COQ6-Related Steroid-Resistant Nephrotic Syndrome with Sensorineural Deafness

MONDO:0013836 Pathograph 37 Show in embeddings browser

Biallelic pathogenic COQ6 variants impair coenzyme Q10 biosynthesis and cause primary coenzyme Q10 deficiency-6. Steroid-resistant nephrotic syndrome and sensorineural hearing loss are characteristic, but isolated proteinuria, hearing loss without renal involvement, and additional neurologic, ocular, or severe infantile manifestations occur. Renal and auditory courses vary, including within families. Early oral CoQ10 supplementation can reduce proteinuria and preserve kidney function; hearing benefit is less consistent. Steroid resistance describes an observed treatment response and does not imply that all antiproteinuric therapies are ineffective.

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1
Inheritance
12
Pathophys.
20
Phenotypes
3
Gaps
37
Pathograph
2
Genes
5
Variants
10
Medical Actions
5
Models
16
References
1
Deep Research
👪

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
Does the reported p.Trp14* variant establish COQ6-related nephropathy?
INTERPRETATION coq6_isoform_variant_interpretation
Attached to
genetic#COQ6 diagnosis#Molecular genetic testing in steroid-resistant nephrotic syndrome
The 2018 FSGS paper reported a heterozygous NM_182480:c.41G>A p.Trp14* variant. The 2019 study found that this transcript encodes inactive isoform c and noted the variant in apparently healthy homozygotes. These observations undermine attribution of that patient's FSGS to this variant, while leaving the independently performed COQ6-knockdown experiments informative.
Show evidence (1 reference)
PMID:31379988 SUPPORT Other
"Overall, these observations indicate that COQ6 isoforms b and c are not essential and are not involved in CoQ deficiency."
The isoform study explains why a premature stop in the alternative first exon need not disrupt the active enzyme.
Which cochlear and optic cell lesions determine the sensory phenotype?
KNOWLEDGE GAP coq6_organ_selectivity
Attached to
pathophysiology#Cochlear Dysfunction pathophysiology#Optic Nerve Involvement
The cited rat study localizes COQ6 to several cochlear compartments but does not demonstrate which fails first. Podocyte rescue and nonspecific zebrafish embryonic apoptosis cannot establish the sensory mechanism. Clinical hearing and visual outcomes therefore should not be explained solely by tissue expression or transferred from renal models.
How do genotype, treatment timing and concurrent therapy influence response?
KNOWLEDGE GAP coq6_treatment_response_variability
Attached to
treatments#Oral Coenzyme Q10 Replacement genetic#COQ8B candidate modifier
The small hearing cohort reported a poorer trajectory with p.Gln229Pro, while apparent benefits for p.Lys64del and p.Pro261Leu were not statistically significant. Historical renal comparisons favor CoQ10 but are not randomized, and concomitant therapies complicate attribution. COQ8B modifier observations remain unconfirmed. These findings do not support delaying treatment based on a predicted poor-response genotype.
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Pathophysiology

12
Biallelic COQ6 Dysfunction
Biallelic pathogenic variants reduce COQ6 function. Missense, in-frame deletion, nonsense, and frameshift alleles have been reported. Residual activity varies; truncating sequence changes do not automatically establish complete functional null alleles.
Downstream
Deficient C5-Ring Hydroxylation in CoQ10 Biosynthesis Reduced enzyme function impairs the C5 modification required for CoQ synthesis.
Show evidence (2 references)
PMID:21540551 SUPPORT Human Clinical
"All 11 affected individuals of the 5 families with 2 recessive COQ6 mutations had SRNS."
The founding series included 11 affected individuals in five families with biallelic variants; two additional single-heterozygous cases were not molecularly resolved.
PMID:24140869 SUPPORT Model Organism
"These data suggest that the human G255R, A353D, Y412C and Q461sf478X mutations are hypomorphic since the corresponding yeast Coq6 mutants display residual activity."
Improved yeast complementation assays detect residual activity missed by the initial assay; these results cannot define every patient allele.
Deficient C5-Ring Hydroxylation in CoQ10 Biosynthesis
COQ6 is a FAD-dependent monooxygenase required for C5 hydroxylation of the CoQ ring. Yeast modeling supports impaired substrate access for the G248R counterpart of human p.Gly255Arg; engineered L382E and double-mutant results do not establish a universal mechanism for human missense alleles.
COQ6 hgnc:20233 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves COQ6 (hgnc:20233). hgnc:20233 is a gene from the HUGO Gene Nomenclature Committee.
ubiquinone biosynthetic process GO:0006744 ↓ DECREASED 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.
FAD-dependent monooxygenase activity GO:0004497 ↓ DECREASED 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. 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.
Animal models
Yeast coq6 Deletion Complemented with Human Alleles Saccharomyces cerevisiae recapitulates Tests allele function and precursor bypass.
Downstream
Coenzyme Q10 Deficiency Impaired ring modification reduces endogenous CoQ10 synthesis.
Show evidence (3 references)
PMID:24140869 SUPPORT BACKGROUND Other
"Human COQ6 encodes a monooxygenase which is responsible for the C5-hydroxylation of the quinone ring of coenzyme Q (CoQ)."
Background functional assignment supported by complementation and bypass experiments.
PMID:26808124 SUPPORT In Vitro
"We show here through biochemical studies that Coq6 is a flavoprotein using FAD as a cofactor."
Biochemical characterization of recombinant yeast Coq6 establishes FAD binding; this is not a patient enzyme assay.
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."
Homology models of yeast Coq6 predict channel narrowing. G248R corresponds to human G255R; L382E and the double mutant were engineered tests.
Coenzyme Q10 Deficiency
Reduced endogenous cellular CoQ10 compromises its electron-carrier and antioxidant functions. The magnitude and tissue distribution of deficiency vary.
Experimental models
COQ6-Delta25 HEK293 Cells CELL LINE Models impaired endogenous synthesis and vanillic-acid bypass rescue.
Downstream
Deficient CoQ-Dependent Electron Transfer Loss of CoQ limits coupled electron transfer between respiratory complexes.
Altered Cellular Redox State Oxidant accumulation varies with cell model and assay; a single mitochondrial ROS pattern is not established.
Podocyte Cytoskeletal Disorganization COQ6 knockdown reduces nephrin/F-actin and disrupts actin organization; intermediates are unresolved.
Podocyte Apoptosis Knockdown-associated apoptosis is partly reversed by CoQ10 supplementation.
Cochlear Dysfunction Genetic disease and rat expression support cochlear involvement, but the initiating cell lesion is unresolved.
Optic Nerve Involvement Optic neuropathy is documented clinically; its cellular route from CoQ deficiency remains unresolved.
Show evidence (1 reference)
PMID:31379988 SUPPORT In Vitro
"Incorporation of 14C-labelled 4-HB was virtually undetectable"
COQ6-delta25 HEK293 cells showed virtually absent endogenous CoQ10 synthesis despite residual CoQ10 acquired from culture medium.
Deficient CoQ-Dependent Electron Transfer
Combined respiratory-chain complex II+III activity falls in COQ6-deficient HEK293 cells despite preserved individual complex activities.
oxidative phosphorylation GO:0006119 ↓ DECREASED 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.
Downstream
Cellular ATP Deficiency Impaired coupled respiration is associated with low cellular ATP in the same edited-cell model.
Show evidence (1 reference)
PMID:31379988 SUPPORT In Vitro
"Activities of individual respiratory chain enzymes were normal; however, combined activity of complexes II and III was markedly reduced in these cells, consistent with severe CoQ10 deficiency"
CoQ-dependent combined respiratory-chain activity was deficient in edited HEK293 cells; individual complex activities were normal.
Cellular ATP Deficiency
COQ6-delta25 HEK293 cells have markedly reduced ATP and coupled respiration. These measurements establish a cellular bioenergetic defect without demonstrating which human organ manifestations are specifically ATP-mediated.
Experimental models
COQ6-Delta25 HEK293 Cells CELL LINE ATP deficiency was reversed with vanillic acid.
Show evidence (1 reference)
PMID:31379988 SUPPORT In Vitro
"ATP levels were markedly reduced in COQ6∆25 cells, but after VA supplementation, they were virtually normal"
Cellular ATP deficiency and bypass rescue were measured in the HEK293 model, not in patient organs.
Altered Cellular Redox State
Mouse podocyte knockdown increases MitoSOX signal. Edited HEK293 cells instead show increased total cellular oxidation without a significant mitochondrial roGFP increase. The relative redox contribution to cell death is not isolated by these experiments.
Experimental models
Murine Podocyte siRNA Cytoskeleton and Redox Assays CELL LINE MitoSOX signal increased after knockdown.
Show evidence (3 references)
PMID:30425193 SUPPORT In Vitro
"ROS levels were increased when the MPCs were incubated with si-COQ6 compared to the normal group."
Mouse podocyte knockdown increased mitochondrial MitoSOX signal; the patient variant claim in this paper is not used as clinical genetic evidence.
PMID:31379988 REFUTE In Vitro
"we did not detect a significant increase of mitochondrial ROS production using mitochondrially targeted ro-GFP"
The HEK293 model did not reproduce increased mitochondrial oxidation on this assay; increased total cellular oxidant signal should not be equated with a universal mitochondrial ROS increase.
PMID:31379988 SUPPORT In Vitro
"we found increased levels in the COQ6∆25 cells. VA treatment was able to decrease ROS to basal levels, while CoQ supplementation was only partially effective"
Total cellular CM-H2DCFDA signal increased in the HEK293 model and responded differently to VA versus exogenous CoQ.
Podocyte Cytoskeletal Disorganization
COQ6 knockdown lowers nephrin and F-actin and disrupts actin organization in cultured mouse podocytes. This is a separate experimental finding from apoptosis; the order of these events has not been demonstrated.
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
Murine Podocyte siRNA Cytoskeleton and Redox Assays CELL LINE Reduced nephrin/F-actin and disorganized actin after knockdown.
Downstream
Glomerular Filtration Barrier Injury Loss of podocyte structural integrity provides a plausible route to impaired filtration; the cellular-to-organ link is inferred.
Show evidence (2 references)
PMID:30425193 SUPPORT In Vitro
"the expression levels of both proteins were significantly lower in the si-RNA-COQ6 group than in the control group"
The measured proteins were nephrin and F-actin in mouse podocytes.
PMID:30425193 SUPPORT In Vitro
"F-actin immunofluorescence in the si-COQ6 group was irregularly distributed"
Actin organization was disturbed after knockdown; timing relative to ROS and apoptosis was not resolved.
Podocyte Apoptosis
COQ6 knockdown causes mitochondrial depolarization and increased caspase-9/3 activity in cultured mouse podocytes. CoQ10 at 50 micromolar for 48 hours reduces caspase activity. Zebrafish embryonic apoptosis is a separate whole-organism observation and was not shown to be podocyte-specific.
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.
apoptotic process GO:0006915 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased apoptotic process (GO:0006915). GO:0006915 is a biological process from the Gene Ontology.
Experimental models
Murine Podocyte COQ6 Knockdown CELL LINE Models COQ6-dependent podocyte survival and partial CoQ10 rescue.
Animal models
coq6 Morpholino Zebrafish Zebrafish recapitulates Supports a conserved association between COQ6 depletion and apoptosis in a whole vertebrate.
Downstream
Glomerular Filtration Barrier Injury Podocyte depletion can impair filtration integrity; the human organ link extends the cell-culture findings.
Show evidence (2 references)
PMID:21540551 SUPPORT In Vitro
"Coq6 downregulation in cultured mouse podocytes induced apoptosis that was diminished by CoQ 10 treatment."
Figure 5A-C demonstrates rescue in cultured murine podocytes. The zebrafish arm did not test rescue.
PMID:30425193 SUPPORT In Vitro
"the number of Annexin V+/PI+ and V+/PI− cells was significantly increased in the si-COQ6 group."
Flow cytometry independently supports increased apoptosis after mouse podocyte knockdown.
Glomerular Filtration Barrier Injury
Podocyte foot-process effacement and glomerular injury accompany COQ6 nephropathy. Protein leakage may occur before extensive sclerosis and need not include all features of nephrotic syndrome.
Downstream
Proteinuria Loss of filtration selectivity permits urinary protein loss.
Focal Segmental Glomerulosclerosis Persistent podocyte injury can lead to segmental scarring; this is not the only reported biopsy pattern.
Hypoalbuminemia Persistent urinary protein loss can lower serum albumin.
Edema Nephrotic protein loss and altered fluid handling can cause edema.
Steroid-Resistant Nephrotic Syndrome Glomerular injury can manifest as nephrotic syndrome; steroid resistance is determined clinically, not inferred from the mechanism.
Show evidence (1 reference)
PMID:21540551 SUPPORT Human Clinical
"Transmission electron microscopy for F1082 showed effacement of podocyte foot processes, resulting in a continuous electron-dense layer"
Human renal ultrastructure demonstrates foot-process effacement.
Focal Segmental Glomerulosclerosis
Segmental glomerular scarring is common, with NOS, collapsing and cellular patterns reported. Diffuse mesangial sclerosis, minimal-change and other patterns also occur; FSGS does not establish a uniform clinical course.
Downstream
Progression to Kidney Failure Chronic renal injury can progress to kidney failure, with substantial variability and potential treatment benefit.
Show evidence (1 reference)
PMID:36124066 SUPPORT Human Clinical
"Kidney biopsy was performed in 11 patients (not in patient 8-2); all exhibited FSGS lesions"
FSGS was found in all biopsied patients in this selected Korean cohort.
Cochlear Dysfunction
The affected cochlear compartment is not established. Rat COQ6 expression includes stria vascularis, spiral ligament and spiral ganglion neurons, and clinical hearing loss is compatible with cochlear dysfunction.
Downstream
Sensorineural Hearing Loss Cochlear dysfunction is a working explanation for sensorineural impairment; localization alone does not identify the causal cell type.
Show evidence (1 reference)
PMID:21540551 SUPPORT Model Organism
"revealed COQ6 expression in the spiral ganglion as well as in cells of stria vascularis and spiral ligament"
Rat expression supports multiple possible cochlear sites; localization does not demonstrate strial failure or exclusive organ vulnerability.
Optic Nerve Involvement
Optic neuropathy with subsequent optic atrophy is a documented, variable manifestation. Visual improvement in an uncontrolled idebenone-treated case does not establish drug efficacy or a distinct pathway unavailable to CoQ10.
Downstream
Optic Atrophy Optic nerve injury can leave persistent atrophy despite improvement in visual acuity.
Show evidence (1 reference)
PMID:32685349 SUPPORT Human Clinical
"The patient did not recover normal vision, still exhibiting a bilateral VA of 20/32 and persistent optic atrophy."
One homozygous p.Ala353Asp patient had residual optic atrophy during follow-up despite improved acuity on idebenone.
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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

20
Cardiovascular 4
Cardiomyopathy HP:0001638 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cardiomyopathy (HP:0001638). HP:0001638 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36124066 SUPPORT Human Clinical
"In addition, mild muscle weakness was detected in 2 patients (16.7%), cardiomyopathy in 1 (8.3%), and atlantoaxial dislocation in 1 (8.3%)."
One of twelve children had cardiomyopathy.
Hypertension HP:0000822 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypertension (HP:0000822). HP:0000822 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://dirros.openscience.si/Dokument.php?id=36089&lang=eng SUPPORT Human Clinical
"Hypertension 28.6 (12/42) 21 (4/19) 39 (32/82)"
Middle column reports 4/19 COQ6 cases.
Atrial Septal Defect HP:0001631 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Atrial septal defect (HP:0001631). HP:0001631 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35111204 SUPPORT Human Clinical
"Cardiac ultrasound revealed an atrial septal defect and pulmonary hypertension, and an electrocardiogram showed altered sinus rhythm T waves."
The male infant had this structural finding during assessment of severe multisystem illness.
Elevated Pulmonary Artery Pressure HP:0004890 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Elevated pulmonary artery pressure (HP:0004890). HP:0004890 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35111204 SUPPORT Human Clinical
"Cardiac ultrasound revealed an atrial septal defect and pulmonary hypertension, and an electrocardiogram showed altered sinus rhythm T waves."
Binds the reported pressure abnormality without asserting precapillary pulmonary arterial hypertension.
Ear 1
Sensorineural Hearing Loss Sensorineural hearing impairment HP:0000407 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sensorineural hearing impairment (HP:0000407). HP:0000407 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
url:https://dirros.openscience.si/Dokument.php?id=36089&lang=eng SUPPORT Human Clinical
"Hearing abnormalities 1.7 (1/59) 73.9 (34/46) 0 (0/140)"
The COQ6 column reports 34/46; this uses the table denominator rather than the inconsistent prose.
PMID:36124066 SUPPORT Human Clinical
"In the last audiological evaluation, 11 patients evidenced SNHL with a median hearing threshold of 81.3 dB (range 3.8–118.8 dB)."
Eleven of twelve patients were affected at final evaluation.
Eye 2
Optic Atrophy HP:0000648 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Optic atrophy (HP:0000648). HP:0000648 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:36124066 SUPPORT Human Clinical
"Ophthalmological abnormalities were found in 3 patients (1 with optic atrophy, 1 with nystagmus, and 1 with both optic atrophy and nystagmus)."
Two of twelve had optic atrophy and two had nystagmus; one had both.
PMID:32685349 SUPPORT Human Clinical
"The patient did not recover normal vision, still exhibiting a bilateral VA of 20/32 and persistent optic atrophy."
One homozygous p.Ala353Asp patient had residual optic atrophy during follow-up despite improved acuity on idebenone.
url:https://dirros.openscience.si/Dokument.php?id=36089&lang=eng SUPPORT INDIRECT Human Clinical
"Retinopathy/ocular abnormalities 20.3 (12/59) 17.4 (8/46) 5 (7/140)"
The COQ6 middle column provides broader ocular context, not an optic-atrophy-specific count.
Nystagmus HP:0000639 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Nystagmus (HP:0000639). HP:0000639 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36124066 SUPPORT Human Clinical
"Ophthalmological abnormalities were found in 3 patients (1 with optic atrophy, 1 with nystagmus, and 1 with both optic atrophy and nystagmus)."
Two of twelve had optic atrophy and two had nystagmus; one had both.
Genitourinary 4
Steroid-Resistant Nephrotic Syndrome HP:0012588 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Steroid-resistant nephrotic syndrome (HP:0012588). HP:0012588 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:36124066 SUPPORT Human Clinical
"All presented with SRNS, except patient 11 who presented with nephrotic range proteinuria without nephrotic syndrome, at a median age of 2.7 years (range 0.8–9.1 years)."
Eleven of twelve children had SRNS, and one had proteinuria without the full syndrome. This selected cohort does not establish population penetrance.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK410087/ SUPPORT BACKGROUND Other
"Because individuals with ... COQ6- ... and ... COQ8B- ... related CoQ ... deficiency were ascertained by the presence of SRNS, the authors cannot exclude the possibility that biallelic pathogenic variants in these two genes could also cause a broader phenotype."
GeneReviews Clinical Characteristics, Table 1 footnote 6, explicitly cautions that renal ascertainment limits the recognized COQ6 spectrum.
Focal Segmental Glomerulosclerosis 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 (2 references)
PMID:36124066 SUPPORT Human Clinical
"Kidney biopsy was performed in 11 patients (not in patient 8-2); all exhibited FSGS lesions"
FSGS was found in all biopsied patients in this selected Korean cohort.
url:https://dirros.openscience.si/Dokument.php?id=36089&lang=eng SUPPORT Human Clinical
"FSGS 69.4 (25/36) 72.2 (26/36) 77.1 (64/83)"
Table 1 middle column is COQ6: 26 of 36 informative biopsies.
Progression to Kidney Failure Stage 5 chronic kidney disease HP:0003774 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Stage 5 chronic kidney disease (HP:0003774). HP:0003774 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
url:https://dirros.openscience.si/Dokument.php?id=36089&lang=eng SUPPORT Human Clinical
"ESKD 50.8 (32/63) 56.2 (27/48) 66.4 (93/140)"
COQ6 middle column reports last-observation ESKD, not an untreated lifetime risk.
PMID:36124066 SUPPORT Human Clinical
"Eight patients progressed to kidney failure at a median of 7.2 (range 1.1–27.0) months after disease onset and underwent kidney transplantation without recurrence of nephropathy in the graft."
The interval is from disease onset, not age at kidney failure.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK410087/ SUPPORT BACKGROUND Other
"If not treated with supplementation of high-dose oral CoQ ... SRNS usually progresses to end-stage kidney disease (ESKD)."
GeneReviews describes the usual untreated renal trajectory across primary CoQ deficiencies, including COQ6; usually does not mean inevitable for every person.
Proteinuria 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 (2 references)
url:https://dirros.openscience.si/Dokument.php?id=36089&lang=eng SUPPORT Human Clinical
"Kidney involvement 93.6 (59/63) 97.9 (47/48) 100 (140/140)"
The middle column is COQ6; ascertainment was enriched for nephropathy.
url:https://dirros.openscience.si/Dokument.php?id=36089&lang=eng SUPPORT Human Clinical
"Nephrotic range proteinuria 85.7 (36/42) 86.1 (31/36) 71.7 (86/120) Non– nephrotic range proteinuria 14.3 (6/42) 13.9 (5/36) 28.3 (34/120)"
Among 36 informative COQ6 patients, 31 had nephrotic-range and five non-nephrotic-range proteinuria.
Limbs 1
Limb Muscle Weakness HP:0003690 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Limb muscle weakness (HP:0003690). HP:0003690 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:36124066 SUPPORT Human Clinical
"mild muscle weakness was detected in 2 patients (16.7%)"
Two children in the Korean cohort had mild muscle weakness.
PMID:36124066 SUPPORT Human Clinical
"Mm weak: mild muscle weakness in the lower extremities"
The table key specifies the limb distribution.
url:https://dirros.openscience.si/Dokument.php?id=36089&lang=eng SUPPORT INDIRECT Human Clinical
"Myopathy 20.3 (12/59) 8.7 (4/46) 0 (0/140)"
The COQ6 middle-column count is for myopathy, not specifically mild limb weakness.
Metabolism 4
Metabolic Acidosis HP:0001942 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Metabolic acidosis (HP:0001942). HP:0001942 is a phenotype from the Human Phenotype Ontology.
Show evidence (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 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.
Edema HP:0000969 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Edema (HP:0000969). HP:0000969 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://dirros.openscience.si/Dokument.php?id=36089&lang=eng SUPPORT Human Clinical
"Oedema 86.6 (39/45) 47.8 (11/23) 40.2 (33/82)"
Middle column reports 11/23 COQ6 cases.
Increased Circulating Lactate Increased circulating lactate concentration HP:0002151 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Increased circulating lactate concentration (HP:0002151). HP:0002151 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35111204 SUPPORT Human Clinical
"Blood gas analysis indicated compensatory respiratory alkalosis combined with metabolic acidosis with lactate at 7.8 mmol/L."
A direct laboratory observation from one severely ill infant, not a disease-wide frequency estimate.
Musculoskeletal 1
Muscle Hypotonia HP:0001252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypotonia (HP:0001252). HP:0001252 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID: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.
Nervous System 2
Seizures HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:21540551 SUPPORT Human Clinical
"Subject A234-21 presented with seizures, and subject F1082-21 had white matter abnormalities and seizures and died of multiorgan failure in sepsis"
The founding series documents seizures, with white-matter abnormalities in another affected child.
url:https://dirros.openscience.si/Dokument.php?id=36089&lang=eng SUPPORT INDIRECT Human Clinical
"Encephalopathy/seizures 42 (25/59) 8.7 (4/46) 7.1 (10/140)"
Table 1 middle column records the combined category in four of forty-six informative COQ6 patients.
Developmental Delay Global developmental delay HP:0001263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://dirros.openscience.si/Dokument.php?id=36089&lang=eng SUPPORT Human Clinical
"Developmental delay/cognitive impairment 5 (3/59) 13 (6/46) 5 (7/140)"
Table 1 combines developmental and cognitive findings; the phenotype binding captures the developmental component only.
Growth 1
Growth Retardation 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.
🧬

Genetic Associations

2
COQ6
Gene: COQ6 hgnc:20233 gene page 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 variant_origin: GERMLINE
Show evidence (3 references)
PMID:21540551 SUPPORT Human Clinical
"All 11 affected individuals of the 5 families with 2 recessive COQ6 mutations had SRNS."
The founding series included 11 affected individuals in five families with biallelic variants; two additional single-heterozygous cases were not molecularly resolved.
PMID:24140869 SUPPORT Model Organism
"These data suggest that the human G255R, A353D, Y412C and Q461sf478X mutations are hypomorphic since the corresponding yeast Coq6 mutants display residual activity."
Improved yeast complementation assays detect residual activity missed by the initial assay; these results cannot define every patient allele.
PMID:30682496 SUPPORT Human Clinical
"Her older brother, who had sensorineural hearing loss with no renal or neurological involvement, had the same mutation in homozygous form."
The affected sister and brother shared homozygous c.1058C>A; the brother lacked renal involvement at the reported observation.
Variants (5)
c.249C>G (p.Tyr83Ter)
Reported on NM_182476.3 in trans with the other nonsense allele in two severely affected infants. Truncation or nonsense-mediated decay was predicted; patient enzyme activity and CoQ10 content were not measured.
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"
The family study establishes segregation and predicted sequence consequences, not a measured complete loss of enzyme function.
c.1381C>T (p.Gln461Ter)
NM_182476.3:c.1381C>T is predicted to remove seven C-terminal residues. It segregated in trans with p.Tyr83Ter in two severely affected infants, but residual function was not measured; it is not a demonstrated null allele.
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"
The family study establishes segregation and predicted sequence consequences, not a measured complete loss of enzyme function.
p.Gly255Arg and p.Ala353Asp
Recurrent homozygous missense alleles in the founding families. Improved yeast assays support residual function. Cohort associations with earlier p.Gly255Arg and later p.Ala353Asp onset are probabilistic.
Show evidence (1 reference)
PMID:24140869 SUPPORT Model Organism
"These data suggest that the human G255R, A353D, Y412C and Q461sf478X mutations are hypomorphic since the corresponding yeast Coq6 mutants display residual activity."
Improved yeast complementation assays detect residual activity missed by the initial assay; these results cannot define every patient allele.
p.Gln461fsTer478 and p.Trp447Ter
The founding compound-heterozygous pair includes a frameshift with residual activity in improved yeast assays. p.Trp447Ter can retain a structural contribution sufficient for vanillic-acid rescue in yeast.
Show evidence (1 reference)
PMID:24140869 SUPPORT Model Organism
"Interestingly this was observed also with the W447X truncating mutation, indicating that this should not be considered a null allele."
Bypass rescue indicates retained structural contribution even though catalytic complementation was absent.
Korean cohort alleles
NM_182476.3 alleles include an in-frame deletion, nonsense and missense variants. The small hearing series does not establish a general clinical treatment-selection rule.
Show evidence (1 reference)
PMID:36124066 SUPPORT Human Clinical
"Four different causative COQ6 variants were identified either homozygous or compound heterozygous: c.189_191delGAA (p.Lys64del), c.484C>T (p.Arg162∗), c.686A>C (p.Gln229Pro), and c.782C>T (p.Pro261Leu)."
These alleles were identified in twelve children and segregated with the familial phenotype.
COQ8B candidate modifier
Gene: COQ8B hgnc:19041 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is COQ8B (hgnc:19041). hgnc:19041 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: MODIFIER
Show evidence (2 references)
PMID:30682496 SUPPORT Human Clinical
"Family segregation and the co-occurrence of biallelic p.Arg174 of COQ8B in a brother with hearing loss implied that the interaction of the altered COQ8B with the mutant COQ6 alleviated the symptoms in this family."
A hypothesis from one discordant sibling pair; this is not proof of a protective effect.
PMID:36124066 REFUTE Human Clinical
"there were no significant differences in the age of onset (P = 0.30, Kruskal-Wallis rank sum test) or the age of onset of hearing loss (P = 0.80, Kruskal-Wallis rank sum test) by COQ8B polymorphism status."
No significant onset association was detected in the ten genotyped patients.
💊

Medical Actions

10
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.
Platform: Small molecule
Early specialist-directed supplementation supplies CoQ10 despite the biosynthetic defect. The international study reported >50% proteinuria reduction in 10/15 informative pre-ESKD COQ6 patients and complete remission in 7/12. Eight matched treated children preserved kidney function, but only three reached five years of follow-up. These observational results support benefit without guaranteeing response. In the Korean hearing series, 3/7 longitudinally assessed patients had stability or improvement; hearing can worsen or first appear during therapy. Published doses and formulations vary.
Mechanism Target:
BYPASSES Coenzyme Q10 Deficiency — Exogenous CoQ10 supplies the deficient product without repairing the enzyme.
Show evidence (2 references)
PMID:21540551 SUPPORT In Vitro
"Coq6 downregulation in cultured mouse podocytes induced apoptosis that was diminished by CoQ 10 treatment."
Figure 5A-C demonstrates rescue in cultured murine podocytes. The zebrafish arm did not test rescue.
PMID:30425193 SUPPORT In Vitro
"the number of Annexin V+/PI+ and V+/PI− cells was significantly increased in the si-COQ6 group."
Flow cytometry independently supports increased apoptosis after mouse podocyte knockdown.
Show evidence (8 references)
url:https://dirros.openscience.si/Dokument.php?id=36087&lang=eng SUPPORT Human Clinical
"Complete remission (UPCR #0.2 mg/mg) a 6 (1/16) 58 (7/12) 16 (4/25)"
Table 2 COQ6 column: seven of twelve informative pre-ESKD patients attained complete proteinuria remission. The table uses # for the less-than-or-equal symbol.
url:https://dirros.openscience.si/Dokument.php?id=36087&lang=eng SUPPORT Human Clinical
"Only 8 patients with COQ6 disease and preserved eGFR received CoQ 10 supplementation. All these patients retained their kidney function during observational period (median annualized loss, 0 ml/min per 1.73 m 2), 3 of them reached 5 years of follow-up with kidney survival of 100%, whereas all..."
Eight matched treated children preserved kidney function; only three reached five years of observation. Historical controls and nonrandom treatment assignment limit causal inference.
PMID:36124066 SUPPORT Human Clinical
"Serial audiograms were available over >1 year after oral CoQ10 administration for 7 patients (14 ears)"
The longitudinal treatment-response denominator was seven patients, not all twelve.
+ 5 more references
Antiproteinuric ACE Inhibition
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: enalapril CHEBI:4784 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses enalapril (CHEBI:4784). CHEBI:4784 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
ACE inhibitors can accompany CoQ10 supplementation for proteinuria under nephrology care. A reported sibling had remission during antiproteinuric therapy before idebenone was initiated; this should not be attributed to idebenone. Treatment of proteinuria does not imply correction of the biosynthetic defect.
Mechanism Target:
INHIBITS Proteinuria — Reduces urinary protein loss as supportive renal therapy.
Show evidence (2 references)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK410087/ SUPPORT BACKGROUND Other
"ACE inhibitors may be used in combination w/CoQ ... supplementation in persons w/proteinuria."
GeneReviews supportive renal management.
PMID:32685349 SUPPORT Human Clinical
"Angiotensin‐converting enzyme (ACE) inhibitor treatment was initiated, consisting of Enalapril."
Enalapril was used in the younger brother for renal protein loss.
Hearing Aids and Audiological Rehabilitation
Platform: Device
Hearing aids, communication support and audiological follow-up are used according to hearing severity. Seven of eleven hearing-impaired children in the Korean cohort used hearing aids, with the other four receiving implants.
Show evidence (1 reference)
PMID:36124066 SUPPORT Human Clinical
"7 (63.6%) were using hearing aids and the remaining 4 (36.4%) had undergone unilateral or bilateral CI."
The denominator is the eleven children with hearing loss at final assessment.
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
Platform: Device
Cochlear implantation can improve auditory performance in selected patients with severe or profound hearing loss. Four children (seven ears) in the Korean cohort had mean CAP scores rising from 3.2 before implantation to 6.7 at twelve months and the last assessment; the results section reports mean follow-up of 61.9 months. This is a small uncontrolled series.
Mechanism Target:
BYPASSES Cochlear Dysfunction — Electrical stimulation supports hearing despite cochlear sensory dysfunction; it does not correct CoQ biosynthesis.
Show evidence (1 reference)
PMID:36124066 SUPPORT Human Clinical
"In the latter 4 patients (7 ears), the average CAP score was 3.2 (SD: 2.7) at baseline, 6.2 (SD: 1.7) at 3 months postoperatively, 6.5 (SD: 1.2) at 6 months postoperatively, 6.7 (SD: 0.8) at 12 months postoperatively, and 6.7 (SD: 0.5) at the last evaluation (Figure 3). The average follow-up..."
The results section supplies longitudinal auditory performance and follow-up for the four implanted patients.
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
Platform: Device
Renal replacement therapy for advanced kidney failure. Peritoneal dialysis was used before transplantation in a reported child; dialysis does not restore endogenous CoQ10 biosynthesis.
Mechanism Target:
BYPASSES Progression to Kidney Failure — Provides solute and fluid removal when native renal function is inadequate.
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 (NCIT:C15265). NCIT:C15265 is a clinical intervention from the NCI Thesaurus. NCIT:C15265
Platform: Surgery
Kidney transplantation replaces failed renal function. Eight patients in the Korean cohort received grafts without nephropathy recurrence during reported follow-up. This outcome does not establish a zero lifetime recurrence risk or treat extrarenal COQ6 deficiency.
Mechanism Target:
BYPASSES Progression to Kidney Failure — Replaces renal function without correcting the systemic genetic defect.
Show evidence (1 reference)
PMID:36124066 SUPPORT Human Clinical
"Eight patients progressed to kidney failure at a median of 7.2 (range 1.1–27.0) months after disease onset and underwent kidney transplantation without recurrence of nephropathy in the graft."
The interval is from disease onset, not age at kidney failure.
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.
Platform: Small molecule
An uncontrolled report describes improved visual acuity in one homozygous p.Ala353Asp adolescent treated after optic neuropathy, with residual optic atrophy and no hearing improvement. His younger brother also received idebenone, but renal remission preceded its initiation. These observations do not establish efficacy, prevention of future manifestations, or superiority to CoQ10. GeneReviews separately reports deterioration with short-chain quinones in some primary-CoQ-deficiency patients, so this case should not be treated as a general treatment recommendation.
Mechanism Target:
Optic Nerve Involvement — The clinical report investigated visual outcomes; whether the observed improvement was caused by treatment is unresolved.
Show evidence (3 references)
PMID:32685349 SUPPORT Human Clinical
"Optical examination performed after 2 years of treatment demonstrated an improved VA at 20/20 for the right eye and 20/25 + for the left."
Visual improvement was observed during treatment in one patient; no controlled comparison was made.
PMID:32685349 SUPPORT Human Clinical
"Idebenone treatment did not, however, improve the hearing loss."
Hearing did not improve in the reported patients.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK410087/ SUPPORT BACKGROUND Other
"Short-chain quinone analogs such as idebenone ... have been reported to cause clinical deterioration in individuals with CoQ ... deficiency"
GeneReviews caution concerns the broader primary CoQ-deficiency group and does not demonstrate deterioration in these two COQ6 cases.
Experimental Vanillic Acid Bypass
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: vanillic acid CHEBI:30816 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses vanillic acid (CHEBI:30816). CHEBI:30816 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Vanillic acid provides a ring precursor already modified at the position requiring COQ6. It restored CoQ production, coupled respiration and ATP in COQ6-delta25 HEK293 cells, and rescued yeast expressing tested human variants. These are preclinical findings; efficacy, safety and dosing in patients with COQ6 deficiency are not established by these studies. The human-cell model may retain protein below assay detection, and off-target editing effects were not excluded.
Mechanism Target:
BYPASSES Deficient C5-Ring Hydroxylation in CoQ10 Biosynthesis — A premodified aromatic precursor bypasses the deficient hydroxylation step in experimental models.
Show evidence (2 references)
PMID:31379988 SUPPORT In Vitro
"Treatment with VA can recover CoQ biosynthesis and ATP production."
Rescue in edited human HEK293 cells, not a human clinical trial.
PMID:24140869 SUPPORT Model Organism
"We detected a partial rescue of the phenotype in the presence of the analogues in all cases. VA seemed more efficient than 3,4 diHB, with effects already evident at 0.1 mM"
Yeast carrying the tested human COQ6 mutant alleles responded to ring-precursor analogues.
Show evidence (2 references)
PMID:31379988 SUPPORT In Vitro
"Treatment with VA can recover CoQ biosynthesis and ATP production."
Rescue in edited human HEK293 cells, not a human clinical trial.
PMID:24140869 SUPPORT Model Organism
"We detected a partial rescue of the phenotype in the presence of the analogues in all cases. VA seemed more efficient than 3,4 diHB, with effects already evident at 0.1 mM"
Yeast carrying the tested human COQ6 mutant alleles responded to ring-precursor analogues.
Genetic Counseling and Family Testing
Category: Counseling / Informational
For parents carrying pathogenic COQ6 variants, each pregnancy has a 25% probability of an affected child, 50% of a carrier and 25% of a child inheriting neither familial variant. Testing at-risk siblings can identify disease before further organ injury. Once familial variants are known, carrier testing and prenatal or preimplantation testing can be discussed.
Show evidence (3 references)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK410087/ SUPPORT BACKGROUND Other
"If both parents are known to be heterozygous for a primary CoQ ... deficiency-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier."
GeneReviews recessive recurrence risks apply when both parents carry pathogenic variants.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK410087/ SUPPORT BACKGROUND Other
"If the pathogenic variants in the family are known, molecular genetic testing can be used to clarify the genetic status of at-risk sibs."
Early family testing identifies siblings who may benefit from prompt treatment.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK410087/ SUPPORT BACKGROUND Other
"Once the primary CoQ ... deficiency-related pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing for primary CoQ ... deficiency are possible."
GeneReviews discusses reproductive testing after the familial molecular cause is established.
Multisystem Surveillance and Support
Category: Monitoring
Follow renal function and proteinuria, hearing, vision and neurologic development, adapting assessment to the individual phenotype. Provide developmental, physical, nutritional and low-vision support when indicated. Baseline cardiac evaluation helps identify cardiac involvement.
Show evidence (2 references)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK410087/ SUPPORT BACKGROUND Other
"Urine analysis for proteinuria and assessment of kidney function ... Ophthalmologic evaluation and electroretinogram for evidence of retinopathy and to determine need for low vison services ... Hearing evaluation with attention to possible sensorineural hearing loss"
GeneReviews surveillance addresses renal, visual and auditory disease.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK410087/ SUPPORT BACKGROUND Other
"Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields"
General primary-CoQ-deficiency supportive management.
🔬

Diagnosis

3
Molecular genetic testing in steroid-resistant nephrotic syndrome
Identify biallelic pathogenic COQ6 variants using an appropriate nephrotic-syndrome or mitochondrial-disease panel, or exome/genome analysis, with segregation and variant interpretation. Hearing loss strengthens suspicion but is not required. A single variant or an isoform-specific premature stop is not sufficient to establish this recessive diagnosis.
molecular genetic testing NCIT:C15709 NCI Thesaurus (NCIT)
Show evidence (5 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.
+ 2 more references
Renal biopsy showing focal segmental glomerulosclerosis
Kidney biopsy can characterize glomerular injury, including FSGS and abnormal podocyte mitochondria. These findings are supportive but neither universal nor specific for COQ6 deficiency; molecular testing establishes the etiology.
biopsy of kidney NCIT:C51699 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:36124066 SUPPORT Human Clinical
"Kidney biopsy was performed in 11 patients (not in patient 8-2); all exhibited FSGS lesions"
FSGS was found in all biopsied patients in this selected Korean cohort.
PMID:36124066 SUPPORT Human Clinical
"Patient 10 evidenced no mitochondrial abnormality, and patient 11 was not evaluated because the specimen was inadequate."
A normal or inadequate electron-microscopy assessment does not exclude molecularly confirmed disease.
CoQ10 Biochemistry and Respiratory-Chain Assessment
Tissue or cell CoQ10 and respiratory-chain assays can help investigate uncertain molecular findings, but cannot by themselves distinguish primary from secondary deficiency. Plasma CoQ10 reflects intake and is not a reliable diagnostic measure. Normal muscle or fibroblast findings do not exclude a genetic diagnosis.
Show evidence (3 references)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK410087/ SUPPORT BACKGROUND Other
"Plasma CoQ ... levels are not useful for the diagnosis of primary CoQ ... deficiency because they reflect dietary intake rather than endogenous CoQ ... production"
GeneReviews explains why plasma concentrations are unsuitable as a stand-alone diagnostic test.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK410087/ SUPPORT BACKGROUND Other
"there are individuals with genetically proven CoQ ... deficiency who had normal CoQ ... levels in both muscle and cultured skin fibroblasts"
Normal tissue measurements do not exclude genetic CoQ deficiency.
PMID:32685349 SUPPORT Human Clinical
"Exploration of the mitochondrial respiratory chain on the muscular biopsy was normal, including the combined activities of complexes I + III and II + III."
Normal muscle respiratory-chain testing was reported in a homozygous COQ6 patient.
📈

Progression

1
Variable Renal and Extrarenal Course
Kidney disease often starts in infancy or childhood, but progression is not inevitable in every observed patient. The international cohort included 27/48 patients with ESKD at last observation and one with isolated hearing loss without renal symptoms through age seventeen. Treatment and ascertainment influence these estimates. Hearing may precede or follow renal disease and may progress despite CoQ10; later optic or neurologic manifestations warrant follow-up. Among those who reached ESKD in the international cohort, median age at ESKD was 3.4 years (interquartile range 1.7–6.3).
Show evidence (5 references)
url:https://dirros.openscience.si/Dokument.php?id=36089&lang=eng SUPPORT Human Clinical
"ESKD 50.8 (32/63) 56.2 (27/48) 66.4 (93/140)"
COQ6 middle column reports last-observation ESKD, not an untreated lifetime risk.
PMID:36124066 SUPPORT Human Clinical
"Eight patients progressed to kidney failure at a median of 7.2 (range 1.1–27.0) months after disease onset and underwent kidney transplantation without recurrence of nephropathy in the graft."
The interval is from disease onset, not age at kidney failure.
PMID:30682496 SUPPORT Human Clinical
"Her older brother, who had sensorineural hearing loss with no renal or neurological involvement, had the same mutation in homozygous form."
The affected sister and brother shared homozygous c.1058C>A; the brother lacked renal involvement at the reported observation.
+ 2 more references
🧫

Experimental Models

3
Murine Podocyte COQ6 Knockdown CELL_LINE
Stable knockdown in immortalized mouse podocytes reduced growth, depolarized mitochondria and increased caspase-9/3 activity; 50 micromolar CoQ10 for 48 hours reduced caspase activity.
Publication
PMID:21540551
Pathograph links
Podocyte Apoptosis recapitulates fidelity: moderate Models COQ6-dependent podocyte survival and partial CoQ10 rescue.
Limitations: Knockdown and culture conditions do not reproduce patient alleles or intact glomerular architecture.
Show evidence (2 references)
PMID:21540551 SUPPORT In Vitro
"Coq6 downregulation in cultured mouse podocytes induced apoptosis that was diminished by CoQ 10 treatment."
Figure 5A-C demonstrates rescue in cultured murine podocytes. The zebrafish arm did not test rescue.
+ 1 more reference
Murine Podocyte siRNA Cytoskeleton and Redox Assays CELL_LINE
Transient COQ6 siRNA in mouse podocytes measures nephrin/F-actin abundance, actin organization, MitoSOX and apoptosis. Its experimental findings are separable from the paper's unsupported interpretation of a human isoform-specific variant.
Publication
PMID:30425193
Pathograph links
Podocyte Cytoskeletal Disorganization recapitulates fidelity: moderate Reduced nephrin/F-actin and disorganized actin after knockdown.
Limitations: No time-resolved causal order among oxidation, cytoskeletal changes and death was established.
Show evidence (2 references)
PMID:30425193 SUPPORT In Vitro
"the expression levels of both proteins were significantly lower in the si-RNA-COQ6 group than in the control group"
The measured proteins were nephrin and F-actin in mouse podocytes.
+ 1 more reference
Altered Cellular Redox State recapitulates fidelity: moderate MitoSOX signal increased after knockdown.
Limitations: This assay does not establish a universal redox phenotype in all cells or tissues.
Show evidence (1 reference)
PMID:30425193 SUPPORT In Vitro
"ROS levels were increased when the MPCs were incubated with si-COQ6 compared to the normal group."
Mouse podocyte knockdown increased mitochondrial MitoSOX signal; the patient variant claim in this paper is not used as clinical genetic evidence.
COQ6-Delta25 HEK293 Cells CELL_LINE
CRISPR editing removed 25 amino acids from a FAD-binding region. Immunoblotting detected no residual protein; endogenous CoQ synthesis, II+III activity, ATP and coupled respiration fell. Vanillic acid restored biochemical function.
Publication
PMID:31379988
Pathograph links
Coenzyme Q10 Deficiency recapitulates fidelity: moderate Models impaired endogenous synthesis and vanillic-acid bypass rescue.
Limitations: Engineered in-frame deletion; protein below detection and off-target effects were not excluded. Cells are not patient podocytes.
Show evidence (2 references)
PMID:31379988 SUPPORT In Vitro
"Incorporation of 14C-labelled 4-HB was virtually undetectable"
COQ6-delta25 HEK293 cells showed virtually absent endogenous CoQ10 synthesis despite residual CoQ10 acquired from culture medium.
+ 1 more reference
Cellular ATP Deficiency recapitulates fidelity: moderate ATP deficiency was reversed with vanillic acid.
Limitations: Cellular rescue is not evidence of clinical efficacy or safety.
Show evidence (1 reference)
PMID:31379988 SUPPORT In Vitro
"ATP levels were markedly reduced in COQ6∆25 cells, but after VA supplementation, they were virtually normal"
Cellular ATP deficiency and bypass rescue were measured in the HEK293 model, not in patient organs.
🐁

Animal Models

2
coq6 Morpholino Zebrafish
Translation- and splice-blocking morpholinos increased apoptosis in embryonic heads and trunks at 28 hours after fertilization. No CoQ10 rescue condition or podocyte-specific renal phenotype was demonstrated.
Species
Zebrafish
Genotype
Transient coq6 morpholino knockdown
Publication
PMID:21540551
Pathograph links
Podocyte Apoptosis recapitulates fidelity: low Supports a conserved association between COQ6 depletion and apoptosis in a whole vertebrate.
Limitations: The measured head/trunk apoptosis is not renal or podocyte-specific, so fidelity to the human kidney lesion is low. No treatment rescue was tested.
Show evidence (1 reference)
PMID:21540551 SUPPORT Model Organism
"coq6 knockdown in zebrafish embryos 28 hours after fertilization increases apoptosis"
Figure 5D-F reports the zebrafish knockdown phenotype.
Yeast coq6 Deletion Complemented with Human Alleles
Respiratory growth and CoQ content characterize residual activity of human variants and the effects of vanillic acid or 3,4-dihydroxybenzoate. Expression system and promoter strength influence complementation.
Species
Saccharomyces cerevisiae
Genotype
coq6 deletion with wild-type or mutant human COQ6 constructs
Publication
PMID:24140869
Pathograph links
Deficient C5-Ring Hydroxylation in CoQ10 Biosynthesis recapitulates fidelity: moderate Tests allele function and precursor bypass.
Limitations: Yeast CoQ-complex stability requirements differ from the human-cell model; residual activity is assay-dependent and does not establish patient severity.
Show evidence (2 references)
PMID:24140869 SUPPORT Model Organism
"These data suggest that the human G255R, A353D, Y412C and Q461sf478X mutations are hypomorphic since the corresponding yeast Coq6 mutants display residual activity."
Improved yeast complementation assays detect residual activity missed by the initial assay; these results cannot define every patient allele.
+ 1 more reference
{ }

Source YAML

click to show 
name: COQ6-Related Steroid-Resistant Nephrotic Syndrome with Sensorineural Deafness
description: Biallelic pathogenic COQ6 variants impair coenzyme Q10 biosynthesis and cause primary coenzyme Q10 deficiency-6. Steroid-resistant nephrotic syndrome and sensorineural hearing loss are characteristic, but isolated proteinuria, hearing loss without renal involvement, and additional neurologic, ocular, or severe infantile manifestations occur. Renal and auditory courses vary, including within families. Early oral CoQ10 supplementation can reduce proteinuria and preserve kidney function; hearing benefit is less consistent. Steroid resistance describes an observed treatment response and does not imply that all antiproteinuric therapies are ineffective.
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'
pathophysiology:
- name: Biallelic COQ6 Dysfunction
  biological_scale: MOLECULAR
  description: Biallelic pathogenic variants reduce COQ6 function. Missense, in-frame deletion, nonsense, and frameshift alleles have been reported. Residual activity varies; truncating sequence changes do not automatically establish complete functional null alleles.
  evidence:
  - &id005
    reference: PMID:21540551
    reference_title: COQ6 mutations in human patients produce nephrotic syndrome with sensorineural deafness.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: All 11 affected individuals of the 5 families with 2 recessive COQ6 mutations had SRNS.
    explanation: The founding series included 11 affected individuals in five families with biallelic variants; two additional single-heterozygous cases were not molecularly resolved.
  - &id004
    reference: PMID:24140869
    reference_title: Effect of vanillic acid on COQ6 mutants identified in patients with coenzyme Q10 deficiency.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: These data suggest that the human G255R, A353D, Y412C and Q461sf478X mutations are hypomorphic since the corresponding yeast Coq6 mutants display residual activity.
    explanation: Improved yeast complementation assays detect residual activity missed by the initial assay; these results cannot define every patient allele.
  downstream:
  - target: Deficient C5-Ring Hydroxylation in CoQ10 Biosynthesis
    causal_link_type: DIRECT
    description: Reduced enzyme function impairs the C5 modification required for CoQ synthesis.
    evidence:
    - reference: PMID:24140869
      reference_title: Effect of vanillic acid on COQ6 mutants identified in patients with coenzyme Q10 deficiency.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: These data suggest that the human G255R, A353D, Y412C and Q461sf478X mutations are hypomorphic since the corresponding yeast Coq6 mutants display residual activity.
      explanation: Improved yeast complementation assays detect residual activity missed by the initial assay; these results cannot define every patient allele.
- name: Deficient C5-Ring Hydroxylation in CoQ10 Biosynthesis
  biological_scale: MOLECULAR
  description: COQ6 is a FAD-dependent monooxygenase required for C5 hydroxylation of the CoQ ring. Yeast modeling supports impaired substrate access for the G248R counterpart of human p.Gly255Arg; engineered L382E and double-mutant results do not establish a universal mechanism for human missense alleles.
  evidence:
  - reference: PMID:24140869
    reference_title: Effect of vanillic acid on COQ6 mutants identified in patients with coenzyme Q10 deficiency.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Human COQ6 encodes a monooxygenase which is responsible for the C5-hydroxylation of the quinone ring of coenzyme Q (CoQ).
    explanation: Background functional assignment supported by complementation and bypass experiments.
    quote_role: BACKGROUND
  - 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: Biochemical characterization of recombinant yeast Coq6 establishes FAD binding; this is not a patient enzyme assay.
  - 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: Homology models of yeast Coq6 predict channel narrowing. G248R corresponds to human G255R; L382E and the double mutant were engineered tests.
  genes:
  - preferred_term: COQ6
    term:
      id: hgnc:20233
      label: COQ6
  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
  downstream:
  - target: Coenzyme Q10 Deficiency
    causal_link_type: DIRECT
    description: Impaired ring modification reduces endogenous CoQ10 synthesis.
    evidence:
    - reference: PMID:31379988
      reference_title: Vanillic Acid Restores Coenzyme Q Biosynthesis and ATP Production in Human Cells Lacking COQ6.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Incorporation of 14C-labelled 4-HB was virtually undetectable
      explanation: COQ6-delta25 HEK293 cells showed virtually absent endogenous CoQ10 synthesis despite residual CoQ10 acquired from culture medium.
- name: Coenzyme Q10 Deficiency
  biological_scale: MOLECULAR
  description: Reduced endogenous cellular CoQ10 compromises its electron-carrier and antioxidant functions. The magnitude and tissue distribution of deficiency vary.
  evidence:
  - reference: PMID:31379988
    reference_title: Vanillic Acid Restores Coenzyme Q Biosynthesis and ATP Production in Human Cells Lacking COQ6.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Incorporation of 14C-labelled 4-HB was virtually undetectable
    explanation: COQ6-delta25 HEK293 cells showed virtually absent endogenous CoQ10 synthesis despite residual CoQ10 acquired from culture medium.
  downstream:
  - target: Deficient CoQ-Dependent Electron Transfer
    causal_link_type: DIRECT
    description: Loss of CoQ limits coupled electron transfer between respiratory complexes.
    evidence:
    - reference: PMID:31379988
      reference_title: Vanillic Acid Restores Coenzyme Q Biosynthesis and ATP Production in Human Cells Lacking COQ6.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Activities of individual respiratory chain enzymes were normal; however, combined activity of complexes II and III was markedly reduced in these cells, consistent with severe CoQ10 deficiency
      explanation: CoQ-dependent combined respiratory-chain activity was deficient in edited HEK293 cells; individual complex activities were normal.
  - target: Altered Cellular Redox State
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Oxidant accumulation varies with cell model and assay; a single mitochondrial ROS pattern is not established.
    evidence:
    - 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: ROS levels were increased when the MPCs were incubated with si-COQ6 compared to the normal group.
      explanation: Mouse podocyte knockdown increased mitochondrial MitoSOX signal; the patient variant claim in this paper is not used as clinical genetic evidence.
    - reference: PMID:31379988
      reference_title: Vanillic Acid Restores Coenzyme Q Biosynthesis and ATP Production in Human Cells Lacking COQ6.
      supports: REFUTE
      evidence_source: IN_VITRO
      snippet: we did not detect a significant increase of mitochondrial ROS production using mitochondrially targeted ro-GFP
      explanation: The HEK293 model did not reproduce increased mitochondrial oxidation on this assay; increased total cellular oxidant signal should not be equated with a universal mitochondrial ROS increase.
    - reference: PMID:31379988
      reference_title: Vanillic Acid Restores Coenzyme Q Biosynthesis and ATP Production in Human Cells Lacking COQ6.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: we found increased levels in the COQ6∆25 cells. VA treatment was able to decrease ROS to basal levels, while CoQ supplementation was only partially effective
      explanation: Total cellular CM-H2DCFDA signal increased in the HEK293 model and responded differently to VA versus exogenous CoQ.
  - target: Podocyte Cytoskeletal Disorganization
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: COQ6 knockdown reduces nephrin/F-actin and disrupts actin organization; intermediates are unresolved.
    evidence:
    - 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: the expression levels of both proteins were significantly lower in the si-RNA-COQ6 group than in the control group
      explanation: The measured proteins were nephrin and F-actin in mouse podocytes.
    - 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: F-actin immunofluorescence in the si-COQ6 group was irregularly distributed
      explanation: Actin organization was disturbed after knockdown; timing relative to ROS and apoptosis was not resolved.
  - target: Podocyte Apoptosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Knockdown-associated apoptosis is partly reversed by CoQ10 supplementation.
    evidence:
    - reference: PMID:21540551
      reference_title: COQ6 mutations in human patients produce nephrotic syndrome with sensorineural deafness.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Coq6 downregulation in cultured mouse podocytes induced apoptosis that was diminished by CoQ 10 treatment.
      explanation: Figure 5A-C demonstrates rescue in cultured murine podocytes. The zebrafish arm did not test rescue.
    - 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: the number of Annexin V+/PI+ and V+/PI− cells was significantly increased in the si-COQ6 group.
      explanation: Flow cytometry independently supports increased apoptosis after mouse podocyte knockdown.
  - target: Cochlear Dysfunction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Genetic disease and rat expression support cochlear involvement, but the initiating cell lesion is unresolved.
    evidence:
    - reference: PMID:21540551
      reference_title: COQ6 mutations in human patients produce nephrotic syndrome with sensorineural deafness.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: revealed COQ6 expression in the spiral ganglion as well as in cells of stria vascularis and spiral ligament
      explanation: Rat expression supports multiple possible cochlear sites; localization does not demonstrate strial failure or exclusive organ vulnerability.
  - target: Optic Nerve Involvement
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Optic neuropathy is documented clinically; its cellular route from CoQ deficiency remains unresolved.
    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 did not recover normal vision, still exhibiting a bilateral VA of 20/32 and persistent optic atrophy.
      explanation: One homozygous p.Ala353Asp patient had residual optic atrophy during follow-up despite improved acuity on idebenone.
- name: Deficient CoQ-Dependent Electron Transfer
  biological_scale: MOLECULAR
  description: Combined respiratory-chain complex II+III activity falls in COQ6-deficient HEK293 cells despite preserved individual complex activities.
  evidence:
  - reference: PMID:31379988
    reference_title: Vanillic Acid Restores Coenzyme Q Biosynthesis and ATP Production in Human Cells Lacking COQ6.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Activities of individual respiratory chain enzymes were normal; however, combined activity of complexes II and III was markedly reduced in these cells, consistent with severe CoQ10 deficiency
    explanation: CoQ-dependent combined respiratory-chain activity was deficient in edited HEK293 cells; individual complex activities were normal.
  biological_processes:
  - preferred_term: oxidative phosphorylation
    term:
      id: GO:0006119
      label: oxidative phosphorylation
    modifier: DECREASED
  downstream:
  - target: Cellular ATP Deficiency
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Impaired coupled respiration is associated with low cellular ATP in the same edited-cell model.
    evidence:
    - reference: PMID:31379988
      reference_title: Vanillic Acid Restores Coenzyme Q Biosynthesis and ATP Production in Human Cells Lacking COQ6.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: ATP levels were markedly reduced in COQ6∆25 cells, but after VA supplementation, they were virtually normal
      explanation: Cellular ATP deficiency and bypass rescue were measured in the HEK293 model, not in patient organs.
- name: Cellular ATP Deficiency
  biological_scale: CELLULAR
  description: COQ6-delta25 HEK293 cells have markedly reduced ATP and coupled respiration. These measurements establish a cellular bioenergetic defect without demonstrating which human organ manifestations are specifically ATP-mediated.
  evidence:
  - reference: PMID:31379988
    reference_title: Vanillic Acid Restores Coenzyme Q Biosynthesis and ATP Production in Human Cells Lacking COQ6.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: ATP levels were markedly reduced in COQ6∆25 cells, but after VA supplementation, they were virtually normal
    explanation: Cellular ATP deficiency and bypass rescue were measured in the HEK293 model, not in patient organs.
- name: Altered Cellular Redox State
  biological_scale: CELLULAR
  description: Mouse podocyte knockdown increases MitoSOX signal. Edited HEK293 cells instead show increased total cellular oxidation without a significant mitochondrial roGFP increase. The relative redox contribution to cell death is not isolated by these experiments.
  evidence:
  - 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: ROS levels were increased when the MPCs were incubated with si-COQ6 compared to the normal group.
    explanation: Mouse podocyte knockdown increased mitochondrial MitoSOX signal; the patient variant claim in this paper is not used as clinical genetic evidence.
  - reference: PMID:31379988
    reference_title: Vanillic Acid Restores Coenzyme Q Biosynthesis and ATP Production in Human Cells Lacking COQ6.
    supports: REFUTE
    evidence_source: IN_VITRO
    snippet: we did not detect a significant increase of mitochondrial ROS production using mitochondrially targeted ro-GFP
    explanation: The HEK293 model did not reproduce increased mitochondrial oxidation on this assay; increased total cellular oxidant signal should not be equated with a universal mitochondrial ROS increase.
  - reference: PMID:31379988
    reference_title: Vanillic Acid Restores Coenzyme Q Biosynthesis and ATP Production in Human Cells Lacking COQ6.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: we found increased levels in the COQ6∆25 cells. VA treatment was able to decrease ROS to basal levels, while CoQ supplementation was only partially effective
    explanation: Total cellular CM-H2DCFDA signal increased in the HEK293 model and responded differently to VA versus exogenous CoQ.
- name: Podocyte Cytoskeletal Disorganization
  biological_scale: CELLULAR
  description: COQ6 knockdown lowers nephrin and F-actin and disrupts actin organization in cultured mouse podocytes. This is a separate experimental finding from apoptosis; the order of these events has not been demonstrated.
  evidence:
  - 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: the expression levels of both proteins were significantly lower in the si-RNA-COQ6 group than in the control group
    explanation: The measured proteins were nephrin and F-actin in mouse podocytes.
  - 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: F-actin immunofluorescence in the si-COQ6 group was irregularly distributed
    explanation: Actin organization was disturbed after knockdown; timing relative to ROS and apoptosis was not resolved.
  cell_types:
  - preferred_term: podocyte
    term:
      id: CL:0000653
      label: podocyte
  downstream:
  - target: Glomerular Filtration Barrier Injury
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Loss of podocyte structural integrity provides a plausible route to impaired filtration; the cellular-to-organ link is inferred.
    evidence:
    - 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: the expression levels of both proteins were significantly lower in the si-RNA-COQ6 group than in the control group
      explanation: The measured proteins were nephrin and F-actin in mouse podocytes.
    - 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: F-actin immunofluorescence in the si-COQ6 group was irregularly distributed
      explanation: Actin organization was disturbed after knockdown; timing relative to ROS and apoptosis was not resolved.
- name: Podocyte Apoptosis
  biological_scale: CELLULAR
  description: COQ6 knockdown causes mitochondrial depolarization and increased caspase-9/3 activity in cultured mouse podocytes. CoQ10 at 50 micromolar for 48 hours reduces caspase activity. Zebrafish embryonic apoptosis is a separate whole-organism observation and was not shown to be podocyte-specific.
  evidence: &id006
  - reference: PMID:21540551
    reference_title: COQ6 mutations in human patients produce nephrotic syndrome with sensorineural deafness.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Coq6 downregulation in cultured mouse podocytes induced apoptosis that was diminished by CoQ 10 treatment.
    explanation: Figure 5A-C demonstrates rescue in cultured murine podocytes. The zebrafish arm did not test rescue.
  - 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: the number of Annexin V+/PI+ and V+/PI− cells was significantly increased in the si-COQ6 group.
    explanation: Flow cytometry independently supports increased apoptosis after mouse podocyte knockdown.
  cell_types:
  - preferred_term: podocyte
    term:
      id: CL:0000653
      label: podocyte
  biological_processes:
  - preferred_term: apoptotic process
    term:
      id: GO:0006915
      label: apoptotic process
    modifier: INCREASED
  downstream:
  - target: Glomerular Filtration Barrier Injury
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Podocyte depletion can impair filtration integrity; the human organ link extends the cell-culture findings.
    evidence:
    - reference: PMID:21540551
      reference_title: COQ6 mutations in human patients produce nephrotic syndrome with sensorineural deafness.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Coq6 downregulation in cultured mouse podocytes induced apoptosis that was diminished by CoQ 10 treatment.
      explanation: Figure 5A-C demonstrates rescue in cultured murine podocytes. The zebrafish arm did not test rescue.
    - 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: the number of Annexin V+/PI+ and V+/PI− cells was significantly increased in the si-COQ6 group.
      explanation: Flow cytometry independently supports increased apoptosis after mouse podocyte knockdown.
- name: Glomerular Filtration Barrier Injury
  biological_scale: TISSUE
  description: Podocyte foot-process effacement and glomerular injury accompany COQ6 nephropathy. Protein leakage may occur before extensive sclerosis and need not include all features of nephrotic syndrome.
  evidence:
  - reference: PMID:21540551
    reference_title: COQ6 mutations in human patients produce nephrotic syndrome with sensorineural deafness.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Transmission electron microscopy for F1082 showed effacement of podocyte foot processes, resulting in a continuous electron-dense layer
    explanation: Human renal ultrastructure demonstrates foot-process effacement.
  downstream:
  - target: Proteinuria
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Loss of filtration selectivity permits urinary protein loss.
    evidence:
    - reference: PMID:21540551
      reference_title: COQ6 mutations in human patients produce nephrotic syndrome with sensorineural deafness.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: All 11 affected individuals of the 5 families with 2 recessive COQ6 mutations had SRNS.
      explanation: The founding series included 11 affected individuals in five families with biallelic variants; two additional single-heterozygous cases were not molecularly resolved.
  - target: Focal Segmental Glomerulosclerosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Persistent podocyte injury can lead to segmental scarring; this is not the only reported biopsy pattern.
    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: Kidney biopsy was performed in 11 patients (not in patient 8-2); all exhibited FSGS lesions
      explanation: FSGS was found in all biopsied patients in this selected Korean cohort.
  - target: Hypoalbuminemia
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Persistent urinary protein loss can lower serum albumin.
    evidence:
    - reference: PMID:21540551
      reference_title: COQ6 mutations in human patients produce nephrotic syndrome with sensorineural deafness.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Nephrotic syndrome (NS), a malfunction of the kidney glomer- ular filter, leads to proteinuria, hypoalbuminemia, and edema.
      explanation: The founding paper describes the general nephrotic filtration-barrier phenotype.
      quote_role: BACKGROUND
  - target: Edema
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Nephrotic protein loss and altered fluid handling can cause edema.
    evidence:
    - reference: PMID:21540551
      reference_title: COQ6 mutations in human patients produce nephrotic syndrome with sensorineural deafness.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Nephrotic syndrome (NS), a malfunction of the kidney glomer- ular filter, leads to proteinuria, hypoalbuminemia, and edema.
      explanation: The founding paper describes the general nephrotic filtration-barrier phenotype.
      quote_role: BACKGROUND
  - target: Steroid-Resistant Nephrotic Syndrome
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Glomerular injury can manifest as nephrotic syndrome; steroid resistance is determined clinically, not inferred from the mechanism.
    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 presented with SRNS, except patient 11 who presented with nephrotic range proteinuria without nephrotic syndrome, at a median age of 2.7 years (range 0.8–9.1 years).
      explanation: Eleven of twelve children had SRNS, and one had proteinuria without the full syndrome. This selected cohort does not establish population penetrance.
- name: Focal Segmental Glomerulosclerosis
  biological_scale: TISSUE
  description: Segmental glomerular scarring is common, with NOS, collapsing and cellular patterns reported. Diffuse mesangial sclerosis, minimal-change and other patterns also occur; FSGS does not establish a uniform clinical course.
  evidence:
  - &id001
    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: Kidney biopsy was performed in 11 patients (not in patient 8-2); all exhibited FSGS lesions
    explanation: FSGS was found in all biopsied patients in this selected Korean cohort.
  downstream:
  - target: Progression to Kidney Failure
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Chronic renal injury can progress to kidney failure, with substantial variability and potential treatment benefit.
    evidence:
    - reference: url:https://dirros.openscience.si/Dokument.php?id=36089&lang=eng  # codespell:ignore dokument
      reference_title: https://dirros.openscience.si/Dokument.php?id=36089&lang=eng  # codespell:ignore dokument
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: ESKD 50.8 (32/63) 56.2 (27/48) 66.4 (93/140)
      explanation: Table 1 middle column reports 27/48 COQ6 patients at last follow-up; the cohort combines treated and untreated cases.
- name: Cochlear Dysfunction
  biological_scale: TISSUE
  description: The affected cochlear compartment is not established. Rat COQ6 expression includes stria vascularis, spiral ligament and spiral ganglion neurons, and clinical hearing loss is compatible with cochlear dysfunction.
  evidence:
  - reference: PMID:21540551
    reference_title: COQ6 mutations in human patients produce nephrotic syndrome with sensorineural deafness.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: revealed COQ6 expression in the spiral ganglion as well as in cells of stria vascularis and spiral ligament
    explanation: Rat expression supports multiple possible cochlear sites; localization does not demonstrate strial failure or exclusive organ vulnerability.
  downstream:
  - target: Sensorineural Hearing Loss
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Cochlear dysfunction is a working explanation for sensorineural impairment; localization alone does not identify the causal cell type.
    evidence:
    - reference: PMID:21540551
      reference_title: COQ6 mutations in human patients produce nephrotic syndrome with sensorineural deafness.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: revealed COQ6 expression in the spiral ganglion as well as in cells of stria vascularis and spiral ligament
      explanation: Rat expression supports multiple possible cochlear sites; localization does not demonstrate strial failure or exclusive organ vulnerability.
- name: Optic Nerve Involvement
  biological_scale: TISSUE
  description: Optic neuropathy with subsequent optic atrophy is a documented, variable manifestation. Visual improvement in an uncontrolled idebenone-treated case does not establish drug efficacy or a distinct pathway unavailable to CoQ10.
  evidence:
  - &id002
    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 did not recover normal vision, still exhibiting a bilateral VA of 20/32 and persistent optic atrophy.
    explanation: One homozygous p.Ala353Asp patient had residual optic atrophy during follow-up despite improved acuity on idebenone.
  downstream:
  - target: Optic Atrophy
    causal_link_type: DIRECT
    description: Optic nerve injury can leave persistent atrophy despite improvement in visual acuity.
    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 did not recover normal vision, still exhibiting a bilateral VA of 20/32 and persistent optic atrophy.
      explanation: One homozygous p.Ala353Asp patient had residual optic atrophy during follow-up despite improved acuity on idebenone.
phenotypes:
- category: Renal
  name: Steroid-Resistant Nephrotic Syndrome
  phenotype_term:
    preferred_term: Steroid-resistant nephrotic syndrome
    term:
      id: HP:0012588
      label: Steroid-resistant 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: All presented with SRNS, except patient 11 who presented with nephrotic range proteinuria without nephrotic syndrome, at a median age of 2.7 years (range 0.8–9.1 years).
    explanation: Eleven of twelve children had SRNS, and one had proteinuria without the full syndrome. This selected cohort does not establish population penetrance.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK410087/
    reference_title: Primary Coenzyme Q10 Deficiency Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Because individuals with ... COQ6- ... and ... COQ8B- ... related CoQ ... deficiency were ascertained by the presence of SRNS, the authors cannot exclude the possibility that biallelic pathogenic variants in these two genes could also cause a broader phenotype.
    explanation: GeneReviews Clinical Characteristics, Table 1 footnote 6, explicitly cautions that renal ascertainment limits the recognized COQ6 spectrum.
    quote_role: BACKGROUND
  description: Characteristic clinical presentation, defined by failure to respond to corticosteroids. Some patients have proteinuria without full nephrotic syndrome.
- category: Renal
  name: Focal Segmental Glomerulosclerosis
  phenotype_term:
    preferred_term: Focal segmental glomerulosclerosis
    term:
      id: HP:0000097
      label: Focal segmental glomerulosclerosis
  evidence:
  - *id001
  - reference: url:https://dirros.openscience.si/Dokument.php?id=36089&lang=eng  # codespell:ignore dokument
    reference_title: https://dirros.openscience.si/Dokument.php?id=36089&lang=eng  # codespell:ignore dokument
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: FSGS 69.4 (25/36) 72.2 (26/36) 77.1 (64/83)
    explanation: 'Table 1 middle column is COQ6: 26 of 36 informative biopsies.'
  description: 'Common but not universal histology: 26/36 informative COQ6 biopsies in the international cohort and 11/11 in the Korean cohort.'
- category: Sensory
  name: Sensorineural Hearing Loss
  phenotype_term:
    preferred_term: Sensorineural hearing impairment
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
  evidence:
  - reference: url:https://dirros.openscience.si/Dokument.php?id=36089&lang=eng  # codespell:ignore dokument
    reference_title: https://dirros.openscience.si/Dokument.php?id=36089&lang=eng  # codespell:ignore dokument
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Hearing abnormalities 1.7 (1/59) 73.9 (34/46) 0 (0/140)
    explanation: The COQ6 column reports 34/46; this uses the table denominator rather than the inconsistent prose.
  - 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 last audiological evaluation, 11 patients evidenced SNHL with a median hearing threshold of 81.3 dB (range 3.8–118.8 dB).
    explanation: Eleven of twelve patients were affected at final evaluation.
  description: Hearing loss can be congenital or later-onset and may precede renal symptoms. Table 1 of the international cohort reports 34/46 informative patients; the Korean cohort found 11/12 affected at last assessment. Progression is common but not universal.
- category: Renal
  name: Progression to Kidney Failure
  phenotype_term:
    preferred_term: Stage 5 chronic kidney disease
    term:
      id: HP:0003774
      label: Stage 5 chronic kidney disease
  evidence:
  - reference: url:https://dirros.openscience.si/Dokument.php?id=36089&lang=eng  # codespell:ignore dokument
    reference_title: https://dirros.openscience.si/Dokument.php?id=36089&lang=eng  # codespell:ignore dokument
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: ESKD 50.8 (32/63) 56.2 (27/48) 66.4 (93/140)
    explanation: COQ6 middle column reports last-observation ESKD, not an untreated lifetime risk.
  - 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: Eight patients progressed to kidney failure at a median of 7.2 (range 1.1–27.0) months after disease onset and underwent kidney transplantation without recurrence of nephropathy in the graft.
    explanation: The interval is from disease onset, not age at kidney failure.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK410087/
    reference_title: Primary Coenzyme Q10 Deficiency Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: If not treated with supplementation of high-dose oral CoQ ... SRNS usually progresses to end-stage kidney disease (ESKD).
    explanation: GeneReviews describes the usual untreated renal trajectory across primary CoQ deficiencies, including COQ6; usually does not mean inevitable for every person.
    quote_role: BACKGROUND
  description: Progression varies. The international cohort reported ESKD in 27/48 COQ6 patients at last follow-up; treated and untreated patients were included. In the Korean cohort eight patients reached kidney failure a median 7.2 months after disease onset.
- category: Ophthalmologic
  name: Optic Atrophy
  description: Optic atrophy was present in two of twelve children in the Korean series; a separate case developed optic neuropathy in adolescence. The international cohort recorded broader retinopathy/ocular abnormalities in 8/46; those findings are not all optic atrophy.
  phenotype_term:
    preferred_term: Optic atrophy
    term:
      id: HP:0000648
      label: Optic atrophy
  evidence:
  - &id003
    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: Ophthalmological abnormalities were found in 3 patients (1 with optic atrophy, 1 with nystagmus, and 1 with both optic atrophy and nystagmus).
    explanation: Two of twelve had optic atrophy and two had nystagmus; one had both.
  - *id002
  - reference: url:https://dirros.openscience.si/Dokument.php?id=36089&lang=eng  # codespell:ignore dokument
    reference_title: https://dirros.openscience.si/Dokument.php?id=36089&lang=eng  # codespell:ignore dokument
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Retinopathy/ocular abnormalities 20.3 (12/59) 17.4 (8/46) 5 (7/140)
    explanation: The COQ6 middle column provides broader ocular context, not an optic-atrophy-specific count.
    directness: INDIRECT
- category: Metabolic
  name: Metabolic Acidosis
  description: Severe metabolic acidosis was reported in two infants with compound heterozygous variants and fatal multisystem disease; the frequency in COQ6 deficiency is unknown.
  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
  description: May be nephrotic or non-nephrotic and may occur without edema or hypoalbuminemia. The international cohort reported renal involvement in 47/48 COQ6 patients.
  phenotype_term:
    preferred_term: Proteinuria
    term:
      id: HP:0000093
      label: Proteinuria
  evidence:
  - reference: url:https://dirros.openscience.si/Dokument.php?id=36089&lang=eng  # codespell:ignore dokument
    reference_title: https://dirros.openscience.si/Dokument.php?id=36089&lang=eng  # codespell:ignore dokument
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Kidney involvement 93.6 (59/63) 97.9 (47/48) 100 (140/140)
    explanation: The middle column is COQ6; ascertainment was enriched for nephropathy.
  - reference: url:https://dirros.openscience.si/Dokument.php?id=36089&lang=eng  # codespell:ignore dokument
    reference_title: https://dirros.openscience.si/Dokument.php?id=36089&lang=eng  # codespell:ignore dokument
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Nephrotic range proteinuria 85.7 (36/42) 86.1 (31/36) 71.7 (86/120) Non– nephrotic range proteinuria 14.3 (6/42) 13.9 (5/36) 28.3 (34/120)
    explanation: Among 36 informative COQ6 patients, 31 had nephrotic-range and five non-nephrotic-range proteinuria.
- category: Metabolic
  name: Hypoalbuminemia
  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
  description: Growth impairment occurs in some patients, including the severe infantile presentation; it is not restricted to a separately established subtype.
  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
  description: Hypotonia was reported in the severe infantile sibling pair. Absence from other presentations has not been established.
  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.
- name: Nystagmus
  category: Ophthalmologic
  description: Reported in two of twelve children in the Korean series.
  phenotype_term:
    preferred_term: Nystagmus
    term:
      id: HP:0000639
      label: Nystagmus
  evidence:
  - *id003
- name: Limb Muscle Weakness
  category: Neurologic
  description: Mild lower-extremity weakness was reported in two of twelve children. The international cohort separately recorded the broader category myopathy in 4/46, without establishing the same limb distribution in every case.
  phenotype_term:
    preferred_term: Limb muscle weakness
    term:
      id: HP:0003690
      label: Limb muscle weakness
  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: mild muscle weakness was detected in 2 patients (16.7%)
    explanation: Two children in the Korean cohort had mild muscle weakness.
  - 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: 'Mm weak: mild muscle weakness in the lower extremities'
    explanation: The table key specifies the limb distribution.
  - reference: url:https://dirros.openscience.si/Dokument.php?id=36089&lang=eng  # codespell:ignore dokument
    reference_title: https://dirros.openscience.si/Dokument.php?id=36089&lang=eng  # codespell:ignore dokument
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Myopathy 20.3 (12/59) 8.7 (4/46) 0 (0/140)
    explanation: The COQ6 middle-column count is for myopathy, not specifically mild limb weakness.
    directness: INDIRECT
- name: Seizures
  category: Neurologic
  description: Seizures occur in a minority, including affected children in the founding families; severe encephalopathy is not universal. In the international cohort, the combined encephalopathy/seizures category involved 4/46 informative COQ6 patients; that is not a seizure-only frequency.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:21540551
    reference_title: COQ6 mutations in human patients produce nephrotic syndrome with sensorineural deafness.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Subject A234-21 presented with seizures, and subject F1082-21 had white matter abnormalities and seizures and died of multiorgan failure in sepsis
    explanation: The founding series documents seizures, with white-matter abnormalities in another affected child.
  - reference: url:https://dirros.openscience.si/Dokument.php?id=36089&lang=eng  # codespell:ignore dokument
    reference_title: https://dirros.openscience.si/Dokument.php?id=36089&lang=eng  # codespell:ignore dokument
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Encephalopathy/seizures 42 (25/59) 8.7 (4/46) 7.1 (10/140)
    explanation: Table 1 middle column records the combined category in four of forty-six informative COQ6 patients.
    directness: INDIRECT
- name: Developmental Delay
  category: Neurologic
  description: Developmental delay or cognitive impairment was recorded as a combined category in 6/46 informative international-cohort patients. This aggregate is not a frequency estimate for global developmental delay alone.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: url:https://dirros.openscience.si/Dokument.php?id=36089&lang=eng  # codespell:ignore dokument
    reference_title: https://dirros.openscience.si/Dokument.php?id=36089&lang=eng  # codespell:ignore dokument
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Developmental delay/cognitive impairment 5 (3/59) 13 (6/46) 5 (7/140)
    explanation: Table 1 combines developmental and cognitive findings; the phenotype binding captures the developmental component only.
- name: Cardiomyopathy
  category: Cardiovascular
  description: Reported in one of twelve Korean children; broader cardiovascular abnormalities should not all be counted as cardiomyopathy.
  phenotype_term:
    preferred_term: Cardiomyopathy
    term:
      id: HP:0001638
      label: Cardiomyopathy
  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: In addition, mild muscle weakness was detected in 2 patients (16.7%), cardiomyopathy in 1 (8.3%), and atlantoaxial dislocation in 1 (8.3%).
    explanation: One of twelve children had cardiomyopathy.
- name: Edema
  category: Renal
  description: Reported in 11/23 informative COQ6 patients in the international cohort; proteinuria may occur without edema.
  phenotype_term:
    preferred_term: Edema
    term:
      id: HP:0000969
      label: Edema
  evidence:
  - reference: url:https://dirros.openscience.si/Dokument.php?id=36089&lang=eng  # codespell:ignore dokument
    reference_title: https://dirros.openscience.si/Dokument.php?id=36089&lang=eng  # codespell:ignore dokument
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Oedema 86.6 (39/45) 47.8 (11/23) 40.2 (33/82)
    explanation: Middle column reports 11/23 COQ6 cases.
- name: Hypertension
  category: Cardiovascular
  description: Reported in 4/19 informative COQ6 patients in the international cohort.
  phenotype_term:
    preferred_term: Hypertension
    term:
      id: HP:0000822
      label: Hypertension
  evidence:
  - reference: url:https://dirros.openscience.si/Dokument.php?id=36089&lang=eng  # codespell:ignore dokument
    reference_title: https://dirros.openscience.si/Dokument.php?id=36089&lang=eng  # codespell:ignore dokument
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Hypertension 28.6 (12/42) 21 (4/19) 39 (32/82)
    explanation: Middle column reports 4/19 COQ6 cases.
- name: Atrial Septal Defect
  category: Cardiovascular
  description: Reported by echocardiography in the male infant of the p.Tyr83Ter/p.Gln461Ter family. A single affected family does not establish frequency or a general causal association with COQ6 deficiency.
  phenotype_term:
    preferred_term: Atrial septal defect
    term:
      id: HP:0001631
      label: Atrial septal defect
  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: Cardiac ultrasound revealed an atrial septal defect and pulmonary hypertension, and an electrocardiogram showed altered sinus rhythm T waves.
    explanation: The male infant had this structural finding during assessment of severe multisystem illness.
- name: Elevated Pulmonary Artery Pressure
  category: Cardiovascular
  description: Pulmonary hypertension was reported by cardiac ultrasound in the same infant during severe respiratory illness with cytomegalovirus infection and an atrial septal defect. The report does not establish a primary pulmonary vascular mechanism or a hemodynamic subtype.
  phenotype_term:
    preferred_term: Elevated pulmonary artery pressure
    term:
      id: HP:0004890
      label: Elevated pulmonary artery pressure
  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: Cardiac ultrasound revealed an atrial septal defect and pulmonary hypertension, and an electrocardiogram showed altered sinus rhythm T waves.
    explanation: Binds the reported pressure abnormality without asserting precapillary pulmonary arterial hypertension.
- name: Increased Circulating Lactate
  category: Metabolic
  description: Raised lactate occurred in the severe infantile family. The male infant had lactate 7.8 mmol/L during acute illness; infection and respiratory compromise complicate attribution solely to the genetic disorder.
  phenotype_term:
    preferred_term: Increased circulating lactate concentration
    term:
      id: HP:0002151
      label: Increased circulating lactate concentration
  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: Blood gas analysis indicated compensatory respiratory alkalosis combined with metabolic acidosis with lactate at 7.8 mmol/L.
    explanation: A direct laboratory observation from one severely ill infant, not a disease-wide frequency estimate.
genetic:
- name: COQ6
  gene_term:
    preferred_term: COQ6
    term:
      id: hgnc:20233
      label: COQ6
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  variants:
  - name: c.249C>G (p.Tyr83Ter)
    description: Reported on NM_182476.3 in trans with the other nonsense allele in two severely affected infants. Truncation or nonsense-mediated decay was predicted; patient enzyme activity and CoQ10 content were not measured.
    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: The family study establishes segregation and predicted sequence consequences, not a measured complete loss of enzyme function.
  - name: c.1381C>T (p.Gln461Ter)
    description: NM_182476.3:c.1381C>T is predicted to remove seven C-terminal residues. It segregated in trans with p.Tyr83Ter in two severely affected infants, but residual function was not measured; it is not a demonstrated null allele.
    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: The family study establishes segregation and predicted sequence consequences, not a measured complete loss of enzyme function.
  - name: p.Gly255Arg and p.Ala353Asp
    description: Recurrent homozygous missense alleles in the founding families. Improved yeast assays support residual function. Cohort associations with earlier p.Gly255Arg and later p.Ala353Asp onset are probabilistic.
    evidence:
    - *id004
  - name: p.Gln461fsTer478 and p.Trp447Ter
    description: The founding compound-heterozygous pair includes a frameshift with residual activity in improved yeast assays. p.Trp447Ter can retain a structural contribution sufficient for vanillic-acid rescue in yeast.
    evidence:
    - reference: PMID:24140869
      reference_title: Effect of vanillic acid on COQ6 mutants identified in patients with coenzyme Q10 deficiency.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Interestingly this was observed also with the W447X truncating mutation, indicating that this should not be considered a null allele.
      explanation: Bypass rescue indicates retained structural contribution even though catalytic complementation was absent.
  - name: Korean cohort alleles
    description: NM_182476.3 alleles include an in-frame deletion, nonsense and missense variants. The small hearing series does not establish a general clinical treatment-selection rule.
    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: 'Four different causative COQ6 variants were identified either homozygous or compound heterozygous: c.189_191delGAA (p.Lys64del), c.484C>T (p.Arg162∗), c.686A>C (p.Gln229Pro), and c.782C>T (p.Pro261Leu).'
      explanation: These alleles were identified in twelve children and segregated with the familial phenotype.
  notes: Disease-associated variants include missense, in-frame deletion, nonsense, and frameshift alleles. Functional residual activity is allele- and assay-dependent; a truncating label alone does not prove a null allele. The same homozygous p.Ala353Asp genotype can produce different renal phenotypes within a family. Reported genotype-course associations are not deterministic predictors.
  evidence:
  - *id005
  - *id004
  - reference: PMID:30682496
    reference_title: 'Primary coenzyme Q10 Deficiency-6 (COQ10D6): Two siblings with variable expressivity of the renal phenotype.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Her older brother, who had sensorineural hearing loss with no renal or neurological involvement, had the same mutation in homozygous form.
    explanation: The affected sister and brother shared homozygous c.1058C>A; the brother lacked renal involvement at the reported observation.
- name: COQ8B candidate modifier
  relationship_type: MODIFIER
  notes: The p.His174Arg polymorphism is a proposed modifier, not an established determinant of penetrance or treatment response. Family observations suggested a milder renal course with Arg174, but the ten genotyped Korean patients showed no significant association with renal or auditory onset age.
  evidence:
  - reference: PMID:30682496
    reference_title: 'Primary coenzyme Q10 Deficiency-6 (COQ10D6): Two siblings with variable expressivity of the renal phenotype.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Family segregation and the co-occurrence of biallelic p.Arg174 of COQ8B in a brother with hearing loss implied that the interaction of the altered COQ8B with the mutant COQ6 alleviated the symptoms in this family.
    explanation: A hypothesis from one discordant sibling pair; this is not proof of a protective effect.
  - reference: PMID:36124066
    reference_title: Effects of CoQ10 Replacement Therapy on the Audiological Characteristics of Pediatric Patients with COQ6 Variants.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: there were no significant differences in the age of onset (P = 0.30, Kruskal-Wallis rank sum test) or the age of onset of hearing loss (P = 0.80, Kruskal-Wallis rank sum test) by COQ8B polymorphism status.
    explanation: No significant onset association was detected in the ten genotyped patients.
  gene_term:
    preferred_term: COQ8B
    term:
      id: hgnc:19041
      label: COQ8B
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: Early specialist-directed supplementation supplies CoQ10 despite the biosynthetic defect. The international study reported >50% proteinuria reduction in 10/15 informative pre-ESKD COQ6 patients and complete remission in 7/12. Eight matched treated children preserved kidney function, but only three reached five years of follow-up. These observational results support benefit without guaranteeing response. In the Korean hearing series, 3/7 longitudinally assessed patients had stability or improvement; hearing can worsen or first appear during therapy. Published doses and formulations vary.
  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
  evidence:
  - reference: url:https://dirros.openscience.si/Dokument.php?id=36087&lang=eng  # codespell:ignore dokument
    reference_title: https://dirros.openscience.si/Dokument.php?id=36087&lang=eng  # codespell:ignore dokument
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Complete remission (UPCR #0.2 mg/mg) a 6 (1/16) 58 (7/12) 16 (4/25)'
    explanation: 'Table 2 COQ6 column: seven of twelve informative pre-ESKD patients attained complete proteinuria remission. The table uses # for the less-than-or-equal symbol.'
  - reference: url:https://dirros.openscience.si/Dokument.php?id=36087&lang=eng  # codespell:ignore dokument
    reference_title: https://dirros.openscience.si/Dokument.php?id=36087&lang=eng  # codespell:ignore dokument
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Only 8 patients with COQ6 disease and preserved eGFR received CoQ 10 supplementation. All these patients retained their kidney function during observational period (median annualized loss, 0 ml/min per 1.73 m 2), 3 of them reached 5 years of follow-up with kidney survival of 100%, whereas all matched untreated control patients progressed to ESKD within 2.3 years
    explanation: Eight matched treated children preserved kidney function; only three reached five years of observation. Historical controls and nonrandom treatment assignment limit causal inference.
  - 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: Serial audiograms were available over >1 year after oral CoQ10 administration for 7 patients (14 ears)
    explanation: The longitudinal treatment-response denominator was seven patients, not all twelve.
  - 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 patients were divided into responders (3 patients) and nonresponders (4 patients) using the threshold shift and regression gradient criteria
    explanation: Stability or improvement was observed in three of seven patients; there was no untreated control group.
  - reference: url:https://dirros.openscience.si/Dokument.php?id=36087&lang=eng  # codespell:ignore dokument
    reference_title: https://dirros.openscience.si/Dokument.php?id=36087&lang=eng  # codespell:ignore dokument
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: '>50% Proteinuria reduction a 66 (14/21) 66 (10/15) 59 (19/32)'
    explanation: COQ6 middle column reports ten of fifteen informative patients before ESKD.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK410087/
    reference_title: Primary Coenzyme Q10 Deficiency Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Individuals with primary CoQ ... deficiency may respond well to high-dose oral CoQ ... supplementation (ranging from 5 to 50 mg/kg/day).
    explanation: GeneReviews gives a broad primary-CoQ-deficiency dose range, not an individually validated COQ6 regimen.
    quote_role: BACKGROUND
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK410087/
    reference_title: Primary Coenzyme Q10 Deficiency Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Treatment should be instituted as early as possible because it can limit disease progression and reverse some manifestations  ... Montini et al 2008 ... ; however, established severe neurologic and/or renal damage cannot be reversed.
    explanation: GeneReviews emphasizes early treatment and the limits imposed by established organ damage.
    quote_role: BACKGROUND
  - 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: therapy with a calcineurin inhibitor — cyclosporine A (CsA). Only partial remission was achieved
    explanation: The full case text reports partial cyclosporine benefit before CoQ10 was added.
  target_mechanisms:
  - target: Coenzyme Q10 Deficiency
    treatment_effect: BYPASSES
    description: Exogenous CoQ10 supplies the deficient product without repairing the enzyme.
    evidence: *id006
  notes: The Polish case reached remission after adding CoQ10 while cyclosporine was initially continued; cyclosporine had already produced partial remission. Concomitant antiproteinuric therapy and retrospective ascertainment complicate attribution. Genotype associations with hearing trajectories need replication.
- name: Antiproteinuric ACE Inhibition
  description: ACE inhibitors can accompany CoQ10 supplementation for proteinuria under nephrology care. A reported sibling had remission during antiproteinuric therapy before idebenone was initiated; this should not be attributed to idebenone. Treatment of proteinuria does not imply correction of the biosynthetic defect.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: enalapril
      term:
        id: CHEBI:4784
        label: enalapril
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK410087/
    reference_title: Primary Coenzyme Q10 Deficiency Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: ACE inhibitors may be used in combination w/CoQ ... supplementation in persons w/proteinuria.
    explanation: GeneReviews supportive renal management.
    quote_role: BACKGROUND
  - reference: PMID:32685349
    reference_title: COQ6 mutation in patients with nephrotic syndrome, sensorineural deafness, and optic atrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Angiotensin‐converting enzyme (ACE) inhibitor treatment was initiated, consisting of Enalapril.
    explanation: Enalapril was used in the younger brother for renal protein loss.
  target_mechanisms:
  - target: Proteinuria
    treatment_effect: INHIBITS
    description: Reduces urinary protein loss as supportive renal therapy.
- name: Hearing Aids and Audiological Rehabilitation
  description: Hearing aids, communication support and audiological follow-up are used according to hearing severity. Seven of eleven hearing-impaired children in the Korean cohort used hearing aids, with the other four receiving implants.
  therapeutic_modality: DEVICE
  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: 7 (63.6%) were using hearing aids and the remaining 4 (36.4%) had undergone unilateral or bilateral CI.
    explanation: The denominator is the eleven children with hearing loss at final assessment.
- name: Cochlear Implantation
  description: Cochlear implantation can improve auditory performance in selected patients with severe or profound hearing loss. Four children (seven ears) in the Korean cohort had mean CAP scores rising from 3.2 before implantation to 6.7 at twelve months and the last assessment; the results section reports mean follow-up of 61.9 months. This is a small uncontrolled series.
  treatment_term:
    preferred_term: cochlear device implantation
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  therapeutic_modality: DEVICE
  target_mechanisms:
  - target: Cochlear Dysfunction
    treatment_effect: BYPASSES
    description: Electrical stimulation supports hearing despite cochlear sensory dysfunction; it does not correct CoQ biosynthesis.
  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: 'In the latter 4 patients (7 ears), the average CAP score was 3.2 (SD: 2.7) at baseline, 6.2 (SD: 1.7) at 3 months postoperatively, 6.5 (SD: 1.2) at 6 months postoperatively, 6.7 (SD: 0.8) at 12 months postoperatively, and 6.7 (SD: 0.5) at the last evaluation (Figure 3). The average follow-up period was 61.9 months (range 24.5–135.5 months).'
    explanation: The results section supplies longitudinal auditory performance and follow-up for the four implanted patients.
- name: Dialysis
  description: Renal replacement therapy for advanced kidney failure. Peritoneal dialysis was used before transplantation in a reported child; dialysis does not restore endogenous CoQ10 biosynthesis.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: renal dialysis
    term:
      id: NCIT:C15221
      label: Dialysis
  target_mechanisms:
  - target: Progression to Kidney Failure
    treatment_effect: BYPASSES
    description: Provides solute and fluid removal when native renal function is inadequate.
  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: Kidney transplantation replaces failed renal function. Eight patients in the Korean cohort received grafts without nephropathy recurrence during reported follow-up. This outcome does not establish a zero lifetime recurrence risk or treat extrarenal COQ6 deficiency.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Kidney Transplantation
    term:
      id: NCIT:C15265
      label: Kidney Transplantation
  target_mechanisms:
  - target: Progression to Kidney Failure
    treatment_effect: BYPASSES
    description: Replaces renal function without correcting the systemic genetic defect.
  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: Eight patients progressed to kidney failure at a median of 7.2 (range 1.1–27.0) months after disease onset and underwent kidney transplantation without recurrence of nephropathy in the graft.
    explanation: The interval is from disease onset, not age at kidney failure.
- name: Idebenone
  description: An uncontrolled report describes improved visual acuity in one homozygous p.Ala353Asp adolescent treated after optic neuropathy, with residual optic atrophy and no hearing improvement. His younger brother also received idebenone, but renal remission preceded its initiation. These observations do not establish efficacy, prevention of future manifestations, or superiority to CoQ10. GeneReviews separately reports deterioration with short-chain quinones in some primary-CoQ-deficiency patients, so this case should not be treated as a general treatment recommendation.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: idebenone
      term:
        id: CHEBI:31687
        label: idebenone
  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: Optical examination performed after 2 years of treatment demonstrated an improved VA at 20/20 for the right eye and 20/25 + for the left.
    explanation: Visual improvement was observed during treatment in one patient; no controlled comparison was made.
  - 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 did not, however, improve the hearing loss.
    explanation: Hearing did not improve in the reported patients.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK410087/
    reference_title: Primary Coenzyme Q10 Deficiency Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Short-chain quinone analogs such as idebenone ... have been reported to cause clinical deterioration in individuals with CoQ ... deficiency
    explanation: GeneReviews caution concerns the broader primary CoQ-deficiency group and does not demonstrate deterioration in these two COQ6 cases.
    quote_role: BACKGROUND
  target_mechanisms:
  - target: Optic Nerve Involvement
    description: The clinical report investigated visual outcomes; whether the observed improvement was caused by treatment is unresolved.
- name: Experimental Vanillic Acid Bypass
  description: Vanillic acid provides a ring precursor already modified at the position requiring COQ6. It restored CoQ production, coupled respiration and ATP in COQ6-delta25 HEK293 cells, and rescued yeast expressing tested human variants. These are preclinical findings; efficacy, safety and dosing in patients with COQ6 deficiency are not established by these studies. The human-cell model may retain protein below assay detection, and off-target editing effects were not excluded.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: vanillic acid
      term:
        id: CHEBI:30816
        label: vanillic acid
  evidence:
  - reference: PMID:31379988
    reference_title: Vanillic Acid Restores Coenzyme Q Biosynthesis and ATP Production in Human Cells Lacking COQ6.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Treatment with VA can recover CoQ biosynthesis and ATP production.
    explanation: Rescue in edited human HEK293 cells, not a human clinical trial.
  - reference: PMID:24140869
    reference_title: Effect of vanillic acid on COQ6 mutants identified in patients with coenzyme Q10 deficiency.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: We detected a partial rescue of the phenotype in the presence of the analogues in all cases. VA seemed more efficient than 3,4 diHB, with effects already evident at 0.1 mM
    explanation: Yeast carrying the tested human COQ6 mutant alleles responded to ring-precursor analogues.
  target_mechanisms:
  - target: Deficient C5-Ring Hydroxylation in CoQ10 Biosynthesis
    treatment_effect: BYPASSES
    description: A premodified aromatic precursor bypasses the deficient hydroxylation step in experimental models.
    evidence:
    - reference: PMID:31379988
      reference_title: Vanillic Acid Restores Coenzyme Q Biosynthesis and ATP Production in Human Cells Lacking COQ6.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Treatment with VA can recover CoQ biosynthesis and ATP production.
      explanation: Rescue in edited human HEK293 cells, not a human clinical trial.
    - reference: PMID:24140869
      reference_title: Effect of vanillic acid on COQ6 mutants identified in patients with coenzyme Q10 deficiency.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: We detected a partial rescue of the phenotype in the presence of the analogues in all cases. VA seemed more efficient than 3,4 diHB, with effects already evident at 0.1 mM
      explanation: Yeast carrying the tested human COQ6 mutant alleles responded to ring-precursor analogues.
- name: Genetic Counseling and Family Testing
  description: For parents carrying pathogenic COQ6 variants, each pregnancy has a 25% probability of an affected child, 50% of a carrier and 25% of a child inheriting neither familial variant. Testing at-risk siblings can identify disease before further organ injury. Once familial variants are known, carrier testing and prenatal or preimplantation testing can be discussed.
  action_category: COUNSELING_INFORMATIONAL
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK410087/
    reference_title: Primary Coenzyme Q10 Deficiency Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: If both parents are known to be heterozygous for a primary CoQ ... deficiency-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
    explanation: GeneReviews recessive recurrence risks apply when both parents carry pathogenic variants.
    quote_role: BACKGROUND
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK410087/
    reference_title: Primary Coenzyme Q10 Deficiency Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: If the pathogenic variants in the family are known, molecular genetic testing can be used to clarify the genetic status of at-risk sibs.
    explanation: Early family testing identifies siblings who may benefit from prompt treatment.
    quote_role: BACKGROUND
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK410087/
    reference_title: Primary Coenzyme Q10 Deficiency Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Once the primary CoQ ... deficiency-related pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing for primary CoQ ... deficiency are possible.
    explanation: GeneReviews discusses reproductive testing after the familial molecular cause is established.
    quote_role: BACKGROUND
- name: Multisystem Surveillance and Support
  description: Follow renal function and proteinuria, hearing, vision and neurologic development, adapting assessment to the individual phenotype. Provide developmental, physical, nutritional and low-vision support when indicated. Baseline cardiac evaluation helps identify cardiac involvement.
  action_category: MONITORING
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK410087/
    reference_title: Primary Coenzyme Q10 Deficiency Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Urine analysis for proteinuria and assessment of kidney function ... Ophthalmologic evaluation and electroretinogram for evidence of retinopathy and to determine need for low vison services ... Hearing evaluation with attention to possible sensorineural hearing loss
    explanation: GeneReviews surveillance addresses renal, visual and auditory disease.
    quote_role: BACKGROUND
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK410087/
    reference_title: Primary Coenzyme Q10 Deficiency Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields
    explanation: General primary-CoQ-deficiency supportive management.
    quote_role: BACKGROUND
diagnosis:
- name: Molecular genetic testing in steroid-resistant nephrotic syndrome
  description: Identify biallelic pathogenic COQ6 variants using an appropriate nephrotic-syndrome or mitochondrial-disease panel, or exome/genome analysis, with segregation and variant interpretation. Hearing loss strengthens suspicion but is not required. A single variant or an isoform-specific premature stop is not sufficient to establish this recessive diagnosis.
  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.
  - reference: PMID:31379988
    reference_title: Vanillic Acid Restores Coenzyme Q Biosynthesis and ATP Production in Human Cells Lacking COQ6.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: One of them NM_182480:c.41G>A p.(Trp14∗) occurs with a minor allelic frequency of 0.05 in Africans and is present also in the homozygous state in apparently normal individuals.
    explanation: The 2019 paper challenges pathogenic interpretation of the inactive-isoform variant reported in the 2018 FSGS paper.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK410087/
    reference_title: Primary Coenzyme Q10 Deficiency Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Comprehensive ... genomic testing ... does not require the clinician to determine which gene is likely involved. Exome sequencing is most commonly used; genome sequencing is also possible.
    explanation: GeneReviews describes genomic alternatives when the phenotype does not identify a specific gene.
    quote_role: BACKGROUND
- name: Renal biopsy showing focal segmental glomerulosclerosis
  description: Kidney biopsy can characterize glomerular injury, including FSGS and abnormal podocyte mitochondria. These findings are supportive but neither universal nor specific for COQ6 deficiency; molecular testing establishes the etiology.
  diagnosis_term:
    preferred_term: biopsy of kidney
    term:
      id: NCIT:C51699
      label: Kidney Biopsy
  evidence:
  - *id001
  - 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: Patient 10 evidenced no mitochondrial abnormality, and patient 11 was not evaluated because the specimen was inadequate.
    explanation: A normal or inadequate electron-microscopy assessment does not exclude molecularly confirmed disease.
- name: CoQ10 Biochemistry and Respiratory-Chain Assessment
  description: Tissue or cell CoQ10 and respiratory-chain assays can help investigate uncertain molecular findings, but cannot by themselves distinguish primary from secondary deficiency. Plasma CoQ10 reflects intake and is not a reliable diagnostic measure. Normal muscle or fibroblast findings do not exclude a genetic diagnosis.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK410087/
    reference_title: Primary Coenzyme Q10 Deficiency Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Plasma CoQ ... levels are not useful for the diagnosis of primary CoQ ... deficiency because they reflect dietary intake rather than endogenous CoQ ... production
    explanation: GeneReviews explains why plasma concentrations are unsuitable as a stand-alone diagnostic test.
    quote_role: BACKGROUND
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK410087/
    reference_title: Primary Coenzyme Q10 Deficiency Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: there are individuals with genetically proven CoQ ... deficiency who had normal CoQ ... levels in both muscle and cultured skin fibroblasts
    explanation: Normal tissue measurements do not exclude genetic CoQ deficiency.
    quote_role: BACKGROUND
  - reference: PMID:32685349
    reference_title: COQ6 mutation in patients with nephrotic syndrome, sensorineural deafness, and optic atrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Exploration of the mitochondrial respiratory chain on the muscular biopsy was normal, including the combined activities of complexes I + III and II + III.
    explanation: Normal muscle respiratory-chain testing was reported in a homozygous COQ6 patient.
progression:
- phase: Variable Renal and Extrarenal Course
  notes: Kidney disease often starts in infancy or childhood, but progression is not inevitable in every observed patient. The international cohort included 27/48 patients with ESKD at last observation and one with isolated hearing loss without renal symptoms through age seventeen. Treatment and ascertainment influence these estimates. Hearing may precede or follow renal disease and may progress despite CoQ10; later optic or neurologic manifestations warrant follow-up. Among those who reached ESKD in the international cohort, median age at ESKD was 3.4 years (interquartile range 1.7–6.3).
  evidence:
  - reference: url:https://dirros.openscience.si/Dokument.php?id=36089&lang=eng  # codespell:ignore dokument
    reference_title: https://dirros.openscience.si/Dokument.php?id=36089&lang=eng  # codespell:ignore dokument
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: ESKD 50.8 (32/63) 56.2 (27/48) 66.4 (93/140)
    explanation: COQ6 middle column reports last-observation ESKD, not an untreated lifetime risk.
  - 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: Eight patients progressed to kidney failure at a median of 7.2 (range 1.1–27.0) months after disease onset and underwent kidney transplantation without recurrence of nephropathy in the graft.
    explanation: The interval is from disease onset, not age at kidney failure.
  - reference: PMID:30682496
    reference_title: 'Primary coenzyme Q10 Deficiency-6 (COQ10D6): Two siblings with variable expressivity of the renal phenotype.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Her older brother, who had sensorineural hearing loss with no renal or neurological involvement, had the same mutation in homozygous form.
    explanation: The affected sister and brother shared homozygous c.1058C>A; the brother lacked renal involvement at the reported observation.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK410087/
    reference_title: Primary Coenzyme Q10 Deficiency Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: If not treated with supplementation of high-dose oral CoQ ... SRNS usually progresses to end-stage kidney disease (ESKD).
    explanation: GeneReviews describes the usual untreated renal trajectory across primary CoQ deficiencies, including COQ6; usually does not mean inevitable for every person.
    quote_role: BACKGROUND
  - reference: url:https://dirros.openscience.si/Dokument.php?id=36089&lang=eng  # codespell:ignore dokument
    reference_title: https://dirros.openscience.si/Dokument.php?id=36089&lang=eng  # codespell:ignore dokument
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Median age at ESKD, yr 2.5 (0.7 – 5.8) 3.4 (1.7 – 6.3) 13 (10 – 16.7)
    explanation: Table 1 middle column describes COQ6 patients who reached ESKD, not the age by which every affected patient will do so.
experimental_models:
- name: Murine Podocyte COQ6 Knockdown
  experimental_model_type: CELL_LINE
  publication: PMID:21540551
  description: Stable knockdown in immortalized mouse podocytes reduced growth, depolarized mitochondria and increased caspase-9/3 activity; 50 micromolar CoQ10 for 48 hours reduced caspase activity.
  modeled_mechanisms:
  - target: Podocyte Apoptosis
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: Models COQ6-dependent podocyte survival and partial CoQ10 rescue.
    limitations: Knockdown and culture conditions do not reproduce patient alleles or intact glomerular architecture.
    evidence:
    - reference: PMID:21540551
      reference_title: COQ6 mutations in human patients produce nephrotic syndrome with sensorineural deafness.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Coq6 downregulation in cultured mouse podocytes induced apoptosis that was diminished by CoQ 10 treatment.
      explanation: Figure 5A-C demonstrates rescue in cultured murine podocytes. The zebrafish arm did not test rescue.
    - 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: the number of Annexin V+/PI+ and V+/PI− cells was significantly increased in the si-COQ6 group.
      explanation: Flow cytometry independently supports increased apoptosis after mouse podocyte knockdown.
- name: Murine Podocyte siRNA Cytoskeleton and Redox Assays
  experimental_model_type: CELL_LINE
  publication: PMID:30425193
  description: Transient COQ6 siRNA in mouse podocytes measures nephrin/F-actin abundance, actin organization, MitoSOX and apoptosis. Its experimental findings are separable from the paper's unsupported interpretation of a human isoform-specific variant.
  modeled_mechanisms:
  - target: Podocyte Cytoskeletal Disorganization
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: Reduced nephrin/F-actin and disorganized actin after knockdown.
    limitations: No time-resolved causal order among oxidation, cytoskeletal changes and death was established.
    evidence:
    - 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: the expression levels of both proteins were significantly lower in the si-RNA-COQ6 group than in the control group
      explanation: The measured proteins were nephrin and F-actin in mouse podocytes.
    - 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: F-actin immunofluorescence in the si-COQ6 group was irregularly distributed
      explanation: Actin organization was disturbed after knockdown; timing relative to ROS and apoptosis was not resolved.
  - target: Altered Cellular Redox State
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: MitoSOX signal increased after knockdown.
    limitations: This assay does not establish a universal redox phenotype in all cells or tissues.
    evidence:
    - 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: ROS levels were increased when the MPCs were incubated with si-COQ6 compared to the normal group.
      explanation: Mouse podocyte knockdown increased mitochondrial MitoSOX signal; the patient variant claim in this paper is not used as clinical genetic evidence.
- name: COQ6-Delta25 HEK293 Cells
  experimental_model_type: CELL_LINE
  publication: PMID:31379988
  description: CRISPR editing removed 25 amino acids from a FAD-binding region. Immunoblotting detected no residual protein; endogenous CoQ synthesis, II+III activity, ATP and coupled respiration fell. Vanillic acid restored biochemical function.
  modeled_mechanisms:
  - target: Coenzyme Q10 Deficiency
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: Models impaired endogenous synthesis and vanillic-acid bypass rescue.
    limitations: Engineered in-frame deletion; protein below detection and off-target effects were not excluded. Cells are not patient podocytes.
    evidence:
    - reference: PMID:31379988
      reference_title: Vanillic Acid Restores Coenzyme Q Biosynthesis and ATP Production in Human Cells Lacking COQ6.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Incorporation of 14C-labelled 4-HB was virtually undetectable
      explanation: COQ6-delta25 HEK293 cells showed virtually absent endogenous CoQ10 synthesis despite residual CoQ10 acquired from culture medium.
    - reference: PMID:31379988
      reference_title: Vanillic Acid Restores Coenzyme Q Biosynthesis and ATP Production in Human Cells Lacking COQ6.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Treatment with VA can recover CoQ biosynthesis and ATP production.
      explanation: Rescue in edited human HEK293 cells, not a human clinical trial.
  - target: Cellular ATP Deficiency
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: ATP deficiency was reversed with vanillic acid.
    limitations: Cellular rescue is not evidence of clinical efficacy or safety.
    evidence:
    - reference: PMID:31379988
      reference_title: Vanillic Acid Restores Coenzyme Q Biosynthesis and ATP Production in Human Cells Lacking COQ6.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: ATP levels were markedly reduced in COQ6∆25 cells, but after VA supplementation, they were virtually normal
      explanation: Cellular ATP deficiency and bypass rescue were measured in the HEK293 model, not in patient organs.
animal_models:
- name: coq6 Morpholino Zebrafish
  species: Zebrafish
  genotype: Transient coq6 morpholino knockdown
  publication: PMID:21540551
  description: Translation- and splice-blocking morpholinos increased apoptosis in embryonic heads and trunks at 28 hours after fertilization. No CoQ10 rescue condition or podocyte-specific renal phenotype was demonstrated.
  modeled_mechanisms:
  - target: Podocyte Apoptosis
    relationship: RECAPITULATES
    fidelity: LOW
    description: Supports a conserved association between COQ6 depletion and apoptosis in a whole vertebrate.
    limitations: The measured head/trunk apoptosis is not renal or podocyte-specific, so fidelity to the human kidney lesion is low. No treatment rescue was tested.
    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: Figure 5D-F reports the zebrafish knockdown phenotype.
- name: Yeast coq6 Deletion Complemented with Human Alleles
  species: Saccharomyces cerevisiae
  genotype: coq6 deletion with wild-type or mutant human COQ6 constructs
  publication: PMID:24140869
  description: Respiratory growth and CoQ content characterize residual activity of human variants and the effects of vanillic acid or 3,4-dihydroxybenzoate. Expression system and promoter strength influence complementation.
  modeled_mechanisms:
  - target: Deficient C5-Ring Hydroxylation in CoQ10 Biosynthesis
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: Tests allele function and precursor bypass.
    limitations: Yeast CoQ-complex stability requirements differ from the human-cell model; residual activity is assay-dependent and does not establish patient severity.
    evidence:
    - reference: PMID:24140869
      reference_title: Effect of vanillic acid on COQ6 mutants identified in patients with coenzyme Q10 deficiency.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: These data suggest that the human G255R, A353D, Y412C and Q461sf478X mutations are hypomorphic since the corresponding yeast Coq6 mutants display residual activity.
      explanation: Improved yeast complementation assays detect residual activity missed by the initial assay; these results cannot define every patient allele.
    - reference: PMID:24140869
      reference_title: Effect of vanillic acid on COQ6 mutants identified in patients with coenzyme Q10 deficiency.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: We detected a partial rescue of the phenotype in the presence of the analogues in all cases. VA seemed more efficient than 3,4 diHB, with effects already evident at 0.1 mM
      explanation: Yeast carrying the tested human COQ6 mutant alleles responded to ring-precursor analogues.
discussions:
- discussion_id: coq6_isoform_variant_interpretation
  kind: INTERPRETATION
  prompt: Does the reported p.Trp14* variant establish COQ6-related nephropathy?
  attaches_to:
  - genetic#COQ6
  - diagnosis#Molecular genetic testing in steroid-resistant nephrotic syndrome
  rationale: The 2018 FSGS paper reported a heterozygous NM_182480:c.41G>A p.Trp14* variant. The 2019 study found that this transcript encodes inactive isoform c and noted the variant in apparently healthy homozygotes. These observations undermine attribution of that patient's FSGS to this variant, while leaving the independently performed COQ6-knockdown experiments informative.
  evidence:
  - reference: PMID:31379988
    reference_title: Vanillic Acid Restores Coenzyme Q Biosynthesis and ATP Production in Human Cells Lacking COQ6.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Overall, these observations indicate that COQ6 isoforms b and c are not essential and are not involved in CoQ deficiency.
    explanation: The isoform study explains why a premature stop in the alternative first exon need not disrupt the active enzyme.
- discussion_id: coq6_organ_selectivity
  kind: KNOWLEDGE_GAP
  prompt: Which cochlear and optic cell lesions determine the sensory phenotype?
  attaches_to:
  - pathophysiology#Cochlear Dysfunction
  - pathophysiology#Optic Nerve Involvement
  rationale: The cited rat study localizes COQ6 to several cochlear compartments but does not demonstrate which fails first. Podocyte rescue and nonspecific zebrafish embryonic apoptosis cannot establish the sensory mechanism. Clinical hearing and visual outcomes therefore should not be explained solely by tissue expression or transferred from renal models.
- discussion_id: coq6_treatment_response_variability
  kind: KNOWLEDGE_GAP
  prompt: How do genotype, treatment timing and concurrent therapy influence response?
  attaches_to:
  - treatments#Oral Coenzyme Q10 Replacement
  - genetic#COQ8B candidate modifier
  rationale: The small hearing cohort reported a poorer trajectory with p.Gln229Pro, while apparent benefits for p.Lys64del and p.Pro261Leu were not statistically significant. Historical renal comparisons favor CoQ10 but are not randomized, and concomitant therapies complicate attribution. COQ8B modifier observations remain unconfirmed. These findings do not support delaying treatment based on a predicted poor-response genotype.
notes: This entry covers the variable biallelic COQ6-deficiency spectrum under its established oto-renal disease name. Hearing loss and complete nephrotic syndrome are not obligatory at every age. Cohort counts describe ascertained patients and are not population prevalence estimates. Clinical management and experimental rescue evidence are distinguished.
synonyms:
- Primary coenzyme Q10 deficiency 6
- COQ10D6
- COQ6-related nephropathy
references:
- reference: PMID:21540551
  title: COQ6 mutations in human patients produce nephrotic syndrome with sensorineural deafness.
- reference: PMID:24140869
  title: Effect of vanillic acid on COQ6 mutants identified in patients with coenzyme Q10 deficiency.
- 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:30682496
  title: 'Primary coenzyme Q10 Deficiency-6 (COQ10D6): Two siblings with variable expressivity of the renal phenotype.'
- reference: PMID:31379988
  title: Vanillic Acid Restores Coenzyme Q Biosynthesis and ATP Production in Human Cells Lacking COQ6.
- 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.
- reference: url:https://dirros.openscience.si/Dokument.php?id=36087&lang=eng  # codespell:ignore dokument
  title: https://dirros.openscience.si/Dokument.php?id=36087&lang=eng  # codespell:ignore dokument
  findings:
  - statement: Full text of Drovandi et al., Oral Coenzyme Q10 supplementation leads to better preservation of kidney function in steroid-resistant nephrotic syndrome due to primary Coenzyme Q10 deficiency (PMID:35643375; DOI:10.1016/j.kint.2022.04.029). Retrospective treatment cohort with matched historical controls, not a randomized trial.
- reference: url:https://dirros.openscience.si/Dokument.php?id=36089&lang=eng  # codespell:ignore dokument
  title: https://dirros.openscience.si/Dokument.php?id=36089&lang=eng  # codespell:ignore dokument
  findings:
  - statement: Full text of Drovandi et al., Variation of the clinical spectrum and genotype-phenotype associations in Coenzyme Q10 deficiency associated glomerulopathy (PMID:35483523; DOI:10.1016/j.kint.2022.02.040). COQ6-specific results use the middle table column; this is an ascertained mixed-treatment cohort.
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK410087/
  title: Primary Coenzyme Q10 Deficiency Overview - GeneReviews® - NCBI Bookshelf
  tags:
  - GeneReviews
  findings:
  - statement: Full Primary Coenzyme Q10 Deficiency Overview, including diagnostic, management, surveillance and genetic-counseling sections.
- reference: PMID:28125198
  title: Primary Coenzyme Q(10) Deficiency Overview.
  tags:
  - GeneReviews
- reference: PMID:35483523
  title: Variation of the clinical spectrum and genotype-phenotype associations in Coenzyme Q10 deficiency associated glomerulopathy.
- reference: PMID:35643375
  title: Oral Coenzyme Q10 supplementation leads to better preservation of kidney function in steroid-resistant nephrotic syndrome due to primary Coenzyme Q10 deficiency.
📚

References & Deep Research

References

16
PMID:21540551
COQ6 mutations in human patients produce nephrotic syndrome with sensorineural deafness.
No top-level findings curated for this source.
PMID:24140869
Effect of vanillic acid on COQ6 mutants identified in patients with coenzyme Q10 deficiency.
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:30682496
Primary coenzyme Q10 Deficiency-6 (COQ10D6): Two siblings with variable expressivity of the renal phenotype.
No top-level findings curated for this source.
PMID:31379988
Vanillic Acid Restores Coenzyme Q Biosynthesis and ATP Production in Human Cells Lacking COQ6.
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.
url:https://dirros.openscience.si/Dokument.php?id=36087&lang=eng
https://dirros.openscience.si/Dokument.php?id=36087&lang=eng
1 finding
Full text of Drovandi et al., Oral Coenzyme Q10 supplementation leads to better preservation of kidney function in steroid-resistant nephrotic syndrome due to primary Coenzyme Q10 deficiency (PMID:35643375; DOI:10.1016/j.kint.2022.04.029). Retrospective treatment cohort with matched historical controls, not a randomized trial.
url:https://dirros.openscience.si/Dokument.php?id=36089&lang=eng
https://dirros.openscience.si/Dokument.php?id=36089&lang=eng
1 finding
Full text of Drovandi et al., Variation of the clinical spectrum and genotype-phenotype associations in Coenzyme Q10 deficiency associated glomerulopathy (PMID:35483523; DOI:10.1016/j.kint.2022.02.040). COQ6-specific results use the middle table column; this is an ascertained mixed-treatment cohort.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK410087/
Primary Coenzyme Q10 Deficiency Overview - GeneReviews® - NCBI Bookshelf
1 finding
Full Primary Coenzyme Q10 Deficiency Overview, including diagnostic, management, surveillance and genetic-counseling sections.
PMID:28125198
Primary Coenzyme Q(10) Deficiency Overview.
No top-level findings curated for this source.
PMID:35483523
Variation of the clinical spectrum and genotype-phenotype associations in Coenzyme Q10 deficiency associated glomerulopathy.
No top-level findings curated for this source.
PMID:35643375
Oral Coenzyme Q10 supplementation leads to better preservation of kidney function in steroid-resistant nephrotic syndrome due to primary Coenzyme Q10 deficiency.
No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (2)

Review COQ6 clinical variability, allele function, treatment evidence and experimental models against full texts · 2026-10-03T07:22:45Z · View source

Reviewed the original entry, matching deep-research report and citation inventory, all eight original citations, full GeneReviews, both international Drovandi cohort papers, and primary isoform and bypass studies. Corrected unsupported complete-null and deterministic genotype claims, immunosuppression and inevitable-progression assertions, hearing-response denominator, peritoneal dialysis wording, rat expression extrapolation and zebrafish rescue attribution. Split cellular findings without inventing temporal ordering. Added cohort-specific clinical counts, developmental and sensory findings, candidate COQ8B modifier with negative association result, genetic counseling, surveillance, biochemical diagnostic limitations, and yeast/HEK293 vanillic-acid evidence. Distinguished the challenged heterozygous inactive-isoform p.Trp14* patient claim from valid mouse podocyte knockdown experiments. Recovered PMID31379988 full text on retry; PMID30682496 remains abstract-only. Research completeness dimensions covered: phenotypes, mechanism, therapy, genetics, diagnostics and references; no separate mechanistic subtype or disease-specific trial was established by the consumed sources. Retained limitations on uncontrolled clinical treatment observations and preclinical rescue. Removed curation-process notes from the disease narrative. Validation: schema and ontology validation passed; all 131 snippets and 144 titles verified against the reference cache. Two targeted disorder tests passed. GeneReviews baseline is TAGGED.

Create: COQ6-Related Steroid-Resistant Nephrotic Syndrome with Sensorineural Deafness · 2026-08-27T19:30:26Z · View source

Curated COQ6-related SRNS with SNHL (MONDO:0013836) from a claude_code deep-research report plus the GeneReviews primary CoQ10 deficiency overview PMID:28125198. Eight pathophysiology nodes, one connected component. The entry treats steroid resistance as part of the causal chain rather than as an adjective in the name: the lesion is a biosynthetic deficiency, so immunosuppression has nothing to act on, and an INTERPRETATION discussion draws out the clinical consequence that resistance should prompt a metabolic question rather than escalation. Tissue selectivity is curated from the localization result showing COQ6 in podocytes and stria vascularis, which is why an oto-renal phenotype rather than a general mitochondrial one. CoQ10 replacement carries three target_mechanisms with different effects: BYPASSES the deficiency node, RESTORES the nephrotic syndrome, MODULATES the hearing loss at a 42.9% response rate graded PARTIAL. A KNOWLEDGE_GAP records that genotype and treatment timing are both offered as explanations for variable response and no reported series separates them. Two corrections to my own prior: the claim issue predicted the deafness would generally not reverse, but the source reports stabilization or improvement in nearly half, so the entry follows the source; and GO:0006744 was initially placed in molecular_functions when it is a biological process, caught by term validation and moved, with GO:0004497 and GO:0071949 used for the monooxygenase and FAD-binding functions. PMID:26808124 is cited twice on one node with different evidence_source values because one sentence reports biochemistry and the other molecular dynamics. Validation: 22/22 snippets verified plus an independent raw-substring re-check; schema, terms, entity-refs, duplicate-keys and reference titles all pass.

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

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