performs C5-ring hydroxylation during coenzyme Q10 biosynthesis, cause a primary CoQ10 deficiency (COQ10D6) presenting as steroid-resistant nephrotic syndrome with sensorineural hearing loss. The tissue selectivity follows the protein's expression: COQ6 is found in glomerular podocytes and in the stria vascularis of the inner ear, and those are the two structures that fail. "Steroid-resistant" here is a mechanistic prediction rather than an empirical label - the lesion is a biosynthetic deficiency, not an immune one, so immunosuppression has nothing to act on. The corresponding prediction is that the disease should respond to the missing metabolite, and oral CoQ10 does induce remission of proteinuria, with benefit depending strongly on how much irreversible damage has already accrued.

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1
Inheritance
9
Pathophys.
10
Phenotypes
3
Gaps
19
Pathograph
1
Genes
2
Variants
5
Medical Actions
2
Models
8
References
1
Deep Research
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Inheritance

1
Autosomal recessive HP:0000007
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:36124066 SUPPORT Human Clinical
"Primary coenzyme Q10 deficiency-6 (COQ10D6) is an autosomal recessive disorder attributable to biallelic COQ6 variants"
States the inheritance pattern and the biallelic requirement.
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Discussions and Knowledge Gaps

3
Is steroid resistance in this disease an empirical finding or a prediction of the mechanism?
INTERPRETATION coq6_steroid_resistance_is_predicted
Attached to
pathophysiology#Steroid-Resistant Nephrotic Syndrome treatments#Oral Coenzyme Q10 Replacement
The phrase "steroid-resistant" entered this entity's name from nephrology, where it classifies nephrotic syndrome by observed response. But once the lesion is known to be a defect of coenzyme Q10 biosynthesis in podocytes, resistance to immunosuppression is what the mechanism predicts: there is no immune process for a steroid or a calcineurin inhibitor to suppress. The reported case in which calcineurin inhibition failed and CoQ10 produced complete remission is the clean demonstration. The practical consequence is that in a child with SRNS, resistance to immunosuppression should prompt a genetic and metabolic question rather than an escalation of immunosuppression - which is why the entry models the resistance as part of the causal chain instead of recording it as an adjective.
The renal arm has models that reproduce it and respond to CoQ10. What supports the hearing and vision arms?
HUMAN MODEL MISMATCH coq6_no_model_for_the_sensory_arms
Attached to
pathophysiology#Stria Vascularis Dysfunction pathophysiology#Optic Nerve Involvement
The podocyte and zebrafish models both reproduce the renal cell-death phenotype, and the podocyte model additionally shows its CoQ10 responsiveness, so the claim that supplying the missing metabolite rescues podocytes is directly supported at the cellular level. It is worth being precise that the rescue was not tested in the whole organism: the abstract summarizes both experiments in one sentence, but the zebrafish panels carry no CoQ10 condition. No cochlear or optic-nerve model of COQ6 deficiency is reported in the sources used here. Those two arms therefore rest on a localization result - COQ6 protein in stria vascularis cells - plus mechanistic analogy to the renal arm, and on the clinical observation that they respond differently to treatment: idebenone improved vision and did not improve hearing in the same patients. That dissociation is exactly what a model would be needed to explain, and there is none. Recorded as a HUMAN_MODEL_MISMATCH rather than a plain knowledge gap because the issue is not that evidence is absent but that the evidence which exists covers one arm and is being extended to two others.
How much of the variation in CoQ10 response is genotype and how much is timing?
KNOWLEDGE GAP coq6_timing_determines_benefit
Attached to
treatments#Oral Coenzyme Q10 Replacement pathophysiology#Focal Segmental Glomerulosclerosis
Two explanations are offered for why some patients respond and others do not, and the available reports do not separate them. The audiological series attributes the 42.9% response rate to genotype, noting the benefit appeared genotype-specific. Other reports attribute non-response to established damage, stating patients may not benefit once severe renal and neurological damage is present. These are not mutually exclusive and would be distinguished by treating patients of the same genotype at different stages, which no reported series does. The distinction matters because it determines whether genotype should modify the urgency of starting treatment or only the expectation of benefit.
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Pathophysiology

9
Biallelic COQ6 Loss of Function
Homozygous or compound heterozygous COQ6 variants. Missense alleles impair the enzyme's substrate access channel; nonsense alleles truncate the protein and are associated with the lethal infantile end of the spectrum.
Downstream
Deficient C5-Ring Hydroxylation in CoQ10 Biosynthesis The variants reduce activity of the monooxygenase.
Show evidence (1 reference)
PMID:21540551 SUPPORT Human Clinical
"Here we have identified 6 different mutations in coenzyme Q10 biosynthesis monooxygenase 6 (COQ6) in 13 individuals from 7 families by homozygosity mapping."
The original gene identification across seven families.
Deficient C5-Ring Hydroxylation in CoQ10 Biosynthesis
COQ6 is a flavoprotein using FAD as cofactor that hydroxylates the benzene ring of the ubiquinone precursor at position C5. Structural work identifies a substrate access channel, and blocking it computationally predicted the loss of activity that was then confirmed in vivo.
ubiquinone biosynthetic process GO:0006744 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased ubiquinone biosynthetic process (GO:0006744). GO:0006744 is a biological process from the Gene Ontology. ↓ DECREASED
FAD-dependent monooxygenase activity GO:0004497 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased FAD-dependent monooxygenase activity, annotated with monooxygenase activity (GO:0004497). GO:0004497 is a molecular function from the Gene Ontology. ↓ DECREASED FAD binding GO:0071949 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves FAD binding (GO:0071949). GO:0071949 is a molecular function from the Gene Ontology.
Downstream
Coenzyme Q10 Deficiency The biosynthetic pathway cannot complete.
Show evidence (2 references)
PMID:26808124 SUPPORT In Vitro
"We show here through biochemical studies that Coq6 is a flavoprotein using FAD as a cofactor."
Establishes the cofactor and enzyme class biochemically.
PMID:26808124 SUPPORT Computational
"We identify a putative access channel for Coq6 in a wild type model and propose in silico mutations positioned at its entrance capable of partially (G248R and L382E single mutations) or completely (a G248R-L382E double-mutation) blocking access to the channel for the substrate."
The structural prediction, split from the biochemical item above because the two sentences report different kinds of evidence in the same paper.
Coenzyme Q10 Deficiency
Reduced cellular coenzyme Q10, the polyisoprenylated benzoquinone lipid that carries electrons in the mitochondrial respiratory chain. This is the node the treatment acts on, by supplying the end product exogenously.
oxidative phosphorylation GO:0006119 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased oxidative phosphorylation (GO:0006119). GO:0006119 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Podocyte Injury and Apoptosis Podocytes are among the cells expressing COQ6 and are the first renal cell type to fail. The route is partly characterized: respiratory-chain compromise raises reactive oxygen species, the actin cytoskeleton is disrupted, and the cells undergo caspase-3-dependent apoptosis.
Stria Vascularis Dysfunction The cochlear structure in which COQ6 is expressed, and the presumed site of the hearing lesion.
Optic Nerve Involvement A third arm, recognized later than the oto-renal core. Its response to a CoQ10 analogue is what marks it as a distinct, and partially reversible, target.
Show evidence (1 reference)
PMID:26808124 SUPPORT Other
"Coq6 is an enzyme involved in the biosynthesis of coenzyme Q, a polyisoprenylated benzoquinone lipid essential to the function of the mitochondrial respiratory chain."
Background statement of the product's role; graded OTHER because it is a definitional sentence rather than a result of this study.
Podocyte Injury and Apoptosis
Podocyte apoptosis is the demonstrated cellular consequence, and it is partially reversible by coenzyme Q10 in both podocyte cell lines and zebrafish - which is the experiment that links the deficiency causally to the cell death rather than merely correlating them. Knockdown work fills in part of the route: loss of COQ6 raises reactive oxygen species and disorganizes the F-actin cytoskeleton before apoptosis, which matters because podocyte function depends on maintaining that cytoskeletal architecture at the filtration slit.
podocyte CL:0000653 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves podocyte (CL:0000653). CL:0000653 is a cell type from the Cell Ontology.
Experimental models
COQ6-knockdown podocyte cell line CELL LINE Reproduces the cell-death phenotype and, critically, its partial reversal by coenzyme Q10 - which is the experiment the treatment's BYPASSES link rests on.
Animal models
coq6 morpholino zebrafish Zebrafish recapitulates Reproduces apoptosis on coq6 knockdown in a vertebrate, establishing that the cell-death phenotype is not an artefact of cultured cells.
Downstream
Focal Segmental Glomerulosclerosis Podocyte loss produces the characteristic glomerular lesion.
Show evidence (2 references)
PMID:21540551 SUPPORT In Vitro
"knockdown of Coq6 in podocyte cell lines and coq6 in zebrafish embryos caused apoptosis that was partially reversed by coenzyme Q10 treatment"
Establishes both the cell-death phenotype and its rescue, which together make the causal claim.
PMID:30425193 SUPPORT In Vitro
"Flow cytometry showed significantly increased in apoptotic podocytes, and Western blotting showed increases in active caspase-3 in si-COQ6 podocytes. Meanwhile, reactive oxygen species (ROS) levels were increased and F-actin immunofluorescence was irregularly distributed in the si-COQ6 group."
Measures the intermediate steps rather than only the endpoint: raised ROS and a disorganized actin cytoskeleton alongside caspase-3 activation in COQ6-knockdown podocytes.
Stria Vascularis Dysfunction
COQ6 is expressed in stria vascularis cells of the inner ear. The co-occurrence of renal and cochlear disease is not coincidental but follows the expression pattern of the enzyme.
stria vascularis of cochlear duct UBERON:0002282 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in stria vascularis of cochlear duct (UBERON:0002282). UBERON:0002282 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Progressive Sensorineural Hearing Loss Strial dysfunction produces the cochlear deficit.
Show evidence (1 reference)
PMID:21540551 SUPPORT Model Organism
"In rats, COQ6 was located within cell processes and the Golgi apparatus of renal glomerular podocytes and in stria vascularis cells of the inner ear, consistent with an oto-renal disease phenotype."
The localization result that explains why these two organs and not others, obtained in rat tissue.
Optic Nerve Involvement
Optic atrophy with visual impairment, reported in a subset and added to the recognized phenotype after the oto-renal core. Unlike the hearing arm, it responded to a hydrophilic CoQ10 analogue.
Show evidence (1 reference)
PMID:32685349 SUPPORT Human Clinical
"This study reports the case of two Turkish siblings with renal impairment, sensorineural deafness, and optic atrophy exhibiting COQ6 mutation."
Establishes optic atrophy as part of the COQ6 phenotype.
Focal Segmental Glomerulosclerosis
The histological lesion underlying the nephrotic syndrome, and the reason it progresses rather than remitting.
Downstream
Steroid-Resistant Nephrotic Syndrome Glomerular scarring produces proteinuria unresponsive to immunosuppression.
Show evidence (1 reference)
PMID:36124066 SUPPORT Human Clinical
"Histologically, SRNS presents principally as focal segmental glomerulosclerosis (FSGS) inevitably leading to chronic kidney disease (CKD)"
Names the lesion and its trajectory.
Steroid-Resistant Nephrotic Syndrome
Proteinuria, hypoalbuminemia and oedema that do not respond to corticosteroids, and in a reported case did not respond to a calcineurin inhibitor either, before remitting completely on coenzyme Q10.
Show evidence (1 reference)
PMID:30232548 SUPPORT Human Clinical
"The disease did not respond for second-line therapy with calcineurin inhibitor, but it remitted completely after oral treatment with 30 mg/kg/d of coenzyme Q10 (CoQ10)."
The clearest single demonstration that the resistance is to immunosuppression specifically, not to treatment in general.
Progressive Sensorineural Hearing Loss
Generally documented after the renal diagnosis, and progressive. Partially responsive to CoQ10 in a genotype-dependent way.
Show evidence (1 reference)
PMID:36124066 SUPPORT Human Clinical
"A diagnosis of SRNS generally precedes SNHL documentation. COQ10D6 is associated with progressive SNHL."
Establishes the sequence and the progressive course.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for COQ6-Related Steroid-Resistant Nephrotic Syndrome with Sensorineural Deafness Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

10
Ear 1
Sensorineural Hearing Loss VERY_FREQUENT Sensorineural hearing impairment HP:0000407 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sensorineural hearing impairment (HP:0000407), qualified as course progressive. HP:0000407 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (1 reference)
PMID:36124066 SUPPORT Human Clinical
"A diagnosis of SRNS generally precedes SNHL documentation. COQ10D6 is associated with progressive SNHL."
Establishes the hearing loss and its progressive course.
Eye 1
Optic Atrophy OCCASIONAL 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:32685349 SUPPORT Human Clinical
"For the first time, COQ6 mutation with optical involvement is associated with renal and hearing impairment."
The report that added the ocular arm to the recognized phenotype.
Genitourinary 2
Progression to Kidney Failure FREQUENT Renal insufficiency HP:0000083 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Renal insufficiency (HP:0000083), qualified as course progressive. HP:0000083 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (1 reference)
PMID:36124066 SUPPORT Human Clinical
"the cardinal phenotypes are steroid-resistant nephrotic syndrome (SRNS), which inevitably progresses to kidney failure, and sensorineural hearing loss (SNHL)"
States the renal trajectory in untreated disease.
Proteinuria FREQUENT HP:0000093 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Proteinuria (HP:0000093). HP:0000093 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35111204 SUPPORT Human Clinical
"we report two Chinese siblings with COQ10D6 who primarily presented with severe metabolic acidosis, proteinuria, hypoalbuminemia, growth retardation, and muscle hypotonia and died in early infancy"
Names proteinuria among the presenting features of the lethal infantile form.
Metabolism 2
Metabolic Acidosis OCCASIONAL HP:0001942 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Metabolic acidosis (HP:0001942). HP:0001942 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35111204 SUPPORT Human Clinical
"we report two Chinese siblings with COQ10D6 who primarily presented with severe metabolic acidosis, proteinuria, hypoalbuminemia, growth retardation, and muscle hypotonia and died in early infancy"
Names metabolic acidosis as a presenting feature of the lethal infantile form.
Hypoalbuminemia OCCASIONAL HP:0003073 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypoalbuminemia (HP:0003073). HP:0003073 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35111204 SUPPORT Human Clinical
"we report two Chinese siblings with COQ10D6 who primarily presented with severe metabolic acidosis, proteinuria, hypoalbuminemia, growth retardation, and muscle hypotonia and died in early infancy"
Names hypoalbuminemia among the presenting features of the lethal infantile form.
Musculoskeletal 1
Muscle Hypotonia OCCASIONAL 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:35111204 SUPPORT Human Clinical
"we report two Chinese siblings with COQ10D6 who primarily presented with severe metabolic acidosis, proteinuria, hypoalbuminemia, growth retardation, and muscle hypotonia and died in early infancy"
Names muscle hypotonia among the presenting features of the lethal infantile form.
Growth 1
Growth Retardation OCCASIONAL Growth delay HP:0001510 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Growth delay (HP:0001510). HP:0001510 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35111204 SUPPORT Human Clinical
"we report two Chinese siblings with COQ10D6 who primarily presented with severe metabolic acidosis, proteinuria, hypoalbuminemia, growth retardation, and muscle hypotonia and died in early infancy"
Names growth retardation among the presenting features of the lethal infantile form.
Other 2
Steroid-Resistant Nephrotic Syndrome VERY_FREQUENT HP:0000100 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Nephrotic syndrome (HP:0000100). HP:0000100 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36124066 SUPPORT Human Clinical
"the cardinal phenotypes are steroid-resistant nephrotic syndrome (SRNS), which inevitably progresses to kidney failure, and sensorineural hearing loss (SNHL)"
Names the two cardinal phenotypes.
Focal Segmental Glomerulosclerosis FREQUENT HP:0000097 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Focal segmental glomerulosclerosis (HP:0000097). HP:0000097 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36124066 SUPPORT Human Clinical
"Histologically, SRNS presents principally as focal segmental glomerulosclerosis (FSGS) inevitably leading to chronic kidney disease (CKD)"
Identifies the predominant histology.
🧬

Genetic Associations

1
COQ6
Gene: COQ6 hgnc:20233 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is COQ6 (hgnc:20233). hgnc:20233 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (1 reference)
PMID:35111204 SUPPORT Human Clinical
"we identified two rare recessive nonsense mutations in the COQ6 gene segregating with disease in affected family members: c.249C > G (p.Tyr83Ter) and c.1381C > T (p.Gln461Ter), resulting in two truncated protein products"
Identifies the truncating alleles found at the severe end.
Variants (2)
c.249C>G (p.Tyr83Ter)
Nonsense allele producing a truncated protein. Reported in trans with p.Gln461Ter in two Chinese siblings who presented with severe metabolic acidosis and died in early infancy.
Functional effects
ubiquinone biosynthesis monooxygenase activity loss-of-function
A stop codon at residue 83 truncates the protein before the FAD-binding monooxygenase domain, so no residual hydroxylase activity is expected.
Show evidence (1 reference)
PMID:35111204 SUPPORT Human Clinical
"we identified two rare recessive nonsense mutations in the COQ6 gene segregating with disease in affected family members: c.249C > G (p.Tyr83Ter) and c.1381C > T (p.Gln461Ter), resulting in two truncated protein products"
Identifies the allele and its truncating consequence.
c.1381C>T (p.Gln461Ter)
The second nonsense allele in the same family, in trans with p.Tyr83Ter.
Functional effects
ubiquinone biosynthesis monooxygenase activity loss-of-function
The later of the two stop codons, and the reason the sibling pair is a compound-heterozygous null rather than a hypomorph. With no functional allele on either chromosome the phenotype was lethal in infancy, which is the extreme this entry's severity spectrum is anchored against.
Show evidence (1 reference)
PMID:35111204 SUPPORT Human Clinical
"we identified two rare recessive nonsense mutations in the COQ6 gene segregating with disease in affected family members: c.249C > G (p.Tyr83Ter) and c.1381C > T (p.Gln461Ter), resulting in two truncated protein products"
Identifies the allele and its truncating consequence.
💊

Medical Actions

5
Oral Coenzyme Q10 Replacement
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: coenzyme Q10 CHEBI:46245 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses coenzyme Q10 (CHEBI:46245). CHEBI:46245 is a therapeutic agent from Chemical Entities of Biological Interest.
Supplies the missing end product, bypassing the biosynthetic block rather than correcting it. Benefit is strongly dependent on how early it is started, because it cannot reverse established glomerular scarring or lost cochlear function.
Mechanism Target:
BYPASSES Coenzyme Q10 Deficiency — Exogenous CoQ10 supplies the product the blocked pathway cannot make. This is the node the treatment acts on; every downstream benefit follows from it.
Show evidence (1 reference)
PMID:21540551 SUPPORT In Vitro
"knockdown of Coq6 in podocyte cell lines and coq6 in zebrafish embryos caused apoptosis that was partially reversed by coenzyme Q10 treatment"
Demonstrates rescue at the cellular level, which is the mechanistic basis for the clinical use.
RESTORES Steroid-Resistant Nephrotic Syndrome — Complete and sustained remission of proteinuria has been reported, including after failure of a calcineurin inhibitor.
Show evidence (1 reference)
PMID:30232548 SUPPORT Human Clinical
"After 12 months of CoQ10 therapy, the child remains in full remission, her physical development accelerated, frequent respiratory airways diseases subsided."
Documents durable remission on treatment.
MODULATES Progressive Sensorineural Hearing Loss — Partial and genotype-dependent: in a 12-patient series just under half showed no further loss or improvement.
Show evidence (1 reference)
PMID:36124066 SUPPORT Human Clinical
"The response rate (no further hearing loss or improvement) was 42.9%; CoQ10 replacement therapy may thus limit and even improve hearing loss."
Quantifies the audiological response. Graded PARTIAL because fewer than half responded and the endpoint combines stabilization with improvement.
Show evidence (2 references)
PMID:28125198 SUPPORT Other
"Review management of primary CoQ10 deficiency, including targeted pharmacologic treatment with high-dose oral CoQ10 supplementation and supportive treatment."
The GeneReviews overview names high-dose oral CoQ10 as the targeted pharmacologic treatment for primary CoQ10 deficiency as a family. Graded OTHER, and cited at family level only: this is an overview article rather than a COQ6 chapter, and its cached record does not mention COQ6.
PMID:35111204 SUPPORT Other
"Nevertheless, patients may not benefit from CoQ10 therapy when severe renal and neurological damage is established."
States the limit on efficacy that makes timing the decisive variable; graded OTHER as a review statement in the paper's introduction rather than its own result.
Cochlear Implantation
Action: cochlear device implantationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is cochlear device implantation, annotated with Surgical Procedure (NCIT:C15329). NCIT:C15329 is a clinical intervention from the NCI Thesaurus. Ontology label: Surgical Procedure NCIT:C15329
For hearing not preserved by early CoQ10, with outcomes reported as generally favourable and sustained.
Mechanism Target:
BYPASSES Progressive Sensorineural Hearing Loss — Bypasses the failed cochlear transduction rather than treating the metabolic lesion.
Show evidence (1 reference)
PMID:36124066 SUPPORT Human Clinical
"The results of cochlear implantation were generally favorable, and the effects were sustained over time."
Reports the outcome of implantation in this patient group.
Dialysis
Action: renal dialysisNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is renal dialysis, annotated with Dialysis (NCIT:C15221). NCIT:C15221 is a clinical intervention from the NCI Thesaurus. Ontology label: Dialysis NCIT:C15221
Extracorporeal solute and fluid clearance once the renal arm reaches kidney failure. It substitutes for excretory function indefinitely rather than correcting anything, and it is where a reported child went immediately at diagnosis, before transplantation became possible.
Mechanism Target:
BYPASSES Steroid-Resistant Nephrotic Syndrome — Substitutes extracorporeally for the excretory function lost as the podocyte lesion progresses, without restoring native kidney function.
Show evidence (1 reference)
PMID:32685349 SUPPORT Human Clinical
"The patient started peritoneal dialysis immediately following diagnosis and underwent successful renal transplantation"
Documents the modality and its timing - started at diagnosis, before the graft.
Kidney Transplantation
Action: kidney transplantationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is kidney transplantation, annotated with Organ Transplantation (NCIT:C15289). NCIT:C15289 is a clinical intervention from the NCI Thesaurus. Ontology label: Organ Transplantation NCIT:C15289
The definitive treatment for the renal arm, and the endpoint the rest of the plan exists to avoid. Post-transplant recurrence of nephrotic syndrome is low in monogenic SRNS, because the lesion is in the podocyte genome and the graft podocytes are someone else's - which makes transplantation curative for this arm in a way it is not for immune-mediated nephrotic syndrome. It does nothing for the biosynthetic defect, so the auditory and any neurological arms continue after a successful graft.
Mechanism Target:
BYPASSES Steroid-Resistant Nephrotic Syndrome — Replaces the organ in which the podocyte lesion manifests, with a graft whose podocytes do not carry the COQ6 genotype.
Show evidence (1 reference)
PMID:32685349 SUPPORT Human Clinical
"The patient started peritoneal dialysis immediately following diagnosis and underwent successful renal transplantation"
Documents a successful graft in a molecularly confirmed patient, following dialysis.
Idebenone
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: idebenone CHEBI:31687 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses idebenone (CHEBI:31687). CHEBI:31687 is a therapeutic agent from Chemical Entities of Biological Interest.
A hydrophilic short-chain coenzyme Q10 analogue. Its interest here is that it acts on the arm oral CoQ10 does not reach: optical symptoms improved on it, while hearing loss did not - a clean per-arm dissociation within a single drug in the same patients.
Mechanism Target:
RESTORES Optic Nerve Involvement — Visual impairment improved on treatment in the reported sibling, started three months after symptom onset.
Show evidence (1 reference)
PMID:32685349 SUPPORT Human Clinical
"Idebenone treatment appeared to be effective in resolving optical impairment."
Reports the ocular response in the treated patient.
Progressive Sensorineural Hearing Loss — The arm idebenone did not reach, in the same patient and over the same treatment course as the ocular response above. The contrast with that optic response is the observation: a per-arm dissociation within one drug in one patient.
Show evidence (1 reference)
PMID:32685349 REFUTE Human Clinical
"Idebenone treatment did not, however, improve the hearing loss."
Refutes an effect of idebenone on the auditory arm specifically. Held here rather than at treatment level, where the same sentence read as a refutation of idebenone as such - which the optic response in the line above contradicts.
Show evidence (1 reference)
PMID:32685349 SUPPORT Human Clinical
"Supplement treatment with Idebenone (hydrophilic short‐chain coenzyme Q 10 analogue) was started 3 months after the onset of optical symptoms."
Identifies the agent's class and the timing of treatment.
🔬

Diagnosis

2
Molecular genetic testing in steroid-resistant nephrotic syndrome
The diagnosis is molecular. There is no biochemical screen that identifies COQ6 specifically - plasma and urine findings are those of nephrotic syndrome from any cause - so the route in is sequencing, either whole-exome or an SRNS/FSGS gene panel. The clinical trigger that should prompt it is the combination the disease is named for: steroid resistance plus sensorineural deafness, in a child. Making the diagnosis is not academic here, because it changes management immediately - monogenic CoQ10 deficiency is one of the few forms of SRNS with a targeted therapy, and the therapy's benefit depends on how early it starts.
molecular genetic testing NCIT:C15709 NCI Thesaurus (NCIT)
Show evidence (3 references)
PMID:36124066 SUPPORT Human Clinical
"All 12 underwent medical review, auditory phenotyping, and molecular genetic testing"
Establishes molecular testing as the diagnostic route applied uniformly across the reported cohort.
PMID:36124066 SUPPORT Human Clinical
"In the remaining three patients, targeted exome sequencing (TES) covering 57 genes known to be associated with SRNS or FSGS at that time was performed, because our strategy for mutational screening of patients with SRNS changed during the course of the study from Sanger sequencing to TES (as a..."
Names the specific testing strategy and records that a targeted SRNS/FSGS panel became the first-tier test, which is the practical form of the recommendation.
PMID:35111204 SUPPORT Human Clinical
"Using whole-exome sequencing and Sanger sequencing, we identified two rare recessive nonsense mutations in the COQ6 gene segregating with disease in affected family members"
The other route, used where no panel fits the presentation - these siblings presented with metabolic acidosis rather than the classic oto-renal picture.
Renal biopsy showing focal segmental glomerulosclerosis
FSGS is what COQ6 disease looks like histologically, but it is the common final appearance of podocyte injury from many causes, so a biopsy identifies the lesion and not its cause. Its value here is directional rather than confirmatory: an FSGS pattern in a steroid-resistant child is what should send the workup to sequencing.
biopsy of kidney NCIT:C51699 NCI Thesaurus (NCIT)
Bound to the procedure term even though the entry's point is that the finding is not diagnostic on its own. The term names what is done, not what it proves; Galloway-Mowat_Syndrome makes the same argument in its description and binds the same term.
Show evidence (1 reference)
PMID:36124066 SUPPORT Human Clinical
"Histologically, SRNS presents principally as focal segmental glomerulosclerosis (FSGS) inevitably leading to chronic kidney disease (CKD) that is the second-most common cause of kidney failure in the first two decades of life"
Gives the histological pattern and its renal trajectory in one sentence.
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Progression

1
Steroid-resistant nephrotic syndrome to kidney failure
The renal arm is progressive and, untreated, terminal for the kidney: the source describes progression to kidney failure as inevitable. The word is the authors' and is worth preserving, because it is what makes the timing of CoQ10 the single decisive variable in this disease - the drug can prevent glomerular scarring and cannot reverse it. The two arms come apart here: renal function can be rescued to normal if treatment starts early enough, while hearing responds in fewer than half of patients and not at all once lost.
Show evidence (2 references)
PMID:36124066 SUPPORT Human Clinical
"the cardinal phenotypes are steroid-resistant nephrotic syndrome (SRNS), which inevitably progresses to kidney failure, and sensorineural hearing loss (SNHL)"
States the renal trajectory in the authors' own terms, as a property of the disease rather than of a particular cohort.
PMID:36124066 SUPPORT Human Clinical
"SRNS of patients with COQ10D6 may respond to CoQ10 replacement therapy that decreases proteinuria and restores normal renal function, particularly if treatment commences before the kidney pathological findings progress"
The modifier on that trajectory, and the reason this entry treats treatment timing rather than treatment choice as the decisive variable.
🧫

Experimental Models

1
COQ6-knockdown podocyte cell line CELL_LINE
The system in which podocyte apoptosis and its CoQ10 rescue were demonstrated, and in which the ROS and cytoskeletal intermediates were measured.
Publication
PMID:21540551
Pathograph links
Podocyte Injury and Apoptosis recapitulates fidelity: moderate Reproduces the cell-death phenotype and, critically, its partial reversal by coenzyme Q10 - which is the experiment the treatment's BYPASSES link rests on.
Limitations: A knockdown in cultured podocytes models neither the hypomorphic alleles patients carry nor the glomerular architecture in which the lesion produces proteinuria.
Show evidence (1 reference)
PMID:21540551 SUPPORT In Vitro
"knockdown of Coq6 in podocyte cell lines and coq6 in zebrafish embryos caused apoptosis that was partially reversed by coenzyme Q10 treatment"
The rescue result that makes this model informative for the treatment claim rather than only for the phenotype.
🐁

Animal Models

1
coq6 morpholino zebrafish
The whole-organism half of the same experiment. It shows apoptosis on coq6 knockdown; it does not test CoQ10 rescue.
Species
Zebrafish
Genotype
coq6 morpholino knockdown
Publication
PMID:21540551
Pathograph links
Podocyte Injury and Apoptosis recapitulates fidelity: moderate Reproduces apoptosis on coq6 knockdown in a vertebrate, establishing that the cell-death phenotype is not an artefact of cultured cells.
Limitations: Morpholino knockdown is transient and not allele-specific. Critically, the zebrafish arm carries no coenzyme Q10 treatment condition - the rescue was demonstrated in cultured podocytes (Figure 5, A-C), while the zebrafish panels (D-F) test knockdown against mismatch and uninjected controls only. So this model supports the phenotype, not the treatment response. And no cochlear or optic-nerve model exists in any species, so the hearing and vision arms of this disease rest on mechanistic analogy rather than on a model.
Show evidence (1 reference)
PMID:21540551 SUPPORT Model Organism
"coq6 knockdown in zebrafish embryos 28 hours after fertilization increases apoptosis"
A zebrafish-only result, quoted rather than the abstract's combined cell-line-and-zebrafish sentence, so this item cites the finding it actually rests on and carries a single evidence type.
{ }

Source YAML

click to show 
name: COQ6-Related Steroid-Resistant Nephrotic Syndrome with Sensorineural Deafness
description: >-
  Biallelic variants in COQ6, a FAD-dependent monooxygenase that performs C5-ring
  hydroxylation during coenzyme Q10 biosynthesis, cause a primary CoQ10 deficiency
  (COQ10D6) presenting as steroid-resistant nephrotic syndrome with sensorineural
  hearing loss. The tissue selectivity follows the protein's expression: COQ6 is found
  in glomerular podocytes and in the stria vascularis of the inner ear, and those are
  the two structures that fail. "Steroid-resistant" here is a mechanistic prediction
  rather than an empirical label - the lesion is a biosynthetic deficiency, not an
  immune one, so immunosuppression has nothing to act on. The corresponding prediction
  is that the disease should respond to the missing metabolite, and oral CoQ10 does
  induce remission of proteinuria, with benefit depending strongly on how much
  irreversible damage has already accrued.
disease_term:
  preferred_term: familial steroid-resistant nephrotic syndrome with sensorineural deafness
  term:
    id: MONDO:0013836
    label: familial steroid-resistant nephrotic syndrome with sensorineural deafness
creation_date: "2026-08-27T18:45:00Z"

references:
- reference: PMID:28125198
  title: Primary Coenzyme Q(10) Deficiency Overview.
  tags:
  - GeneReviews
- reference: PMID:21540551
  title: >-
    COQ6 mutations in human patients produce nephrotic syndrome with sensorineural
    deafness.
- reference: PMID:26808124
  title: >-
    Coenzyme Q Biosynthesis: Evidence for a Substrate Access Channel in the
    FAD-Dependent Monooxygenase Coq6.
- reference: PMID:30232548
  title: >-
    CoQ10-related sustained remission of proteinuria in a child with COQ6
    glomerulopathy-a case report.
- reference: PMID:30425193
  title: >-
    New Mutation of Coenzyme Q(10) Monooxygenase 6 Causing Podocyte Injury in a Focal
    Segmental Glomerulosclerosis Patient.
- reference: PMID:32685349
  title: >-
    COQ6 mutation in patients with nephrotic syndrome, sensorineural deafness, and
    optic atrophy.
- reference: PMID:35111204
  title: >-
    A Family Segregating Lethal Primary Coenzyme Q10 Deficiency Due to Two Novel COQ6
    Variants.
- reference: PMID:36124066
  title: >-
    Effects of CoQ10 Replacement Therapy on the Audiological Characteristics of
    Pediatric Patients with COQ6 Variants.

pathophysiology:
- name: Biallelic COQ6 Loss of Function
  biological_scale: MOLECULAR
  description: >-
    Homozygous or compound heterozygous COQ6 variants. Missense alleles impair the
    enzyme's substrate access channel; nonsense alleles truncate the protein and are
    associated with the lethal infantile end of the spectrum.
  evidence:
  - reference: PMID:21540551
    reference_title: "COQ6 mutations in human patients produce nephrotic syndrome with sensorineural deafness."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we have identified 6 different mutations in coenzyme Q10 biosynthesis
      monooxygenase 6 (COQ6) in 13 individuals from 7 families by homozygosity mapping.
    explanation: The original gene identification across seven families.
  downstream:
  - target: Deficient C5-Ring Hydroxylation in CoQ10 Biosynthesis
    causal_link_type: DIRECT
    description: The variants reduce activity of the monooxygenase.

- name: Deficient C5-Ring Hydroxylation in CoQ10 Biosynthesis
  biological_scale: MOLECULAR
  description: >-
    COQ6 is a flavoprotein using FAD as cofactor that hydroxylates the benzene ring of
    the ubiquinone precursor at position C5. Structural work identifies a substrate
    access channel, and blocking it computationally predicted the loss of activity that
    was then confirmed in vivo.
  molecular_functions:
  - preferred_term: FAD-dependent monooxygenase activity
    modifier: DECREASED
    term:
      id: GO:0004497
      label: monooxygenase activity
  - preferred_term: FAD binding
    term:
      id: GO:0071949
      label: FAD binding
  biological_processes:
  - preferred_term: ubiquinone biosynthetic process
    modifier: DECREASED
    term:
      id: GO:0006744
      label: ubiquinone biosynthetic process
  evidence:
  - reference: PMID:26808124
    reference_title: "Coenzyme Q Biosynthesis: Evidence for a Substrate Access Channel in the FAD-Dependent Monooxygenase Coq6."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We show here through biochemical studies that Coq6 is a flavoprotein using FAD as
      a cofactor.
    explanation: Establishes the cofactor and enzyme class biochemically.
  - reference: PMID:26808124
    reference_title: "Coenzyme Q Biosynthesis: Evidence for a Substrate Access Channel in the FAD-Dependent Monooxygenase Coq6."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      We identify a putative access channel for Coq6 in a wild type model and propose
      in silico mutations positioned at its entrance capable of partially (G248R and
      L382E single mutations) or completely (a G248R-L382E double-mutation) blocking
      access to the channel for the substrate.
    explanation: >-
      The structural prediction, split from the biochemical item above because the two
      sentences report different kinds of evidence in the same paper.
  downstream:
  - target: Coenzyme Q10 Deficiency
    causal_link_type: DIRECT
    description: The biosynthetic pathway cannot complete.

- name: Coenzyme Q10 Deficiency
  biological_scale: MOLECULAR
  description: >-
    Reduced cellular coenzyme Q10, the polyisoprenylated benzoquinone lipid that
    carries electrons in the mitochondrial respiratory chain. This is the node the
    treatment acts on, by supplying the end product exogenously.
  biological_processes:
  - preferred_term: oxidative phosphorylation
    modifier: DECREASED
    term:
      id: GO:0006119
      label: oxidative phosphorylation
  evidence:
  - reference: PMID:26808124
    reference_title: "Coenzyme Q Biosynthesis: Evidence for a Substrate Access Channel in the FAD-Dependent Monooxygenase Coq6."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Coq6 is an enzyme involved in the biosynthesis of coenzyme Q, a polyisoprenylated
      benzoquinone lipid essential to the function of the mitochondrial respiratory
      chain.
    explanation: >-
      Background statement of the product's role; graded OTHER because it is a
      definitional sentence rather than a result of this study.
  downstream:
  - target: Podocyte Injury and Apoptosis
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Podocytes are among the cells expressing COQ6 and are the first renal cell type to
      fail. The route is partly characterized: respiratory-chain compromise raises
      reactive oxygen species, the actin cytoskeleton is disrupted, and the cells
      undergo caspase-3-dependent apoptosis.
  - target: Stria Vascularis Dysfunction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The cochlear structure in which COQ6 is expressed, and the presumed site of the
      hearing lesion.
  - target: Optic Nerve Involvement
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      A third arm, recognized later than the oto-renal core. Its response to a CoQ10
      analogue is what marks it as a distinct, and partially reversible, target.

- name: Podocyte Injury and Apoptosis
  biological_scale: CELLULAR
  description: >-
    Podocyte apoptosis is the demonstrated cellular consequence, and it is partially
    reversible by coenzyme Q10 in both podocyte cell lines and zebrafish - which is the
    experiment that links the deficiency causally to the cell death rather than merely
    correlating them. Knockdown work fills in part of the route: loss of COQ6 raises
    reactive oxygen species and disorganizes the F-actin cytoskeleton before apoptosis,
    which matters because podocyte function depends on maintaining that cytoskeletal
    architecture at the filtration slit.
  cell_types:
  - preferred_term: podocyte
    term:
      id: CL:0000653
      label: podocyte
  evidence:
  - reference: PMID:21540551
    reference_title: "COQ6 mutations in human patients produce nephrotic syndrome with sensorineural deafness."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      knockdown of Coq6 in podocyte cell lines and coq6 in zebrafish embryos caused
      apoptosis that was partially reversed by coenzyme Q10 treatment
    explanation: >-
      Establishes both the cell-death phenotype and its rescue, which together make the
      causal claim.
  - reference: PMID:30425193
    reference_title: "New Mutation of Coenzyme Q(10) Monooxygenase 6 Causing Podocyte Injury in a Focal Segmental Glomerulosclerosis Patient."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Flow cytometry showed significantly increased in apoptotic podocytes, and Western
      blotting showed increases in active caspase-3 in si-COQ6 podocytes. Meanwhile,
      reactive oxygen species (ROS) levels were increased and F-actin immunofluorescence
      was irregularly distributed in the si-COQ6 group.
    explanation: >-
      Measures the intermediate steps rather than only the endpoint: raised ROS and a
      disorganized actin cytoskeleton alongside caspase-3 activation in COQ6-knockdown
      podocytes.
  downstream:
  - target: Focal Segmental Glomerulosclerosis
    causal_link_type: DIRECT
    description: Podocyte loss produces the characteristic glomerular lesion.

- name: Stria Vascularis Dysfunction
  biological_scale: TISSUE
  description: >-
    COQ6 is expressed in stria vascularis cells of the inner ear. The co-occurrence of
    renal and cochlear disease is not coincidental but follows the expression pattern of
    the enzyme.
  locations:
  - preferred_term: stria vascularis of cochlear duct
    term:
      id: UBERON:0002282
      label: stria vascularis of cochlear duct
  evidence:
  - reference: PMID:21540551
    reference_title: "COQ6 mutations in human patients produce nephrotic syndrome with sensorineural deafness."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In rats, COQ6 was located within cell processes and the Golgi apparatus of renal
      glomerular podocytes and in stria vascularis cells of the inner ear, consistent
      with an oto-renal disease phenotype.
    explanation: >-
      The localization result that explains why these two organs and not others,
      obtained in rat tissue.
  downstream:
  - target: Progressive Sensorineural Hearing Loss
    causal_link_type: DIRECT
    description: Strial dysfunction produces the cochlear deficit.

- name: Optic Nerve Involvement
  biological_scale: TISSUE
  description: >-
    Optic atrophy with visual impairment, reported in a subset and added to the
    recognized phenotype after the oto-renal core. Unlike the hearing arm, it responded
    to a hydrophilic CoQ10 analogue.
  evidence:
  - reference: PMID:32685349
    reference_title: "COQ6 mutation in patients with nephrotic syndrome, sensorineural deafness, and optic atrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This study reports the case of two Turkish siblings with renal impairment,
      sensorineural deafness, and optic atrophy exhibiting COQ6 mutation.
    explanation: Establishes optic atrophy as part of the COQ6 phenotype.

- name: Focal Segmental Glomerulosclerosis
  biological_scale: TISSUE
  description: >-
    The histological lesion underlying the nephrotic syndrome, and the reason it
    progresses rather than remitting.
  evidence:
  - reference: PMID:36124066
    reference_title: "Effects of CoQ10 Replacement Therapy on the Audiological Characteristics of Pediatric Patients with COQ6 Variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Histologically, SRNS presents principally as focal segmental glomerulosclerosis
      (FSGS) inevitably leading to chronic kidney disease (CKD)
    explanation: Names the lesion and its trajectory.
  downstream:
  - target: Steroid-Resistant Nephrotic Syndrome
    causal_link_type: DIRECT
    description: Glomerular scarring produces proteinuria unresponsive to immunosuppression.

- name: Steroid-Resistant Nephrotic Syndrome
  biological_scale: ORGANISM
  description: >-
    Proteinuria, hypoalbuminemia and oedema that do not respond to corticosteroids, and
    in a reported case did not respond to a calcineurin inhibitor either, before
    remitting completely on coenzyme Q10.
  evidence:
  - reference: PMID:30232548
    reference_title: "CoQ10-related sustained remission of proteinuria in a child with COQ6 glomerulopathy-a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The disease did not respond for second-line therapy with calcineurin inhibitor,
      but it remitted completely after oral treatment with 30 mg/kg/d of coenzyme Q10
      (CoQ10).
    explanation: >-
      The clearest single demonstration that the resistance is to immunosuppression
      specifically, not to treatment in general.

- name: Progressive Sensorineural Hearing Loss
  biological_scale: ORGANISM
  description: >-
    Generally documented after the renal diagnosis, and progressive. Partially
    responsive to CoQ10 in a genotype-dependent way.
  evidence:
  - reference: PMID:36124066
    reference_title: "Effects of CoQ10 Replacement Therapy on the Audiological Characteristics of Pediatric Patients with COQ6 Variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A diagnosis of SRNS generally precedes SNHL documentation. COQ10D6 is associated
      with progressive SNHL.
    explanation: Establishes the sequence and the progressive course.

phenotypes:
- category: Renal
  name: Steroid-Resistant Nephrotic Syndrome
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Nephrotic syndrome
    term:
      id: HP:0000100
      label: Nephrotic syndrome
  evidence:
  - reference: PMID:36124066
    reference_title: "Effects of CoQ10 Replacement Therapy on the Audiological Characteristics of Pediatric Patients with COQ6 Variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the cardinal phenotypes are steroid-resistant nephrotic syndrome (SRNS), which
      inevitably progresses to kidney failure, and sensorineural hearing loss (SNHL)
    explanation: Names the two cardinal phenotypes.

- category: Renal
  name: Focal Segmental Glomerulosclerosis
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Focal segmental glomerulosclerosis
    term:
      id: HP:0000097
      label: Focal segmental glomerulosclerosis
  evidence:
  - reference: PMID:36124066
    reference_title: "Effects of CoQ10 Replacement Therapy on the Audiological Characteristics of Pediatric Patients with COQ6 Variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Histologically, SRNS presents principally as focal segmental glomerulosclerosis
      (FSGS) inevitably leading to chronic kidney disease (CKD)
    explanation: Identifies the predominant histology.

- category: Sensory
  name: Sensorineural Hearing Loss
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Sensorineural hearing impairment
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:36124066
    reference_title: "Effects of CoQ10 Replacement Therapy on the Audiological Characteristics of Pediatric Patients with COQ6 Variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A diagnosis of SRNS generally precedes SNHL documentation. COQ10D6 is associated
      with progressive SNHL.
    explanation: Establishes the hearing loss and its progressive course.

- category: Renal
  name: Progression to Kidney Failure
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Renal insufficiency
    term:
      id: HP:0000083
      label: Renal insufficiency
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:36124066
    reference_title: "Effects of CoQ10 Replacement Therapy on the Audiological Characteristics of Pediatric Patients with COQ6 Variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the cardinal phenotypes are steroid-resistant nephrotic syndrome (SRNS), which
      inevitably progresses to kidney failure, and sensorineural hearing loss (SNHL)
    explanation: States the renal trajectory in untreated disease.

- category: Ophthalmologic
  name: Optic Atrophy
  frequency: OCCASIONAL
  description: >-
    Reported in a subset, expanding the phenotype beyond the oto-renal core.
  phenotype_term:
    preferred_term: Optic atrophy
    term:
      id: HP:0000648
      label: Optic atrophy
  evidence:
  - reference: PMID:32685349
    reference_title: "COQ6 mutation in patients with nephrotic syndrome, sensorineural deafness, and optic atrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      For the first time, COQ6 mutation with optical involvement is associated with
      renal and hearing impairment.
    explanation: The report that added the ocular arm to the recognized phenotype.

- category: Metabolic
  name: Metabolic Acidosis
  frequency: OCCASIONAL
  description: >-
    Reported in the lethal infantile presentation, and the feature that marks this end of
    the spectrum as a systemic mitochondrial decompensation rather than an oto-renal
    disease. Both reported siblings died in early infancy; that outcome is recorded in
    the genetic notes rather than as a phenotype, since HP:0001522 is a clinical-course
    concept outside the PhenotypeTerm enum.
  phenotype_term:
    preferred_term: Metabolic acidosis
    term:
      id: HP:0001942
      label: Metabolic acidosis
  evidence:
  - reference: PMID:35111204
    reference_title: "A Family Segregating Lethal Primary Coenzyme Q10 Deficiency Due to Two Novel COQ6 Variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we report two Chinese siblings with COQ10D6 who primarily presented with severe
      metabolic acidosis, proteinuria, hypoalbuminemia, growth retardation, and muscle
      hypotonia and died in early infancy
    explanation: Names metabolic acidosis as a presenting feature of the lethal infantile form.

- category: Renal
  name: Proteinuria
  frequency: FREQUENT
  description: >-
    Present in the infantile form as in the classic presentation, though here alongside
    systemic features rather than in isolation.
  phenotype_term:
    preferred_term: Proteinuria
    term:
      id: HP:0000093
      label: Proteinuria
  evidence:
  - reference: PMID:35111204
    reference_title: "A Family Segregating Lethal Primary Coenzyme Q10 Deficiency Due to Two Novel COQ6 Variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we report two Chinese siblings with COQ10D6 who primarily presented with severe
      metabolic acidosis, proteinuria, hypoalbuminemia, growth retardation, and muscle
      hypotonia and died in early infancy
    explanation: Names proteinuria among the presenting features of the lethal infantile form.

- category: Metabolic
  name: Hypoalbuminemia
  frequency: OCCASIONAL
  description: >-
    The biochemical consequence of the protein loss.
  phenotype_term:
    preferred_term: Hypoalbuminemia
    term:
      id: HP:0003073
      label: Hypoalbuminemia
  evidence:
  - reference: PMID:35111204
    reference_title: "A Family Segregating Lethal Primary Coenzyme Q10 Deficiency Due to Two Novel COQ6 Variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we report two Chinese siblings with COQ10D6 who primarily presented with severe
      metabolic acidosis, proteinuria, hypoalbuminemia, growth retardation, and muscle
      hypotonia and died in early infancy
    explanation: Names hypoalbuminemia among the presenting features of the lethal infantile form.

- category: Growth
  name: Growth Retardation
  frequency: OCCASIONAL
  description: >-
    Reported in the infantile presentation.
  phenotype_term:
    preferred_term: Growth delay
    term:
      id: HP:0001510
      label: Growth delay
  evidence:
  - reference: PMID:35111204
    reference_title: "A Family Segregating Lethal Primary Coenzyme Q10 Deficiency Due to Two Novel COQ6 Variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we report two Chinese siblings with COQ10D6 who primarily presented with severe
      metabolic acidosis, proteinuria, hypoalbuminemia, growth retardation, and muscle
      hypotonia and died in early infancy
    explanation: Names growth retardation among the presenting features of the lethal infantile form.

- category: Neurologic
  name: Muscle Hypotonia
  frequency: OCCASIONAL
  description: >-
    Reported in the infantile presentation; not a feature of the classic oto-renal form.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:35111204
    reference_title: "A Family Segregating Lethal Primary Coenzyme Q10 Deficiency Due to Two Novel COQ6 Variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we report two Chinese siblings with COQ10D6 who primarily presented with severe
      metabolic acidosis, proteinuria, hypoalbuminemia, growth retardation, and muscle
      hypotonia and died in early infancy
    explanation: Names muscle hypotonia among the presenting features of the lethal infantile form.

genetic:
- name: COQ6
  gene_term:
    preferred_term: COQ6
    term:
      id: hgnc:20233
      label: COQ6
  relationship_type: CAUSATIVE
  variants:
  - name: c.249C>G (p.Tyr83Ter)
    description: >-
      Nonsense allele producing a truncated protein. Reported in trans with
      p.Gln461Ter in two Chinese siblings who presented with severe metabolic acidosis
      and died in early infancy.
    functional_effects:
    - function: ubiquinone biosynthesis monooxygenase activity
      type: loss-of-function
      description: >-
        A stop codon at residue 83 truncates the protein before the FAD-binding
        monooxygenase domain, so no residual hydroxylase activity is expected.
    evidence:
    - reference: PMID:35111204
      reference_title: "A Family Segregating Lethal Primary Coenzyme Q10 Deficiency Due to Two Novel COQ6 Variants."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        we identified two rare recessive nonsense mutations in the COQ6 gene segregating
        with disease in affected family members: c.249C > G (p.Tyr83Ter) and c.1381C > T
        (p.Gln461Ter), resulting in two truncated protein products
      explanation: Identifies the allele and its truncating consequence.
  - name: c.1381C>T (p.Gln461Ter)
    description: >-
      The second nonsense allele in the same family, in trans with p.Tyr83Ter.
    functional_effects:
    - function: ubiquinone biosynthesis monooxygenase activity
      type: loss-of-function
      description: >-
        The later of the two stop codons, and the reason the sibling pair is a
        compound-heterozygous null rather than a hypomorph. With no functional allele
        on either chromosome the phenotype was lethal in infancy, which is the extreme
        this entry's severity spectrum is anchored against.
    evidence:
    - reference: PMID:35111204
      reference_title: "A Family Segregating Lethal Primary Coenzyme Q10 Deficiency Due to Two Novel COQ6 Variants."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        we identified two rare recessive nonsense mutations in the COQ6 gene segregating
        with disease in affected family members: c.249C > G (p.Tyr83Ter) and c.1381C > T
        (p.Gln461Ter), resulting in two truncated protein products
      explanation: Identifies the allele and its truncating consequence.
  notes: >-
    Biallelic variants on chromosome 14q24.3. Missense alleles predominate in the
    classic oto-renal presentation; the two nonsense alleles above segregated with
    death in early infancy, consistent with residual activity setting position on the
    severity spectrum. Audiological response to CoQ10 appears genotype-specific.
  evidence:
  - reference: PMID:35111204
    reference_title: "A Family Segregating Lethal Primary Coenzyme Q10 Deficiency Due to Two Novel COQ6 Variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we identified two rare recessive nonsense mutations in the COQ6 gene segregating
      with disease in affected family members: c.249C > G (p.Tyr83Ter) and c.1381C > T
      (p.Gln461Ter), resulting in two truncated protein products
    explanation: Identifies the truncating alleles found at the severe end.

inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:36124066
    reference_title: "Effects of CoQ10 Replacement Therapy on the Audiological Characteristics of Pediatric Patients with COQ6 Variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Primary coenzyme Q10 deficiency-6 (COQ10D6) is an autosomal recessive disorder
      attributable to biallelic COQ6 variants
    explanation: States the inheritance pattern and the biallelic requirement.

treatments:
- name: Oral Coenzyme Q10 Replacement
  description: >-
    Supplies the missing end product, bypassing the biosynthetic block rather than
    correcting it. Benefit is strongly dependent on how early it is started, because it
    cannot reverse established glomerular scarring or lost cochlear function.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: coenzyme Q10
      term:
        id: CHEBI:46245
        label: coenzyme Q10
  target_mechanisms:
  - target: Coenzyme Q10 Deficiency
    treatment_effect: BYPASSES
    description: >-
      Exogenous CoQ10 supplies the product the blocked pathway cannot make. This is the
      node the treatment acts on; every downstream benefit follows from it.
    evidence:
    - reference: PMID:21540551
      reference_title: "COQ6 mutations in human patients produce nephrotic syndrome with sensorineural deafness."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        knockdown of Coq6 in podocyte cell lines and coq6 in zebrafish embryos caused
        apoptosis that was partially reversed by coenzyme Q10 treatment
      explanation: >-
        Demonstrates rescue at the cellular level, which is the mechanistic basis for
        the clinical use.
  - target: Steroid-Resistant Nephrotic Syndrome
    treatment_effect: RESTORES
    description: >-
      Complete and sustained remission of proteinuria has been reported, including
      after failure of a calcineurin inhibitor.
    evidence:
    - reference: PMID:30232548
      reference_title: "CoQ10-related sustained remission of proteinuria in a child with COQ6 glomerulopathy-a case report."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        After 12 months of CoQ10 therapy, the child remains in full remission, her
        physical development accelerated, frequent respiratory airways diseases
        subsided.
      explanation: Documents durable remission on treatment.
  - target: Progressive Sensorineural Hearing Loss
    treatment_effect: MODULATES
    description: >-
      Partial and genotype-dependent: in a 12-patient series just under half showed no
      further loss or improvement.
    evidence:
    - reference: PMID:36124066
      reference_title: "Effects of CoQ10 Replacement Therapy on the Audiological Characteristics of Pediatric Patients with COQ6 Variants."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The response rate (no further hearing loss or improvement) was 42.9%; CoQ10
        replacement therapy may thus limit and even improve hearing loss.
      explanation: >-
        Quantifies the audiological response. Graded PARTIAL because fewer than half
        responded and the endpoint combines stabilization with improvement.
  evidence:
  - reference: PMID:28125198
    reference_title: "Primary Coenzyme Q(10) Deficiency Overview."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Review management of primary CoQ10 deficiency, including targeted pharmacologic
      treatment with high-dose oral CoQ10 supplementation and supportive treatment.
    explanation: >-
      The GeneReviews overview names high-dose oral CoQ10 as the targeted pharmacologic
      treatment for primary CoQ10 deficiency as a family. Graded OTHER, and cited at
      family level only: this is an overview article rather than a COQ6 chapter, and its
      cached record does not mention COQ6.
  - reference: PMID:35111204
    reference_title: "A Family Segregating Lethal Primary Coenzyme Q10 Deficiency Due to Two Novel COQ6 Variants."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Nevertheless, patients may not benefit from CoQ10 therapy when severe renal and
      neurological damage is established.
    explanation: >-
      States the limit on efficacy that makes timing the decisive variable; graded
      OTHER as a review statement in the paper's introduction rather than its own
      result.

- name: Cochlear Implantation
  description: >-
    For hearing not preserved by early CoQ10, with outcomes reported as generally
    favourable and sustained.
  treatment_term:
    preferred_term: cochlear device implantation
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  therapeutic_modality: DEVICE
  notes: >-
    Bound to the generic surgical-procedure term because NCIT:C157820 "Cochlear
    Implant" names the device rather than the clinical action, and so is not reachable
    from NCIT:C25218 (Clinical Intervention or Procedure) where TreatmentTerm is
    rooted. The specificity is carried by preferred_term, which is the documented
    pattern for exactly this case. NCIT:C15747 (Supportive Care) was the previous
    binding; implantation is a surgical procedure, and NCIT:C15329 is what the other
    twenty cochlear-implantation treatments across kb/disorders use.
  target_mechanisms:
  - target: Progressive Sensorineural Hearing Loss
    treatment_effect: BYPASSES
    description: >-
      Bypasses the failed cochlear transduction rather than treating the metabolic
      lesion.
  evidence:
  - reference: PMID:36124066
    reference_title: "Effects of CoQ10 Replacement Therapy on the Audiological Characteristics of Pediatric Patients with COQ6 Variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The results of cochlear implantation were generally favorable, and the effects
      were sustained over time.
    explanation: Reports the outcome of implantation in this patient group.

- name: Dialysis
  description: >-
    Extracorporeal solute and fluid clearance once the renal arm reaches kidney
    failure. It substitutes for excretory function indefinitely rather than correcting
    anything, and it is where a reported child went immediately at diagnosis, before
    transplantation became possible.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: renal dialysis
    term:
      id: NCIT:C15221
      label: Dialysis
  target_mechanisms:
  - target: Steroid-Resistant Nephrotic Syndrome
    treatment_effect: BYPASSES
    description: >-
      Substitutes extracorporeally for the excretory function lost as the podocyte
      lesion progresses, without restoring native kidney function.
  evidence:
  - reference: PMID:32685349
    reference_title: "COQ6 mutation in patients with nephrotic syndrome, sensorineural deafness, and optic atrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient started peritoneal dialysis immediately following diagnosis and
      underwent successful renal transplantation
    explanation: >-
      Documents the modality and its timing - started at diagnosis, before the graft.

- name: Kidney Transplantation
  description: >-
    The definitive treatment for the renal arm, and the endpoint the rest of the plan
    exists to avoid. Post-transplant recurrence of nephrotic syndrome is low in
    monogenic SRNS, because the lesion is in the podocyte genome and the graft podocytes
    are someone else's - which makes transplantation curative for this arm in a way it
    is not for immune-mediated nephrotic syndrome. It does nothing for the biosynthetic
    defect, so the auditory and any neurological arms continue after a successful graft.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: kidney transplantation
    term:
      id: NCIT:C15289
      label: Organ Transplantation
  notes: >-
    The low-recurrence reasoning is a prediction this entry can make from its own
    pathophysiology rather than a claim sourced to the references below, which report
    the transplantation but not the recurrence rate. It is stated in the description
    because it is what distinguishes transplantation from dialysis here; it should not
    be read as evidenced by the cited papers.
  target_mechanisms:
  - target: Steroid-Resistant Nephrotic Syndrome
    treatment_effect: BYPASSES
    description: >-
      Replaces the organ in which the podocyte lesion manifests, with a graft whose
      podocytes do not carry the COQ6 genotype.
  evidence:
  - reference: PMID:32685349
    reference_title: "COQ6 mutation in patients with nephrotic syndrome, sensorineural deafness, and optic atrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient started peritoneal dialysis immediately following diagnosis and
      underwent successful renal transplantation
    explanation: >-
      Documents a successful graft in a molecularly confirmed patient, following
      dialysis.

- name: Idebenone
  description: >-
    A hydrophilic short-chain coenzyme Q10 analogue. Its interest here is that it acts
    on the arm oral CoQ10 does not reach: optical symptoms improved on it, while hearing
    loss did not - a clean per-arm dissociation within a single drug in the same
    patients.
  therapeutic_modality: SMALL_MOLECULE
  notes: >-
    The hearing-loss link deliberately carries no treatment_effect. Every available
    value asserts that the drug acts on the node, and the finding is that it did not;
    recording the arm as targeted-and-negative is more informative than omitting it,
    because the contrast with the optic response is the whole observation.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: idebenone
      term:
        id: CHEBI:31687
        label: idebenone
  target_mechanisms:
  - target: Optic Nerve Involvement
    treatment_effect: RESTORES
    description: >-
      Visual impairment improved on treatment in the reported sibling, started three
      months after symptom onset.
    evidence:
    - reference: PMID:32685349
      reference_title: "COQ6 mutation in patients with nephrotic syndrome, sensorineural deafness, and optic atrophy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Idebenone treatment appeared to be effective in resolving optical impairment.
      explanation: Reports the ocular response in the treated patient.
  - target: Progressive Sensorineural Hearing Loss
    description: >-
      The arm idebenone did not reach, in the same patient and over the same treatment
      course as the ocular response above. The contrast with that optic response is the
      observation: a per-arm dissociation within one drug in one patient.
    evidence:
    - reference: PMID:32685349
      reference_title: "COQ6 mutation in patients with nephrotic syndrome, sensorineural deafness, and optic atrophy."
      supports: REFUTE
      evidence_source: HUMAN_CLINICAL
      snippet: Idebenone treatment did not, however, improve the hearing loss.
      explanation: >-
        Refutes an effect of idebenone on the auditory arm specifically. Held here
        rather than at treatment level, where the same sentence read as a refutation of
        idebenone as such - which the optic response in the line above contradicts.
  evidence:
  - reference: PMID:32685349
    reference_title: "COQ6 mutation in patients with nephrotic syndrome, sensorineural deafness, and optic atrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Supplement treatment with Idebenone (hydrophilic short‐chain coenzyme Q 10
      analogue) was started 3 months after the onset of optical symptoms.
    explanation: Identifies the agent's class and the timing of treatment.

diagnosis:
- name: Molecular genetic testing in steroid-resistant nephrotic syndrome
  description: >-
    The diagnosis is molecular. There is no biochemical screen that identifies COQ6
    specifically - plasma and urine findings are those of nephrotic syndrome from any
    cause - so the route in is sequencing, either whole-exome or an SRNS/FSGS gene
    panel. The clinical trigger that should prompt it is the combination the disease is
    named for: steroid resistance plus sensorineural deafness, in a child. Making the
    diagnosis is not academic here, because it changes management immediately -
    monogenic CoQ10 deficiency is one of the few forms of SRNS with a targeted therapy,
    and the therapy's benefit depends on how early it starts.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:36124066
    reference_title: "Effects of CoQ10 Replacement Therapy on the Audiological Characteristics of Pediatric Patients with COQ6 Variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All 12 underwent medical review, auditory phenotyping, and molecular genetic
      testing
    explanation: >-
      Establishes molecular testing as the diagnostic route applied uniformly across the
      reported cohort.
  - reference: PMID:36124066
    reference_title: "Effects of CoQ10 Replacement Therapy on the Audiological Characteristics of Pediatric Patients with COQ6 Variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In the remaining three patients, targeted exome sequencing (TES) covering 57 genes
      known to be associated with SRNS or FSGS at that time was performed, because our
      strategy for mutational screening of patients with SRNS changed during the course
      of the study from Sanger sequencing to TES (as a first-tier test)
    explanation: >-
      Names the specific testing strategy and records that a targeted SRNS/FSGS panel
      became the first-tier test, which is the practical form of the recommendation.
  - reference: PMID:35111204
    reference_title: "A Family Segregating Lethal Primary Coenzyme Q10 Deficiency Due to Two Novel COQ6 Variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Using whole-exome sequencing and Sanger sequencing, we identified two rare
      recessive nonsense mutations in the COQ6 gene segregating with disease in affected
      family members
    explanation: >-
      The other route, used where no panel fits the presentation - these siblings
      presented with metabolic acidosis rather than the classic oto-renal picture.

- name: Renal biopsy showing focal segmental glomerulosclerosis
  description: >-
    FSGS is what COQ6 disease looks like histologically, but it is the common final
    appearance of podocyte injury from many causes, so a biopsy identifies the lesion
    and not its cause. Its value here is directional rather than confirmatory: an FSGS
    pattern in a steroid-resistant child is what should send the workup to sequencing.
  diagnosis_term:
    preferred_term: biopsy of kidney
    term:
      id: NCIT:C51699
      label: Kidney Biopsy
  notes: >-
    Bound to the procedure term even though the entry's point is that the finding is
    not diagnostic on its own. The term names what is done, not what it proves;
    Galloway-Mowat_Syndrome makes the same argument in its description and binds the
    same term.
  evidence:
  - reference: PMID:36124066
    reference_title: "Effects of CoQ10 Replacement Therapy on the Audiological Characteristics of Pediatric Patients with COQ6 Variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Histologically, SRNS presents principally as focal segmental glomerulosclerosis
      (FSGS) inevitably leading to chronic kidney disease (CKD) that is the second-most
      common cause of kidney failure in the first two decades of life
    explanation: >-
      Gives the histological pattern and its renal trajectory in one sentence.

progression:
- phase: Steroid-resistant nephrotic syndrome to kidney failure
  notes: >-
    The renal arm is progressive and, untreated, terminal for the kidney: the source
    describes progression to kidney failure as inevitable. The word is the authors' and
    is worth preserving, because it is what makes the timing of CoQ10 the single
    decisive variable in this disease - the drug can prevent glomerular scarring and
    cannot reverse it. The two arms come apart here: renal function can be rescued to
    normal if treatment starts early enough, while hearing responds in fewer than half
    of patients and not at all once lost.
  evidence:
  - reference: PMID:36124066
    reference_title: "Effects of CoQ10 Replacement Therapy on the Audiological Characteristics of Pediatric Patients with COQ6 Variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the cardinal phenotypes are steroid-resistant nephrotic syndrome (SRNS), which
      inevitably progresses to kidney failure, and sensorineural hearing loss (SNHL)
    explanation: >-
      States the renal trajectory in the authors' own terms, as a property of the
      disease rather than of a particular cohort.
  - reference: PMID:36124066
    reference_title: "Effects of CoQ10 Replacement Therapy on the Audiological Characteristics of Pediatric Patients with COQ6 Variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      SRNS of patients with COQ10D6 may respond to CoQ10 replacement therapy that
      decreases proteinuria and restores normal renal function, particularly if
      treatment commences before the kidney pathological findings progress
    explanation: >-
      The modifier on that trajectory, and the reason this entry treats treatment timing
      rather than treatment choice as the decisive variable.

experimental_models:
- name: COQ6-knockdown podocyte cell line
  experimental_model_type: CELL_LINE
  description: >-
    The system in which podocyte apoptosis and its CoQ10 rescue were demonstrated, and
    in which the ROS and cytoskeletal intermediates were measured.
  publication: PMID:21540551
  modeled_mechanisms:
  - target: Podocyte Injury and Apoptosis
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Reproduces the cell-death phenotype and, critically, its partial reversal by
      coenzyme Q10 - which is the experiment the treatment's BYPASSES link rests on.
    limitations: >-
      A knockdown in cultured podocytes models neither the hypomorphic alleles patients
      carry nor the glomerular architecture in which the lesion produces proteinuria.
    evidence:
    - reference: PMID:21540551
      reference_title: >-
        COQ6 mutations in human patients produce nephrotic syndrome with sensorineural
        deafness.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        knockdown of Coq6 in podocyte cell lines and coq6 in zebrafish embryos caused
        apoptosis that was partially reversed by coenzyme Q10 treatment
      explanation: >-
        The rescue result that makes this model informative for the treatment claim
        rather than only for the phenotype.

animal_models:
- name: coq6 morpholino zebrafish
  species: Zebrafish
  genotype: coq6 morpholino knockdown
  publication: PMID:21540551
  description: >-
    The whole-organism half of the same experiment. It shows apoptosis on coq6
    knockdown; it does not test CoQ10 rescue.
  modeled_mechanisms:
  - target: Podocyte Injury and Apoptosis
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Reproduces apoptosis on coq6 knockdown in a vertebrate, establishing that the
      cell-death phenotype is not an artefact of cultured cells.
    limitations: >-
      Morpholino knockdown is transient and not allele-specific. Critically, the
      zebrafish arm carries no coenzyme Q10 treatment condition - the rescue was
      demonstrated in cultured podocytes (Figure 5, A-C), while the zebrafish panels
      (D-F) test knockdown against mismatch and uninjected controls only. So this model
      supports the phenotype, not the treatment response. And no cochlear or
      optic-nerve model exists in any species, so the hearing and vision arms of this
      disease rest on mechanistic analogy rather than on a model.
    evidence:
    - reference: PMID:21540551
      reference_title: >-
        COQ6 mutations in human patients produce nephrotic syndrome with sensorineural
        deafness.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        coq6 knockdown in zebrafish embryos 28 hours after fertilization increases
        apoptosis
      explanation: >-
        A zebrafish-only result, quoted rather than the abstract's combined
        cell-line-and-zebrafish sentence, so this item cites the finding it actually
        rests on and carries a single evidence type.

discussions:
- discussion_id: coq6_steroid_resistance_is_predicted
  kind: INTERPRETATION
  prompt: >-
    Is steroid resistance in this disease an empirical finding or a prediction of the
    mechanism?
  attaches_to:
  - pathophysiology#Steroid-Resistant Nephrotic Syndrome
  - treatments#Oral Coenzyme Q10 Replacement
  rationale: >-
    The phrase "steroid-resistant" entered this entity's name from nephrology, where it
    classifies nephrotic syndrome by observed response. But once the lesion is known to
    be a defect of coenzyme Q10 biosynthesis in podocytes, resistance to
    immunosuppression is what the mechanism predicts: there is no immune process for a
    steroid or a calcineurin inhibitor to suppress. The reported case in which
    calcineurin inhibition failed and CoQ10 produced complete remission is the clean
    demonstration. The practical consequence is that in a child with SRNS, resistance
    to immunosuppression should prompt a genetic and metabolic question rather than an
    escalation of immunosuppression - which is why the entry models the resistance as
    part of the causal chain instead of recording it as an adjective.

- discussion_id: coq6_no_model_for_the_sensory_arms
  kind: HUMAN_MODEL_MISMATCH
  prompt: >-
    The renal arm has models that reproduce it and respond to CoQ10. What supports the
    hearing and vision arms?
  attaches_to:
  - pathophysiology#Stria Vascularis Dysfunction
  - pathophysiology#Optic Nerve Involvement
  rationale: >-
    The podocyte and zebrafish models both reproduce the renal cell-death phenotype,
    and the podocyte model additionally shows its CoQ10 responsiveness, so the claim
    that supplying the missing metabolite rescues podocytes is directly supported at
    the cellular level. It is worth being precise that the rescue was not tested in the
    whole organism: the abstract summarizes both experiments in one sentence, but the
    zebrafish panels carry no CoQ10 condition. No cochlear or optic-nerve model of COQ6 deficiency is
    reported in the sources used here. Those two arms therefore rest on a localization
    result - COQ6 protein in stria vascularis cells - plus mechanistic analogy to the
    renal arm, and on the clinical observation that they respond differently to
    treatment: idebenone improved vision and did not improve hearing in the same
    patients. That dissociation is exactly what a model would be needed to explain, and
    there is none. Recorded as a HUMAN_MODEL_MISMATCH rather than a plain knowledge gap
    because the issue is not that evidence is absent but that the evidence which exists
    covers one arm and is being extended to two others.

- discussion_id: coq6_timing_determines_benefit
  kind: KNOWLEDGE_GAP
  prompt: >-
    How much of the variation in CoQ10 response is genotype and how much is timing?
  attaches_to:
  - treatments#Oral Coenzyme Q10 Replacement
  - pathophysiology#Focal Segmental Glomerulosclerosis
  rationale: >-
    Two explanations are offered for why some patients respond and others do not, and
    the available reports do not separate them. The audiological series attributes the
    42.9% response rate to genotype, noting the benefit appeared genotype-specific.
    Other reports attribute non-response to established damage, stating patients may not
    benefit once severe renal and neurological damage is present. These are not
    mutually exclusive and would be distinguished by treating patients of the same
    genotype at different stages, which no reported series does. The distinction
    matters because it determines whether genotype should modify the urgency of
    starting treatment or only the expectation of benefit.

notes: >-
  Identifiers. OMIM:614650; ORPHA:280406. Both are xrefs of the curated disease_term
  MONDO:0013836, alongside DOID:0070243, GARD:0017295, MEDGEN:766263 and
  UMLS:C3553349. They are recorded here rather than under mappings: because the
  mappings block has slots for ICD-10-CM, ICD-11, MONDO and NCIT only, and MONDO
  already carries these two - re-asserting an ontology's own xrefs is the thing the
  design register tells curators not to do. OMIM names the disease Coenzyme Q10
  deficiency, primary, 6 (COQ10D6), which is the label most of the primary literature
  cited here uses.

  GeneReviews. PMID:28125198 is the primary CoQ10 deficiency Overview, not a
  COQ6-specific chapter. Its cached record is the article's six-point purpose statement
  and does not mention COQ6 at all, so there are no Clinical Characteristics,
  Diagnosis/Testing, Management or Genetic Counseling sections to mine here. It is cited
  once for the family-level statement that high-dose oral CoQ10 is the targeted
  pharmacological treatment, and the evidence explanation says so. Declaring and
  tagging a reference without citing it is the failure mode this paragraph exists to
  guard against.

  Relationship to existing entries. kb/disorders/Primary_Coenzyme_Q10_Deficiency.yaml
  curates the umbrella and already carries COQ6 in its has_subtypes list. A standalone
  entry alongside that umbrella follows the precedent already set by
  kb/disorders/COQ4-Related_Neonatal_Encephalomyopathy.yaml, which likewise exists both
  as its own entry and as a subtype there. This entry should be read as the detailed
  treatment of the COQ6 form, not as a competing definition.

  Naming. MONDO's label for this entity leads with the clinical description
  ("familial steroid-resistant nephrotic syndrome with sensorineural deafness"). The
  entry name leads with the gene, following the KB's prevailing convention for
  gene-defined entities and matching the COQ4 sibling. The MONDO label is preserved in
  disease_term.

  On the claim's expectation about hearing. The claim issue for this disease predicted
  that the deafness would generally not reverse. The Korean series reports a 42.9%
  audiological response rate, with stabilization or improvement, and describes the
  benefit as genotype-specific. The entry follows the source rather than the prior
  expectation, and grades the treatment link PARTIAL rather than asserting either
  outcome.

  Evidence splitting. PMID:26808124 is cited twice on the same node with different
  evidence_source values, because one quoted sentence reports a biochemical result
  (IN_VITRO) and the other reports molecular dynamics and docking (COMPUTATIONAL).
  These are separate items rather than one, per the rule that a paper mixing evidence
  types should have its evidence split.
📚

References & Deep Research

References

8
PMID:28125198
Primary Coenzyme Q(10) Deficiency Overview.
No top-level findings curated for this source.
PMID:21540551
COQ6 mutations in human patients produce nephrotic syndrome with sensorineural deafness.
No top-level findings curated for this source.
PMID:26808124
Coenzyme Q Biosynthesis: Evidence for a Substrate Access Channel in the FAD-Dependent Monooxygenase Coq6.
No top-level findings curated for this source.
PMID:30232548
CoQ10-related sustained remission of proteinuria in a child with COQ6 glomerulopathy-a case report.
No top-level findings curated for this source.
PMID:30425193
New Mutation of Coenzyme Q(10) Monooxygenase 6 Causing Podocyte Injury in a Focal Segmental Glomerulosclerosis Patient.
No top-level findings curated for this source.
PMID:32685349
COQ6 mutation in patients with nephrotic syndrome, sensorineural deafness, and optic atrophy.
No top-level findings curated for this source.
PMID:35111204
A Family Segregating Lethal Primary Coenzyme Q10 Deficiency Due to Two Novel COQ6 Variants.
No top-level findings curated for this source.
PMID:36124066
Effects of CoQ10 Replacement Therapy on the Audiological Characteristics of Pediatric Patients with COQ6 Variants.
No top-level findings curated for this source.

Deep Research

1
Claude Code ▸
COQ6-Related Steroid-Resistant Nephrotic Syndrome with Sensorineural Deafness (Primary Coenzyme Q10 Deficiency-6, COQ10D6): Comprehensive Research Report
claude-haiku-4-5-20251001, claude-sonnet-5 21 citations 2026-08-27T18:56:53.518767

COQ6-Related Steroid-Resistant Nephrotic Syndrome with Sensorineural Deafness (Primary Coenzyme Q10 Deficiency-6, COQ10D6): Comprehensive Research Report

1. Disease Information

Overview. COQ6-related nephrotic syndrome with sensorineural deafness — designated Primary Coenzyme Q10 Deficiency, Type 6 (COQ10D6) — is an ultra-rare, autosomal recessive mitochondrial disorder caused by biallelic loss-of-function variants in COQ6, a gene required for biosynthesis of coenzyme Q10 (ubiquinone). The disease is defined by the combination of infantile-onset steroid-resistant nephrotic syndrome (SRNS) progressing to end-stage renal failure, together with bilateral sensorineural hearing loss; a subset of patients also develop optic atrophy and/or neurological involvement. It is one of the few genetic causes of SRNS that is potentially treatable, since high-dose CoQ10 (or the analogue idebenone) supplementation can, in a genotype-dependent fashion, halt or reverse disease progression (PMC7358665; GeneReviews NBK410087).

Key identifiers: - OMIM Gene: 614647 — COENZYME Q6, MONOOXYGENASE; COQ6 (omim.org/entry/614647) - OMIM Phenotype: #614650 — COENZYME Q10 DEFICIENCY, PRIMARY, 6 (COQ10D6) (omim.org/entry/614650) - Orphanet: ORPHA:280406 — Familial steroid-resistant nephrotic syndrome with sensorineural deafness caused by COQ6 mutations (orpha.net) - Gene location: Chromosome 14q24.3 - Broader disease group: Primary Coenzyme Q10 Deficiency (a mitochondrial respiratory-chain disorder), GeneReviews overview NBK410087 - HGNC:* COQ6 (gene symbol), NM_182480 (reference transcript)

Synonyms: COQ10D6; Primary ubiquinone deficiency-6; COQ6 nephropathy; COQ6 glomerulopathy; SRNS-deafness syndrome (COQ6-related); COQ6-associated Coenzyme Q10 deficiency.

Evidence base: This is a disease characterized almost entirely from aggregated case series and individual case reports in the literature (originally 11–13 patients in the founding 2011 study, with subsequent single-family and small-cohort reports from Turkey, Lebanon, China, Korea, and other populations) rather than large-scale registries or EHR-derived cohorts — reflecting its rarity (fewer than a few dozen molecularly confirmed families reported to date).

2. Etiology

Disease Causal Factor: Monogenic — biallelic (homozygous or compound heterozygous) pathogenic variants in COQ6, disrupting a step of the CoQ10 (ubiquinone) biosynthetic pathway. There is no known environmental, infectious, or purely mechanistic (non-genetic) cause; this is a primary genetic mitochondrial disease.

Genetic risk factors: - Homozygous or compound heterozygous loss-of-function or missense COQ6 variants are causal. - The founding study (Heeringa et al., 2011, J Clin Invest, PMID 21540551) identified six different COQ6 mutations in 13 individuals from 7 families by homozygosity mapping, establishing the SRNS+deafness phenotype. - Reported pathogenic variants across the literature include: p.Gly255Arg, p.Ala353Asp (c.1058C>A), p.Arg360Trp (c.1078C>T), c.804delC (frameshift), p.Trp14Ter (c.41G>A, nonsense), p.Tyr83Ter (c.249C>G, nonsense), p.Gln461Ter (c.1381C>T), c.189_191delGAA (p.Lys64del), p.Arg162Ter (c.484C>T), p.Gln229Pro (c.686A>C), and p.Pro261Leu (c.782C>T). - ClinVar currently lists 307 reported COQ6 variants, of which 32 alleles are classified pathogenic and 12 likely pathogenic (MARRVEL/ClinVar aggregate, accessed via marrvel.org/human/gene/51004). - All missense variants identified in disease cohorts are predicted damaging by PolyPhen2/SIFT; all premature-stop, frameshift, or splice variants are predicted high-confidence loss-of-function (Sci Rep 2017, DOI 10.1038/s41598-017-17564-y). - Possible genetic modifiers: a 2026 review (Wiley MGG 2026, DOI 10.1002/mgg3.70221) notes that among siblings carrying the same COQ6 variant, co-inheritance of a COQ8B p.(Arg174)/p.(His174) polymorphism was associated with differing severity of renal involvement, suggesting COQ8B may act as a phenotypic modifier of COQ6 disease. - No environmental risk factors, occupational exposures, or infectious triggers have been identified — this is a purely Mendelian condition.

Protective factors: None identified beyond therapeutic CoQ10/idebenone supplementation (see Treatment, §12), which is disease-modifying rather than truly "protective" in a population-genetics sense. No protective alleles have been described.

Gene-environment interactions: Not established; the phenotype is driven by the biosynthetic enzyme defect itself, and no environmental modifier of expressivity has been reported.

3. Phenotypes

Renal phenotype (defining feature)

  • Steroid-resistant nephrotic syndrome (SRNS): proteinuria at a median age of onset 1.2 years (range 0.2–6.4 years) in the original cohort (PMC7358665, summarizing Heeringa et al. 2011). Median progression to end-stage renal failure (ESRF) at 1.7 years (range 0.4–9.3 years).
  • Renal biopsy: focal segmental glomerulosclerosis (FSGS) is the most common histologic finding; diffuse mesangial sclerosis has also been reported.
  • Suggested HP terms: HP:0000100 (Nephrotic syndrome), HP:0000097 (Focal segmental glomerulosclerosis), HP:0000093 (Proteinuria), HP:0003774 / HP:0000083 (Stage 5 chronic kidney disease / Renal insufficiency), HP:0000822 (Hypertension, in some patients).

Auditory phenotype (defining feature)

  • Bilateral sensorineural hearing loss (SNHL), typically diagnosed between ages 4–6 years in reported cases, though age of onset is variable and it can be congenital in more severe genotypes.
  • Suggested HP term: HP:0000407 (Sensorineural hearing impairment).
  • A Korean cohort study (PMC9482153) of 12 patients found the response rate to CoQ10 (no further hearing loss or improvement) was 42.9% among 7 patients with >1 year of serial audiograms; genotype strongly predicted response (see §12).

Ophthalmologic phenotype (variable)

  • Optic atrophy, papilledema, and progressive visual loss have been reported in a subset of patients (e.g., visual acuity 20/200 at age 17 in one case, improving to 20/25+ after 3 years of idebenone; PMC7358665).
  • Suggested HP terms: HP:0000648 (Optic atrophy), HP:0001622 (Premature birth — not typical), HP:0000587 (Bilateral cataracts — not typical here).

Neurological/systemic phenotype (severe/lethal cases only)

  • In the most severe (lethal infantile) presentations: severe metabolic acidosis (lactate up to 7.8 mmol/L), seizures, muscle hypotonia, growth retardation, delayed white matter myelination, bifrontal subarachnoid space widening, atrial septal defect, and pulmonary hypertension — death occurring before 6 months of age in the reported family (PMC8802230).
  • Suggested HP terms: HP:0001250 (Seizure), HP:0001943 (Hypoglycemia, not directly reported but common in mitochondrial disease), HP:0002151 (Increased serum lactate), HP:0001252 (Hypotonia), HP:0001510 (Growth delay), HP:0006530 (Interstitial pulmonary disease — n/a), HP:0001631 (Atrial septal defect), HP:0002092 (Pulmonary hypertension).

Phenotype variability and severity spectrum

Clinical severity ranges widely: from isolated, slowly progressive SRNS+SNHL surviving into adulthood, to a lethal infantile multisystem mitochondrial disease with cardiac, neurological, and metabolic involvement dying within months. Even siblings sharing the identical COQ6 genotype can show markedly different renal-phenotype severity (ScienceDirect, "Two siblings with variable expressivity of the renal phenotype"), consistent with modifier effects and/or stochastic factors.

Quality of life impact

No disease-specific QoL instrument data were found in the literature searched; QoL burden is inferable from the combination of ESRD (dialysis/transplant dependency), profound hearing loss (often requiring cochlear implantation), and, in some patients, progressive visual impairment — a multisensory and renal-replacement burden concentrated in early childhood.

4. Genetic/Molecular Information

Causal gene: COQ6 (OMIM *614647), chromosome 14q24.3.

Protein: Coenzyme Q6, monooxygenase — a mitochondrial FAD-dependent monooxygenase of the UbiH/COQ6 family. Two isoforms are described: isoform A (468 aa, ~54 kDa, with an N-terminal mitochondrial targeting leader peptide) and isoform B (~51 kDa, lacking the leader peptide). The protein carries three FAD-binding motifs and catalyzes C5-ring hydroxylation in ubiquinone biosynthesis — specifically the conversion of 3-polyprenyl-4-hydroxybenzoic acid to 3-polyprenyl-4,5-dihydroxybenzoic acid (GeneCards/Wikipedia COQ6; PMC4726752, "Substrate Access Channel in the FAD-Dependent Monooxygenase Coq6"). Human COQ6 shares 66% sequence identity with zebrafish Coq6 and 33% with the E. coli ortholog UbiH, indicating deep evolutionary conservation of this biosynthetic step.

Variant classification and types: Reported pathogenic variants span missense (e.g., p.Ala353Asp, p.Arg360Trp, p.Gly255Arg, p.Gln229Pro, p.Pro261Leu), nonsense (p.Trp14Ter, p.Tyr83Ter, p.Gln461Ter, p.Arg162Ter), and small in-frame/frameshift deletions (c.189_191delGAA/p.Lys64del, c.804delC). All are classified via ACMG/AMP criteria on ClinVar (32 pathogenic, 12 likely pathogenic alleles of 307 total reported variants).

Allele frequency: Individually rare (gnomAD-derived global allele frequencies for ubiquinone-pathway pathogenic variants collectively range 4.1×10⁻⁶–1.7×10⁻⁴, combined ≈1.76×10⁻³ across all CoQ-biosynthesis genes; Sci Rep 2017, DOI 10.1038/s41598-017-17564-y). No COQ6-specific founder allele frequency was identified, though clusters of cases have been reported from Turkish, Lebanese, Chinese, and Korean cohorts, suggesting possible regional enrichment of specific alleles without confirmed founder-effect data in the literature reviewed.

Origin: Germline, autosomal recessive — no somatic COQ6 variants are implicated in this disease.

Functional consequences: Loss-of-function (nonsense/frameshift alleles) or hypomorphic/damaging missense variants reduce COQ6 monooxygenase activity, impairing CoQ10 biosynthesis (a "loss of function" mechanism rather than dominant-negative or gain-of-function). Functional impact category: LOSS_OF_FUNCTION (nonsense/frameshift) or PARTIAL_LOSS_OF_FUNCTION (hypomorphic missense with residual, genotype-dependent enzymatic activity — consistent with the graded CoQ10-treatment response by genotype).

Modifier genes: COQ8B polymorphism (p.Arg174/His174) proposed as a phenotype modifier in siblings sharing an identical COQ6 genotype (Wiley MGG 2026 review).

Epigenetic/chromosomal information: No epigenetic regulation or chromosomal-abnormality mechanism has been reported for this disease; it is driven purely by coding-sequence variants in COQ6.

5. Environmental Information

No environmental, lifestyle, or infectious contributing factors have been identified in the literature. This is a monogenic mitochondrial biosynthetic disorder; disease expression is not modulated by toxin exposure, diet (beyond therapeutic CoQ10 supplementation, which is a treatment rather than a preventive environmental factor), or infectious agents. This section is therefore not applicable beyond noting the absence of such associations.

6. Mechanism / Pathophysiology

Causal chain (upstream → downstream):

  1. Molecular defect: Biallelic pathogenic COQ6 variants → loss/reduction of COQ6 FAD-dependent monooxygenase activity → failure of the C5-ring hydroxylation step of ubiquinone (CoQ10) biosynthesis.
  2. Biochemical consequence: Reduced cellular/tissue CoQ10 levels. GeneReviews (NBK410087) documents "reduced levels of CoQ10 in skeletal muscle" and "reduced activities of complex I+III and II+III of the mitochondrial respiratory chain" in affected patients — since CoQ10 is the mobile electron carrier shuttling electrons from Complexes I and II to Complex III.
  3. Mitochondrial dysfunction: Impaired electron transport chain flux → decreased oxidative phosphorylation/ATP generation and, critically, loss of CoQ10's antioxidant function in the inner mitochondrial membrane.
  4. Oxidative stress: In podocyte and zebrafish knockdown models, Coq6 deficiency significantly increased reactive oxygen species (ROS), demonstrated by MitoSOX staining (PMC6247592).
  5. Cytoskeletal/structural podocyte injury: ROS-driven damage reduces F-actin expression (with irregular distribution) and decreases nephrin expression, compromising the slit-diaphragm/cytoskeletal integrity essential to the glomerular filtration barrier.
  6. Apoptosis: Increased active caspase-3 and caspase-9 (intrinsic mitochondrial apoptotic pathway) documented by flow cytometry and western blot in Coq6-knockdown mouse podocyte cell lines (PMC6247592; original JCI paper PMID 21540551).
  7. Clinical/histologic outcome — kidney: Podocyte loss and dysfunction manifest as proteinuria/nephrotic syndrome, progressing histologically to FSGS or diffuse mesangial sclerosis and clinically to ESRF.
  8. Clinical outcome — cochlea/eye/CNS: Analogous CoQ10-deficiency-driven oxidative/bioenergetic injury is presumed to underlie sensorineural hearing loss (cochlear hair cells are highly energy-dependent) and optic atrophy/neurologic disease in more severe genotypes, though the cochlear and optic mechanisms are less directly modeled experimentally than the podocyte pathway.

Cell types involved: Podocytes (kidney glomerular visceral epithelial cells) are the best-characterized cellular site of injury (Cell Ontology: CL:0000653, podocyte). Cochlear hair cells and the auditory pathway are presumed targets for SNHL; retinal ganglion cells/optic nerve for optic atrophy.

Key pathway/process annotations (suggested GO terms): - GO:0006744 — ubiquinone biosynthetic process (upstream defective pathway) - GO:0016709 — oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, NAD(P)H as one donor and incorporation of one atom of oxygen (COQ6 monooxygenase activity) - GO:0055114 — oxidation-reduction process - GO:0006979 — response to oxidative stress - GO:0006915 — apoptotic process - GO:0030036 — actin cytoskeleton organization (F-actin/podocyte cytoskeletal injury) - GO:0022900 — electron transport chain

Biochemical abnormalities: Reduced tissue CoQ10; reduced mitochondrial respiratory chain complex I+III and II+III activity (measurable in muscle biopsy or cultured fibroblasts) — the biochemical diagnostic correlate of the genetic defect.

Molecular profiling: No large-scale transcriptomic, proteomic, or single-cell datasets specific to human COQ6-deficient kidney/cochlear tissue were identified in this search; mechanistic data derive principally from candidate-gene knockdown studies (siRNA in mouse podocyte cell lines; morpholino knockdown in zebrafish embryos), not from unbiased omics profiling of patient tissue.

7. Anatomical Structures Affected

Organ level: - Primary: Kidney (glomerulus/podocytes) — nephrotic syndrome, FSGS; Inner ear (cochlea) — sensorineural hearing loss. - Secondary: Eye (optic nerve) — optic atrophy in a subset; in severe infantile cases, heart (atrial septal defect, pulmonary hypertension) and central nervous system (seizures, delayed white matter myelination). - Body systems: Renal/urinary system (primary), auditory system (primary), visual system (secondary), cardiovascular and central nervous systems (secondary, severe cases only).

Tissue/cell level: - Glomerular visceral epithelial cells (podocytes), CL:0000653. - Cochlear hair cells / spiral ganglion neurons (inferred target, not directly demonstrated at single-cell resolution in the literature reviewed). - Retinal ganglion cells / optic nerve axons (optic atrophy).

Subcellular level: Mitochondria — specifically the inner mitochondrial membrane, site of CoQ10's electron-shuttling and antioxidant functions (GO Cellular Component: GO:0005743, mitochondrial inner membrane; GO:0005739, mitochondrion).

Localization (UBERON terms, suggested): - UBERON:0001225 — renal glomerulus - UBERON:0002113 — kidney - UBERON:0000959 — cochlea (auditory system) - UBERON:0001784 — optic nerve - UBERON:0000948 — heart (atrial septal defect in severe cases)

Laterality: Renal disease is systemic/bilateral (both kidneys); sensorineural hearing loss and optic atrophy are typically bilateral.

8. Temporal Development

Onset: Congenital-to-infantile in most reported cases. Proteinuria/nephrotic syndrome onset at a median age of 1.2 years (range 0.2–6.4 years); the most severe (lethal) cases present within the first months of life (3–5 months in the reported lethal sibling pair). Sensorineural hearing loss is typically identified in early childhood (age 4–6 years in several reports), though it can be congenital in severe genotypes.

Onset pattern: Generally insidious/subacute for the renal and auditory phenotypes; acute and rapidly fulminant in the lethal infantile multisystem presentations (metabolic acidosis, seizures, cardiac involvement within weeks to months).

Progression: - Renal: progresses from proteinuria → steroid-resistant nephrotic syndrome → FSGS on biopsy → ESRF, with median time to ESRF of 1.7 years (range 0.4–9.3 years) in the original cohort. Progression is not universal or inevitable in all genotypes when CoQ10 treatment is initiated promptly (see Treatment). - Auditory: progressive in genotype-dependent fashion; some genotypes show ongoing threshold deterioration despite treatment (mean shift +24.1 dB in "non-responders"), others remain stable or even improve (mean shift −5.4 dB in "responders") (PMC9482153). - Ophthalmologic: progressive optic atrophy/visual loss reported in adolescence in some patients, partially reversible with idebenone. - Course pattern: Predominantly progressive, though CoQ10/idebenone therapy can achieve durable remission of proteinuria (sustained ≥12 months in one well-documented case, PMC6208703) and stabilization or improvement of hearing/vision in a genotype-dependent subset — making this a rare example of a "modifiable progressive" course among genetic SRNS syndromes. - Duration: Chronic, lifelong for survivors (renal replacement therapy/transplant, hearing aids/cochlear implants); the most severe infantile-onset multisystem form is fatal within the first year of life.

Remission patterns: Treatment-induced remission of nephrotic-range proteinuria has been documented with CoQ10 supplementation (complete remission within 1 month of initiating 30 mg/kg/day CoQ10 in one case, sustained to at least 12-month follow-up; PMC6208703). No spontaneous remission has been reported.

Critical periods: Early diagnosis and prompt initiation of CoQ10/idebenone therapy — ideally before irreversible glomerular scarring, cochlear damage, or optic nerve injury has occurred — is repeatedly emphasized in the literature as the key window for effective intervention ("Early recognition of this genetic SRNS is mandatory since... can be avoided by adequate treatment based on CoQ10 supplement or an analogue," PMC7358665).

9. Inheritance and Population

Epidemiology: COQ10D6 is ultra-rare; only a few dozen molecularly confirmed cases/families have been reported worldwide since the disease was first delineated in 2011. The broader category of primary CoQ10 deficiency (all 10+ causal genes combined) has an estimated overall incidence of <1:100,000 (GeneReviews NBK410087). No disease-specific prevalence/incidence estimate isolated to COQ6 was found; it should be regarded as one of the rarer genetic subtypes within this already-rare disease group.

Inheritance pattern: Autosomal recessive. At-risk siblings of an affected individual have a 25% recurrence risk when both parents are heterozygous carriers; heterozygous carriers are asymptomatic (GeneReviews NBK410087).

Penetrance: Appears fully penetrant for the core renal phenotype among individuals carrying two pathogenic alleles, though severity (age of onset, rate of progression, extrarenal involvement) is highly variable — including divergent severity between siblings sharing the identical genotype, implicating modifier loci (e.g., COQ8B) and/or environmental/stochastic factors.

Expressivity: Markedly variable — spanning isolated, slowly progressive SRNS+SNHL to lethal infantile multisystem mitochondrial disease, even within the same family/genotype.

Genetic anticipation: Not reported/applicable (not a repeat-expansion disorder).

Germline mosaicism: Not specifically documented in the literature reviewed for COQ6.

Founder effects/consanguinity: The original discovery cohort was identified via homozygosity mapping, implying at least some families were consanguineous; case series have originated from Turkish, Lebanese, Chinese, and Korean populations, suggesting the disease is not confined to a single ethnic group, though no single well-characterized founder allele with quantified frequency was identified in this search.

Carrier frequency: Not specifically reported for COQ6 alone; aggregate carrier/allele-frequency data for CoQ-biosynthesis-pathway pathogenic variants collectively (441 carriers identified across genes in gnomAD) yield a combined pathogenic allele frequency of ~1.76×10⁻³ (Sci Rep 2017).

Population demographics: Reported cases span multiple ethnicities (Turkish, Lebanese, Chinese, Korean, and others); no strong sex predilection has been reported (autosomal recessive inheritance predicts equal sex distribution). Age distribution of affected individuals is concentrated in infancy/early childhood at diagnosis, consistent with the disease's early onset.

10. Diagnostics

Laboratory/clinical tests: - Urinalysis for proteinuria (nephrotic-range), serum albumin, creatinine/eGFR for renal function staging. - Serum/plasma lactate (elevated in severe multisystem presentations, e.g., 5.4–7.8 mmol/L in the lethal sibling case). - Renal biopsy with light and electron microscopy: FSGS or diffuse mesangial sclerosis pattern. - Biochemical CoQ10 assay: reduced CoQ10 levels measurable in skeletal muscle biopsy (the gold-standard tissue) or cultured skin fibroblasts; reduced mitochondrial respiratory chain complex I+III and II+III activities support the diagnosis (GeneReviews NBK410087).

Genetic testing: - Molecular genetic testing is the primary diagnostic approach. Recommended strategies per GeneReviews: multigene panels targeting steroid-resistant nephrotic syndrome, mitochondrial disorders, or ataxia gene panels; or exome/genome sequencing for comprehensive assessment, using sequence analysis plus deletion/duplication analysis of COQ6. - Historically, homozygosity mapping was used in consanguineous families to localize the causal locus (original 2011 discovery cohort). - Single-gene COQ6 Sanger sequencing is an option when the phenotype (SRNS + SNHL) is highly suggestive.

Audiological testing: Serial pure-tone audiometry is recommended for surveillance and to monitor treatment response; Categorical Auditory Performance (CAP) scoring is used post-cochlear-implantation.

Ophthalmologic testing: Formal ophthalmologic evaluation (visual acuity, fundoscopy for optic atrophy/papilledema) is recommended, especially in patients on long-term follow-up.

Differential diagnosis: Other genetic causes of SRNS (e.g., NPHS1, NPHS2, WT1, COQ2, COQ8B [note: COQ8B nephropathy is a closely related, better-characterized CoQ-pathway SRNS disorder, also CoQ10-responsive, but classically without deafness]), other mitochondrial CoQ10 deficiency subtypes (COQ2, COQ4, COQ7, COQ8A, COQ8B, COQ9, PDSS1, PDSS2, ADCK3/4), and syndromic deafness-nephropathy conditions (e.g., Alport syndrome — differentiated by lack of hematuria/lens abnormalities typical of Alport, and by biochemical/molecular confirmation of the CoQ pathway defect).

Screening: No population-based newborn or carrier screening program specific to COQ6 was identified; given its rarity, targeted carrier screening would typically only be pursued in families with a known proband or in consanguineous unions with a positive family history.

11. Outcome / Prognosis

Survival/mortality: Highly variable by genotype and treatment timing. Without treatment, the disease inexorably progresses to ESRF (median age 1.7 years in the founding cohort), and the most severe genotypes are lethal in infancy (reported deaths at 4–6 months of age in a compound-heterozygous nonsense-variant sibling pair, PMC8802230). In the original 11-patient cohort referenced by later reports, "five [were] dying in early childhood (median age: 5.0 years)" — indicating substantial early mortality historically, prior to widespread recognition of CoQ10-treatment responsiveness.

Morbidity/function: Survivors face ESRD requiring dialysis and/or renal transplantation, profound bilateral sensorineural hearing loss frequently requiring cochlear implantation, and in some cases progressive visual impairment. No formal QoL instrument data (EQ-5D, SF-36) specific to this condition were found.

Complications: ESRD, hypertension, growth retardation, and — in the most severe multisystem cases — cardiac defects (atrial septal defect, pulmonary hypertension), seizures, and CNS white-matter abnormalities.

Recovery potential with treatment: This is the most distinctive feature of the prognosis — early, appropriately dosed CoQ10 (or idebenone) treatment can produce complete and sustained remission of proteinuria (documented to ≥12 months follow-up), stabilization or improvement in visual acuity (idebenone), and — in a genotype-dependent subset (~43% response rate for stable/improved hearing in one cohort) — preservation of hearing.

Prognostic factors: - Genotype is the dominant prognostic variable. Homozygosity for p.Gly255Arg or p.Ala353Asp was associated with good CoQ10 response (GeneReviews). Conversely, c.686A>C (p.Gln229Pro) was associated with poor audiological response, while c.189_191delGAA and c.782C>T were associated with better audiological outcomes (PMC9482153); a patient homozygous for p.Pro261Leu (c.782C>T) maintained entirely normal hearing throughout follow-up. - Timing of diagnosis/treatment initiation relative to onset of irreversible organ damage is repeatedly cited as critical. - Compound heterozygous truncating (nonsense) variants appear to correlate with the most severe, multisystem, and lethal presentations.

12. Treatment

Pharmacotherapy (targeted, disease-modifying): - Coenzyme Q10 (ubiquinone-10) oral supplementation is the cornerstone treatment. Doses reported in the literature range from 5–50 mg/kg/day (GeneReviews range), with 30 mg/kg/day (in three divided doses) used in several published cohorts/case reports (PMC9482153; PMC6208703; PMC6247592). CHEBI term: CHEBI:46245 (ubiquinone-10 / coenzyme Q10). NCIT treatment-action term: NCIT:C15986 (Pharmacotherapy), with therapeutic_agent = coenzyme Q10 (CHEBI:46245); modality classification: SMALL_MOLECULE (or arguably PROTEIN_REPLACEMENT-adjacent "metabolite replacement," though CoQ10 itself is a lipophilic small molecule). - Idebenone, a hydrophilic short-chain synthetic CoQ10 analogue with improved bioavailability/tissue penetration, has been used successfully particularly for the ophthalmologic (optic atrophy) manifestation, at doses of 10–15 mg/kg/day (PMC7358665). CHEBI term: CHEBI:81816 (idebenone). - Prior to CoQ10/idebenone diagnosis, patients are frequently trialed unsuccessfully on standard nephrotic-syndrome immunosuppression — prednisone/corticosteroids (ineffective, consistent with the "steroid-resistant" designation), ACE inhibitors/ARBs (e.g., ramipril; supportive antiproteinuric effect only), and calcineurin inhibitors (e.g., cyclosporine A, achieving only partial remission in one reported case before CoQ10 achieved complete remission) (PMC6208703; PMC7358665).

Pharmacogenomics: Treatment response to CoQ10/idebenone is strongly genotype-dependent (see §11), representing an emerging genotype-guided precision-medicine approach within this single-gene disease, though no formal CPIC/PharmGKB guideline exists given the disease's rarity.

Renal replacement/surgical: - Renal transplantation (NCIT:C15289, Organ Transplantation) and dialysis/hemodialysis for patients progressing to ESRF despite treatment.

Auditory intervention: - Cochlear implantation for patients with severe/progressive sensorineural hearing loss unresponsive to CoQ10; a case series of 4 implanted patients showed Categorical Auditory Performance (CAP) scores improving from an average of 3.2 preoperatively to 6.7 at final follow-up, sustained over an average 61.9 months (PMC9482153). - Hearing aids for milder hearing loss (inferred standard-of-care, not specifically detailed in sources reviewed).

Supportive care: Nutritional support/growth monitoring (accelerated growth was noted as a positive secondary outcome of successful CoQ10 treatment in one case report, alongside improved dental health and reduced respiratory infections — PMC6208703), blood pressure management, and general chronic kidney disease supportive management.

Experimental/investigational: No COQ6-specific registered clinical trials were identified on ClinicalTrials.gov. General CoQ10-in-CKD trials exist (e.g., NCT03579693, NCT05942027) but target broader chronic kidney disease populations, not the COQ6-specific genetic subtype, and used much higher, non-weight-based adult dosing (1,200 mg/day) without disease-specific benefit in short-term endpoints — underscoring that the genetically targeted, weight-based dosing paradigm used in COQ6 case reports is distinct from generic CoQ10-for-CKD approaches.

Treatment outcomes/adverse events: No significant CoQ10-related adverse events were reported in the case series reviewed; the main "failure mode" is incomplete or absent response in genotypes with more severe loss-of-function variants, and interestingly, one report noted that serum CoQ10 levels remained variable despite consistent dosing and clinical improvement, suggesting the therapeutic effect may act locally at the tissue level rather than being reliably tracked by serum levels (PMC6208703).

Treatment strategy summary: Early genetic diagnosis → immediate high-dose oral CoQ10 (and/or idebenone, particularly if optic involvement) → serial monitoring of proteinuria, audiometry, and visual acuity → escalation to cochlear implantation for non-responsive hearing loss and renal replacement therapy/transplantation for those progressing to ESRF despite treatment.

13. Prevention

Primary prevention: None possible for the genetic defect itself (autosomal recessive Mendelian disease); the only "primary prevention" analog is reproductive genetic counseling and prenatal/preimplantation genetic testing in families with a known proband, given the 25% recurrence risk to future siblings.

Secondary prevention (early detection): This is where intervention is most impactful for this disease — early recognition of the SRNS + SNHL phenotype (or a positive family history) and prompt genetic diagnosis enables initiation of CoQ10/idebenone therapy before irreversible glomerular, cochlear, or optic nerve damage occurs, which the literature repeatedly frames as the key modifiable determinant of outcome.

Genetic counseling: Standard autosomal recessive counseling applies — carrier parents have a 25% risk per pregnancy of an affected child; carrier testing of at-risk relatives and prenatal diagnosis are options once the familial pathogenic variants are known (GeneReviews NBK410087).

Screening: No population-level newborn or carrier screening program specific to COQ6 exists; targeted testing is reserved for families with an identified proband, given the disease's extreme rarity.

Public health/environmental interventions: Not applicable — this is not a disease with an environmental or public-health prevention dimension.

Prophylaxis: Continuous CoQ10 supplementation functions as ongoing secondary/tertiary prophylaxis against further nephron loss, hearing deterioration, and optic nerve injury once diagnosis is established, rather than as a true "primary preventive" measure.

14. Other Species / Natural Disease

No naturally occurring veterinary or wildlife disease caused by Coq6 mutations has been reported in the literature searched (e.g., no OMIA entries or veterinary case series were identified). The Coq6 gene is broadly conserved across vertebrates (mouse ortholog: MGI:1924408; zebrafish ortholog: 66% identity to human COQ6). No zoonotic or cross-species transmission relevance applies, as this is a non-infectious, purely genetic disease.

Comparative biology: The deep evolutionary conservation of the ubiquinone biosynthesis pathway — from the bacterial E. coli ortholog UbiH (33% identity to human COQ6) through zebrafish (66% identity) — underlies why zebrafish and mouse-cell models have proven experimentally tractable despite the absence of documented spontaneous natural disease in non-human species.

15. Model Organisms

Cellular/in vitro models: - Mouse podocyte cell line, siRNA knockdown of Coq6: Decreased cell growth, increased apoptosis (increased caspase-3 and caspase-9 activation), increased ROS (via MitoSOX staining), reduced F-actin expression with cytoskeletal disorganization, and reduced nephrin expression. CoQ10 treatment partially reversed the apoptotic phenotype in knockdown podocytes (PMID 21540551; PMC6247592). Notably, exogenously expressed human COQ6 isoform A localized correctly to mitochondria when transfected into mouse podocyte cell lines, functionally validating the mitochondrial targeting/localization predicted from the protein's leader-peptide sequence.

Zebrafish model: - Morpholino knockdown of zebrafish coq6: Induced apoptosis preferentially in the head and trunk of embryos, partially rescued by co-treatment with CoQ10 (original JCI discovery paper, PMID 21540551). This in vivo functional assay was used to validate candidate variant pathogenicity identified by human homozygosity mapping — a standard approach for genes mutated in human renal-disease patients, given the zebrafish's established utility for studying podocyte biology and glomerular filtration barrier development.

Model characteristics — recapitulation and limitations: - Both the mouse-podocyte and zebrafish knockdown models recapitulate the core cellular pathology (apoptosis, oxidative stress) and, importantly, recapitulate CoQ10 treatment responsiveness, making them directly relevant translational models supporting the clinical use of CoQ10 supplementation. - Neither model is reported to recapitulate the sensorineural hearing loss or optic atrophy components of the human phenotype — the auditory and ophthalmologic aspects of disease remain modeled only indirectly (by analogy to the shared mitochondrial/oxidative-stress mechanism), which represents a translational gap: no cochlear or optic-nerve-specific Coq6 animal or cellular model was identified in this search. A curator populating a knowledge-base entry may wish to flag this using a HUMAN_MODEL_MISMATCH-type discussion, since fidelity of the podocyte models to human renal disease is well-supported (RECAPITULATES) but no equivalent auditory/ophthalmologic model exists to assess fidelity for those organ systems. - No germline mouse knockout (constitutive Coq6-null) model with a full multisystem phenotype (analogous to the human lethal infantile form) was identified in this search; existing genetic-model resources are limited to the MGI gene record (MGI:1924408) without a described knockout-phenotype allele series specific to nephrotic/deafness phenotyping.

Research applications: These models have been used specifically to (1) establish causality of candidate human COQ6 variants via functional rescue experiments, (2) dissect the oxidative-stress/apoptosis mechanism of podocyte injury, and (3) provide preclinical justification for CoQ10 supplementation as a targeted, genotype-informed therapy — directly informing the clinical treatment paradigm described in §12.

Ontology Term Summary for KB Curation

Category Suggested terms
Disease/gene identifiers OMIM:614650 (phenotype), OMIM:614647 (gene), Orphanet ORPHA:280406, HGNC COQ6
Phenotypes (HP) HP:0000100 (Nephrotic syndrome), HP:0000097 (FSGS), HP:0000093 (Proteinuria), HP:0000083 (Renal insufficiency), HP:0000407 (Sensorineural hearing impairment), HP:0000648 (Optic atrophy), HP:0001250 (Seizure), HP:0002151 (Increased serum lactate), HP:0001252 (Hypotonia), HP:0001510 (Growth delay), HP:0001631 (Atrial septal defect), HP:0002092 (Pulmonary hypertension), HP:0000822 (Hypertension)
Cell types (CL) CL:0000653 (podocyte)
Anatomy (UBERON) UBERON:0002113 (kidney), UBERON:0001225 (renal glomerulus), UBERON:0000959 (cochlea), UBERON:0001784 (optic nerve), UBERON:0000948 (heart)
Biological process (GO) GO:0006744 (ubiquinone biosynthetic process), GO:0016709 (FAD monooxygenase activity, relevant catalytic class), GO:0055114 (oxidation-reduction process), GO:0006979 (response to oxidative stress), GO:0006915 (apoptotic process), GO:0030036 (actin cytoskeleton organization)
Chemicals (CHEBI) CHEBI:46245 (ubiquinone-10 / coenzyme Q10), CHEBI:81816 (idebenone)
Treatments (NCIT) NCIT:C15986 (Pharmacotherapy), NCIT:C15289 (Organ Transplantation — renal transplant), NCIT:C15305-class hemodialysis term

Key Citations

  • Heeringa SF et al. COQ6 mutations in human patients produce nephrotic syndrome with sensorineural deafness. J Clin Invest. 2011. PMID: 21540551; JCI full text
  • COQ6 mutation in patients with nephrotic syndrome, sensorineural deafness, and optic atrophy. PMID: 32685349; PMC7358665
  • Effects of CoQ10 Replacement Therapy on the Audiological Characteristics of Pediatric Patients with COQ6 Variants. PMC9482153
  • A Family Segregating Lethal Primary Coenzyme Q10 Deficiency Due to Two Novel COQ6 Variants. PMC8802230
  • New Mutation of Coenzyme Q10 Monooxygenase 6 Causing Podocyte Injury in a Focal Segmental Glomerulosclerosis Patient. PMC6247592; DOI: 10.4103/0366-6999.245158
  • CoQ10-related sustained remission of proteinuria in a child with COQ6 glomerulopathy—a case report. PMC6208703
  • Primary coenzyme Q10 Deficiency-6 (COQ10D6): Two siblings with variable expressivity of the renal phenotype. ScienceDirect
  • OMIM: *614647 — COQ6; #614650 — COQ10D6
  • Orphanet: COQ6 gene page (ORPHA:280406)
  • GeneReviews: Primary Coenzyme Q10 Deficiency Overview. NBK410087
  • MedlinePlus Genetics: COQ6 gene
  • Coenzyme Q Biosynthesis: Evidence for a Substrate Access Channel in the FAD-Dependent Monooxygenase Coq6. PMC4726752
  • Estimating the occurrence of primary ubiquinone deficiency by analysis of large-scale sequencing data. Sci Rep. 2017. DOI: 10.1038/s41598-017-17564-y
  • COQ2‐Associated Primary Coenzyme Q10 Deficiency Presenting With Proteinuria: A Case Report and Literature Review (context review discussing COQ6 modifier data). Mol Genet Genomic Med. 2026. DOI: 10.1002/mgg3.70221
  • MARRVEL COQ6 gene aggregate (ClinVar variant counts): marrvel.org/human/gene/51004
  • GeneCards: COQ6; MGI: Coq6 mouse gene

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 11
Resolved 11
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 11
On topic 8
Off topic 0

All extracted references resolved successfully.