Leber-like Hereditary Optic Neuropathy, Autosomal Recessive 1

Mendelian MONDO:0958183 Pathograph 15 Show in embeddings browser Leber Hereditary Optic Neuropathy Mitochondrial Disease

Leber-like hereditary optic neuropathy, autosomal recessive 1 (LHONAR1, arLHON) is caused by biallelic variants in the nuclear gene DNAJC30. It matters because of what it overturned. Leber hereditary optic neuropathy had been the textbook example of maternal transmission, defined since 1988 by point mutations in mitochondrial DNA, and a patient with a convincing LHON phenotype and no mtDNA mutation had no diagnosis to be given. In 2021 a single-exon nuclear gene accounted for 33 such patients from 29 families, and the resulting entity recapitulated every hallmark of the mitochondrial form: subacute painless bilateral central visual loss in young adults, incomplete penetrance, marked male predominance, and responsiveness to idebenone. LHON is therefore a clinical description independent of the mode of transmission, and the entity divides into mtLHON and arLHON. The mechanism is not a defect of complex I structure or assembly, which is what mtDNA LHON and the nuclear complex I subunit deficiencies produce. DNAJC30 is a chaperone that services complex I after it has been built. Subunits of the complex I N module sit closest to the site of electron entry and take the highest oxidative damage, and the cell exchanges them individually rather than rebuilding the whole enzyme, which is far cheaper in energy. DNAJC30 is what makes that exchange happen. Tracking protein turnover in patient fibroblasts and in a DNAJC30 knockout cell line showed the turnover of exactly those N module subunits to be selectively slowed, so damaged subunits are retained and the cell accumulates assembled complex I of reduced catalytic quality. This is a disease of impaired repair rather than of impaired construction, and it was the first such disease described for a respiratory chain complex. The genetics are dominated by one allele. The missense variant c.152A>G p.(Tyr51Cys) is an Eastern European founder allele carried by the great majority of patients, common enough in Russia, Poland, Ukraine and Romania that DNAJC30 accounts for a fifth of molecularly solved LHON in a Moscow centre and outnumbers the mitochondrial form in a Polish series. Rarer alleles include p.(Pro78Ser), p.(Leu101Gln), p.(His77del), the nonsense p.(Glu204*) and p.(Trp8*), and the frameshift p.(Ser44ValfsTer8). Because the gene has a single exon, Sanger sequencing of DNAJC30 is cheap, and the practical recommendation is to sequence it in parallel with the full mtDNA in any unsolved LHON. Two features complicate the picture and are curated here as open questions rather than settled mechanism. The first is that a recessive disease should not show incomplete penetrance or a sex bias, and this one shows both, more strongly than the mitochondrial form does; DNAJC30 expression does not differ between sexes, so the modifier lies downstream and is unidentified. The second is a Leigh syndrome branch. A minority of patients, including some homozygous for the same founder allele, present instead with dystonia, ataxia and bilateral basal ganglia necrosis, with or without optic involvement, and in the one reported case treated with idebenone the drug did not arrest that course. Whether a second hit in another complex I gene explains the branch is proposed but not established.

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Mappings
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Inheritance
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Pathophys.
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Phenotypes
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Gaps
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Pathograph
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Genes
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Variants
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Medical Actions
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Differentials
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Models
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References
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Deep Research
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Classifications

Harrison's Part
NEUROLOGIC ENDOCRINOLOGY METABOLISM GENETICS ENVIRONMENT DISEASE
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Mappings

MONDO
MONDO:0958183 Leber-like hereditary optic neuropathy, autosomal recessive 1
skos:exactMatch MONDO
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Inheritance

1
Autosomal recessive inheritance HP:0000007
Biallelic DNAJC30 variants, most often homozygosity for the p.(Tyr51Cys) founder allele but also compound heterozygosity with a second rare allele. Segregation and allelic cloning have confirmed true biallelism in compound heterozygotes. The recessive mode is the whole point of the entity: it removes the maternal family history that had been treated as a prerequisite for a LHON diagnosis, and it changes recurrence counselling from maternal-line risk to a one-in-four sibling risk.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:33465056 SUPPORT Human Clinical
"We describe biallelic mutations in a nuclear encoded gene, DNAJC30, in 33 unsolved patients from 29 families and establish an autosomal recessive mode of inheritance for LHON (arLHON), which to date has been a prime example of a maternally inherited disorder."
The founding demonstration of autosomal recessive transmission for a phenotype previously defined as maternally inherited.
PMID:35091433 SUPPORT Human Clinical
"Segregation and allelic cloning confirmed the expected recessive mode of inheritance and true biallelism."
Independent confirmation that the two variants in compound heterozygotes lie on opposite alleles.
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Discussions and Knowledge Gaps

2
Why does a recessive disease with a defined biallelic genotype show incomplete penetrance and a strong male predominance, and what is the modifier?
KNOWLEDGE GAP OPEN arlhon_sex_dependent_incomplete_penetrance
Attached to
pathophysiology#DNAJC30 Loss of Function pathophysiology#Retinal Ganglion Cell Degeneration
This is the entity's most conspicuous anomaly. Incomplete penetrance and a sex bias are expected in the mitochondrial form and are among the oldest puzzles in LHON, but they are not what a biallelic recessive genotype normally produces. Here they are not merely present but more extreme than in the mitochondrial form: roughly 97 percent of homozygous males but only 43 percent of homozygous females expressed a phenotype in the founding cohort, a ten to one ratio of affected males to affected females against five to one in mtLHON. Asymptomatic homozygous carriers exist and have been confirmed in a second cohort. Three explanations were tested and eliminated in the founding study. The amount of DNAJC30 protein and message does not differ by sex, so it is not a dosage effect on the chaperone itself. Whole exome data from patients carried no rare biallelic variants in other complex I subunit or assembly genes, so a second nuclear locus was not detected. No rare mtDNA variants were found either. The one positive association is with mitochondrial haplogroup J, which was over-represented among arLHON patients relative to the European background, mirroring its role in the mitochondrial form; but that is a partial and correlative finding on small numbers, not a mechanism. The gnomAD allele frequency of the founder variant is equal in males and females, which is the observation that makes the sex bias a downstream phenomenon rather than an ascertainment artefact. So the modifier acts somewhere between having the genotype and losing vision, and it is unidentified. Note also that the penetrance figures are acknowledged overestimates, drawn from a small number of pedigrees with few unaffected siblings of known carrier status.
Proposed experiments
Population-based penetrance estimate from unselected founder-population biobank genotypes
arlhon_biobank_penetrance
Identify p.(Tyr51Cys) homozygotes in an unselected Eastern European biobank rather than through affected probands, and determine visual status and age. This is the design that removes the ascertainment bias the founding authors flag, and it is the only way to get a penetrance figure that is not an overestimate.
Hormonal and oxidative-stress modifier testing in patient-derived retinal ganglion cells
arlhon_rgc_modifier_assay
Differentiate retinal ganglion cells from patient and control induced pluripotent stem cells and test whether oestrogen exposure, or graded oxidative challenge, shifts the complex I N module turnover defect or cell survival. A sex-hormone effect acting downstream of the chaperone would fit both the equal allele frequency between sexes and the absence of a sex difference in DNAJC30 expression.
Show evidence (4 references)
PMID:33465056 SUPPORT Human Clinical
"In total, 30 of 31 (96.8%) homozygous carrier males and just 3 of 7 (42.9%) homozygous carrier females express a phenotype."
Quantifies the sex-dependent penetrance that this gap is about.
PMID:33465056 SUPPORT Human Clinical
"Therefore, akin to mtLHON, the factor influencing sex-dependent penetrance remains elusive at this time."
The authors' explicit statement that the modifier is unidentified.
PMID:33465056 SUPPORT Human Clinical
"we measured DNAJC30 expression on the RNA and protein level in over 75 and 100 controls, respectively; however, we did not detect a significant difference"
Eliminates chaperone dosage as the explanation for the sex bias.
+ 1 more reference
What decides whether a patient with biallelic DNAJC30 variants develops an isolated optic neuropathy or Leigh syndrome, and does that also explain why idebenone helps the first and not the second?
KNOWLEDGE GAP OPEN arlhon_leigh_branch_determinant
Attached to
pathophysiology#Subacute Necrotizing Encephalopathy of Basal Ganglia and Brainstem pathophysiology#Reduced Complex I-Dependent Respiration and ATP Output
The same p.(Tyr51Cys) homozygous genotype produces isolated adult-onset optic neuropathy in most patients and childhood Leigh syndrome in a few, and the two branches respond to treatment differently. The leading hypothesis is digenic: a heterozygous variant in another complex I gene supplies a second hit that tips the phenotype. That hypothesis has direct support in one report, where two siblings with the Leigh presentation carried a novel heterozygous NDUFS8 variant in addition to their DNAJC30 alleles. The evidence against treating it as settled is equally direct. In the one DNAJC30 Leigh patient given idebenone, reanalysis of genome sequencing and mtDNA found no second variant in any gene linked to Leigh syndrome, LHON or the respiratory chain complexes, and the drug failed. The authors offer two alternatives that the data cannot distinguish: an undetected second hit in a gene not yet associated with mitochondrial disease or missed because filtering targets rare variants, or a genuine difference in cellular biology between the two phenotypes that has nothing to do with a second locus. Truncating alleles complicate the picture further. Both patients homozygous for the p.(Trp8*) nonsense variant had a Leigh-like course with markedly earlier onset than the missense cohort, which suggests residual chaperone function may matter independently of any second gene. Whether allele severity and a second hit are competing or additive explanations is untested.
Proposed experiments
Systematic second-hit search across all DNAJC30 Leigh cases
arlhon_leigh_second_hit_search
Apply uniform genome sequencing with relaxed allele-frequency filtering, plus copy-number and mitochondrial heteroplasmy analysis, to every reported DNAJC30 Leigh patient and to matched DNAJC30 optic-only patients. The digenic hypothesis predicts an excess of heterozygous complex I variants in the Leigh group; the current evidence for it rests on a single sibling pair.
Genotype-stratified complex I repair assay across the allelic series
arlhon_allelic_series_repair_assay
Measure N module subunit turnover and complex I activity in cells carrying missense, in-frame deletion and truncating DNAJC30 alleles, and test whether residual repair capacity separates the optic-only from the Leigh cases independently of any second variant.
Show evidence (3 references)
PMID:35861300 SUPPORT Human Clinical
"Identification of a candidate heterozygous variant in NDUFS8 supports the hypothesis of digenic inheritance."
The positive evidence for the digenic hypothesis, in two siblings with the Leigh presentation.
PMID:39132756 REFUTE Human Clinical
"Re-analysis of GS and mtDNA sequencing data showed no other potential variants in genes linked with LS, LHON, or the respiratory chain enzyme complexes."
A Leigh patient in whom no second hit was found despite a targeted search, which is why the digenic hypothesis cannot be treated as the general explanation.
PMID:37397562 SUPPORT Human Clinical
"In contrast, our patients experienced markedly earlier onset of symptoms containing rapid progression of bilateral optic atrophy and severe motor difficulties"
Suggests allele severity as a competing explanation, since both patients with the complete loss-of-function nonsense allele had earlier and more severe disease than the missense cohort.
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Pathophysiology

8
DNAJC30 Loss of Function
DNAJC30 is a single-exon nuclear gene encoding a DnaJ/HSP40 family co-chaperone expressed mainly in neurons. Disease alleles are biallelic and are dominated by one founder missense change, c.152A>G p.(Tyr51Cys), which lies in the J domain; the rarer p.(Pro78Ser), p.(Leu101Gln) and p.(His77del) alleles lie in the same domain, while p.(Glu204*) truncates upstream of the transmembrane domain. Truncating alleles are informative about the mechanism because they abolish the protein outright: the p.(Trp8*) nonsense allele produced no detectable DNAJC30 protein in transfected cells, so the disease state is loss of the chaperone, not a gain of an aberrant activity. Heterozygous carriers, including carriers of outright loss-of-function alleles in population databases, are healthy.
DNAJC30 hgnc:16410 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves DNAJC30 (hgnc:16410). hgnc:16410 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context variant_origin: GERMLINE zygosity: HOMOZYGOUS functional_impact_category: LOSS_OF_FUNCTION
Biallelic germline DNAJC30 variants, most often homozygosity for the Eastern European founder allele c.152A>G p.(Tyr51Cys), less often compound heterozygosity or homozygosity for a truncating allele.
protein folding chaperone GO:0044183 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves protein folding chaperone (GO:0044183), qualified as loss of function. GO:0044183 is a molecular function from the Gene Ontology. ⇓ LOSS OF FUNCTION
Downstream
Impaired Complex I N-Module Subunit Exchange Loss of the co-chaperone removes the activity that presents oxidatively damaged N module subunits to the degradation machinery for replacement.
Show evidence (3 references)
PMID:33465056 SUPPORT Human Clinical
"Of the 33 subjects, 29 harbored the same NM_032317.2 c.152A>G (7:73097602, NP_115693.2 p.Tyr51Cys) homozygous variant"
Records the founder allele that accounts for the great majority of patients, and its homozygous state.
PMID:35091433 SUPPORT Human Clinical
"All detected variants are located in the J domain of the DNAJC30 protein, with the exception of the nonsense variant which is located upstream of the transmembrane domain"
Locates the disease alleles within the co-chaperone J domain, consistent with a chaperone-function defect.
PMID:37397562 SUPPORT In Vitro
"c.24G>A mutation failed to express DNAJC30 protein in 293 T cells"
Demonstrates that a nonsense allele abolishes the protein, establishing loss of function as the disease mechanism rather than a dominant-negative or gain-of-function effect.
Impaired Complex I N-Module Subunit Exchange
Complex I subunits do not all turn over at the same rate. Those of the N module, where NADH is oxidized and reactive oxygen species are generated, are exchanged individually and rapidly, which maintains a functional enzyme at a fraction of the energetic cost of rebuilding it. In control fibroblasts five subunits (NDUFV3, NDUFS4, NDUFS6, NDUFA6 and NDUFA7) turn over more than a quarter of their pool in twelve hours, against under a tenth for the rest of the complex. Four of those five are direct interaction partners of DNAJC30 in protein interaction data, and in patient fibroblasts and in a DNAJC30 knockout line their turnover is selectively and significantly slowed. The selectivity is the load-bearing observation: of 145 protein complexes surveyed in the knockout, only complex I, and within it only the N module, showed altered turnover. The proposal is that DNAJC30 hands damaged subunits to the CLPXP protease, with which it co-occurs evolutionarily.
Fibroblast CL:0000057 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Fibroblast (CL:0000057). CL:0000057 is a cell type from the Cell Ontology.
NADH dehydrogenase complex GO:0030964 Gene Ontology (GO) Relation: this pathophysiological event involves this protein complex This pathophysiological event involves NADH dehydrogenase complex (GO:0030964). GO:0030964 is a protein complex from the Gene Ontology.
protein quality control for misfolded or incompletely synthesized proteins GO:0006515 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased protein quality control for misfolded or incompletely synthesized proteins (GO:0006515). GO:0006515 is a biological process from the Gene Ontology. ↓ DECREASED
Experimental models
DNAJC30 patient-derived skin fibroblast lines PRIMARY CELL CULTURE Pulse stable isotope labelling combined with mass spectrometry of assembled respiratory chain complexes measures the turnover of individual complex I subunits, which is the defect this node asserts.
DNAJC30-knockout HEK293 cell line CELL LINE The knockout reproduces the selective slowing of complex I N module subunit turnover seen in patient cells, and the proteome-wide design establishes that no other protein complex is affected.
Downstream
Accumulation of Functionally Impaired Complex I Subunits damaged by reactive oxygen species are no longer replaced, so they remain incorporated in the assembled enzyme.
Show evidence (3 references)
PMID:33465056 SUPPORT In Vitro
"Together, these data indicate that the interaction of DNAJC30 with specific complex I subunits facilitates the high turnover of complex I N-module subunits in a complex I repair mechanism."
States the mechanism this node asserts, in the words of the study that measured it.
PMID:33465056 SUPPORT In Vitro
"we verified that among all captured protein complexes (n = 145), only mitochondrial complex I, and specifically the complex I N-module, had significantly altered turnover due to the knockout of DNAJC30"
Establishes that the turnover defect is confined to the complex I N module rather than being a general proteostasis defect.
PMID:33465056 SUPPORT In Vitro
"This defect was not found in mtLHON (n = 3) and is therefore specific to arLHON"
Distinguishes the arLHON mechanism from that of the mitochondrial form, which shares the clinical phenotype but not this repair defect.
Accumulation of Functionally Impaired Complex I
The consequence is unusual among complex I disorders and is what separates this entity from the nuclear subunit deficiencies. The amount of assembled complex I is not reduced; if anything patient fibroblasts show a slight increase in complex I subunit abundance, without a matching rise in transcript levels, which is itself the signal that the problem is degradation rather than synthesis. What is lost is the quality of the enzyme that is present: the complex accumulates with damaged N module subunits still in place and reduced catalytic competence. Complex I activity is specifically affected while complex IV and complex V activities are not, so the lesion is not a general respiratory chain failure.
NADH dehydrogenase (ubiquinone) activity GO:0008137 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased NADH dehydrogenase (ubiquinone) activity (GO:0008137). GO:0008137 is a molecular function from the Gene Ontology. ↓ DECREASED
Downstream
Reduced Complex I-Dependent Respiration and ATP Output Reduced complex I catalytic competence lowers electron flux and proton pumping, and so lowers respiration and ATP output.
Increased Mitochondrial Reactive Oxygen Species Production A less catalytically competent complex I leaks more electrons, raising reactive oxygen species production.
Show evidence (3 references)
PMID:33465056 SUPPORT In Vitro
"Although the quantitative proteomic data in patient-derived fibroblast cell lines indicates a subtle increase in complex I subunit abundance due to DNAJC30 defect, RNA sequencing did not reveal a corresponding increase in complex I subunit expression"
Shows the enzyme is present in normal or slightly raised amount, so the defect is not one of assembly, and points to impaired degradation.
PMID:37397562 SUPPORT In Vitro
"we demonstrated that DNAJC30 depletion specifically decreased enzyme activity of complex I but not complex IV or V"
Independent confirmation, in a knockout cell model, that the enzymatic deficit is confined to complex I.
PMID:33465056 SUPPORT In Vitro
"The subtlety of the complex I–dependent respiration defect in the patient-derived fibroblast cell lines reflects the role of DNAJC30 in maintenance rather than in the structure or assembly of complex I"
The authors' own framing of why the biochemical defect is mild in fibroblasts and why it is a maintenance rather than an assembly defect.
Reduced Complex I-Dependent Respiration and ATP Output
Cells lacking DNAJC30 respire less. Oxygen consumption falls at basal, ATP-linked and maximal capacity, and the mitochondrial membrane potential drops with it. This is the energy-supply arm of the cellular lesion, kept separate from the oxidative arm because the two have different downstream consequences and because the oxidative arm feeds back onto the complex itself.
oxidative phosphorylation GO:0006119 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased oxidative phosphorylation (GO:0006119). GO:0006119 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Retinal Ganglion Cell Degeneration Retinal ganglion cells, and the unmyelinated small-calibre axons of the papillomacular bundle in particular, are the cells that fail first when ATP supply falls.
Subacute Necrotizing Encephalopathy of Basal Ganglia and Brainstem In a minority of patients the same biochemical lesion produces the Leigh syndrome pattern of symmetric basal ganglia and brainstem necrosis instead of, or in addition to, the optic phenotype. Why the same genotype takes this route is unresolved and is recorded as a knowledge gap.
Show evidence (2 references)
PMID:37397562 SUPPORT In Vitro
"DNAJC30 depletion caused a decrease in oxygen consumption rate concerning basal, ATP production, and maximum conditions"
Measures the respiratory deficit directly across three respiratory states.
PMID:37397562 SUPPORT In Vitro
"we found that DNAJC30 depletion decreased mitochondrial membrane potential (Fig. 1H; Fig. S2A) while increasing cellular and mitochondrial ROS levels"
Records the fall in mitochondrial membrane potential that accompanies the respiratory deficit.
Increased Mitochondrial Reactive Oxygen Species Production
The oxidative arm, and the reason this disease is self-amplifying. Cells lacking DNAJC30 generate more reactive oxygen species at both the cellular and the mitochondrial level. Reactive oxygen species are what damage the complex I N module subunits in the first place, which is why those subunits need exchanging at all, so raising them increases the demand for exactly the repair activity that has been lost. That loop is drawn explicitly as an edge below rather than left in prose.
response to oxidative stress GO:0006979 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased response to oxidative stress (GO:0006979). GO:0006979 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Accumulation of Functionally Impaired Complex I Reactive oxygen species are the source of the damage to the N module subunits that DNAJC30 normally clears, so rising oxidative load adds to the pool of damaged subunits that can no longer be exchanged. This is the feed-forward loop of the disease.
Retinal Ganglion Cell Degeneration Oxidative load acts on the same cells as the energy deficit.
Show evidence (1 reference)
PMID:37397562 SUPPORT In Vitro
"we found that DNAJC30 depletion decreased mitochondrial membrane potential (Fig. 1H; Fig. S2A) while increasing cellular and mitochondrial ROS levels"
Measures the rise in cellular and mitochondrial reactive oxygen species in a DNAJC30 knockout line.
Retinal Ganglion Cell Degeneration
Retinal ganglion cells are the tissue-selective target, and the reason the disease presents as an optic neuropathy rather than a systemic mitochondrial disorder. Their loss can be measured objectively before subjective visual loss is bilateral: photopic negative response electroretinography in an arLHON family showed abnormal ganglion cell function in both eyes of patients whose visual acuity had fallen in only one. Axonal degeneration follows the initial cell body dysfunction.
Retinal ganglion cell CL:0000740 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Retinal ganglion cell (CL:0000740). CL:0000740 is a cell type from the Cell Ontology.
retina UBERON:0000966 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in retina (UBERON:0000966). UBERON:0000966 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Optic Nerve Atrophy Loss of ganglion cell axons thins the retinal nerve fibre layer and leaves a pale, atrophic optic disc.
Show evidence (2 references)
PMID:38139324 SUPPORT Human Clinical
"LHON is a neurodegenerative disease of the optic nerve, causing the initial dysfunction of retinal ganglion cells, followed by axon degeneration."
States the cellular sequence, dysfunction of the ganglion cell followed by degeneration of its axon.
PMID:36359543 SUPPORT Human Clinical
"In Leber hereditary optic neuropathy, abnormal retinal ganglion cells function can be found in both eyes, even if visual acuity loss only occurs in one eye."
Reports objective electrophysiological evidence of bilateral ganglion cell dysfunction in an arLHON family, including eyes still clinically unaffected.
Optic Nerve Atrophy
The chronic endpoint. After the acute phase, in which the disc is hyperaemic and the nerve fibre layer swollen, the disc becomes pale and the peripapillary nerve fibre layer thins, most conspicuously in the temporal sector that carries the papillomacular bundle. Structural loss continues even in patients whose visual acuity is recovering, which is why the optical coherence tomography appearance and the functional outcome can diverge.
optic nerve UBERON:0000941 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in optic nerve, annotated with cranial nerve II (UBERON:0000941). UBERON:0000941 is an anatomical location from the Uberon multi-species anatomy ontology.
Show evidence (2 references)
PMID:37397562 SUPPORT Human Clinical
"He then developed bilateral optic atrophy and rapid progressive bilateral visual loss."
Documents bilateral optic atrophy in a patient with a confirmed homozygous DNAJC30 nonsense variant.
PMID:36388184 SUPPORT Human Clinical
"Presented are two autosomal recessive LHON (arLHON, OMIM:619382) cases with the same DNAJC30:c.152G>A pathogenic variant and different degrees of spontaneous visual recovery despite progressive RNFL thinning during a long-term follow-up."
Establishes that structural loss continues even while visual function recovers, which is why the structural endpoint and the functional outcome must be read separately in this disease.
Subacute Necrotizing Encephalopathy of Basal Ganglia and Brainstem
A minority branch, and the reason DNAJC30 belongs on a Leigh syndrome gene panel as well as an optic neuropathy panel. Patients present with dystonia, ataxia, gait disturbance and hemiparesis, and imaging shows symmetric or asymmetric hyperintensities and necrosis in the putamen, other basal ganglia nuclei, thalamus and brainstem. Optic involvement may follow, may accompany it, or may be absent altogether. Blood lactate is normal or only moderately raised, so a normal lactate does not exclude the diagnosis. The branch occurs on the same founder genotype that elsewhere produces isolated optic neuropathy, and also on truncating alleles.
basal ganglion UBERON:0002420 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in basal ganglion (UBERON:0002420). UBERON:0002420 is an anatomical location from the Uberon multi-species anatomy ontology.
Show evidence (4 references)
PMID:37397562 SUPPORT Human Clinical
"Brain magnetic resonance imaging (MRI) showed bilateral basal ganglion and thalamic hyperintensities concerning putaminal necrosis."
Documents the imaging lesion that defines this branch, in a patient with a homozygous DNAJC30 nonsense variant.
PMID:35861300 SUPPORT Human Clinical
"DNAJC30-associated LS is characterized by variable age at onset, movement disorder phenotype and normal or moderately elevated blood lactate level."
Characterises the branch, including the clinically important point that lactate may be normal.
PMID:35861300 SUPPORT Human Clinical
"Importantly, DNAJC30 pathogenic variants should be suspected in patients with LS irrespective of optic nerve involvement."
Establishes that the Leigh branch can occur without any optic phenotype.
+ 1 more reference
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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 Leber-like Hereditary Optic Neuropathy, Autosomal Recessive 1 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

8
Eye 3
Reduced Visual Acuity VERY_FREQUENT HP:0007663 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Reduced visual acuity (HP:0007663). HP:0007663 is a phenotype from the Human Phenotype Ontology.
Show evidence (4 references)
PMID:38139324 SUPPORT Human Clinical
"Most patients' first symptom of LHON was the deterioration or loss of visual acuity."
In a series of 46 Polish patients all carrying DNAJC30 variants, loss of visual acuity was the presenting symptom in most, supporting the VERY_FREQUENT band.
PMID:38107630 SUPPORT Human Clinical
"we report the cases of three Eastern European individuals presenting with bilateral painless visual loss, one of whom was also exhibiting motor symptoms"
Documents the painless bilateral character of the visual loss in three genetically confirmed arLHON patients.
PMID:35091433 SUPPORT Human Clinical
"Clinical investigation of the patients with arLHON revealed a younger age of onset, a more frequent bilateral onset and an increased clinically relevant recovery compared with LHON associated with disease-causing variants in the mitochondrial DNA."
Establishes the three clinical respects in which arLHON differs from the mitochondrial form.
+ 1 more reference
Optic Atrophy VERY_FREQUENT 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:35091433 SUPPORT Human Clinical
"In the course of the disease, mostly temporally accentuated papillary atrophy was observed in 91.7% (n=22)."
Quantifies optic atrophy in the Central European DNAJC30 cohort at 91.7 percent, supporting the VERY_FREQUENT band, and records its characteristic temporal accentuation.
PMID:37397562 SUPPORT Human Clinical
"He also showed acute bilateral optic atrophy, subacute central vision loss, and abnormal brain MRI."
Documents bilateral optic atrophy in the second of two unrelated patients homozygous for the same DNAJC30 nonsense allele.
PMID:36388184 SUPPORT Human Clinical
"Both experienced further deterioration several months after the onset accompanied by thinning of the peripapillary retinal nerve fiber layer (RNFL)."
Documents the structural correlate of optic atrophy in two genetically confirmed arLHON patients.
Color Vision Defect FREQUENT HP:0000551 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Color vision defect (HP:0000551). HP:0000551 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:35091433 SUPPORT Human Clinical
"Colour vision disturbances were observed in 68.8% (n=11) and were non-specific."
Quantifies colour vision disturbance in the Central European DNAJC30 cohort at 68.8 percent, which falls in the FREQUENT band.
PMID:36388184 SUPPORT Human Clinical
"Interestingly, pain in eye movements was present in Case 1, and color vision seemed to be preserved in early phases in both, which is not typical for mtLHON."
Records that early colour vision may be relatively preserved in arLHON, unlike the mitochondrial form.
Nervous System 2
Dystonia HP:0001332 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dystonia (HP:0001332). HP:0001332 is a phenotype from the Human Phenotype Ontology.
Frequency deliberately omitted. Dystonia belongs to the Leigh branch, which is a minority of DNAJC30 patients, and no source quantifies its frequency either across all DNAJC30 patients or within the Leigh subgroup.
Show evidence (2 references)
PMID:37397562 SUPPORT Human Clinical
"Here we report a 12-year-old boy with acute dystonia onset at age 10."
Documents dystonia as the presenting feature in a patient homozygous for a DNAJC30 nonsense variant, preceding the optic phenotype.
PMID:35861300 SUPPORT Human Clinical
"DNAJC30-associated LS is characterized by variable age at onset, movement disorder phenotype and normal or moderately elevated blood lactate level."
Establishes a movement disorder phenotype as characteristic of the Leigh branch.
Ataxia HP:0001251 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ataxia (HP:0001251). HP:0001251 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39132756 SUPPORT Human Clinical
"Over the years, he experienced progressive optic neuropathy, ataxia, left-sided hemiparesis, and limb dystonia."
Documents ataxia in a patient homozygous for the p.(Tyr51Cys) founder allele with the Leigh presentation.
Other 3
Centrocecal Scotoma VERY_FREQUENT HP:0000576 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Centrocecal scotoma (HP:0000576). HP:0000576 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:35091433 SUPPORT Human Clinical
"Visual field defects (figure 4) were central or cecocentral in 96.6% (n=28)."
Quantifies the field defect in the Central European DNAJC30 cohort at 96.6 percent, which places it in the VERY_FREQUENT band.
PMID:38139324 SUPPORT Human Clinical
"Most patients reported centrocecal scotoma or other visual field defects, and some patients noticed impaired color perception."
Independent replication in the 46-patient Polish DNAJC30 series.
PMID:36388184 SUPPORT Human Clinical
"The visual loss was characterized by centrocecal scotoma, abnormal PERG N95 and VEP, and retinal nerve fiber thinning on the OCT."
Characterises the field defect in two patients homozygous for the founder allele.
Optic Disc Hyperemia in the Acute Phase VERY_FREQUENT Abnormal optic disc morphology HP:0012795 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal optic disc morphology (HP:0012795), qualified as temporality acute. HP:0012795 is a phenotype from the Human Phenotype Ontology.
Temporal: ACUTE
Bound to the parent term HP:0012795 because HPO has no term for optic disc hyperaemia or for acute-phase disc swelling with preserved angiography; HP:0000543 Optic disc pallor describes the opposite, chronic appearance and would be wrong here. Searched with runoak against sqlite:obo:hp for "optic disc" and reviewed all eleven descendants.
Show evidence (3 references)
PMID:35091433 SUPPORT Human Clinical
"Initial papillary microangiopathy (figure 4) was common and occurred in 94.1% (n=16)."
Quantifies the acute-phase peripapillary microangiopathy in the Central European DNAJC30 cohort at 94.1 percent, supporting the VERY_FREQUENT band.
PMID:38139324 SUPPORT Human Clinical
"Fundus examination showed hyperemic optic nerves during the acute phase of LHON in most patients."
Reports acute-phase disc hyperaemia in the DNAJC30 Polish series.
PMID:36388184 SUPPORT Human Clinical
"Both had hyperemic optic disks (PNO) and central scotoma in their visual fields."
Documents the acute-phase disc appearance in two genetically confirmed patients.
Bilateral Basal Ganglia Lesions HP:0007146 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bilateral basal ganglia lesions (HP:0007146). HP:0007146 is a phenotype from the Human Phenotype Ontology.
Frequency deliberately omitted for the same reason as Dystonia: the Leigh branch is a minority of DNAJC30 patients and its size is not quantified in the cited sources.
Show evidence (2 references)
PMID:37397562 SUPPORT Human Clinical
"Brain magnetic resonance imaging (MRI) showed bilateral basal ganglion and thalamic hyperintensities concerning putaminal necrosis."
Documents bilateral basal ganglia and thalamic lesions in a patient with a homozygous DNAJC30 nonsense variant.
PMID:33465056 SUPPORT Human Clinical
"bilateral necrosis of the putamen with lesions in the pedunculi cerebelli suggestive of Leigh syndrome on brain MRI"
Documents the same imaging pattern in the Leigh syndrome patient of the founding arLHON cohort.
🧬

Genetic Associations

1
DNAJC30
Gene: DNAJC30 hgnc:16410 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is DNAJC30 (hgnc:16410). hgnc:16410 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (3 references)
PMID:33465056 SUPPORT Human Clinical
"Given that the majority of the patients originate from Russia, Poland, Romania, and Ukraine, the p.Tyr51Cys DNAJC30 variant is ascribed to an Eastern European founder event."
Establishes the founder origin and geographic distribution of the dominant disease allele.
PMID:35091433 SUPPORT Human Clinical
"The previously described missense variant c.152A>G;p.(Tyr51Cys) accounts for 90% of disease-associated alleles in our cohort and we confirmed a strong founder effect."
Independent confirmation of the founder effect and of the allele's dominance of the mutational spectrum.
PMID:38139324 SUPPORT Human Clinical
"Based on our data, the autosomal recessive form of LHON caused by DNAJC30 gene mutations is more frequent than the mitochondrial form in Polish patients."
Shows that in one national series the nuclear form outnumbers the mitochondrial form, which is the strongest statement of ancestry dependence available.
Variants (3)
c.152A>G (p.Tyr51Cys) founder variant Pathogenic
Gene: DNAJC30 hgnc:16410 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in DNAJC30 (hgnc:16410). hgnc:16410 is a gene from the HUGO Gene Nomenclature Committee. missense variant
The Eastern European founder allele, carried homozygously by 29 of the 33 patients in the founding cohort and accounting for about 90 percent of disease alleles in a Central European series. It lies in the J domain and was estimated to have arisen about 85 generations ago. Its gnomAD allele frequency of 0.125 percent, with no homozygotes recorded, is high enough that full penetrance would predict more disease than is observed, which is itself part of the evidence for incomplete penetrance.
Show evidence (2 references)
PMID:33465056 SUPPORT Human Clinical
"Of the 33 subjects, 29 harbored the same NM_032317.2 c.152A>G (7:73097602, NP_115693.2 p.Tyr51Cys) homozygous variant with an allele frequency of 0.125%"
Records the allele, its homozygous state in most patients, and its population frequency.
PMID:35091433 SUPPORT Human Clinical
"The previously described missense variant c.152A>G;p.(Tyr51Cys) accounts for 90% of disease-associated alleles in our cohort and we confirmed a strong founder effect."
Independent confirmation of the allele's dominance and founder origin.
c.610G>T (p.Glu204*) Pathogenic
Gene: DNAJC30 hgnc:16410 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in DNAJC30 (hgnc:16410). hgnc:16410 is a gene from the HUGO Gene Nomenclature Committee. nonsense variant
A nonsense allele found in three unrelated patients, in each case in compound heterozygosity with the founder variant and confirmed to be in trans by allelic cloning. It is the one reported allele lying outside the J domain, truncating instead upstream of the transmembrane domain.
Show evidence (1 reference)
PMID:35091433 SUPPORT Human Clinical
"The nonsense variant c.610G>T;p.(Glu204*) was observed in three unrelated patients with LHON in compound heterozygous state with the common c.152A>G;p.(Tyr51Cys) variant, as confirmed by allelic cloning"
Records the allele, its compound heterozygous context, and the phasing evidence.
c.24G>A (p.Trp8*) Pathogenic
Gene: DNAJC30 hgnc:16410 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in DNAJC30 (hgnc:16410). hgnc:16410 is a gene from the HUGO Gene Nomenclature Committee. nonsense variant
A nonsense allele reported homozygously in two unrelated patients, both of whom had a Leigh-like course with earlier onset than the missense cohort. It is mechanistically the most informative allele in the gene: it abolishes the protein outright in cells, which is what establishes loss of function rather than a dominant-negative or aberrant activity as the disease mechanism.
Show evidence (1 reference)
PMID:37397562 SUPPORT Human Clinical
"Exome sequencing analysis of his peripheral blood sample revealed a homozygous nonsense germline variant, c.24G>A (p.W8X) in the DNAJC30 gene, proven to result in a complete loss of DNAJC30 protein expression in cells."
Records the allele and the demonstration that it eliminates the protein.
💊

Medical Actions

1
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.
Idebenone is a short-chain benzoquinone that, once reduced, can accept electrons and deliver them to complex III, routing around the defective complex I. It is authorised for LHON by the European Medicines Agency and is given at 900 mg per day. Its use here is not merely inherited from the mitochondrial form: the arLHON cohorts report a treated recovery rate above that reported for mtLHON, which makes reaching a DNAJC30 diagnosis prognostically as well as genetically consequential. The important qualification is that the reported benefit is in the optic phenotype. In the one published patient with DNAJC30-associated Leigh syndrome treated with idebenone, the drug neither halted neurological progression nor prevented new lesions on imaging.
Mechanism Target:
BYPASSES Accumulation of Functionally Impaired Complex I — Reduced idebenone donates electrons to complex III, so electron flux and downstream ATP synthesis are partly restored without the damaged complex I being repaired. The predicate is BYPASSES rather than RESTORES because the drug does not act on the chaperone defect or on the retained damaged subunits.
Show evidence (1 reference)
PMID:33465056 SUPPORT Human Clinical
"Idebenone therapy was received by 18 patients, as a potent antioxidant and electron donor approved for LHON by EMA"
States the drug's mechanism of action and its regulatory status in the arLHON cohort that received it.
Show evidence (4 references)
PMID:33465056 SUPPORT Human Clinical
"Of the 36 treated and 26 untreated eyes, CRR was reported in 29 (80.6%) and 13 (50.0%), respectively."
Quantifies clinically relevant recovery in treated versus untreated eyes in the founding arLHON cohort. This is an uncontrolled within-cohort comparison, not a randomised trial.
PMID:35148383 SUPPORT Human Clinical
"The autosomal recessive LHON patients demonstrate an earlier age of disease onset and a higher rate of idebenone-treated and spontaneous recovery of vision in comparison to reported figures for maternally inherited disease."
Independent replication that treated recovery in arLHON exceeds published figures for the mitochondrial form. Note it also reports higher spontaneous recovery, so the treated figure cannot be attributed to the drug alone.
PMID:39132756 REFUTE Human Clinical
"As evidenced in our case, idebenone did not halt progression of the disease, nor induce any neuroprotective effect apparent in neuroimaging."
Refutes the extension of idebenone benefit from the optic phenotype to the Leigh branch, in a patient carrying the same founder allele as the responsive optic cases.
+ 1 more reference
🔬

Diagnosis

1
Parallel Sequencing of Mitochondrial DNA and the Single-Exon DNAJC30 Gene
The diagnostic recommendation that follows from the entity's existence. A patient with a convincing LHON phenotype and a negative mtDNA result used to be left unsolved, sometimes for years. Because DNAJC30 has a single exon, Sanger sequencing of the whole gene is inexpensive, so it can be run alongside full mtDNA sequencing rather than after it. In founder populations the argument is stronger still: in one Polish series the nuclear form outnumbered the mitochondrial form, which inverts the usual testing order.
Show evidence (2 references)
PMID:33465056 SUPPORT Human Clinical
"We therefore recommend parallel sequencing of the complete mtDNA sequence and the 1-exon gene DNAJC30 to close the diagnostic gap in LHON."
The explicit diagnostic recommendation made by the study that defined the entity.
PMID:38139324 SUPPORT Human Clinical
"The results of our study suggest that Sanger sequencing of the single-exon DNAJC30 gene should be a method of choice applied to identify a molecular background of clinically confirmed LHON in Polish patients."
Extends the recommendation to first-line testing in a founder population.
📈

Progression

3
Acute and subacute visual loss
Age: Second to third decade, median age at onset 18.5 years
Painless central visual loss begins in one eye or in both at once, with bilateral onset in 40 percent of patients and a median of 3.5 weeks between eyes when onset is sequential. The disc is hyperaemic with peripapillary microangiopathy. Onset is earlier and more tightly clustered than in the mitochondrial form, and involvement becomes bilateral in every patient.
Show evidence (2 references)
PMID:35091433 SUPPORT Human Clinical
"The median age at onset of the disease was 18.5 years (range 9.5–45.1). All patients showed involvement of both eyes. Bilateral onset was observed in 40% (n=8)."
Gives the age at onset and the laterality pattern of the acute phase.
PMID:35091433 SUPPORT Human Clinical
"In cases with bilateral onset, a median of 3.5 weeks (range 1–17) elapsed between the first eye and the second eye."
Quantifies the interval between eyes in sequentially affected patients.
Nadir and spontaneous recovery
This phase is what most distinguishes arLHON prognostically, and it is partly independent of treatment. In the Central European cohort only one of 35 patients received idebenone, and he had already recovered before starting it; clinically relevant recovery nonetheless occurred in 45 percent, at a median of 19 months from onset. Median visual acuity improved from 1.3 logMAR at nadir to 0.5 logMAR at last visit. The founding cohort likewise reported recovery in 50 percent of untreated eyes. Recovery is therefore a feature of the natural history and not solely a drug effect, which is why the treated figures under Idebenone should not be read as the treatment's attributable benefit.
Show evidence (4 references)
PMID:35091433 SUPPORT Human Clinical
"CRR was seen in 45% (n=9) at a median of 19 months (range 1–58) after onset."
Quantifies spontaneous clinically relevant recovery in a cohort that was effectively untreated.
PMID:35091433 SUPPORT Human Clinical
"Only one patient received idebenone over a period of 6 months. He developed a CRR even before the start of idebenone therapy."
Establishes that the 45 percent recovery rate in this cohort is not attributable to idebenone, since essentially nobody received it.
PMID:33465056 SUPPORT Human Clinical
"Of the 36 treated and 26 untreated eyes, CRR was reported in 29 (80.6%) and 13 (50.0%), respectively."
Gives the untreated recovery rate from the founding cohort, 50 percent of eyes, alongside the treated rate.
+ 1 more reference
Chronic phase
Optic disc pallor and peripapillary retinal nerve fibre layer thinning are established and continue. Structural loss is progressive even in patients whose visual acuity is improving, so optical coherence tomography and visual function diverge in this phase. Visual function itself, once recovered, remained stable over follow-up of twelve and fourteen years in the two patients followed longest.
Show evidence (2 references)
PMID:36388184 SUPPORT Human Clinical
"Presented are two autosomal recessive LHON (arLHON, OMIM:619382) cases with the same DNAJC30:c.152G>A pathogenic variant and different degrees of spontaneous visual recovery despite progressive RNFL thinning during a long-term follow-up."
Establishes the divergence between continuing structural loss and recovering function that characterises the chronic phase.
PMID:36388184 SUPPORT Human Clinical
"The patient's visual function remained stable during the entire 12-year follow-up period."
Records long-term functional stability after recovery, which is a statement about visual function and not about the optic nerve structure.
📊

Prevalence

1
Worldwide, derived from the founder allele frequency
Point Prevalence 0.109 per 100,000 1–9 per 1,000,000
Estimated from the gnomAD allele frequency of the p.(Tyr51Cys) founder variant under Hardy-Weinberg with adjustment for the observed incomplete penetrance. The estimate is anchored on one allele in one population and should be read as an order of magnitude, not a measured rate; local prevalence in the Eastern European founder population is substantially higher.
Show evidence (1 reference)
PMID:33465056 SUPPORT Human Clinical
"Taking the allele frequency of the variant (0.125%) and applying the Hardy-Weinberg equation with adjustment for the observed incomplete penetrance, arLHON is estimated to affect 1.09 per million individuals"
States the derivation and the value normalised here to 0.109 per 100,000.
🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from Leber-like Hereditary Optic Neuropathy, Autosomal Recessive 1:

Mitochondrial (maternally inherited) Leber hereditary optic neuropathy
Overlapping Features Clinically the same disease. Subacute painless bilateral central visual loss in a young adult, incomplete penetrance, male predominance, response to idebenone. It is caused instead by one of three mitochondrial DNA point mutations in complex I subunit genes, accounts for roughly 90 percent of LHON, and was for a century the only recognised form.
Distinguishing Features
  • Family history. Maternal transmission points to the mitochondrial form; an affected sibling with unaffected parents, or no family history at all, points here.
  • Testing. Full mitochondrial DNA sequencing separates them, and because DNAJC30 has a single exon both can be sequenced in parallel rather than in sequence.
  • Onset and outcome. Onset in arLHON is earlier and more tightly clustered, bilateral onset is more common, and both spontaneous and treated recovery rates are higher.
  • Mechanism, in a research setting. The complex I N module turnover defect is present in arLHON cells and absent in mitochondrial LHON cells.
Show evidence (2 references)
PMID:33465056 SUPPORT In Vitro
"This defect was not found in mtLHON (n = 3) and is therefore specific to arLHON"
The mechanistic discriminator between the two forms.
PMID:33465056 SUPPORT Human Clinical
"Given this, we would suggest LHON to be subdivided as mtLHON and arLHON, due to the important impact on genetic counseling."
States why the distinction is worth making clinically, which is genetic counselling rather than treatment.
Other nuclear-gene LHON-like optic neuropathies
Overlapping Features Biallelic variants in NDUFS2, MCAT and NDUFA12 produce a typical LHON phenotype and are also nuclear and recessive, so they are not separated from this entity by inheritance pattern or by mitochondrial DNA testing. They have each been reported in only a few families, against roughly a hundred for DNAJC30.
Distinguishing Features
  • Gene. Only sequencing distinguishes them; there is no reported clinical feature that does.
  • Ancestry shifts the prior. In Eastern and Central Europe the DNAJC30 founder allele is far more likely than any of these.
Show evidence (1 reference)
PMID:38139324 SUPPORT Human Clinical
"Typical LHON phenotypes have also been reported to be the effects of variants in other genes, namely NDUFS2, MCAT, and NDUFA12, detected only in a few families"
Names the other nuclear genes producing the same phenotype and records how few families each accounts for.
Optic neuritis
Overlapping Features The differential that actually costs patients time. In the acute phase the disc is hyperaemic and the retinal nerve fibre layer is swollen, which is routinely read as inflammation. Patients are investigated for and treated as demyelinating disease before the diagnosis is reached, sometimes for years.
Distinguishing Features
  • Fluorescein angiography shows no leakage in this disorder, unlike inflammatory disc swelling.
  • Pain on eye movement is characteristically absent, though it has been reported in at least one genetically confirmed arLHON patient, so its presence does not exclude the diagnosis.
  • Aquaporin-4 and myelin oligodendrocyte glycoprotein antibodies are negative, and intravenous corticosteroids do not improve vision.
Show evidence (3 references)
PMID:38139324 SUPPORT Human Clinical
"the swelling of the retinal nerve fiber layer, which, unfortunately, is often mistakenly considered a sign of an inflammatory process"
Names the specific finding that leads to the misdiagnosis.
PMID:36388184 SUPPORT Human Clinical
"Extensive clinical workout, including brain magnetic resonance imaging (MRI), aquaporin 4 (Aq4), and anti-myelin oligodendrocyte protein (anti-MOG) antibodies, was negative."
Records the negative inflammatory workup in two genetically confirmed arLHON patients.
PMID:36388184 SUPPORT Human Clinical
"Intravenous corticosteroids did not improve vision."
Records the failure of the treatment that would be given if the misdiagnosis were acted on.
🧫

Experimental Models

2
DNAJC30 patient-derived skin fibroblast lines PRIMARY_CELL_CULTURE
Six fibroblast lines spanning all three DNAJC30 alleles known at the time, compared against seven control lines and against three mitochondrial LHON lines. The mtLHON comparison arm is what makes this model discriminating rather than merely descriptive: it shows the turnover defect is specific to the nuclear disease.
Fibroblast CL:0000057 Cell Ontology (CL) Relation: this experimental model uses this cell type This experimental model uses Fibroblast (CL:0000057). CL:0000057 is a cell type from the Cell Ontology.
Organism
human NCBITaxon:9606 NCBI Taxonomy (NCBITaxon) Relation: this experimental model is built in this organism This experimental model is built in human, annotated with Homo sapiens (NCBITaxon:9606). NCBITaxon:9606 is an organism from the NCBI Taxonomy.
Cell source
Patient-derived, from individuals carrying p.Tyr51Cys, p.Pro78Ser or p.Leu101Gln
Publication
PMID:33465056
Pathograph links
Impaired Complex I N-Module Subunit Exchange measures fidelity: moderate Pulse stable isotope labelling combined with mass spectrometry of assembled respiratory chain complexes measures the turnover of individual complex I subunits, which is the defect this node asserts.
Limitations: Fibroblasts are not the affected cell type. Retinal ganglion cells are, and the complex I dependent respiration defect in fibroblasts is subtle, which the reporting authors attribute to the maintenance rather than structural role of the protein. A fibroblast measurement therefore establishes the molecular lesion but says nothing about why the retina fails and other tissues do not.
Readouts
Turnover of complex I N-module subunits in assembled complex I
Direction: DECREASED
Interpretation: Reduced fractional replacement of the high-turnover N module subunits over twelve hours, relative to controls.
Show evidence (1 reference)
PMID:33465056 SUPPORT In Vitro
"The patient-derived fibroblast cell lines (n = 6), spanning all 3 DNAJC30 mutations, demonstrated a significant decrease in the turnover of N-module subunits in assembled complex I"
Reports the measurement and its direction in the patient lines.
Show evidence (1 reference)
PMID:33465056 SUPPORT In Vitro
"This defect was not found in mtLHON (n = 3) and is therefore specific to arLHON"
Establishes that the model reports on the nuclear disease specifically, by showing the defect is absent in cells from the phenotypically identical mitochondrial disease.
DNAJC30-knockout HEK293 cell line CELL_LINE
A complete knockout used to test whether the turnover defect seen in patient fibroblasts is specific to complex I, by measuring turnover across more than 1,200 proteins and 145 protein complexes rather than only the complex of interest.
Organism
human NCBITaxon:9606 NCBI Taxonomy (NCBITaxon) Relation: this experimental model is built in this organism This experimental model is built in human, annotated with Homo sapiens (NCBITaxon:9606). NCBITaxon:9606 is an organism from the NCBI Taxonomy.
Cell source
Immortalized HEK293, DNAJC30 knockout
Publication
PMID:33465056
Pathograph links
Impaired Complex I N-Module Subunit Exchange recapitulates fidelity: moderate The knockout reproduces the selective slowing of complex I N module subunit turnover seen in patient cells, and the proteome-wide design establishes that no other protein complex is affected.
Limitations: HEK293 cells are an immortalized embryonic kidney line, neither neural nor retinal, and a knockout is a more severe perturbation than the missense alleles that cause most human disease. The model therefore supports the molecular claim but not the tissue selectivity of the disease.
Readouts
Differential turnover across 145 assembled protein complexes
Direction: DECREASED
Interpretation: Only complex I, and within it only the N module, showed significantly altered turnover on knockout.
Show evidence (1 reference)
PMID:33465056 SUPPORT In Vitro
"we verified that among all captured protein complexes (n = 145), only mitochondrial complex I, and specifically the complex I N-module, had significantly altered turnover due to the knockout of DNAJC30"
Reports the proteome-wide result that establishes the selectivity of the defect.
Show evidence (1 reference)
PMID:33465056 SUPPORT In Vitro
"The data recapitulate the defect seen in the patient-derived fibroblast cell lines, with a mean turnover in CIHIGH subunits of 31.0% in the DNAJC30-KO, in comparison with 48.7% in the control"
States that the knockout reproduces the patient-cell defect, with the quantities.
{ }

Source YAML

click to show 
name: Leber-like Hereditary Optic Neuropathy, Autosomal Recessive 1
creation_date: "2026-08-27T00:00:00Z"
category: Mendelian
description: >-
  Leber-like hereditary optic neuropathy, autosomal recessive 1 (LHONAR1,
  arLHON) is caused by biallelic variants in the nuclear gene DNAJC30. It
  matters because of what it overturned. Leber hereditary optic neuropathy had
  been the textbook example of maternal transmission, defined since 1988 by
  point mutations in mitochondrial DNA, and a patient with a convincing LHON
  phenotype and no mtDNA mutation had no diagnosis to be given. In 2021 a
  single-exon nuclear gene accounted for 33 such patients from 29 families, and
  the resulting entity recapitulated every hallmark of the mitochondrial form:
  subacute painless bilateral central visual loss in young adults, incomplete
  penetrance, marked male predominance, and responsiveness to idebenone. LHON
  is therefore a clinical description independent of the mode of transmission,
  and the entity divides into mtLHON and arLHON.

  The mechanism is not a defect of complex I structure or assembly, which is
  what mtDNA LHON and the nuclear complex I subunit deficiencies produce.
  DNAJC30 is a chaperone that services complex I after it has been built.
  Subunits of the complex I N module sit closest to the site of electron entry
  and take the highest oxidative damage, and the cell exchanges them
  individually rather than rebuilding the whole enzyme, which is far cheaper in
  energy. DNAJC30 is what makes that exchange happen. Tracking protein turnover
  in patient fibroblasts and in a DNAJC30 knockout cell line showed the turnover
  of exactly those N module subunits to be selectively slowed, so damaged
  subunits are retained and the cell accumulates assembled complex I of reduced
  catalytic quality. This is a disease of impaired repair rather than of
  impaired construction, and it was the first such disease described for a
  respiratory chain complex.

  The genetics are dominated by one allele. The missense variant
  c.152A>G p.(Tyr51Cys) is an Eastern European founder allele carried by the
  great majority of patients, common enough in Russia, Poland, Ukraine and
  Romania that DNAJC30 accounts for a fifth of molecularly solved LHON in a
  Moscow centre and outnumbers the mitochondrial form in a Polish series. Rarer
  alleles include p.(Pro78Ser), p.(Leu101Gln), p.(His77del), the nonsense
  p.(Glu204*) and p.(Trp8*), and the frameshift p.(Ser44ValfsTer8). Because the
  gene has a single exon, Sanger sequencing of DNAJC30 is cheap, and the
  practical recommendation is to sequence it in parallel with the full mtDNA in
  any unsolved LHON.

  Two features complicate the picture and are curated here as open questions
  rather than settled mechanism. The first is that a recessive disease should
  not show incomplete penetrance or a sex bias, and this one shows both, more
  strongly than the mitochondrial form does; DNAJC30 expression does not differ
  between sexes, so the modifier lies downstream and is unidentified. The
  second is a Leigh syndrome branch. A minority of patients, including some
  homozygous for the same founder allele, present instead with dystonia,
  ataxia and bilateral basal ganglia necrosis, with or without optic
  involvement, and in the one reported case treated with idebenone the drug did
  not arrest that course. Whether a second hit in another complex I gene
  explains the branch is proposed but not established.
parents:
- Leber Hereditary Optic Neuropathy
- Mitochondrial Disease
synonyms:
- LHONAR1
- arLHON
- autosomal recessive Leber hereditary optic neuropathy
- DNAJC30-related Leber hereditary optic neuropathy
- Leber optic atrophy, autosomal recessive 1
disease_term:
  preferred_term: Leber-like hereditary optic neuropathy, autosomal recessive 1
  term:
    id: MONDO:0958183
    label: Leber-like hereditary optic neuropathy, autosomal recessive 1
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0958183
      label: Leber-like hereditary optic neuropathy, autosomal recessive 1
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
classifications:
  harrisons_chapter:
  - classification_value: NEUROLOGIC
    evidence:
    - reference: PMID:38139324
      reference_title: "DNAJC30 Gene Variants Are a Frequent Cause of a Rare Disease: Leber Hereditary Optic Neuropathy in Polish Patients."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        LHON is a neurodegenerative disease of the optic nerve, causing the
        initial dysfunction of retinal ganglion cells, followed by axon
        degeneration.
      explanation: >-
        Places the entity among neurodegenerative disorders of the optic nerve,
        covered under Harrison's neurologic disorders.
  - classification_value: ENDOCRINOLOGY_METABOLISM
    evidence:
    - reference: PMID:33465056
      reference_title: "Impaired complex I repair causes recessive Leber's hereditary optic neuropathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        LHON mutations characteristically disrupt subunits of mitochondrial
        complex I, the first and largest of the electron transfer complexes,
        encoded by both nuclear DNA and mtDNA.
      explanation: >-
        Establishes the disorder as a respiratory chain and inherited metabolic
        disease.
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    evidence:
    - reference: PMID:33465056
      reference_title: "Impaired complex I repair causes recessive Leber's hereditary optic neuropathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We describe biallelic mutations in a nuclear encoded gene, DNAJC30, in
        33 unsolved patients from 29 families and establish an autosomal
        recessive mode of inheritance for LHON (arLHON), which to date has been
        a prime example of a maternally inherited disorder.
      explanation: >-
        Establishes the single nuclear gene and the recessive transmission that
        define the entity.
references:
- reference: PMID:33465056
  title: "Impaired complex I repair causes recessive Leber's hereditary optic neuropathy."
- reference: PMID:35148383
  title: "DNAJC30 defect: a frequent cause of recessive Leber hereditary optic neuropathy and Leigh syndrome."
- reference: PMID:35091433
  title: "DNAJC30 disease-causing gene variants in a large Central European cohort of patients with suspected Leber's hereditary optic neuropathy and optic atrophy."
- reference: PMID:38139324
  title: "DNAJC30 Gene Variants Are a Frequent Cause of a Rare Disease: Leber Hereditary Optic Neuropathy in Polish Patients."
- reference: PMID:37397562
  title: "A homozygous nonsense mutation in DNAJC30 causes Leber's hereditary optic neuropathy with Leigh-like phenotypes."
- reference: PMID:35861300
  title: "Expanding the phenotype of DNAJC30-associated Leigh syndrome."
- reference: PMID:39132756
  title: "Effects of idebenone treatment in a patient with DNAJC30-associated Leigh Syndrome."
- reference: PMID:37071596
  title: "Autosomal recessive Leber hereditary optic neuropathy, a new neuro-ophthalmo-genetic paradigm."
- reference: PMID:36388184
  title: "Case report: Long-term follow-up of two patients with LHON caused by DNAJC30:c.152G>A pathogenic variant-case series."
- reference: PMID:38107630
  title: "Case report: Mutations in DNAJC30 causing autosomal recessive Leber hereditary optic neuropathy are common amongst Eastern European individuals."
- reference: PMID:36359543
  title: "Phenotypic Variation of Autosomal Recessive Leber Hereditary Optic Neuropathy (arLHON) in One Family."

inheritance:
- name: Autosomal recessive inheritance
  description: >-
    Biallelic DNAJC30 variants, most often homozygosity for the p.(Tyr51Cys)
    founder allele but also compound heterozygosity with a second rare allele.
    Segregation and allelic cloning have confirmed true biallelism in
    compound heterozygotes. The recessive mode is the whole point of the
    entity: it removes the maternal family history that had been treated as a
    prerequisite for a LHON diagnosis, and it changes recurrence counselling
    from maternal-line risk to a one-in-four sibling risk.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:33465056
    reference_title: "Impaired complex I repair causes recessive Leber's hereditary optic neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We describe biallelic mutations in a nuclear encoded gene, DNAJC30, in 33
      unsolved patients from 29 families and establish an autosomal recessive
      mode of inheritance for LHON (arLHON), which to date has been a prime
      example of a maternally inherited disorder.
    explanation: >-
      The founding demonstration of autosomal recessive transmission for a
      phenotype previously defined as maternally inherited.
  - reference: PMID:35091433
    reference_title: "DNAJC30 disease-causing gene variants in a large Central European cohort of patients with suspected Leber's hereditary optic neuropathy and optic atrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Segregation and allelic cloning confirmed the expected recessive mode of
      inheritance and true biallelism.
    explanation: >-
      Independent confirmation that the two variants in compound heterozygotes
      lie on opposite alleles.

pathophysiology:
- name: DNAJC30 Loss of Function
  biological_scale: MOLECULAR
  role: trigger
  mechanism_confidence: ESTABLISHED
  description: >-
    DNAJC30 is a single-exon nuclear gene encoding a DnaJ/HSP40 family
    co-chaperone expressed mainly in neurons. Disease alleles are biallelic and
    are dominated by one founder missense change, c.152A>G p.(Tyr51Cys), which
    lies in the J domain; the rarer p.(Pro78Ser), p.(Leu101Gln) and
    p.(His77del) alleles lie in the same domain, while p.(Glu204*) truncates
    upstream of the transmembrane domain. Truncating alleles are informative
    about the mechanism because they abolish the protein outright: the
    p.(Trp8*) nonsense allele produced no detectable DNAJC30 protein in
    transfected cells, so the disease state is loss of the chaperone, not a
    gain of an aberrant activity. Heterozygous carriers, including carriers of
    outright loss-of-function alleles in population databases, are healthy.
  genes:
  - preferred_term: DNAJC30
    term:
      id: hgnc:16410
      label: DNAJC30
  genetic_context:
    functional_impact_category: LOSS_OF_FUNCTION
    variant_origin: GERMLINE
    zygosity: HOMOZYGOUS
    description: >-
      Biallelic germline DNAJC30 variants, most often homozygosity for the
      Eastern European founder allele c.152A>G p.(Tyr51Cys), less often
      compound heterozygosity or homozygosity for a truncating allele.
  molecular_functions:
  - preferred_term: protein folding chaperone
    modifier: LOSS_OF_FUNCTION
    term:
      id: GO:0044183
      label: protein folding chaperone
  evidence:
  - reference: PMID:33465056
    reference_title: "Impaired complex I repair causes recessive Leber's hereditary optic neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Of the 33 subjects, 29 harbored the same NM_032317.2 c.152A>G
      (7:73097602, NP_115693.2 p.Tyr51Cys) homozygous variant
    explanation: >-
      Records the founder allele that accounts for the great majority of
      patients, and its homozygous state.
  - reference: PMID:35091433
    reference_title: "DNAJC30 disease-causing gene variants in a large Central European cohort of patients with suspected Leber's hereditary optic neuropathy and optic atrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All detected variants are located in the J domain of the DNAJC30 protein,
      with the exception of the nonsense variant which is located upstream of
      the transmembrane domain
    explanation: >-
      Locates the disease alleles within the co-chaperone J domain, consistent
      with a chaperone-function defect.
  - reference: PMID:37397562
    reference_title: "A homozygous nonsense mutation in DNAJC30 causes Leber's hereditary optic neuropathy with Leigh-like phenotypes."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      c.24G>A mutation failed to express DNAJC30 protein in 293 T cells
    explanation: >-
      Demonstrates that a nonsense allele abolishes the protein, establishing
      loss of function as the disease mechanism rather than a dominant-negative
      or gain-of-function effect.
  downstream:
  - target: Impaired Complex I N-Module Subunit Exchange
    causal_link_type: DIRECT
    description: >-
      Loss of the co-chaperone removes the activity that presents oxidatively
      damaged N module subunits to the degradation machinery for replacement.
    evidence:
    - reference: PMID:33465056
      reference_title: "Impaired complex I repair causes recessive Leber's hereditary optic neuropathy."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        The patient-derived fibroblast cell lines (n = 6), spanning all 3
        DNAJC30 mutations, demonstrated a significant decrease in the turnover
        of N-module subunits in assembled complex I
      explanation: >-
        Directly links the patient genotype to slowed exchange of the N module
        subunits.

- name: Impaired Complex I N-Module Subunit Exchange
  biological_scale: MOLECULAR
  role: central_effector
  mechanism_confidence: ESTABLISHED
  description: >-
    Complex I subunits do not all turn over at the same rate. Those of the N
    module, where NADH is oxidized and reactive oxygen species are generated,
    are exchanged individually and rapidly, which maintains a functional enzyme
    at a fraction of the energetic cost of rebuilding it. In control
    fibroblasts five subunits (NDUFV3, NDUFS4, NDUFS6, NDUFA6 and NDUFA7) turn
    over more than a quarter of their pool in twelve hours, against under a
    tenth for the rest of the complex. Four of those five are direct
    interaction partners of DNAJC30 in protein interaction data, and in patient
    fibroblasts and in a DNAJC30 knockout line their turnover is selectively
    and significantly slowed. The selectivity is the load-bearing observation:
    of 145 protein complexes surveyed in the knockout, only complex I, and
    within it only the N module, showed altered turnover. The proposal is that
    DNAJC30 hands damaged subunits to the CLPXP protease, with which it
    co-occurs evolutionarily.
  biological_processes:
  - preferred_term: protein quality control for misfolded or incompletely synthesized proteins
    modifier: DECREASED
    term:
      id: GO:0006515
      label: protein quality control for misfolded or incompletely synthesized proteins
  protein_complexes:
  - preferred_term: NADH dehydrogenase complex
    term:
      id: GO:0030964
      label: NADH dehydrogenase complex
  cell_types:
  - preferred_term: Fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  evidence:
  - reference: PMID:33465056
    reference_title: "Impaired complex I repair causes recessive Leber's hereditary optic neuropathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Together, these data indicate that the interaction of DNAJC30 with
      specific complex I subunits facilitates the high turnover of complex I
      N-module subunits in a complex I repair mechanism.
    explanation: >-
      States the mechanism this node asserts, in the words of the study that
      measured it.
  - reference: PMID:33465056
    reference_title: "Impaired complex I repair causes recessive Leber's hereditary optic neuropathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      we verified that among all captured protein complexes (n = 145), only
      mitochondrial complex I, and specifically the complex I N-module, had
      significantly altered turnover due to the knockout of DNAJC30
    explanation: >-
      Establishes that the turnover defect is confined to the complex I N
      module rather than being a general proteostasis defect.
  - reference: PMID:33465056
    reference_title: "Impaired complex I repair causes recessive Leber's hereditary optic neuropathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      This defect was not found in mtLHON (n = 3) and is therefore specific to
      arLHON
    explanation: >-
      Distinguishes the arLHON mechanism from that of the mitochondrial form,
      which shares the clinical phenotype but not this repair defect.
  downstream:
  - target: Accumulation of Functionally Impaired Complex I
    causal_link_type: DIRECT
    description: >-
      Subunits damaged by reactive oxygen species are no longer replaced, so
      they remain incorporated in the assembled enzyme.
    evidence:
    - reference: PMID:33465056
      reference_title: "Impaired complex I repair causes recessive Leber's hereditary optic neuropathy."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        in the absence of DNAJC30 the complex I N-module subunits may no longer
        be readily exchangeable, resulting in an accumulation of complex I with
        lower function
      explanation: >-
        States the causal step from failed exchange to accumulation of
        low-function enzyme.

- name: Accumulation of Functionally Impaired Complex I
  biological_scale: MOLECULAR
  role: intermediate
  mechanism_confidence: ESTABLISHED
  description: >-
    The consequence is unusual among complex I disorders and is what separates
    this entity from the nuclear subunit deficiencies. The amount of assembled
    complex I is not reduced; if anything patient fibroblasts show a slight
    increase in complex I subunit abundance, without a matching rise in
    transcript levels, which is itself the signal that the problem is
    degradation rather than synthesis. What is lost is the quality of the
    enzyme that is present: the complex accumulates with damaged N module
    subunits still in place and reduced catalytic competence. Complex I
    activity is specifically affected while complex IV and complex V activities
    are not, so the lesion is not a general respiratory chain failure.
  molecular_functions:
  - preferred_term: NADH dehydrogenase (ubiquinone) activity
    modifier: DECREASED
    term:
      id: GO:0008137
      label: NADH dehydrogenase (ubiquinone) activity
  evidence:
  - reference: PMID:33465056
    reference_title: "Impaired complex I repair causes recessive Leber's hereditary optic neuropathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Although the quantitative proteomic data in patient-derived fibroblast
      cell lines indicates a subtle increase in complex I subunit abundance due
      to DNAJC30 defect, RNA sequencing did not reveal a corresponding increase
      in complex I subunit expression
    explanation: >-
      Shows the enzyme is present in normal or slightly raised amount, so the
      defect is not one of assembly, and points to impaired degradation.
  - reference: PMID:37397562
    reference_title: "A homozygous nonsense mutation in DNAJC30 causes Leber's hereditary optic neuropathy with Leigh-like phenotypes."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      we demonstrated that DNAJC30 depletion specifically decreased enzyme
      activity of complex I but not complex IV or V
    explanation: >-
      Independent confirmation, in a knockout cell model, that the enzymatic
      deficit is confined to complex I.
  - reference: PMID:33465056
    reference_title: "Impaired complex I repair causes recessive Leber's hereditary optic neuropathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The subtlety of the complex I–dependent respiration defect in the
      patient-derived fibroblast cell lines reflects the role of DNAJC30 in
      maintenance rather than in the structure or assembly of complex I
    explanation: >-
      The authors' own framing of why the biochemical defect is mild in
      fibroblasts and why it is a maintenance rather than an assembly defect.
  downstream:
  - target: Reduced Complex I-Dependent Respiration and ATP Output
    causal_link_type: DIRECT
    description: >-
      Reduced complex I catalytic competence lowers electron flux and proton
      pumping, and so lowers respiration and ATP output.
    evidence:
    - reference: PMID:37397562
      reference_title: "A homozygous nonsense mutation in DNAJC30 causes Leber's hereditary optic neuropathy with Leigh-like phenotypes."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        DNAJC30 depletion caused a decrease in oxygen consumption rate
        concerning basal, ATP production, and maximum conditions
      explanation: >-
        Links the complex I defect to a measured fall in respiration.
  - target: Increased Mitochondrial Reactive Oxygen Species Production
    causal_link_type: DIRECT
    description: >-
      A less catalytically competent complex I leaks more electrons, raising
      reactive oxygen species production.
    evidence:
    - reference: PMID:37397562
      reference_title: "A homozygous nonsense mutation in DNAJC30 causes Leber's hereditary optic neuropathy with Leigh-like phenotypes."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        we found that DNAJC30 depletion decreased mitochondrial membrane
        potential (Fig. 1H; Fig. S2A) while increasing cellular and mitochondrial
        ROS levels
      explanation: >-
        Links loss of DNAJC30, and so the accumulation of impaired complex I,
        to a measured rise in reactive oxygen species.

- name: Reduced Complex I-Dependent Respiration and ATP Output
  biological_scale: CELLULAR
  role: intermediate
  mechanism_confidence: ESTABLISHED
  description: >-
    Cells lacking DNAJC30 respire less. Oxygen consumption falls at basal,
    ATP-linked and maximal capacity, and the mitochondrial membrane potential
    drops with it. This is the energy-supply arm of the cellular lesion, kept
    separate from the oxidative arm because the two have different downstream
    consequences and because the oxidative arm feeds back onto the complex
    itself.
  biological_processes:
  - preferred_term: oxidative phosphorylation
    modifier: DECREASED
    term:
      id: GO:0006119
      label: oxidative phosphorylation
  evidence:
  - reference: PMID:37397562
    reference_title: "A homozygous nonsense mutation in DNAJC30 causes Leber's hereditary optic neuropathy with Leigh-like phenotypes."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      DNAJC30 depletion caused a decrease in oxygen consumption rate concerning
      basal, ATP production, and maximum conditions
    explanation: >-
      Measures the respiratory deficit directly across three respiratory
      states.
  - reference: PMID:37397562
    reference_title: "A homozygous nonsense mutation in DNAJC30 causes Leber's hereditary optic neuropathy with Leigh-like phenotypes."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      we found that DNAJC30 depletion decreased mitochondrial membrane
      potential (Fig. 1H; Fig. S2A) while increasing cellular and mitochondrial
      ROS levels
    explanation: >-
      Records the fall in mitochondrial membrane potential that accompanies the
      respiratory deficit.
  downstream:
  - target: Retinal Ganglion Cell Degeneration
    causal_link_type: DIRECT
    description: >-
      Retinal ganglion cells, and the unmyelinated small-calibre axons of the
      papillomacular bundle in particular, are the cells that fail first when
      ATP supply falls.
    evidence:
    - reference: PMID:38139324
      reference_title: "DNAJC30 Gene Variants Are a Frequent Cause of a Rare Disease: Leber Hereditary Optic Neuropathy in Polish Patients."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        It results in low ATP synthesis and high levels of reactive oxygen
        species, which causes the degeneration of retinal ganglion cells.
      explanation: >-
        States the causal step from low ATP synthesis to retinal ganglion cell
        degeneration.
  - target: Subacute Necrotizing Encephalopathy of Basal Ganglia and Brainstem
    causal_link_type: DIRECT
    description: >-
      In a minority of patients the same biochemical lesion produces the Leigh
      syndrome pattern of symmetric basal ganglia and brainstem necrosis
      instead of, or in addition to, the optic phenotype. Why the same genotype
      takes this route is unresolved and is recorded as a knowledge gap.
    evidence:
    - reference: PMID:35861300
      reference_title: "Expanding the phenotype of DNAJC30-associated Leigh syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Recently, biallelic variants in DNAJC30 gene, encoding a protein
        crucial for the repair of mitochondrial complex I subunits, have been
        associated with Leber hereditary optic neuropathy and LS.
      explanation: >-
        Links the same repair defect to the Leigh syndrome presentation.

- name: Increased Mitochondrial Reactive Oxygen Species Production
  biological_scale: CELLULAR
  role: intermediate
  mechanism_confidence: ESTABLISHED
  description: >-
    The oxidative arm, and the reason this disease is self-amplifying. Cells
    lacking DNAJC30 generate more reactive oxygen species at both the cellular
    and the mitochondrial level. Reactive oxygen species are what damage the
    complex I N module subunits in the first place, which is why those subunits
    need exchanging at all, so raising them increases the demand for exactly
    the repair activity that has been lost. That loop is drawn explicitly as an
    edge below rather than left in prose.
  biological_processes:
  - preferred_term: response to oxidative stress
    modifier: INCREASED
    term:
      id: GO:0006979
      label: response to oxidative stress
  evidence:
  - reference: PMID:37397562
    reference_title: "A homozygous nonsense mutation in DNAJC30 causes Leber's hereditary optic neuropathy with Leigh-like phenotypes."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      we found that DNAJC30 depletion decreased mitochondrial membrane
      potential (Fig. 1H; Fig. S2A) while increasing cellular and mitochondrial
      ROS levels
    explanation: >-
      Measures the rise in cellular and mitochondrial reactive oxygen species
      in a DNAJC30 knockout line.
  downstream:
  - target: Accumulation of Functionally Impaired Complex I
    causal_link_type: DIRECT
    description: >-
      Reactive oxygen species are the source of the damage to the N module
      subunits that DNAJC30 normally clears, so rising oxidative load adds to
      the pool of damaged subunits that can no longer be exchanged. This is the
      feed-forward loop of the disease.
    evidence:
    - reference: PMID:33465056
      reference_title: "Impaired complex I repair causes recessive Leber's hereditary optic neuropathy."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        We demonstrate DNAJC30 to be a chaperone protein integral to a complex I
        repair mechanism, controlling the exchange of complex I subunits likely
        damaged by exposure to reactive oxygen species.
      explanation: >-
        Establishes that the subunits requiring exchange are those damaged by
        reactive oxygen species, which is what makes raised reactive oxygen
        species add to the burden on a repair pathway that has already failed.
  - target: Retinal Ganglion Cell Degeneration
    causal_link_type: DIRECT
    description: >-
      Oxidative load acts on the same cells as the energy deficit.
    evidence:
    - reference: PMID:38139324
      reference_title: "DNAJC30 Gene Variants Are a Frequent Cause of a Rare Disease: Leber Hereditary Optic Neuropathy in Polish Patients."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        It results in low ATP synthesis and high levels of reactive oxygen
        species, which causes the degeneration of retinal ganglion cells.
      explanation: >-
        States the causal step from high reactive oxygen species to retinal
        ganglion cell degeneration.

- name: Retinal Ganglion Cell Degeneration
  biological_scale: CELLULAR
  role: consequence
  mechanism_confidence: ESTABLISHED
  description: >-
    Retinal ganglion cells are the tissue-selective target, and the reason the
    disease presents as an optic neuropathy rather than a systemic
    mitochondrial disorder. Their loss can be measured objectively before
    subjective visual loss is bilateral: photopic negative response
    electroretinography in an arLHON family showed abnormal ganglion cell
    function in both eyes of patients whose visual acuity had fallen in only
    one. Axonal degeneration follows the initial cell body dysfunction.
  cell_types:
  - preferred_term: Retinal ganglion cell
    term:
      id: CL:0000740
      label: retinal ganglion cell
  locations:
  - preferred_term: retina
    term:
      id: UBERON:0000966
      label: retina
  evidence:
  - reference: PMID:38139324
    reference_title: "DNAJC30 Gene Variants Are a Frequent Cause of a Rare Disease: Leber Hereditary Optic Neuropathy in Polish Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      LHON is a neurodegenerative disease of the optic nerve, causing the
      initial dysfunction of retinal ganglion cells, followed by axon
      degeneration.
    explanation: >-
      States the cellular sequence, dysfunction of the ganglion cell followed
      by degeneration of its axon.
  - reference: PMID:36359543
    reference_title: "Phenotypic Variation of Autosomal Recessive Leber Hereditary Optic Neuropathy (arLHON) in One Family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In Leber hereditary optic neuropathy, abnormal retinal ganglion cells
      function can be found in both eyes, even if visual acuity loss only
      occurs in one eye.
    explanation: >-
      Reports objective electrophysiological evidence of bilateral ganglion
      cell dysfunction in an arLHON family, including eyes still clinically
      unaffected.
  downstream:
  - target: Optic Nerve Atrophy
    causal_link_type: DIRECT
    description: >-
      Loss of ganglion cell axons thins the retinal nerve fibre layer and
      leaves a pale, atrophic optic disc.
    evidence:
    - reference: PMID:36388184
      reference_title: "Case report: Long-term follow-up of two patients with LHON caused by DNAJC30:c.152G>A pathogenic variant-case series."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Both experienced further deterioration several months after the onset
        accompanied by thinning of the peripapillary retinal nerve fiber layer
        (RNFL).
      explanation: >-
        Documents progressive nerve fibre layer thinning in two genetically
        confirmed arLHON patients.

- name: Optic Nerve Atrophy
  biological_scale: TISSUE
  role: consequence
  mechanism_confidence: ESTABLISHED
  description: >-
    The chronic endpoint. After the acute phase, in which the disc is
    hyperaemic and the nerve fibre layer swollen, the disc becomes pale and the
    peripapillary nerve fibre layer thins, most conspicuously in the temporal
    sector that carries the papillomacular bundle. Structural loss continues
    even in patients whose visual acuity is recovering, which is why the
    optical coherence tomography appearance and the functional outcome can
    diverge.
  locations:
  - preferred_term: optic nerve
    term:
      id: UBERON:0000941
      label: cranial nerve II
  evidence:
  - reference: PMID:37397562
    reference_title: "A homozygous nonsense mutation in DNAJC30 causes Leber's hereditary optic neuropathy with Leigh-like phenotypes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He then developed bilateral optic atrophy and rapid progressive bilateral
      visual loss.
    explanation: >-
      Documents bilateral optic atrophy in a patient with a confirmed
      homozygous DNAJC30 nonsense variant.
  - reference: PMID:36388184
    reference_title: "Case report: Long-term follow-up of two patients with LHON caused by DNAJC30:c.152G>A pathogenic variant-case series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Presented are two autosomal recessive LHON (arLHON, OMIM:619382) cases
      with the same DNAJC30:c.152G>A pathogenic variant and different degrees
      of spontaneous visual recovery despite progressive RNFL thinning during a
      long-term follow-up.
    explanation: >-
      Establishes that structural loss continues even while visual function
      recovers, which is why the structural endpoint and the functional outcome
      must be read separately in this disease.

- name: Subacute Necrotizing Encephalopathy of Basal Ganglia and Brainstem
  biological_scale: TISSUE
  role: consequence
  mechanism_confidence: ESTABLISHED
  description: >-
    A minority branch, and the reason DNAJC30 belongs on a Leigh syndrome gene
    panel as well as an optic neuropathy panel. Patients present with dystonia,
    ataxia, gait disturbance and hemiparesis, and imaging shows symmetric or
    asymmetric hyperintensities and necrosis in the putamen, other basal
    ganglia nuclei, thalamus and brainstem. Optic involvement may follow, may
    accompany it, or may be absent altogether. Blood lactate is normal or only
    moderately raised, so a normal lactate does not exclude the diagnosis. The
    branch occurs on the same founder genotype that elsewhere produces isolated
    optic neuropathy, and also on truncating alleles.
  locations:
  - preferred_term: basal ganglion
    term:
      id: UBERON:0002420
      label: basal ganglion
  evidence:
  - reference: PMID:37397562
    reference_title: "A homozygous nonsense mutation in DNAJC30 causes Leber's hereditary optic neuropathy with Leigh-like phenotypes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Brain magnetic resonance imaging (MRI) showed bilateral basal ganglion
      and thalamic hyperintensities concerning putaminal necrosis.
    explanation: >-
      Documents the imaging lesion that defines this branch, in a patient with
      a homozygous DNAJC30 nonsense variant.
  - reference: PMID:35861300
    reference_title: "Expanding the phenotype of DNAJC30-associated Leigh syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      DNAJC30-associated LS is characterized by variable age at onset, movement
      disorder phenotype and normal or moderately elevated blood lactate level.
    explanation: >-
      Characterises the branch, including the clinically important point that
      lactate may be normal.
  - reference: PMID:35861300
    reference_title: "Expanding the phenotype of DNAJC30-associated Leigh syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Importantly, DNAJC30 pathogenic variants should be suspected in patients
      with LS irrespective of optic nerve involvement.
    explanation: >-
      Establishes that the Leigh branch can occur without any optic phenotype.
  - reference: PMID:35091433
    reference_title: "DNAJC30 disease-causing gene variants in a large Central European cohort of patients with suspected Leber's hereditary optic neuropathy and optic atrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      No extra-ocular manifestation were found in our DNAJC30-linked patients
      with arLHON.
    explanation: >-
      Bounds the size of this branch rather than denying it. Thirty-five
      DNAJC30 patients in a Central European cohort had purely ocular disease,
      so the Leigh presentation is a minority route and should not be expected
      in a patient presenting with optic neuropathy.

phenotypes:
- category: Ophthalmological
  name: Reduced Visual Acuity
  description: >-
    Subacute, painless loss of central visual acuity is the presenting feature
    in the great majority of patients. Onset is typically in the second or
    third decade and is earlier than in the mitochondrial form. One eye is
    usually affected first with the fellow eye following within days to months,
    though bilateral onset at presentation is more common in arLHON than in
    mtLHON.
  phenotype_term:
    preferred_term: Reduced visual acuity
    term:
      id: HP:0007663
      label: Reduced visual acuity
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:38139324
    reference_title: "DNAJC30 Gene Variants Are a Frequent Cause of a Rare Disease: Leber Hereditary Optic Neuropathy in Polish Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Most patients' first symptom of LHON was the deterioration or loss of
      visual acuity.
    explanation: >-
      In a series of 46 Polish patients all carrying DNAJC30 variants, loss of
      visual acuity was the presenting symptom in most, supporting the
      VERY_FREQUENT band.
  - reference: PMID:38107630
    reference_title: "Case report: Mutations in DNAJC30 causing autosomal recessive Leber hereditary optic neuropathy are common amongst Eastern European individuals."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we report the cases of three Eastern European individuals presenting with
      bilateral painless visual loss, one of whom was also exhibiting motor
      symptoms
    explanation: >-
      Documents the painless bilateral character of the visual loss in three
      genetically confirmed arLHON patients.
  - reference: PMID:35091433
    reference_title: "DNAJC30 disease-causing gene variants in a large Central European cohort of patients with suspected Leber's hereditary optic neuropathy and optic atrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical investigation of the patients with arLHON revealed a younger age
      of onset, a more frequent bilateral onset and an increased clinically
      relevant recovery compared with LHON associated with disease-causing
      variants in the mitochondrial DNA.
    explanation: >-
      Establishes the three clinical respects in which arLHON differs from the
      mitochondrial form.
  - reference: PMID:35091433
    reference_title: "DNAJC30 disease-causing gene variants in a large Central European cohort of patients with suspected Leber's hereditary optic neuropathy and optic atrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The median age at onset of the disease was 18.5 years (range 9.5–45.1).
      All patients showed involvement of both eyes. Bilateral onset was
      observed in 40% (n=8).
    explanation: >-
      Quantifies age at onset and establishes that involvement becomes
      bilateral in every patient, with simultaneous bilateral onset in 40
      percent.

- category: Ophthalmological
  name: Optic Atrophy
  description: >-
    The structural endpoint of retinal ganglion cell axon loss. The optic disc
    becomes pale, initially in the temporal sector, and the peripapillary
    retinal nerve fibre layer thins on optical coherence tomography. It is
    bilateral even when the two eyes were affected sequentially.
  phenotype_term:
    preferred_term: Optic atrophy
    term:
      id: HP:0000648
      label: Optic atrophy
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:35091433
    reference_title: "DNAJC30 disease-causing gene variants in a large Central European cohort of patients with suspected Leber's hereditary optic neuropathy and optic atrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In the course of the disease, mostly temporally accentuated papillary
      atrophy was observed in 91.7% (n=22).
    explanation: >-
      Quantifies optic atrophy in the Central European DNAJC30 cohort at 91.7
      percent, supporting the VERY_FREQUENT band, and records its
      characteristic temporal accentuation.
  - reference: PMID:37397562
    reference_title: "A homozygous nonsense mutation in DNAJC30 causes Leber's hereditary optic neuropathy with Leigh-like phenotypes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He also showed acute bilateral optic atrophy, subacute central vision
      loss, and abnormal brain MRI.
    explanation: >-
      Documents bilateral optic atrophy in the second of two unrelated patients
      homozygous for the same DNAJC30 nonsense allele.
  - reference: PMID:36388184
    reference_title: "Case report: Long-term follow-up of two patients with LHON caused by DNAJC30:c.152G>A pathogenic variant-case series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Both experienced further deterioration several months after the onset
      accompanied by thinning of the peripapillary retinal nerve fiber layer
      (RNFL).
    explanation: >-
      Documents the structural correlate of optic atrophy in two genetically
      confirmed arLHON patients.

- category: Ophthalmological
  name: Centrocecal Scotoma
  description: >-
    The characteristic visual field defect, reflecting selective loss of the
    papillomacular bundle. It is central or centrocecal, enlarges as visual
    acuity falls, and in patients who recover it breaks up into islands of
    preserved vision within the scotoma rather than shrinking uniformly from
    the edge.
  phenotype_term:
    preferred_term: Centrocecal scotoma
    term:
      id: HP:0000576
      label: Centrocecal scotoma
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:35091433
    reference_title: "DNAJC30 disease-causing gene variants in a large Central European cohort of patients with suspected Leber's hereditary optic neuropathy and optic atrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Visual field defects (figure 4) were central or cecocentral in 96.6%
      (n=28).
    explanation: >-
      Quantifies the field defect in the Central European DNAJC30 cohort at
      96.6 percent, which places it in the VERY_FREQUENT band.
  - reference: PMID:38139324
    reference_title: "DNAJC30 Gene Variants Are a Frequent Cause of a Rare Disease: Leber Hereditary Optic Neuropathy in Polish Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Most patients reported centrocecal scotoma or other visual field defects,
      and some patients noticed impaired color perception.
    explanation: >-
      Independent replication in the 46-patient Polish DNAJC30 series.
  - reference: PMID:36388184
    reference_title: "Case report: Long-term follow-up of two patients with LHON caused by DNAJC30:c.152G>A pathogenic variant-case series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The visual loss was characterized by centrocecal scotoma, abnormal PERG
      N95 and VEP, and retinal nerve fiber thinning on the OCT.
    explanation: >-
      Characterises the field defect in two patients homozygous for the founder
      allele.

- category: Ophthalmological
  name: Color Vision Defect
  description: >-
    Impaired colour perception accompanies the visual loss and is often an
    early sign. In arLHON it may be relatively preserved in the early phase,
    which the reporting authors note is atypical for the mitochondrial form,
    and it can recover substantially alongside visual acuity.
  phenotype_term:
    preferred_term: Color vision defect
    term:
      id: HP:0000551
      label: Color vision defect
  frequency: FREQUENT
  evidence:
  - reference: PMID:35091433
    reference_title: "DNAJC30 disease-causing gene variants in a large Central European cohort of patients with suspected Leber's hereditary optic neuropathy and optic atrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Colour vision disturbances were observed in 68.8% (n=11) and were
      non-specific.
    explanation: >-
      Quantifies colour vision disturbance in the Central European DNAJC30
      cohort at 68.8 percent, which falls in the FREQUENT band.
  - reference: PMID:36388184
    reference_title: "Case report: Long-term follow-up of two patients with LHON caused by DNAJC30:c.152G>A pathogenic variant-case series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Interestingly, pain in eye movements was present in Case 1, and color
      vision seemed to be preserved in early phases in both, which is not
      typical for mtLHON.
    explanation: >-
      Records that early colour vision may be relatively preserved in arLHON,
      unlike the mitochondrial form.

- category: Ophthalmological
  name: Optic Disc Hyperemia in the Acute Phase
  description: >-
    During the acute phase the optic disc is hyperaemic and swollen, often with
    peripapillary telangiectatic microangiopathy, and there is no leakage on
    fluorescein angiography. The appearance is regularly mistaken for optic
    neuritis, and the absence of angiographic leakage is what distinguishes it.
    The pallor of the chronic phase follows months later.
  phenotype_term:
    preferred_term: Abnormal optic disc morphology
    term:
      id: HP:0012795
      label: Abnormal optic disc morphology
    temporality: ACUTE
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:35091433
    reference_title: "DNAJC30 disease-causing gene variants in a large Central European cohort of patients with suspected Leber's hereditary optic neuropathy and optic atrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Initial papillary microangiopathy (figure 4) was common and occurred in
      94.1% (n=16).
    explanation: >-
      Quantifies the acute-phase peripapillary microangiopathy in the Central
      European DNAJC30 cohort at 94.1 percent, supporting the VERY_FREQUENT
      band.
  - reference: PMID:38139324
    reference_title: "DNAJC30 Gene Variants Are a Frequent Cause of a Rare Disease: Leber Hereditary Optic Neuropathy in Polish Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Fundus examination showed hyperemic optic nerves during the acute phase
      of LHON in most patients.
    explanation: >-
      Reports acute-phase disc hyperaemia in the DNAJC30 Polish series.
  - reference: PMID:36388184
    reference_title: "Case report: Long-term follow-up of two patients with LHON caused by DNAJC30:c.152G>A pathogenic variant-case series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Both had hyperemic optic disks (PNO) and central scotoma in their visual
      fields.
    explanation: >-
      Documents the acute-phase disc appearance in two genetically confirmed
      patients.
  notes: >-
    Bound to the parent term HP:0012795 because HPO has no term for optic disc
    hyperaemia or for acute-phase disc swelling with preserved angiography;
    HP:0000543 Optic disc pallor describes the opposite, chronic appearance and
    would be wrong here. Searched with runoak against sqlite:obo:hp for "optic
    disc" and reviewed all eleven descendants.

- category: Neurological
  name: Dystonia
  description: >-
    A feature of the Leigh syndrome branch rather than of isolated optic
    neuropathy. Onset may be acute, and dystonia may precede any visual
    symptom by years. It reflects the basal ganglia lesions rather than the
    optic pathway.
  phenotype_term:
    preferred_term: Dystonia
    term:
      id: HP:0001332
      label: Dystonia
  evidence:
  - reference: PMID:37397562
    reference_title: "A homozygous nonsense mutation in DNAJC30 causes Leber's hereditary optic neuropathy with Leigh-like phenotypes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we report a 12-year-old boy with acute dystonia onset at age 10.
    explanation: >-
      Documents dystonia as the presenting feature in a patient homozygous for
      a DNAJC30 nonsense variant, preceding the optic phenotype.
  - reference: PMID:35861300
    reference_title: "Expanding the phenotype of DNAJC30-associated Leigh syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      DNAJC30-associated LS is characterized by variable age at onset, movement
      disorder phenotype and normal or moderately elevated blood lactate level.
    explanation: >-
      Establishes a movement disorder phenotype as characteristic of the Leigh
      branch.
  notes: >-
    Frequency deliberately omitted. Dystonia belongs to the Leigh branch, which
    is a minority of DNAJC30 patients, and no source quantifies its frequency
    either across all DNAJC30 patients or within the Leigh subgroup.

- category: Neurological
  name: Bilateral Basal Ganglia Lesions
  description: >-
    Symmetric or bilateral signal change and necrosis of the putamen and other
    basal ganglia nuclei, sometimes extending to thalamus, midbrain,
    periaqueductal grey and medulla. This is the imaging finding that
    establishes the Leigh syndrome branch, and it may be present with or
    without optic involvement.
  phenotype_term:
    preferred_term: Bilateral basal ganglia lesions
    term:
      id: HP:0007146
      label: Bilateral basal ganglia lesions
  evidence:
  - reference: PMID:37397562
    reference_title: "A homozygous nonsense mutation in DNAJC30 causes Leber's hereditary optic neuropathy with Leigh-like phenotypes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Brain magnetic resonance imaging (MRI) showed bilateral basal ganglion
      and thalamic hyperintensities concerning putaminal necrosis.
    explanation: >-
      Documents bilateral basal ganglia and thalamic lesions in a patient with
      a homozygous DNAJC30 nonsense variant.
  - reference: PMID:33465056
    reference_title: "Impaired complex I repair causes recessive Leber's hereditary optic neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      bilateral necrosis of the putamen with lesions in the pedunculi
      cerebelli suggestive of Leigh syndrome on brain MRI
    explanation: >-
      Documents the same imaging pattern in the Leigh syndrome patient of the
      founding arLHON cohort.
  notes: >-
    Frequency deliberately omitted for the same reason as Dystonia: the Leigh
    branch is a minority of DNAJC30 patients and its size is not quantified in
    the cited sources.

- category: Neurological
  name: Ataxia
  description: >-
    Part of the movement disorder of the Leigh branch, alongside dystonia,
    gait disturbance and hemiparesis. It progresses in stepwise decrements
    rather than smoothly.
  phenotype_term:
    preferred_term: Ataxia
    term:
      id: HP:0001251
      label: Ataxia
  evidence:
  - reference: PMID:39132756
    reference_title: "Effects of idebenone treatment in a patient with DNAJC30-associated Leigh Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Over the years, he experienced progressive optic neuropathy, ataxia,
      left-sided hemiparesis, and limb dystonia.
    explanation: >-
      Documents ataxia in a patient homozygous for the p.(Tyr51Cys) founder
      allele with the Leigh presentation.

genetic:
- name: DNAJC30
  notes: >-
    The single causative gene. It has one exon, which makes Sanger sequencing
    of the whole coding region cheap and is the practical argument for testing
    it in parallel with the mitochondrial genome in any unsolved LHON. The
    founder allele c.152A>G p.(Tyr51Cys) accounts for the overwhelming majority
    of disease alleles across Eastern and Central Europe; the contribution of
    the gene to the LHON caseload therefore varies sharply with ancestry,
    from roughly 3 percent of an unsolved Central European optic neuropathy
    cohort to over a fifth of molecularly solved LHON in Moscow, and in one
    Polish series it exceeded the mitochondrial form.
  gene_term:
    preferred_term: DNAJC30
    term:
      id: hgnc:16410
      label: DNAJC30
  relationship_type: CAUSATIVE
  variants:
  - name: c.152A>G (p.Tyr51Cys) founder variant
    description: >-
      The Eastern European founder allele, carried homozygously by 29 of the 33
      patients in the founding cohort and accounting for about 90 percent of
      disease alleles in a Central European series. It lies in the J domain and
      was estimated to have arisen about 85 generations ago. Its gnomAD allele
      frequency of 0.125 percent, with no homozygotes recorded, is high enough
      that full penetrance would predict more disease than is observed, which is
      itself part of the evidence for incomplete penetrance.
    gene:
      preferred_term: DNAJC30
      term:
        id: hgnc:16410
        label: DNAJC30
    clinical_significance: PATHOGENIC
    type: missense_variant
    evidence:
    - reference: PMID:33465056
      reference_title: "Impaired complex I repair causes recessive Leber's hereditary optic neuropathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Of the 33 subjects, 29 harbored the same NM_032317.2 c.152A>G
        (7:73097602, NP_115693.2 p.Tyr51Cys) homozygous variant with an allele
        frequency of 0.125%
      explanation: >-
        Records the allele, its homozygous state in most patients, and its
        population frequency.
    - reference: PMID:35091433
      reference_title: "DNAJC30 disease-causing gene variants in a large Central European cohort of patients with suspected Leber's hereditary optic neuropathy and optic atrophy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The previously described missense variant c.152A>G;p.(Tyr51Cys) accounts
        for 90% of disease-associated alleles in our cohort and we confirmed a
        strong founder effect.
      explanation: >-
        Independent confirmation of the allele's dominance and founder origin.
  - name: c.610G>T (p.Glu204*)
    description: >-
      A nonsense allele found in three unrelated patients, in each case in
      compound heterozygosity with the founder variant and confirmed to be in
      trans by allelic cloning. It is the one reported allele lying outside the
      J domain, truncating instead upstream of the transmembrane domain.
    gene:
      preferred_term: DNAJC30
      term:
        id: hgnc:16410
        label: DNAJC30
    clinical_significance: PATHOGENIC
    type: nonsense_variant
    evidence:
    - reference: PMID:35091433
      reference_title: "DNAJC30 disease-causing gene variants in a large Central European cohort of patients with suspected Leber's hereditary optic neuropathy and optic atrophy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The nonsense variant c.610G>T;p.(Glu204*) was observed in three
        unrelated patients with LHON in compound heterozygous state with the
        common c.152A>G;p.(Tyr51Cys) variant, as confirmed by allelic cloning
      explanation: >-
        Records the allele, its compound heterozygous context, and the phasing
        evidence.
  - name: c.24G>A (p.Trp8*)
    description: >-
      A nonsense allele reported homozygously in two unrelated patients, both
      of whom had a Leigh-like course with earlier onset than the missense
      cohort. It is mechanistically the most informative allele in the gene: it
      abolishes the protein outright in cells, which is what establishes loss of
      function rather than a dominant-negative or aberrant activity as the
      disease mechanism.
    gene:
      preferred_term: DNAJC30
      term:
        id: hgnc:16410
        label: DNAJC30
    clinical_significance: PATHOGENIC
    type: nonsense_variant
    evidence:
    - reference: PMID:37397562
      reference_title: "A homozygous nonsense mutation in DNAJC30 causes Leber's hereditary optic neuropathy with Leigh-like phenotypes."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Exome sequencing analysis of his peripheral blood sample revealed a
        homozygous nonsense germline variant, c.24G>A (p.W8X) in the DNAJC30
        gene, proven to result in a complete loss of DNAJC30 protein expression
        in cells.
      explanation: >-
        Records the allele and the demonstration that it eliminates the protein.
  case_fractions:
  - population: Central European cohort with clinical LHON or other inherited optic atrophy, previously genetically unsolved
    case_fraction_percent: 2.9
    cohort_size: 1202
    notes: >-
      Detection rate across the whole screened cohort of 800 LHON and 402 optic
      atrophy patients. Within the LHON subgroup alone the rate was 3.6 percent.
    evidence:
    - reference: PMID:35091433
      reference_title: "DNAJC30 disease-causing gene variants in a large Central European cohort of patients with suspected Leber's hereditary optic neuropathy and optic atrophy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We identified likely pathogenic variants in 35/1202 patients,
        corresponding to a detection rate of 2.9%.
      explanation: >-
        Quantifies the share of a previously unsolved Central European cohort
        explained by DNAJC30.
  - population: Molecularly confirmed LHON patients, Research Centre for Medical Genetics, Moscow
    case_fraction_percent: 20.9
    cohort_size: 86
    notes: >-
      Founder-population estimate. The remaining 79.1 percent carried pathogenic
      mtDNA mutations.
    evidence:
    - reference: PMID:33465056
      reference_title: "Impaired complex I repair causes recessive Leber's hereditary optic neuropathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Of 86 molecularly confirmed LHON patients investigated by full mtDNA
        sequencing and WES in the Research Centre for Medical Genetics in
        Moscow, 18 (20.9%) harbored the homozygous p.Tyr51Cys DNAJC30 mutation
      explanation: >-
        Quantifies the much higher share of LHON attributable to DNAJC30 within
        the founder population.
  evidence:
  - reference: PMID:33465056
    reference_title: "Impaired complex I repair causes recessive Leber's hereditary optic neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Given that the majority of the patients originate from Russia, Poland,
      Romania, and Ukraine, the p.Tyr51Cys DNAJC30 variant is ascribed to an
      Eastern European founder event.
    explanation: >-
      Establishes the founder origin and geographic distribution of the
      dominant disease allele.
  - reference: PMID:35091433
    reference_title: "DNAJC30 disease-causing gene variants in a large Central European cohort of patients with suspected Leber's hereditary optic neuropathy and optic atrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The previously described missense variant c.152A>G;p.(Tyr51Cys) accounts
      for 90% of disease-associated alleles in our cohort and we confirmed a
      strong founder effect.
    explanation: >-
      Independent confirmation of the founder effect and of the allele's
      dominance of the mutational spectrum.
  - reference: PMID:38139324
    reference_title: "DNAJC30 Gene Variants Are a Frequent Cause of a Rare Disease: Leber Hereditary Optic Neuropathy in Polish Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Based on our data, the autosomal recessive form of LHON caused by DNAJC30
      gene mutations is more frequent than the mitochondrial form in Polish
      patients.
    explanation: >-
      Shows that in one national series the nuclear form outnumbers the
      mitochondrial form, which is the strongest statement of ancestry
      dependence available.

prevalence:
- population: Worldwide, derived from the founder allele frequency
  measure_type: POINT_PREVALENCE
  prevalence_class: BAND_1_9_PER_1000000
  rate_per_100000: 0.109
  notes: >-
    Estimated from the gnomAD allele frequency of the p.(Tyr51Cys) founder
    variant under Hardy-Weinberg with adjustment for the observed incomplete
    penetrance. The estimate is anchored on one allele in one population and
    should be read as an order of magnitude, not a measured rate; local
    prevalence in the Eastern European founder population is substantially
    higher.
  evidence:
  - reference: PMID:33465056
    reference_title: "Impaired complex I repair causes recessive Leber's hereditary optic neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Taking the allele frequency of the variant (0.125%) and applying the
      Hardy-Weinberg equation with adjustment for the observed incomplete
      penetrance, arLHON is estimated to affect 1.09 per million individuals
    explanation: >-
      States the derivation and the value normalised here to 0.109 per 100,000.

progression:
- phase: Acute and subacute visual loss
  age_range: Second to third decade, median age at onset 18.5 years
  notes: >-
    Painless central visual loss begins in one eye or in both at once, with
    bilateral onset in 40 percent of patients and a median of 3.5 weeks
    between eyes when onset is sequential. The disc is hyperaemic with
    peripapillary microangiopathy. Onset is earlier and more tightly clustered
    than in the mitochondrial form, and involvement becomes bilateral in every
    patient.
  evidence:
  - reference: PMID:35091433
    reference_title: "DNAJC30 disease-causing gene variants in a large Central European cohort of patients with suspected Leber's hereditary optic neuropathy and optic atrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The median age at onset of the disease was 18.5 years (range 9.5–45.1).
      All patients showed involvement of both eyes. Bilateral onset was
      observed in 40% (n=8).
    explanation: >-
      Gives the age at onset and the laterality pattern of the acute phase.
  - reference: PMID:35091433
    reference_title: "DNAJC30 disease-causing gene variants in a large Central European cohort of patients with suspected Leber's hereditary optic neuropathy and optic atrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In cases with bilateral onset, a median of 3.5 weeks (range 1–17) elapsed
      between the first eye and the second eye.
    explanation: >-
      Quantifies the interval between eyes in sequentially affected patients.
- phase: Nadir and spontaneous recovery
  notes: >-
    This phase is what most distinguishes arLHON prognostically, and it is
    partly independent of treatment. In the Central European cohort only one
    of 35 patients received idebenone, and he had already recovered before
    starting it; clinically relevant recovery nonetheless occurred in 45
    percent, at a median of 19 months from onset. Median visual acuity
    improved from 1.3 logMAR at nadir to 0.5 logMAR at last visit. The
    founding cohort likewise reported recovery in 50 percent of untreated
    eyes. Recovery is therefore a feature of the natural history and not
    solely a drug effect, which is why the treated figures under Idebenone
    should not be read as the treatment's attributable benefit.
  evidence:
  - reference: PMID:35091433
    reference_title: "DNAJC30 disease-causing gene variants in a large Central European cohort of patients with suspected Leber's hereditary optic neuropathy and optic atrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      CRR was seen in 45% (n=9) at a median of 19 months (range 1–58) after
      onset.
    explanation: >-
      Quantifies spontaneous clinically relevant recovery in a cohort that was
      effectively untreated.
  - reference: PMID:35091433
    reference_title: "DNAJC30 disease-causing gene variants in a large Central European cohort of patients with suspected Leber's hereditary optic neuropathy and optic atrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Only one patient received idebenone over a period of 6 months. He
      developed a CRR even before the start of idebenone therapy.
    explanation: >-
      Establishes that the 45 percent recovery rate in this cohort is not
      attributable to idebenone, since essentially nobody received it.
  - reference: PMID:33465056
    reference_title: "Impaired complex I repair causes recessive Leber's hereditary optic neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Of the 36 treated and 26 untreated eyes, CRR was reported in 29 (80.6%)
      and 13 (50.0%), respectively.
    explanation: >-
      Gives the untreated recovery rate from the founding cohort, 50 percent of
      eyes, alongside the treated rate.
  - reference: PMID:35148383
    reference_title: "DNAJC30 defect: a frequent cause of recessive Leber hereditary optic neuropathy and Leigh syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The autosomal recessive LHON patients demonstrate an earlier age of
      disease onset and a higher rate of idebenone-treated and spontaneous
      recovery of vision in comparison to reported figures for maternally
      inherited disease.
    explanation: >-
      States that both treated and spontaneous recovery exceed the figures
      reported for the mitochondrial form, which is the prognostic claim this
      phase records.
- phase: Chronic phase
  notes: >-
    Optic disc pallor and peripapillary retinal nerve fibre layer thinning are
    established and continue. Structural loss is progressive even in patients
    whose visual acuity is improving, so optical coherence tomography and
    visual function diverge in this phase. Visual function itself, once
    recovered, remained stable over follow-up of twelve and fourteen years in
    the two patients followed longest.
  evidence:
  - reference: PMID:36388184
    reference_title: "Case report: Long-term follow-up of two patients with LHON caused by DNAJC30:c.152G>A pathogenic variant-case series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Presented are two autosomal recessive LHON (arLHON, OMIM:619382) cases
      with the same DNAJC30:c.152G>A pathogenic variant and different degrees
      of spontaneous visual recovery despite progressive RNFL thinning during a
      long-term follow-up.
    explanation: >-
      Establishes the divergence between continuing structural loss and
      recovering function that characterises the chronic phase.
  - reference: PMID:36388184
    reference_title: "Case report: Long-term follow-up of two patients with LHON caused by DNAJC30:c.152G>A pathogenic variant-case series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient's visual function remained stable during the entire 12-year
      follow-up period.
    explanation: >-
      Records long-term functional stability after recovery, which is a
      statement about visual function and not about the optic nerve structure.

differential_diagnoses:
- name: Mitochondrial (maternally inherited) Leber hereditary optic neuropathy
  description: >-
    Clinically the same disease. Subacute painless bilateral central visual
    loss in a young adult, incomplete penetrance, male predominance, response
    to idebenone. It is caused instead by one of three mitochondrial DNA point
    mutations in complex I subunit genes, accounts for roughly 90 percent of
    LHON, and was for a century the only recognised form.
  distinguishing_features:
  - >-
    Family history. Maternal transmission points to the mitochondrial form; an
    affected sibling with unaffected parents, or no family history at all,
    points here.
  - >-
    Testing. Full mitochondrial DNA sequencing separates them, and because
    DNAJC30 has a single exon both can be sequenced in parallel rather than in
    sequence.
  - >-
    Onset and outcome. Onset in arLHON is earlier and more tightly clustered,
    bilateral onset is more common, and both spontaneous and treated recovery
    rates are higher.
  - >-
    Mechanism, in a research setting. The complex I N module turnover defect is
    present in arLHON cells and absent in mitochondrial LHON cells.
  evidence:
  - reference: PMID:33465056
    reference_title: "Impaired complex I repair causes recessive Leber's hereditary optic neuropathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      This defect was not found in mtLHON (n = 3) and is therefore specific to
      arLHON
    explanation: >-
      The mechanistic discriminator between the two forms.
  - reference: PMID:33465056
    reference_title: "Impaired complex I repair causes recessive Leber's hereditary optic neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Given this, we would suggest LHON to be subdivided as mtLHON and arLHON,
      due to the important impact on genetic counseling.
    explanation: >-
      States why the distinction is worth making clinically, which is genetic
      counselling rather than treatment.
- name: Other nuclear-gene LHON-like optic neuropathies
  description: >-
    Biallelic variants in NDUFS2, MCAT and NDUFA12 produce a typical LHON
    phenotype and are also nuclear and recessive, so they are not separated
    from this entity by inheritance pattern or by mitochondrial DNA testing.
    They have each been reported in only a few families, against roughly a
    hundred for DNAJC30.
  distinguishing_features:
  - >-
    Gene. Only sequencing distinguishes them; there is no reported clinical
    feature that does.
  - >-
    Ancestry shifts the prior. In Eastern and Central Europe the DNAJC30
    founder allele is far more likely than any of these.
  evidence:
  - reference: PMID:38139324
    reference_title: "DNAJC30 Gene Variants Are a Frequent Cause of a Rare Disease: Leber Hereditary Optic Neuropathy in Polish Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Typical LHON phenotypes have also been reported to be the effects of
      variants in other genes, namely NDUFS2, MCAT, and NDUFA12, detected only
      in a few families
    explanation: >-
      Names the other nuclear genes producing the same phenotype and records
      how few families each accounts for.
- name: Optic neuritis
  description: >-
    The differential that actually costs patients time. In the acute phase the
    disc is hyperaemic and the retinal nerve fibre layer is swollen, which is
    routinely read as inflammation. Patients are investigated for and treated
    as demyelinating disease before the diagnosis is reached, sometimes for
    years.
  distinguishing_features:
  - >-
    Fluorescein angiography shows no leakage in this disorder, unlike
    inflammatory disc swelling.
  - >-
    Pain on eye movement is characteristically absent, though it has been
    reported in at least one genetically confirmed arLHON patient, so its
    presence does not exclude the diagnosis.
  - >-
    Aquaporin-4 and myelin oligodendrocyte glycoprotein antibodies are
    negative, and intravenous corticosteroids do not improve vision.
  evidence:
  - reference: PMID:38139324
    reference_title: "DNAJC30 Gene Variants Are a Frequent Cause of a Rare Disease: Leber Hereditary Optic Neuropathy in Polish Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the swelling of the retinal nerve fiber layer, which, unfortunately, is
      often mistakenly considered a sign of an inflammatory process
    explanation: >-
      Names the specific finding that leads to the misdiagnosis.
  - reference: PMID:36388184
    reference_title: "Case report: Long-term follow-up of two patients with LHON caused by DNAJC30:c.152G>A pathogenic variant-case series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Extensive clinical workout, including brain magnetic resonance imaging
      (MRI), aquaporin 4 (Aq4), and anti-myelin oligodendrocyte protein
      (anti-MOG) antibodies, was negative.
    explanation: >-
      Records the negative inflammatory workup in two genetically confirmed
      arLHON patients.
  - reference: PMID:36388184
    reference_title: "Case report: Long-term follow-up of two patients with LHON caused by DNAJC30:c.152G>A pathogenic variant-case series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Intravenous corticosteroids did not improve vision.
    explanation: >-
      Records the failure of the treatment that would be given if the
      misdiagnosis were acted on.

treatments:
- name: Idebenone
  description: >-
    Idebenone is a short-chain benzoquinone that, once reduced, can accept
    electrons and deliver them to complex III, routing around the defective
    complex I. It is authorised for LHON by the European Medicines Agency and
    is given at 900 mg per day. Its use here is not merely inherited from the
    mitochondrial form: the arLHON cohorts report a treated recovery rate above
    that reported for mtLHON, which makes reaching a DNAJC30 diagnosis
    prognostically as well as genetically consequential. The important
    qualification is that the reported benefit is in the optic phenotype. In
    the one published patient with DNAJC30-associated Leigh syndrome treated
    with idebenone, the drug neither halted neurological progression nor
    prevented new lesions on imaging.
  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
  target_mechanisms:
  - target: Accumulation of Functionally Impaired Complex I
    treatment_effect: BYPASSES
    description: >-
      Reduced idebenone donates electrons to complex III, so electron flux and
      downstream ATP synthesis are partly restored without the damaged complex
      I being repaired. The predicate is BYPASSES rather than RESTORES because
      the drug does not act on the chaperone defect or on the retained damaged
      subunits.
    evidence:
    - reference: PMID:33465056
      reference_title: "Impaired complex I repair causes recessive Leber's hereditary optic neuropathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Idebenone therapy was received by 18 patients, as a potent antioxidant
        and electron donor approved for LHON by EMA
      explanation: >-
        States the drug's mechanism of action and its regulatory status in the
        arLHON cohort that received it.
  evidence:
  - reference: PMID:33465056
    reference_title: "Impaired complex I repair causes recessive Leber's hereditary optic neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Of the 36 treated and 26 untreated eyes, CRR was reported in 29 (80.6%)
      and 13 (50.0%), respectively.
    explanation: >-
      Quantifies clinically relevant recovery in treated versus untreated eyes
      in the founding arLHON cohort. This is an uncontrolled within-cohort
      comparison, not a randomised trial.
  - reference: PMID:35148383
    reference_title: "DNAJC30 defect: a frequent cause of recessive Leber hereditary optic neuropathy and Leigh syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The autosomal recessive LHON patients demonstrate an earlier age of
      disease onset and a higher rate of idebenone-treated and spontaneous
      recovery of vision in comparison to reported figures for maternally
      inherited disease.
    explanation: >-
      Independent replication that treated recovery in arLHON exceeds published
      figures for the mitochondrial form. Note it also reports higher
      spontaneous recovery, so the treated figure cannot be attributed to the
      drug alone.
  - reference: PMID:39132756
    reference_title: "Effects of idebenone treatment in a patient with DNAJC30-associated Leigh Syndrome."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      As evidenced in our case, idebenone did not halt progression of the
      disease, nor induce any neuroprotective effect apparent in neuroimaging.
    explanation: >-
      Refutes the extension of idebenone benefit from the optic phenotype to
      the Leigh branch, in a patient carrying the same founder allele as the
      responsive optic cases.
  - reference: PMID:39132756
    reference_title: "Effects of idebenone treatment in a patient with DNAJC30-associated Leigh Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In conclusion, despite the significant efficacy of idebenone in arLHON,
      its benefit in LS remains uncertain.
    explanation: >-
      The authors' own framing: efficacy in the optic phenotype is accepted,
      benefit in the Leigh branch is unresolved on a single case.

experimental_models:
- name: DNAJC30 patient-derived skin fibroblast lines
  experimental_model_type: PRIMARY_CELL_CULTURE
  cell_source: Patient-derived, from individuals carrying p.Tyr51Cys, p.Pro78Ser or p.Leu101Gln
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_types:
  - preferred_term: Fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  publication: PMID:33465056
  description: >-
    Six fibroblast lines spanning all three DNAJC30 alleles known at the time,
    compared against seven control lines and against three mitochondrial LHON
    lines. The mtLHON comparison arm is what makes this model discriminating
    rather than merely descriptive: it shows the turnover defect is specific to
    the nuclear disease.
  modeled_mechanisms:
  - target: Impaired Complex I N-Module Subunit Exchange
    relationship: MEASURES
    fidelity: MODERATE
    description: >-
      Pulse stable isotope labelling combined with mass spectrometry of
      assembled respiratory chain complexes measures the turnover of individual
      complex I subunits, which is the defect this node asserts.
    limitations: >-
      Fibroblasts are not the affected cell type. Retinal ganglion cells are,
      and the complex I dependent respiration defect in fibroblasts is subtle,
      which the reporting authors attribute to the maintenance rather than
      structural role of the protein. A fibroblast measurement therefore
      establishes the molecular lesion but says nothing about why the retina
      fails and other tissues do not.
    readouts:
    - name: Turnover of complex I N-module subunits in assembled complex I
      target: Impaired Complex I N-Module Subunit Exchange
      direction: DECREASED
      interpretation: >-
        Reduced fractional replacement of the high-turnover N module subunits
        over twelve hours, relative to controls.
      evidence:
      - reference: PMID:33465056
        reference_title: "Impaired complex I repair causes recessive Leber's hereditary optic neuropathy."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          The patient-derived fibroblast cell lines (n = 6), spanning all 3
          DNAJC30 mutations, demonstrated a significant decrease in the turnover
          of N-module subunits in assembled complex I
        explanation: >-
          Reports the measurement and its direction in the patient lines.
    evidence:
    - reference: PMID:33465056
      reference_title: "Impaired complex I repair causes recessive Leber's hereditary optic neuropathy."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        This defect was not found in mtLHON (n = 3) and is therefore specific to
        arLHON
      explanation: >-
        Establishes that the model reports on the nuclear disease specifically,
        by showing the defect is absent in cells from the phenotypically
        identical mitochondrial disease.
- name: DNAJC30-knockout HEK293 cell line
  experimental_model_type: CELL_LINE
  cell_source: Immortalized HEK293, DNAJC30 knockout
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  publication: PMID:33465056
  description: >-
    A complete knockout used to test whether the turnover defect seen in patient
    fibroblasts is specific to complex I, by measuring turnover across more than
    1,200 proteins and 145 protein complexes rather than only the complex of
    interest.
  modeled_mechanisms:
  - target: Impaired Complex I N-Module Subunit Exchange
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      The knockout reproduces the selective slowing of complex I N module
      subunit turnover seen in patient cells, and the proteome-wide design
      establishes that no other protein complex is affected.
    limitations: >-
      HEK293 cells are an immortalized embryonic kidney line, neither neural nor
      retinal, and a knockout is a more severe perturbation than the missense
      alleles that cause most human disease. The model therefore supports the
      molecular claim but not the tissue selectivity of the disease.
    readouts:
    - name: Differential turnover across 145 assembled protein complexes
      target: Impaired Complex I N-Module Subunit Exchange
      direction: DECREASED
      interpretation: >-
        Only complex I, and within it only the N module, showed significantly
        altered turnover on knockout.
      evidence:
      - reference: PMID:33465056
        reference_title: "Impaired complex I repair causes recessive Leber's hereditary optic neuropathy."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          we verified that among all captured protein complexes (n = 145), only
          mitochondrial complex I, and specifically the complex I N-module, had
          significantly altered turnover due to the knockout of DNAJC30
        explanation: >-
          Reports the proteome-wide result that establishes the selectivity of
          the defect.
    evidence:
    - reference: PMID:33465056
      reference_title: "Impaired complex I repair causes recessive Leber's hereditary optic neuropathy."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        The data recapitulate the defect seen in the patient-derived fibroblast
        cell lines, with a mean turnover in CIHIGH subunits of 31.0% in the
        DNAJC30-KO, in comparison with 48.7% in the control
      explanation: >-
        States that the knockout reproduces the patient-cell defect, with the
        quantities.

diagnosis:
- name: Parallel Sequencing of Mitochondrial DNA and the Single-Exon DNAJC30 Gene
  description: >-
    The diagnostic recommendation that follows from the entity's existence. A
    patient with a convincing LHON phenotype and a negative mtDNA result used
    to be left unsolved, sometimes for years. Because DNAJC30 has a single
    exon, Sanger sequencing of the whole gene is inexpensive, so it can be run
    alongside full mtDNA sequencing rather than after it. In founder
    populations the argument is stronger still: in one Polish series the
    nuclear form outnumbered the mitochondrial form, which inverts the usual
    testing order.
  evidence:
  - reference: PMID:33465056
    reference_title: "Impaired complex I repair causes recessive Leber's hereditary optic neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We therefore recommend parallel sequencing of the complete mtDNA sequence
      and the 1-exon gene DNAJC30 to close the diagnostic gap in LHON.
    explanation: >-
      The explicit diagnostic recommendation made by the study that defined the
      entity.
  - reference: PMID:38139324
    reference_title: "DNAJC30 Gene Variants Are a Frequent Cause of a Rare Disease: Leber Hereditary Optic Neuropathy in Polish Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The results of our study suggest that Sanger sequencing of the
      single-exon DNAJC30 gene should be a method of choice applied to identify
      a molecular background of clinically confirmed LHON in Polish patients.
    explanation: >-
      Extends the recommendation to first-line testing in a founder population.

discussions:
- discussion_id: arlhon_sex_dependent_incomplete_penetrance
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Why does a recessive disease with a defined biallelic genotype show
    incomplete penetrance and a strong male predominance, and what is the
    modifier?
  attaches_to:
  - "pathophysiology#DNAJC30 Loss of Function"
  - "pathophysiology#Retinal Ganglion Cell Degeneration"
  rationale: >-
    This is the entity's most conspicuous anomaly. Incomplete penetrance and a
    sex bias are expected in the mitochondrial form and are among the oldest
    puzzles in LHON, but they are not what a biallelic recessive genotype
    normally produces. Here they are not merely present but more extreme than
    in the mitochondrial form: roughly 97 percent of homozygous males but only
    43 percent of homozygous females expressed a phenotype in the founding
    cohort, a ten to one ratio of affected males to affected females against
    five to one in mtLHON. Asymptomatic homozygous carriers exist and have been
    confirmed in a second cohort.

    Three explanations were tested and eliminated in the founding study. The
    amount of DNAJC30 protein and message does not differ by sex, so it is not
    a dosage effect on the chaperone itself. Whole exome data from patients
    carried no rare biallelic variants in other complex I subunit or assembly
    genes, so a second nuclear locus was not detected. No rare mtDNA variants
    were found either. The one positive association is with mitochondrial
    haplogroup J, which was over-represented among arLHON patients relative to
    the European background, mirroring its role in the mitochondrial form; but
    that is a partial and correlative finding on small numbers, not a
    mechanism.

    The gnomAD allele frequency of the founder variant is equal in males and
    females, which is the observation that makes the sex bias a downstream
    phenomenon rather than an ascertainment artefact. So the modifier acts
    somewhere between having the genotype and losing vision, and it is
    unidentified. Note also that the penetrance figures are acknowledged
    overestimates, drawn from a small number of pedigrees with few unaffected
    siblings of known carrier status.
  proposed_experiments:
  - experiment_id: arlhon_biobank_penetrance
    name: Population-based penetrance estimate from unselected founder-population biobank genotypes
    description: >-
      Identify p.(Tyr51Cys) homozygotes in an unselected Eastern European
      biobank rather than through affected probands, and determine visual
      status and age. This is the design that removes the ascertainment bias
      the founding authors flag, and it is the only way to get a penetrance
      figure that is not an overestimate.
  - experiment_id: arlhon_rgc_modifier_assay
    name: Hormonal and oxidative-stress modifier testing in patient-derived retinal ganglion cells
    description: >-
      Differentiate retinal ganglion cells from patient and control induced
      pluripotent stem cells and test whether oestrogen exposure, or graded
      oxidative challenge, shifts the complex I N module turnover defect or
      cell survival. A sex-hormone effect acting downstream of the chaperone
      would fit both the equal allele frequency between sexes and the absence
      of a sex difference in DNAJC30 expression.
  evidence:
  - reference: PMID:33465056
    reference_title: "Impaired complex I repair causes recessive Leber's hereditary optic neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In total, 30 of 31 (96.8%) homozygous carrier males and just 3 of 7
      (42.9%) homozygous carrier females express a phenotype.
    explanation: >-
      Quantifies the sex-dependent penetrance that this gap is about.
  - reference: PMID:33465056
    reference_title: "Impaired complex I repair causes recessive Leber's hereditary optic neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Therefore, akin to mtLHON, the factor influencing sex-dependent
      penetrance remains elusive at this time.
    explanation: >-
      The authors' explicit statement that the modifier is unidentified.
  - reference: PMID:33465056
    reference_title: "Impaired complex I repair causes recessive Leber's hereditary optic neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we measured DNAJC30 expression on the RNA and protein level in over 75
      and 100 controls, respectively; however, we did not detect a significant
      difference
    explanation: >-
      Eliminates chaperone dosage as the explanation for the sex bias.
  - reference: PMID:35148383
    reference_title: "DNAJC30 defect: a frequent cause of recessive Leber hereditary optic neuropathy and Leigh syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This collection of unreported variant carriers confirms sex-dependent
      incomplete penetrance of the homozygous variant given a significant male
      predominance of disease and the report of asymptomatic homozygous variant
      carriers.
    explanation: >-
      Independent replication of both the sex bias and the existence of
      asymptomatic homozygotes.

- discussion_id: arlhon_leigh_branch_determinant
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    What decides whether a patient with biallelic DNAJC30 variants develops an
    isolated optic neuropathy or Leigh syndrome, and does that also explain why
    idebenone helps the first and not the second?
  attaches_to:
  - "pathophysiology#Subacute Necrotizing Encephalopathy of Basal Ganglia and Brainstem"
  - "pathophysiology#Reduced Complex I-Dependent Respiration and ATP Output"
  rationale: >-
    The same p.(Tyr51Cys) homozygous genotype produces isolated adult-onset
    optic neuropathy in most patients and childhood Leigh syndrome in a few, and
    the two branches respond to treatment differently. The leading hypothesis is
    digenic: a heterozygous variant in another complex I gene supplies a second
    hit that tips the phenotype. That hypothesis has direct support in one
    report, where two siblings with the Leigh presentation carried a novel
    heterozygous NDUFS8 variant in addition to their DNAJC30 alleles.

    The evidence against treating it as settled is equally direct. In the one
    DNAJC30 Leigh patient given idebenone, reanalysis of genome sequencing and
    mtDNA found no second variant in any gene linked to Leigh syndrome, LHON or
    the respiratory chain complexes, and the drug failed. The authors offer two
    alternatives that the data cannot distinguish: an undetected second hit in a
    gene not yet associated with mitochondrial disease or missed because
    filtering targets rare variants, or a genuine difference in cellular biology
    between the two phenotypes that has nothing to do with a second locus.

    Truncating alleles complicate the picture further. Both patients homozygous
    for the p.(Trp8*) nonsense variant had a Leigh-like course with markedly
    earlier onset than the missense cohort, which suggests residual chaperone
    function may matter independently of any second gene. Whether allele
    severity and a second hit are competing or additive explanations is
    untested.
  proposed_experiments:
  - experiment_id: arlhon_leigh_second_hit_search
    name: Systematic second-hit search across all DNAJC30 Leigh cases
    description: >-
      Apply uniform genome sequencing with relaxed allele-frequency filtering,
      plus copy-number and mitochondrial heteroplasmy analysis, to every
      reported DNAJC30 Leigh patient and to matched DNAJC30 optic-only
      patients. The digenic hypothesis predicts an excess of heterozygous
      complex I variants in the Leigh group; the current evidence for it rests
      on a single sibling pair.
  - experiment_id: arlhon_allelic_series_repair_assay
    name: Genotype-stratified complex I repair assay across the allelic series
    description: >-
      Measure N module subunit turnover and complex I activity in cells
      carrying missense, in-frame deletion and truncating DNAJC30 alleles, and
      test whether residual repair capacity separates the optic-only from the
      Leigh cases independently of any second variant.
  evidence:
  - reference: PMID:35861300
    reference_title: "Expanding the phenotype of DNAJC30-associated Leigh syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Identification of a candidate heterozygous variant in NDUFS8 supports the
      hypothesis of digenic inheritance.
    explanation: >-
      The positive evidence for the digenic hypothesis, in two siblings with
      the Leigh presentation.
  - reference: PMID:39132756
    reference_title: "Effects of idebenone treatment in a patient with DNAJC30-associated Leigh Syndrome."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Re-analysis of GS and mtDNA sequencing data showed no other potential
      variants in genes linked with LS, LHON, or the respiratory chain enzyme
      complexes.
    explanation: >-
      A Leigh patient in whom no second hit was found despite a targeted
      search, which is why the digenic hypothesis cannot be treated as the
      general explanation.
  - reference: PMID:37397562
    reference_title: "A homozygous nonsense mutation in DNAJC30 causes Leber's hereditary optic neuropathy with Leigh-like phenotypes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In contrast, our patients experienced markedly earlier onset of symptoms
      containing rapid progression of bilateral optic atrophy and severe motor
      difficulties
    explanation: >-
      Suggests allele severity as a competing explanation, since both patients
      with the complete loss-of-function nonsense allele had earlier and more
      severe disease than the missense cohort.

notes: >-
  Relationship to the existing dismech LHON entry. Leber Hereditary Optic
  Neuropathy in this knowledge base models the maternally inherited mtDNA form
  and carries an arLHON subtype bound to the parent term MONDO:0030309, which
  lumps DNAJC30 together with NDUFS2, MCAT and NDUFA12. This entry is the
  DNAJC30-specific child concept, MONDO:0958183 and OMIM 619382, curated
  separately because its mechanism is not a variant of the mtDNA one: mtLHON is
  a defect in complex I subunits, and this is a defect in the machinery that
  repairs an intact complex, a distinction the founding study demonstrated
  directly by showing the turnover defect is absent in mtLHON cells. Curators
  editing either entry should keep the mechanism claims separate.

  Not curated here, and why. Williams syndrome is a 7q11.23 deletion that
  removes DNAJC30 along with 25 or more other genes, and DNAJC30 has been
  proposed to contribute to its neuronal phenotype; the founding arLHON study
  found no Williams features in homozygous or heterozygous DNAJC30 variant
  carriers, so the two are not modelled as related here. An earlier report
  attributed to DNAJC30 an interaction with complex V that facilitates ATP
  synthesis; the arLHON study found no effect of the defect on complex V
  function, abundance, or subunit turnover, and a knockout study independently
  found complex I activity affected while complex IV and V were not, so the
  complex V role is not carried into this entry's mechanism. Environmental
  triggers such as tobacco and alcohol are well established for the
  mitochondrial form but no source examined here reports them in DNAJC30
  patients, so no environmental section is curated.

  GeneReviews has no chapter for this entity. The Nuclear Gene-Encoded Leigh
  Syndrome Spectrum overview does not list DNAJC30, and searches for a
  DNAJC30 or arLHON GeneReviews chapter returned none, so the phenotype
  baseline for this entry comes from the primary cohorts and case series
  instead.
📚

References & Deep Research

References

11
PMID:33465056
Impaired complex I repair causes recessive Leber's hereditary optic neuropathy.
No top-level findings curated for this source.
PMID:35148383
DNAJC30 defect: a frequent cause of recessive Leber hereditary optic neuropathy and Leigh syndrome.
No top-level findings curated for this source.
PMID:35091433
DNAJC30 disease-causing gene variants in a large Central European cohort of patients with suspected Leber's hereditary optic neuropathy and optic atrophy.
No top-level findings curated for this source.
PMID:38139324
DNAJC30 Gene Variants Are a Frequent Cause of a Rare Disease: Leber Hereditary Optic Neuropathy in Polish Patients.
No top-level findings curated for this source.
PMID:37397562
A homozygous nonsense mutation in DNAJC30 causes Leber's hereditary optic neuropathy with Leigh-like phenotypes.
No top-level findings curated for this source.
PMID:35861300
Expanding the phenotype of DNAJC30-associated Leigh syndrome.
No top-level findings curated for this source.
PMID:39132756
Effects of idebenone treatment in a patient with DNAJC30-associated Leigh Syndrome.
No top-level findings curated for this source.
PMID:37071596
Autosomal recessive Leber hereditary optic neuropathy, a new neuro-ophthalmo-genetic paradigm.
No top-level findings curated for this source.
PMID:36388184
Case report: Long-term follow-up of two patients with LHON caused by DNAJC30:c.152G>A pathogenic variant-case series.
No top-level findings curated for this source.
PMID:38107630
Case report: Mutations in DNAJC30 causing autosomal recessive Leber hereditary optic neuropathy are common amongst Eastern European individuals.
No top-level findings curated for this source.
PMID:36359543
Phenotypic Variation of Autosomal Recessive Leber Hereditary Optic Neuropathy (arLHON) in One Family.
No top-level findings curated for this source.

Deep Research

1
Falcon ▸
Disease Characteristics Research Template
Edison Scientific Literature 14 citations 2026-08-27T02:38:56.534623

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

  • Disease Name: Leber-like Hereditary Optic Neuropathy, Autosomal Recessive 1
  • MONDO ID: (if available)
  • Category: Mendelian

Research Objectives

Please provide a comprehensive research report on Leber-like Hereditary Optic Neuropathy, Autosomal Recessive 1 covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

  • What is the disease? Provide a concise overview.
  • What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
  • What are the common synonyms and alternative names?
  • Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

  • Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
  • Risk Factors:

    Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases

  • Genetic risk factors (causal variants, susceptibility loci, modifier genes)
  • Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
  • Protective Factors:

    Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases

  • Genetic protective factors (protective variants, modifier alleles)
  • Environmental protective factors (diet, lifestyle, exposures that reduce risk)
  • Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

    Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

  • Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

    Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene

  • Pathogenic Variants:
  • Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
  • Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
  • Variant type/class (missense, frameshift, nonsense, splice-site, structural)
  • Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
  • Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
  • Functional consequences (loss of function, gain of function, dominant negative)
  • Modifier Genes: Genes that modify disease severity or expression
  • Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

    Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

  • Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

    Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases

  • Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

    Search first: CDC databases, WHO, PubMed, NHANES

  • Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

    Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

  • Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

    Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc

  • Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

    Search first: Gene Ontology (GO), Reactome, KEGG, PubMed

  • Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

    Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold

  • Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

    Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA

  • Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

    Search first: ImmPort, Immunome Database, IEDB, Gene Ontology

  • Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

    Search first: PubMed, Gene Ontology, Reactome

  • Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

    Search first: BRENDA, UniProt, KEGG, OMIM, PubMed

  • Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Molecular Profiling (if available):
  • Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
  • Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
  • Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
  • Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
  • Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
  • Advanced Technologies (if applicable):
  • Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
  • Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
  • Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
  • Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

  • Organ Level:
  • Primary organs directly affected
  • Secondary organ involvement (complications, secondary effects)
  • Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

    Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT

  • Tissue and Cell Level:
  • Specific tissue types affected (epithelial, connective, muscle, nervous)
  • Specific cell populations targeted (with Cell Ontology terms)

    Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB

  • Subcellular Level:
  • Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

    Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas

  • Localization:
  • Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
  • Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

  • Onset:
  • Typical age of onset (congenital, pediatric, adult, geriatric)
  • Onset pattern (acute, subacute, chronic, insidious)

    Search first: OMIM, Orphanet, HPO, PubMed

  • Progression:
  • Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
  • Progression rate (rapid, slow, variable)
  • Disease course pattern (episodic, relapsing-remitting, progressive, stable)
  • Disease duration (self-limited, chronic lifelong)

    Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM

  • Patterns:
  • Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
  • Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

  • Epidemiology:
  • Prevalence (cases per 100,000 at given time)
  • Incidence (new cases per 100,000 per year)

    Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries

  • For Genetic Etiology:
  • Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
  • Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
  • Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
  • Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
  • Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
  • Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
  • Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
  • Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
  • Population Demographics:
  • Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
  • Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
  • Geographic distribution of specific variants
  • Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
  • Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

  • Clinical Tests:
  • Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
  • Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
  • Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
  • Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
  • Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
  • Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
  • Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
  • Genetic Testing:

    Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen

  • Overview of recommended genetic testing approach
  • Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
  • Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
  • Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
  • Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
  • Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
  • Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
  • FISH > Search first: ClinVar, cytogenetics databases, PubMed
  • Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
  • Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
  • Omics-Based Diagnostics (if applicable):
  • RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
  • Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
  • Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
  • Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
  • Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
  • Clinical Criteria:
  • Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
  • Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
  • Screening:
  • Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

  • Survival and Mortality:
  • Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
  • Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
  • Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
  • Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
  • Morbidity and Function:
  • Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
  • Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
  • Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
  • Disease Course:
  • Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
  • Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
  • Prediction:
  • Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
  • Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

  • Pharmacotherapy:
  • Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
  • Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
  • Advanced Therapeutics:
  • Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
  • Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
  • RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
  • Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
  • Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
  • Surgical and Interventional:
  • Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
  • Supportive and Rehabilitative:
  • Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
  • Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
  • Experimental:
  • Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
  • Treatment Outcomes:
  • Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
  • Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
  • Treatment Strategy:
  • Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
  • Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
  • Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest NCIT (NCI Thesaurus) clinical-intervention terms where applicable.

13. Prevention

  • Prevention Levels:
  • Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
  • Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
  • Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
  • Immunization: Vaccine strategies (if applicable)

    Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database

  • Screening and Early Detection:
  • Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
  • Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
  • Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
  • Behavioral Interventions: Lifestyle modifications to reduce risk

    Search first: CDC, WHO, behavioral intervention databases, Cochrane Library

  • Counseling: Genetic counseling (risk assessment, family planning guidance)

    Search first: NSGC resources, ACMG guidelines, GeneReviews

  • Public Health:
  • Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
  • Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
  • Prophylaxis: Preventive medications or procedures

    Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

  • Taxonomy: Species affected (with NCBI Taxon identifiers)

    Search first: NCBI Taxonomy

  • Breed: Specific breeds affected (with VBO identifiers if applicable)

    Search first: VBO (Vertebrate Breed Ontology)

  • Gene: Orthologous genes in other species (with NCBI Gene IDs)

    Search first: NCBI Gene

  • Natural Disease:
  • Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
  • Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
  • Comparative Biology:
  • Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
  • Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
  • Transmission (if applicable):
  • Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
  • Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

  • Model Types:
  • Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
  • Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
  • Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
  • Genetic Models:
  • Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
  • Model Characteristics:
  • Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
  • Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
  • Applications:
  • Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
  • Resources:
  • Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

  • Cite primary literature (PMID preferred) for all mechanistic and clinical claims
  • Prioritize recent reviews and landmark papers
  • Include direct quotes from abstracts where possible to support key statements
  • Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, NCIT, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (NCIT terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

Leber-like Hereditary Optic Neuropathy, Autosomal Recessive 1

Executive summary

Leber-like hereditary optic neuropathy, autosomal recessive 1 is DNAJC30-associated autosomal recessive Leber hereditary optic neuropathy, commonly abbreviated LHONAR1, arLHON, or DNAJC30-LHON. It is a nuclear-encoded mitochondrial disease that clinically resembles classical, maternally inherited mtDNA-LHON: affected people—predominantly adolescent or young-adult males—develop painless, subacute central visual loss from bilateral retinal-ganglion-cell/optic-nerve degeneration. The defining cause is biallelic pathogenic variants in DNAJC30, most often the Eastern/Central European founder variant NM_032317.3:c.152A>G, p.(Tyr51Cys). The strongest mechanistic model is defective repair/turnover of mitochondrial respiratory-chain complex I, causing complex-I deficiency and selective vulnerability of retinal ganglion cells. (OpenTargets Search: Leber-like hereditary optic neuropathy, autosomal recessive 1, kieninger2022dnajc30diseasecausinggene pages 1-2, stenton2022dnajc30defecta pages 1-2)

The disease has incomplete, sex-dependent penetrance, relatively frequent simultaneous bilateral onset, and—compared with mtDNA-LHON—an earlier average onset and better probability of meaningful visual recovery. Idebenone is used clinically, but DNAJC30-specific efficacy evidence remains observational rather than randomized. No DNAJC30-targeted gene therapy or disease-specific interventional trial was identified. (kieninger2022dnajc30diseasecausinggene pages 4-5, stenton2022dnajc30defecta pages 1-2, stenton2022dnajc30defecta pages 3-5)

The following table provides a knowledge-base-oriented synopsis.

Domain Evidence-based finding Quantitative data Suggested ontology IDs/terms Evidence limitations
Identifiers Disease resolves to DNAJC30-associated autosomal recessive Leber hereditary optic neuropathy, also called LHONAR1 / arLHON; Open Targets links the entity to MONDO_0958183 and DNAJC30; OMIM phenotype reported as 619382. Information here is disease-level synthesis from published cohorts/case series, not EHR-derived. (OpenTargets Search: Leber-like hereditary optic neuropathy, autosomal recessive 1, kieninger2022dnajc30diseasecausinggene pages 1-2, kieninger2022dnajc30diseasecausinggene pages 1-1) MONDO:0958183; OMIM:619382 MONDO:0958183; Leber-like hereditary optic neuropathy, autosomal recessive 1 Orphanet, ICD, MeSH identifiers were not established in the retrieved evidence set.
Gene / variants Causal gene is DNAJC30. Recurrent founder variant c.152A>G (p.Tyr51Cys) is the predominant disease allele; additional pathogenic/likely pathogenic variants reported include c.610G>T (p.Glu204*), c.230_232del (p.His77del), c.293A>G (p.Tyr98Cys), c.293A>C (p.Tyr98Ser), and c.130_131delTC (p.Ser44ValfsTer8). (OpenTargets Search: Leber-like hereditary optic neuropathy, autosomal recessive 1, major2023casereportmutations pages 1-2, kieninger2022dnajc30diseasecausinggene pages 6-6, kieninger2022dnajc30diseasecausinggene pages 5-6, stenton2022dnajc30defecta pages 1-2, skorczykwerner2023dnajc30genevariants pages 10-11) c.152A>G accounts for ~90% of disease alleles in Central Europe and ~95% of alleles in the Polish cohort; gnomAD frequency for p.Tyr51Cys reported as 0.12% with no homozygotes reported in Stenton 2022. (kieninger2022dnajc30diseasecausinggene pages 3-4, stenton2022dnajc30defecta pages 1-2, skorczykwerner2023dnajc30genevariants pages 10-11) HGNC: DNAJC30; Sequence variants as HGVS terms No ClinVar accession numbers or HGNC numeric gene ID were provided in retrieved contexts.
Inheritance Inheritance is autosomal recessive with biallelic DNAJC30 variants. Penetrance is incomplete and sex-dependent, with marked male predominance among manifesting patients. (stenton2022dnajc30defecta pages 1-2, wiggs2021dnajc30biallelicmutations pages 2-3) In one Central European cohort, 5/35 patients were female (14.3%), ~6:1 male:female. Two asymptomatic homozygous carriers were reported in Stenton 2022. (kieninger2022dnajc30diseasecausinggene pages 4-5, kieninger2022dnajc30diseasecausinggene pages 6-6, stenton2022dnajc30defecta pages 1-2) HP:0000007 Autosomal recessive inheritance; HP:0001411 Decreased penetrance Formal penetrance percentage was not established in retrieved evidence.
Epidemiology / population arLHON due to DNAJC30 is a recurrent cause of inherited optic neuropathy in Central/Eastern Europe and may be particularly common in Poland because of a founder effect. (major2023casereportmutations pages 1-2, kieninger2022dnajc30diseasecausinggene pages 3-4, skorczykwerner2023dnajc30genevariants pages 10-11) 35/1202 screened Central European patients carried likely pathogenic DNAJC30 variants (2.9% detection rate); DNAJC30 accounted for 7.7% of LHON cases in one database; across European centers, DNAJC30 variants accounted for 4-27% of genetically confirmed LHON in the cited synthesis. (kieninger2022dnajc30diseasecausinggene pages 4-5, kieninger2022dnajc30diseasecausinggene pages 1-1, stenton2022dnajc30defecta pages 3-5) Population descriptor only; no ontology ID established No population-based prevalence or incidence per 100,000 was established. Data are referral/cohort based and geographically enriched.
Phenotype Core presentation closely mimics mtDNA-LHON: painless subacute central visual loss, dyschromatopsia, central/cecocentral scotoma, optic disc microangiopathy early and temporal optic atrophy later. Bilateral involvement is the rule at follow-up. (kieninger2022dnajc30diseasecausinggene pages 3-4, kieninger2022dnajc30diseasecausinggene pages 6-6, skorczykwerner2023dnajc30genevariants pages 10-11) Central/cecocentral field defects 96.6%; papillary microangiopathy 94.1%; temporally accentuated optic atrophy 91.7%; color vision disturbance 68.8%; bilateral onset 40%, unilateral then fellow-eye involvement 60%, all bilateral at follow-up. (kieninger2022dnajc30diseasecausinggene pages 3-4, kieninger2022dnajc30diseasecausinggene pages 6-6) HP:0000648 Optic atrophy; HP:0000572 Loss of visual acuity; HP:0000555 Visual field defect; HP:0001098 Abnormality of color vision; HP:0007686 Scotoma; HP:0012800 Bilateral visual impairment Detailed HPO mapping for fundus microangiopathy and OCT/VEP findings was not fully established from retrieved evidence.
Onset / course Typically juvenile-to-young-adult onset, earlier than mtDNA-LHON, with subacute progression and relatively frequent spontaneous or treatment-associated recovery. (kieninger2022dnajc30diseasecausinggene pages 3-4, stenton2022dnajc30defecta pages 1-2, skorczykwerner2023dnajc30genevariants pages 10-11) Mean/median onset about 18.5-19 years; reported range 9.5-45.1 years in Central Europe; one Polish case onset at 68 years. Median interval between eyes 3.5 weeks (range 1-17) in one subset. Spontaneous complete recovery of remaining vision reported in 45% at median 19 months in one cohort. (kieninger2022dnajc30diseasecausinggene pages 4-5, kieninger2022dnajc30diseasecausinggene pages 3-4, skorczykwerner2023dnajc30genevariants pages 10-11) HP:0003596 Middle age onset not typical; HP:0011462 Young adult onset; course descriptors not uniquely ontologized here Staging schema is not established; recovery definitions vary across studies.
Mechanism / pathophysiology DNAJC30 encodes a mitochondrial chaperone implicated in respiratory-chain complex I maintenance/repair/turnover; loss leads to isolated complex I deficiency, impaired ATP-linked bioenergetics and likely increased oxidative stress, producing selective retinal ganglion-cell vulnerability analogous to LHON biology. DNAJC30 also has reported interaction with ATP synthase/complex V. (kieninger2022dnajc30diseasecausinggene pages 1-2, stenton2022dnajc30defecta pages 1-2, wiggs2021dnajc30biallelicmutations pages 2-3) Near-complete loss of DNAJC30 protein expression reported for the founder variant; patient/Leigh cases showed isolated RCCI deficiency on enzyme analysis. (stenton2022dnajc30defecta pages 1-2, stenton2022dnajc30defecta pages 3-5) GO:0005747 mitochondrial respiratory chain complex I; GO:0006119 oxidative phosphorylation; GO:0006979 response to oxidative stress; GO:0006091 generation of precursor metabolites and energy Much downstream ROS/RGC apoptosis detail is inferred from broader LHON biology rather than directly quantified in DNAJC30 patient retina.
Anatomy / cells / subcellular location Primary affected tissue is the optic nerve/retinal ganglion cell pathway. Subcellular localization is mitochondrial, especially respiratory-chain machinery. (kieninger2022dnajc30diseasecausinggene pages 1-2, wiggs2021dnajc30biallelicmutations pages 2-3) Bilateral optic neuropathy predominates; extraocular manifestations absent in most arLHON cases, but Leigh syndrome and occasional motor features were reported in a minority. (major2023casereportmutations pages 1-2, kieninger2022dnajc30diseasecausinggene pages 6-6, stenton2022dnajc30defecta pages 1-2) UBERON:0000966 retina; UBERON:0000390 optic nerve; CL:0000705 retinal ganglion cell; GO:0005739 mitochondrion; GO:0005743 mitochondrial inner membrane No direct retinal histopathology or single-cell localization studies were identified for this disease.
Diagnostics Diagnosis relies on clinical recognition of LHON-like optic neuropathy plus molecular confirmation of biallelic DNAJC30 variants. DNAJC30 screening is recommended in mtDNA-negative LHON, especially in Central/Eastern European patients; because DNAJC30 is single exon, Sanger sequencing can be a practical first test in Poland. (major2023casereportmutations pages 1-2, kieninger2022dnajc30diseasecausinggene pages 1-1, skorczykwerner2023dnajc30genevariants pages 10-11) Central European detection rate 2.9% (35/1202). In the Polish study, 46 clinically diagnosed LHON patients had DNAJC30 findings and 32 were diagnosed after DNAJC30 testing was introduced locally. (kieninger2022dnajc30diseasecausinggene pages 1-1, skorczykwerner2023dnajc30genevariants pages 10-11) Diagnostic concepts: molecular genetic testing; ophthalmic exam; visual field testing; OCT/VEP not fully ontologized here No disease-specific formal diagnostic criteria, biomarker panel, or screening guideline were retrieved.
Prognosis Compared with mtDNA-LHON, DNAJC30 arLHON generally shows better visual prognosis, including higher spontaneous recovery and more favorable idebenone-associated outcomes. (major2023casereportmutations pages 1-2, stenton2022dnajc30defecta pages 1-2, stenton2022dnajc30defecta pages 3-5) Median visual acuity improved from 1.3 logMAR at nadir to 0.5 logMAR at last visit in one cohort; clinically relevant recovery with idebenone in at least one eye 77% in arLHON versus 43% in mtLHON; spontaneous recovery 69% untreated arLHON versus 30% untreated mtLHON. (kieninger2022dnajc30diseasecausinggene pages 3-4, stenton2022dnajc30defecta pages 3-5) Outcome terms: visual recovery; optic atrophy No survival, mortality, or life-expectancy estimates specific to isolated arLHON were established. Leigh-spectrum cases likely have different prognosis.
Treatment No DNAJC30-specific approved therapy exists. Idebenone is the principal disease-directed treatment used in practice by extrapolation from LHON and supported by observational DNAJC30 data suggesting higher recovery rates/shorter recovery time. Low-vision/visual rehabilitation is supportive standard care. MT-ND4 gene therapy trials are not genotype-matched for DNAJC30 disease. (major2023casereportmutations pages 1-2, stenton2022dnajc30defecta pages 3-5, kieninger2022dnajc30diseasecausinggene pages 1-1) No randomized DNAJC30-specific trial identified; one Central European patient had taken idebenone for 6 months but recovered before treatment initiation; observational cohort comparisons favored idebenone-treated arLHON. (kieninger2022dnajc30diseasecausinggene pages 3-4, stenton2022dnajc30defecta pages 3-5) NCIT:C952 Idebenone; NCIT terms for low vision rehabilitation/supportive care if used in downstream curation Evidence is observational and partly extrapolated from mtDNA-LHON; no DNAJC30-targeted interventional trial was retrieved.
Prevention / counseling Primary prevention is not established. Practical prevention focuses on genetic counseling, carrier/family testing, and reproductive counseling for an autosomal recessive condition. General LHON advice on smoking/alcohol avoidance may be reasonable but is extrapolated, not disease-specific evidence. (wiggs2021dnajc30biallelicmutations pages 2-3, kieninger2022dnajc30diseasecausinggene pages 1-1) Not established quantitatively for DNAJC30 arLHON HP:0000007 Autosomal recessive inheritance; carrier testing/cascade testing concepts No disease-specific studies of environmental triggers, protective factors, prenatal screening uptake, or PGT outcomes were retrieved.
Other species / natural disease No naturally occurring veterinary disease equivalent was established from retrieved evidence. (OpenTargets Search: Leber-like hereditary optic neuropathy, autosomal recessive 1) Not established NCBI Taxon IDs not established Evidence absent in retrieved set.
Model organisms / experimental systems Disease mechanism is supported mainly by patient-based biochemical evidence and broader mitochondrial functional studies; no validated DNAJC30-specific optic-neuropathy animal model was established in the retrieved evidence. Leigh-spectrum/digenic observations suggest useful mechanistic complexity but not a dedicated model system. (stenton2022dnajc30defecta pages 1-2, wiggs2021dnajc30biallelicmutations pages 2-3) Not established Experimental system concepts: patient fibroblasts; mitochondrial enzyme assay Model-organism availability, recapitulation fidelity, and resource identifiers were not established from retrieved sources.

Table: This table condenses the current evidence base for DNAJC30-associated autosomal recessive Leber hereditary optic neuropathy into knowledge-base-ready domains. It highlights what is well supported by cohort data and what remains unknown or only extrapolated from broader LHON literature.

1. Disease information

Definition and identifiers

  • Preferred disease name: Leber-like hereditary optic neuropathy, autosomal recessive 1.
  • Common names: autosomal recessive Leber hereditary optic neuropathy; recessive LHON; arLHON; LHONAR1; DNAJC30-associated LHON; DNAJC30 optic neuropathy.
  • MONDO: MONDO:0958183.
  • OMIM phenotype: 619382.
  • Causal gene: DNAJC30, ENSG00000176410, encoding DnaJ heat-shock-protein-family member C30. Open Targets associates this disease entity with DNAJC30 and cites the discovery and replication literature, including PMID 33465056. (OpenTargets Search: Leber-like hereditary optic neuropathy, autosomal recessive 1)
  • Orphanet, MeSH, ICD-10 and ICD-11: no unique disease-specific identifiers were verified in the retrieved evidence. In practice, the disorder may be indexed under LHON, hereditary optic atrophy, or mitochondrial disease, but these broader codes should not be represented as unique LHONAR1 identifiers without terminology-service confirmation.

The evidence is primarily aggregated disease-level information from published referral cohorts and case series, with underlying observations derived from individual patients. It is not an EHR-derived population study.

Key primary sources

  • Stenton et al., Brain, published February 2022, DOI: 10.1093/brain/awac052. The abstract states: “The recent description of biallelic DNAJC30 variants in Leber hereditary optic neuropathy (LHON) and Leigh syndrome challenged the longstanding assumption for LHON to be exclusively maternally inherited.” (stenton2022dnajc30defecta pages 1-2)
  • Kieninger et al., Journal of Medical Genetics, online/publication record January 2022, DOI: 10.1136/jmedgenet-2021-108235. Its abstract reports likely pathogenic variants in 35/1,202 patients (2.9%). (kieninger2022dnajc30diseasecausinggene pages 1-1)
  • Major et al., Frontiers in Neurology, December 2023, DOI: 10.3389/fneur.2023.1292320. The abstract describes three Eastern European patients with homozygous p.Tyr51Cys and emphasizes diagnostic screening in molecularly unresolved LHON. (major2023casereportmutations pages 1-2)
  • Skorczyk-Werner et al., International Journal of Molecular Sciences, December 2023, DOI: 10.3390/ijms242417496. This is a large Polish DNAJC30-LHON series. (skorczykwerner2023dnajc30genevariants pages 10-11)

2. Etiology, risk, and protective factors

Causal factor

The primary cause is biallelic germline pathogenic or likely pathogenic DNAJC30 variants. This is a Mendelian, autosomal recessive nuclear-genome disorder—not mitochondrial inheritance—although the affected protein operates within mitochondria. (OpenTargets Search: Leber-like hereditary optic neuropathy, autosomal recessive 1, stenton2022dnajc30defecta pages 1-2)

Genetic risk factors

The major risk genotype in Europe is homozygosity or compound heterozygosity involving c.152A>G, p.(Tyr51Cys). A Central European analysis found this allele on approximately 90% of disease chromosomes; a Polish analysis estimated approximately 95%. Founder-haplotype evidence included a linked 287-bp microsatellite allele on 85% of disease chromosomes versus 12.5% of controls. The founder event has been estimated at approximately 85 generations ago. (kieninger2022dnajc30diseasecausinggene pages 4-5, major2023casereportmutations pages 1-2, skorczykwerner2023dnajc30genevariants pages 10-11)

Male sex strongly increases the probability of clinical expression among biallelic carriers. In one 35-patient cohort only 5 patients, or 14.3%, were female, approximating a 6:1 male:female ratio. Nevertheless, females can be affected and sex is a penetrance modifier, not an inheritance rule. (kieninger2022dnajc30diseasecausinggene pages 4-5, kieninger2022dnajc30diseasecausinggene pages 6-6)

Possible second-locus modifiers have been proposed where severe Leigh-spectrum disease co-occurred with heterozygous variants in complex-I genes such as NDUFS8, NDUFA9, or NDUFS2. This is emerging digenic evidence rather than a validated clinical risk model. Mitochondrial haplogroup J was reportedly enriched in early DNAJC30 series but did not fully explain penetrance or male bias. (wiggs2021dnajc30biallelicmutations pages 2-3, stenton2022dnajc30defecta pages 3-5)

Environmental and protective factors

No DNAJC30-specific study established smoking, alcohol, occupational toxins, diet, exercise, infection, or medication exposure as penetrance modifiers. Avoidance of smoking, heavy alcohol use, and mitochondrial toxins is often advised in LHON care, but for LHONAR1 this is extrapolated from mtDNA-LHON, not demonstrated gene–environment evidence.

No verified genetic protective allele, diet, supplement, vaccine, or lifestyle intervention prevents disease expression. Asymptomatic homozygotes demonstrate incomplete penetrance, but the protective determinants remain unknown. (stenton2022dnajc30defecta pages 1-2, wiggs2021dnajc30biallelicmutations pages 2-3)

3. Phenotypes

The phenotype is an optic neuropathy rather than a primary photoreceptor or retinal-pigment-epithelium dystrophy.

Manifestation Type and characteristics Frequency/data Suggested HPO
Reduced central visual acuity Clinical sign; painless, acute/subacute; severe at nadir but variably recoverable Median 1.3 logMAR at nadir and 0.5 logMAR at last observation in one cohort HP:0000572, visual-acuity loss
Bilateral visual impairment Sign; simultaneous or sequential 40% bilateral at onset; 60% initially unilateral; 100% bilateral by documented follow-up HP:0012800
Central/cecocentral scotoma Visual-field abnormality reflecting papillomacular-bundle injury 96.6% HP:0007686; HP:0000555
Optic-disc microangiopathy Early funduscopic sign, including peripapillary telangiectatic/microvascular change 94.1% Use an abnormal optic-disc morphology/vasculature term after HPO terminology validation
Temporal optic atrophy/pallor Later physical sign; progressive structural consequence 91.7% HP:0000648
Dyschromatopsia Functional sign; impaired color perception 68.8% HP:0001098
Fellow-eye conversion Temporal feature Median 3.5 weeks; range 1–17 weeks in one documented subset Encode as bilateral/sequential involvement rather than a distinct phenotype

These quantitative findings come principally from the Central European cohort and should not be treated as universal population frequencies. (kieninger2022dnajc30diseasecausinggene pages 4-5, kieninger2022dnajc30diseasecausinggene pages 3-4, kieninger2022dnajc30diseasecausinggene pages 6-6)

OCT is expected to show acute retinal-nerve-fiber-layer swelling followed by thinning, particularly in papillomacular/temporal sectors, and visual evoked potentials may show optic-nerve dysfunction. However, robust DNAJC30-specific OCT and VEP frequency estimates were not available in the retrieved evidence.

Most patients have isolated optic neuropathy. Rare biallelic DNAJC30 presentations include childhood- or adult-onset Leigh syndrome, movement/motor manifestations, and proposed digenic complex-I disease. These severe syndromic presentations should be recorded separately from isolated LHONAR1 rather than assumed to be routine disease features. (major2023casereportmutations pages 1-2, stenton2022dnajc30defecta pages 1-2, stenton2022dnajc30defecta pages 3-5)

Central vision loss affects reading, facial recognition, education, employment, driving, and independent navigation. No LHONAR1-specific EQ-5D, SF-36, PROMIS, or vision-related quality-of-life dataset was identified.

4. Genetic and molecular information

Causal gene and protein

DNAJC30 is a single-exon nuclear gene on chromosome 7q11.23. It encodes a mitochondrial DnaJ/Hsp40-family co-chaperone. Reported functional domains include a conserved J domain and a C-terminal transmembrane region. The protein participates in complex-I maintenance/repair and has also been reported to interact with ATP-synthase/complex V. (kieninger2022dnajc30diseasecausinggene pages 1-2, kieninger2022dnajc30diseasecausinggene pages 5-6, stenton2022dnajc30defecta pages 1-2)

Reported pathogenic/likely pathogenic variants

  • c.152A>G, p.(Tyr51Cys): recurrent missense founder allele; dominant contributor to European LHONAR1. Reported gnomAD frequency was approximately 0.12% with no homozygotes in the cited dataset. Functional evidence indicates near-complete loss of DNAJC30 protein. (stenton2022dnajc30defecta pages 1-2)
  • c.230_232del, p.(His77del): in-frame deletion within the conserved J domain; reported homozygously in two Turkish brothers. (kieninger2022dnajc30diseasecausinggene pages 6-6, kieninger2022dnajc30diseasecausinggene pages 5-6)
  • c.610G>T, p.(Glu204Ter): nonsense variant upstream of the transmembrane domain. (kieninger2022dnajc30diseasecausinggene pages 6-6, kieninger2022dnajc30diseasecausinggene pages 5-6)
  • c.293A>G, p.(Tyr98Cys): novel missense variant reported in the 2023 Polish cohort. (skorczykwerner2023dnajc30genevariants pages 10-11)
  • c.293A>C, p.(Tyr98Ser): ultra-rare missense variant reported in LHONAR1. (skorczykwerner2023dnajc30genevariants pages 10-11)
  • c.130_131delTC, p.(Ser44ValfsTer8): frameshift allele also reported in Leigh syndrome. (major2023casereportmutations pages 1-2, skorczykwerner2023dnajc30genevariants pages 10-11)
  • Other reported rare substitutions include c.232C>T and c.302T>A; variant-level ClinVar assertions should be checked directly before assigning ACMG classes in a production knowledge base. (major2023casereportmutations pages 1-2)

All are presumed or demonstrated germline variants. Somatic causation is not supported. Loss of protein or disruption of chaperone-domain function is consistent with loss of function, although the recurrent missense allele may act through protein instability rather than a simple null transcript.

No disease-specific pathogenic chromosomal rearrangement, repeat expansion, or epigenetic lesion is established. DNAJC30 lies within the Williams–Beuren critical region, but heterozygous 7q11.23 deletion is a different genomic disorder and does not establish recessive LHONAR1.

5. Environmental information

No infectious agent causes or triggers LHONAR1. No radiation, pollutant, occupational exposure, or lifestyle exposure has been proven causal. Likewise, no disease-specific CTD-style chemical interaction or prospective exposure study was identified. Smoking and excessive alcohol avoidance are prudent mitochondrial-health recommendations but remain indirect for this genotype.

Suggested chemical annotations for broader mechanistic curation include oxygen-derived reactive species (CHEBI:26523) and ATP (CHEBI:15422); these describe downstream bioenergetic biology, not diagnostic biomarkers.

6. Mechanism and pathophysiology

Causal chain

  1. Upstream genetic lesion: biallelic DNAJC30 pathogenic variants reduce or abolish functional mitochondrial DNAJC30.
  2. Primary molecular defect: defective chaperone-dependent repair/turnover of damaged respiratory-chain complex-I subunits permits dysfunctional complex I to accumulate.
  3. Biochemical defect: isolated complex-I deficiency impairs NADH-linked electron transport, oxidative phosphorylation, and ATP generation; electron leakage is expected to increase oxidative stress.
  4. Cellular stress: highly energy-dependent retinal ganglion cells, especially those forming the papillomacular bundle, cannot maintain axonal bioenergetics and redox homeostasis.
  5. Tissue injury: retinal-ganglion-cell dysfunction and subsequent cell/axon loss produce central scotoma, dyschromatopsia, temporal retinal-nerve-fiber loss, and optic atrophy.
  6. Clinical outcome: painless subacute central visual loss, usually involving both eyes over days to weeks.

Patient and Leigh-spectrum biochemical studies demonstrated isolated respiratory-chain complex-I deficiency; p.Tyr51Cys was associated with near-complete loss of DNAJC30 protein. These are direct DNAJC30 observations. The precise ROS-to-apoptosis sequence in human retinal ganglion cells is principally inferred from broader LHON biology because affected retinal tissue is rarely available. (stenton2022dnajc30defecta pages 1-2, stenton2022dnajc30defecta pages 3-5)

Suggested GO annotations: mitochondrion (GO:0005739); mitochondrial inner membrane (GO:0005743); mitochondrial respiratory-chain complex I (GO:0005747); oxidative phosphorylation (GO:0006119); respiratory electron transport chain (GO:0022904); response to oxidative stress (GO:0006979); ATP metabolic process (GO:0046034); protein-folding/chaperone-mediated protein-quality-control terms after gene-specific GO validation.

Suggested Cell Ontology: retinal ganglion cell (CL:0000705). Other relevant but indirect cells include optic-nerve oligodendrocytes and astrocytes; primary causal injury is neuronal/axonal rather than an established immune-mediated process.

No disease-specific immune, inflammatory, transcriptomic, proteomic, metabolomic, lipidomic, single-cell, spatial-transcriptomic, or multi-omic signature has been validated for clinical use. A 2024 LHON epigenetics study concerned mtDNA-ND4/NDUFS4-related biology and should not be attributed specifically to DNAJC30-LHON.

7. Anatomical structures affected

  • Primary organ/system: eye–central nervous system visual pathway.
  • Primary anatomical sites: retina (UBERON:0000966), retinal nerve-fiber layer, optic disc/optic-nerve head, optic nerve (UBERON:0000390), particularly papillomacular fibers.
  • Primary cell: retinal ganglion cell (CL:0000705) and its axon.
  • Subcellular compartment: mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743), respiratory-chain complex I (GO:0005747).
  • Laterality: bilateral; onset may be synchronous or sequential and can initially be asymmetric. (kieninger2022dnajc30diseasecausinggene pages 4-5, kieninger2022dnajc30diseasecausinggene pages 3-4)

Secondary brain involvement is not characteristic of isolated LHONAR1. Basal-ganglia/brainstem disease pertains to the rarer DNAJC30-associated Leigh-spectrum phenotype.

8. Temporal development

Typical onset is in adolescence or young adulthood. Central European estimates center around 18.5–19 years, with a 9.5–45.1-year range; a Polish patient with onset at 68 years demonstrates that late onset is possible. (kieninger2022dnajc30diseasecausinggene pages 4-5, skorczykwerner2023dnajc30genevariants pages 10-11)

A practical clinical sequence is:

  • Presymptomatic: biallelic carrier with normal functional vision; penetrance is incomplete.
  • Acute/subacute phase: painless central blur and color loss in one or both eyes; disc microangiopathy may be visible.
  • Dynamic phase: fellow-eye involvement commonly follows within weeks; central/cecocentral scotoma deepens.
  • Atrophic phase: temporal disc pallor and retinal-nerve-fiber loss emerge.
  • Recovery/stable chronic phase: some patients recover meaningful acuity over months to years, although central field and color deficits may persist.

In one cohort, spontaneous complete recovery occurred in 45% at a median 19 months. Another synthesis found spontaneous clinically relevant recovery in 69% of untreated arLHON versus 30% of untreated mtDNA-LHON. Definitions and follow-up differed, so these estimates should not be pooled uncritically. (kieninger2022dnajc30diseasecausinggene pages 3-4, stenton2022dnajc30defecta pages 3-5)

There is no validated staging system, remission definition, or proven preclinical intervention window. Biologically, treatment before irreversible ganglion-cell loss is considered preferable.

9. Inheritance and population

Inheritance is autosomal recessive. For two heterozygous parents, each pregnancy has the standard theoretical probabilities of 25% biallelic, 50% heterozygous carrier, and 25% inheriting neither familial allele. Because penetrance is incomplete, a biallelic genotype does not guarantee optic neuropathy; male carriers are substantially more likely to manifest disease. Two asymptomatic homozygous carriers were documented in the 2022 Brain series. (stenton2022dnajc30defecta pages 1-2)

No anticipation is expected. Germline mosaicism has not emerged as a characteristic mechanism. Consanguinity can increase the probability of biallelic rare variants, but the common European founder allele permits disease in non-consanguineous families.

Population-based prevalence and annual incidence are unknown. Referral-series statistics include:

  • 35/1,202 suspected LHON/optic-atrophy patients, or 2.9%, in a Central European screen;
  • 7.7% of LHON cases in one diagnostic database;
  • 4–27% of genetically confirmed LHON across cited European centers;
  • a 2023 Polish cohort in which DNAJC30-associated disease was reported as more frequent than mtDNA-LHON among tested Polish patients. (kieninger2022dnajc30diseasecausinggene pages 4-5, kieninger2022dnajc30diseasecausinggene pages 1-1, skorczykwerner2023dnajc30genevariants pages 10-11, stenton2022dnajc30defecta pages 3-5)

These are diagnostic yields, not general-population prevalence estimates. Geographic enrichment is strongest in Poland and broader Central/Eastern Europe, including Germany, Austria, Russia, Ukraine, and Romania. (major2023casereportmutations pages 1-2, kieninger2022dnajc30diseasecausinggene pages 1-2)

10. Diagnostics

Clinical evaluation

Recommended evaluation includes best-corrected visual acuity, color vision, automated or kinetic visual fields, dilated fundus examination, optic-disc photography, OCT of the peripapillary RNFL and macular ganglion-cell complex, and—when uncertainty remains—visual evoked potentials/electroretinography. MRI of brain and orbits with contrast is appropriate when inflammation, compression, demyelination, or atypical syndromic disease is suspected.

There is no specific blood metabolite or enzyme biomarker for isolated LHONAR1. Respiratory-chain enzyme testing can demonstrate complex-I deficiency but is not required when phenotype and genotype are definitive.

Genetic workflow

  1. In clinically suspected LHON, test the three common mtDNA variants and preferably sequence the complete mitochondrial genome.
  2. If mtDNA testing is negative—or immediately in a population with high founder frequency—test DNAJC30, ensuring detection of biallelic sequence variants.
  3. A hereditary optic-neuropathy/mitochondrial panel should include DNAJC30 plus relevant differential genes such as OPA1, OPA3, WFS1, TMEM126A, ACO2, RTN4IP1, NDUFS2, MCAT, MECR, and other complex-I/optic-atrophy genes.
  4. WES or WGS is useful for panel-negative or syndromic cases and can identify second-locus complex-I variants. CNV analysis should accompany broad sequencing where technically appropriate.
  5. Confirm segregation and phase in parents; test at-risk siblings and adult relatives with counseling.

Because DNAJC30 is single exon and p.Tyr51Cys dominates Polish cases, the 2023 Polish investigators proposed Sanger sequencing as a cost-efficient first-line local strategy. In genetically heterogeneous populations, a combined mtDNA+nuclear panel is more comprehensive. (major2023casereportmutations pages 1-2, kieninger2022dnajc30diseasecausinggene pages 1-1, skorczykwerner2023dnajc30genevariants pages 10-11)

CMA, karyotyping, FISH, and repeat-expansion testing are not routine for isolated LHONAR1. mtDNA testing remains essential to exclude classical LHON but cannot diagnose nuclear DNAJC30 disease.

Differential diagnosis

Major differentials are mtDNA-LHON; dominant optic atrophy; recessive optic atrophies; toxic/nutritional optic neuropathy; optic neuritis and multiple-sclerosis-spectrum disease; neuromyelitis optica/MOG-associated disease; compressive/infiltrative optic neuropathy; glaucoma; macular disease; and inherited retinal dystrophy. Painless central/cecocentral loss, sequential bilateral disease, early disc microangiopathy, later temporal pallor, and a biallelic DNAJC30 genotype support LHONAR1.

11. Outcome and prognosis

Isolated LHONAR1 is vision-threatening but is not known to reduce life expectancy. Disease-specific mortality and survival statistics are not applicable/available. Leigh-spectrum DNAJC30 disease is clinically distinct and may carry neurological morbidity and mortality not representative of isolated optic neuropathy.

Visual prognosis appears better than in common mtDNA-LHON. One cohort improved from median 1.3 logMAR at nadir to 0.5 logMAR at last assessment. In a comparative observational analysis, 77% of idebenone-treated arLHON patients achieved clinically relevant recovery in at least one eye versus 43% of mtDNA-LHON patients; untreated recovery was 69% versus 30%, respectively. Younger onset, genotype, treatment timing, and residual ganglion-cell reserve may influence outcome, but no validated prognostic calculator exists. (kieninger2022dnajc30diseasecausinggene pages 3-4, stenton2022dnajc30defecta pages 3-5)

Persistent morbidity can include central scotoma, impaired color discrimination, reduced contrast sensitivity, inability to drive/read ordinary print, and educational or occupational disruption. Formal LHONAR1-specific patient-reported-outcome statistics are lacking.

12. Treatment

Idebenone

Idebenone, a short-chain benzoquinone/CoQ analog, can accept electrons upstream of complex III and partly bypass complex-I dysfunction while acting in redox pathways. It is the principal disease-directed pharmacotherapy used for LHON. Suggested ontology: NCIT:C952; chemical curation should verify the corresponding ChEBI record.

DNAJC30-specific evidence is favorable but nonrandomized. Stenton and colleagues reported shorter recovery time and 77% clinically relevant recovery in at least one eye among treated arLHON patients. However, substantial spontaneous recovery—69% in untreated arLHON—creates confounding by natural history. One Central European patient received idebenone for six months only after recovery had begun, illustrating why isolated case responses cannot prove efficacy. (kieninger2022dnajc30diseasecausinggene pages 3-4, stenton2022dnajc30defecta pages 3-5)

The commonly used European LHON regimen is 900 mg/day orally in divided doses, continued for at least 12 months or until a sustained plateau after recovery; this regimen is extrapolated from general LHON authorization and consensus practice rather than a DNAJC30-specific randomized trial. Gastrointestinal symptoms and nasopharyngitis are among commonly reported adverse effects in broader idebenone experience. Treatment should be supervised by a mitochondrial/neuro-ophthalmology specialist.

Supportive care

Low-vision rehabilitation, magnification and electronic reading aids, contrast optimization, orientation/mobility training, educational/workplace accommodations, occupational therapy, and psychosocial support are important real-world interventions. Suggested NCIT concepts include supportive care, rehabilitation therapy, occupational therapy, and genetic counseling after terminology validation.

Experimental treatment

No DNAJC30 replacement, CRISPR, RNA therapy, cell therapy, or targeted small molecule has established clinical efficacy. MT-ND4 allotopic gene-replacement products such as lenadogene nolparvovec target the mitochondrial m.11778G>A/MT-ND4 genotype and are not directly applicable to DNAJC30-LHON. No recruiting DNAJC30-specific interventional trial was identified by the trial search.

Complex-I bypass with yeast NDI1 has protected retinal ganglion cells and improved mitochondrial function in experimental rotenone and patient-fibroblast systems, but this is a mutation-agnostic preclinical strategy rather than a validated DNAJC30 model or treatment.

13. Prevention

There is no vaccine or pharmacologic primary prophylaxis. Prevention is principally genetic and anticipatory:

  • confirm the familial variants and offer cascade testing;
  • provide autosomal recessive recurrence counseling;
  • discuss prenatal diagnosis or preimplantation genetic testing where desired and legally available;
  • monitor biallelic asymptomatic relatives with baseline acuity, color testing, fields, and OCT;
  • encourage prompt assessment of new central blur or dyschromatopsia;
  • avoid smoking, excessive alcohol, and avoidable mitochondrial-toxic exposures, explicitly recognizing that DNAJC30-specific benefit is unproven.

Population newborn screening is not recommended: prevalence is very low, penetrance is incomplete, onset is usually later, and no proven presymptomatic therapy exists.

14. Other species and natural disease

No naturally occurring DNAJC30-associated LHON equivalent was identified in companion animals, livestock, or wildlife, and no breed-specific VBO annotation can currently be recommended. The condition is genetic and noninfectious, with no zoonotic or cross-species transmission.

DNAJC30 is evolutionarily conserved, and ortholog studies can illuminate mitochondrial chaperone biology. However, evidence from Williams–Beuren deletion models or general mitochondrial dysfunction should not be labeled as a natural animal model of LHONAR1.

15. Model organisms and research systems

The strongest disease-specific experimental evidence comes from human patient-derived fibroblasts and mitochondrial biochemical assays, showing loss of DNAJC30 and isolated complex-I deficiency. These models establish molecular causality but do not reproduce the retinal-ganglion-cell selectivity, bilateral temporal course, or visual recovery of human disease. (stenton2022dnajc30defecta pages 1-2, stenton2022dnajc30defecta pages 3-5)

No well-validated DNAJC30 knockout/knock-in mouse, zebrafish, Drosophila, retinal organoid, or iPSC-derived retinal-ganglion-cell model that recapitulates LHONAR1 was established in the retrieved literature. A priority model would combine homozygous p.Tyr51Cys or a null allele with human iPSC-derived retinal ganglion cells and an in-vivo knock-in system, measuring complex-I turnover, oxygen consumption, ATP, ROS, axonal transport, RNFL thickness, and visual function.

Rotenone-induced complex-I retinal injury and AAV-NDI1 rescue models are useful for testing downstream complex-I bypass, but are induced general models, not genotype-faithful DNAJC30 disease models.

Evidence appraisal and current research gaps

The best-supported claims are the causal relationship with biallelic DNAJC30 variants, European p.Tyr51Cys founder effect, male-biased incomplete penetrance, LHON-like ocular phenotype, complex-I repair defect, and relatively favorable recovery. Evidence derives from several independent human cohorts and functional studies. (OpenTargets Search: Leber-like hereditary optic neuropathy, autosomal recessive 1, kieninger2022dnajc30diseasecausinggene pages 3-4, stenton2022dnajc30defecta pages 1-2)

Important unresolved issues are: population prevalence and carrier frequency outside Europe; precise age- and sex-specific penetrance; environmental triggers; genotype–phenotype relationships for non-founder alleles; disease-specific OCT and patient-reported outcomes; prospective idebenone effectiveness; biomarkers of reversible versus irreversible ganglion-cell injury; and genotype-faithful retinal models. Recent 2023 studies mainly strengthened the Eastern European founder association and demonstrated the practical diagnostic value of routine DNAJC30 sequencing; no transformative DNAJC30-specific therapeutic development was identified in 2023–2024. (major2023casereportmutations pages 1-2, skorczykwerner2023dnajc30genevariants pages 10-11)

Bottom line

LHONAR1 should be suspected whenever a patient has an mtDNA-negative LHON phenotype, especially a young male of Central/Eastern European ancestry, synchronous bilateral involvement, or a family pattern inconsistent with maternal transmission. The highest-yield implementation is combined mtDNA and nuclear optic-neuropathy testing that includes DNAJC30, followed by segregation/cascade testing, early consideration of idebenone, and visual rehabilitation. Prognosis is often better than classical mtDNA-LHON, but irreversible central visual disability remains possible and the treatment evidence is not yet randomized.

References

  1. (OpenTargets Search: Leber-like hereditary optic neuropathy, autosomal recessive 1): Open Targets Query (Leber-like hereditary optic neuropathy, autosomal recessive 1, 1 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.

  2. (kieninger2022dnajc30diseasecausinggene pages 1-2): Sinja Kieninger, Ting Xiao, Nicole Weisschuh, Susanne Kohl, Klaus Rüther, Peter Michael Kroisel, Tobias Brockmann, Steffi Knappe, Ulrich Kellner, Wolf Lagrèze, Pascale Mazzola, Tobias B Haack, Bernd Wissinger, and Felix Tonagel. dnajc30 disease-causing gene variants in a large central european cohort of patients with suspected leber’s hereditary optic neuropathy and optic atrophy. Journal of Medical Genetics, 59(10):1027-1034, Jan 2022. URL: https://doi.org/10.1136/jmedgenet-2021-108235, doi:10.1136/jmedgenet-2021-108235. This article has 35 citations and is from a domain leading peer-reviewed journal.

  3. (stenton2022dnajc30defecta pages 1-2): Sarah L. Stenton, Marketa Tesarova, Natalia L. Sheremet, Claudia B. Catarino, Valerio Carelli, Elżbieta Ciara, Kathryn Curry, Martin Engvall, Leah R. Fleming, Peter Freisinger, Katarzyna Iwanicka-Pronicka, Elżbieta Jurkiewicz, Thomas Klopstock, Mary K. Koenig, Hana Kolářová, Bohdan Kousal, Tatiana Krylova, Chiara La Morgia, Lenka Nosková, Dorota Piekutowska-Abramczuk, Sam N. Russo, Viktor Stránecký, Iveta Tóthová, Frank Träisk, and Holger Prokisch. dnajc30 defect: a frequent cause of recessive leber hereditary optic neuropathy and leigh syndrome. Brain, 145:1624-1631, Feb 2022. URL: https://doi.org/10.1093/brain/awac052, doi:10.1093/brain/awac052. This article has 51 citations and is from a highest quality peer-reviewed journal.

  4. (kieninger2022dnajc30diseasecausinggene pages 4-5): Sinja Kieninger, Ting Xiao, Nicole Weisschuh, Susanne Kohl, Klaus Rüther, Peter Michael Kroisel, Tobias Brockmann, Steffi Knappe, Ulrich Kellner, Wolf Lagrèze, Pascale Mazzola, Tobias B Haack, Bernd Wissinger, and Felix Tonagel. dnajc30 disease-causing gene variants in a large central european cohort of patients with suspected leber’s hereditary optic neuropathy and optic atrophy. Journal of Medical Genetics, 59(10):1027-1034, Jan 2022. URL: https://doi.org/10.1136/jmedgenet-2021-108235, doi:10.1136/jmedgenet-2021-108235. This article has 35 citations and is from a domain leading peer-reviewed journal.

  5. (stenton2022dnajc30defecta pages 3-5): Sarah L. Stenton, Marketa Tesarova, Natalia L. Sheremet, Claudia B. Catarino, Valerio Carelli, Elżbieta Ciara, Kathryn Curry, Martin Engvall, Leah R. Fleming, Peter Freisinger, Katarzyna Iwanicka-Pronicka, Elżbieta Jurkiewicz, Thomas Klopstock, Mary K. Koenig, Hana Kolářová, Bohdan Kousal, Tatiana Krylova, Chiara La Morgia, Lenka Nosková, Dorota Piekutowska-Abramczuk, Sam N. Russo, Viktor Stránecký, Iveta Tóthová, Frank Träisk, and Holger Prokisch. dnajc30 defect: a frequent cause of recessive leber hereditary optic neuropathy and leigh syndrome. Brain, 145:1624-1631, Feb 2022. URL: https://doi.org/10.1093/brain/awac052, doi:10.1093/brain/awac052. This article has 51 citations and is from a highest quality peer-reviewed journal.

  6. (kieninger2022dnajc30diseasecausinggene pages 1-1): Sinja Kieninger, Ting Xiao, Nicole Weisschuh, Susanne Kohl, Klaus Rüther, Peter Michael Kroisel, Tobias Brockmann, Steffi Knappe, Ulrich Kellner, Wolf Lagrèze, Pascale Mazzola, Tobias B Haack, Bernd Wissinger, and Felix Tonagel. dnajc30 disease-causing gene variants in a large central european cohort of patients with suspected leber’s hereditary optic neuropathy and optic atrophy. Journal of Medical Genetics, 59(10):1027-1034, Jan 2022. URL: https://doi.org/10.1136/jmedgenet-2021-108235, doi:10.1136/jmedgenet-2021-108235. This article has 35 citations and is from a domain leading peer-reviewed journal.

  7. (major2023casereportmutations pages 1-2): Toby Charles Major, Eszter Sara Arany, Katherine Schon, Magdolna Simo, Veronika Karcagi, Jelle van den Ameele, Patrick Yu Wai Man, Patrick F. Chinnery, Catarina Olimpio, and Rita Horvath. Case report: mutations in dnajc30 causing autosomal recessive leber hereditary optic neuropathy are common amongst eastern european individuals. Frontiers in Neurology, Dec 2023. URL: https://doi.org/10.3389/fneur.2023.1292320, doi:10.3389/fneur.2023.1292320. This article has 2 citations and is from a peer-reviewed journal.

  8. (kieninger2022dnajc30diseasecausinggene pages 6-6): Sinja Kieninger, Ting Xiao, Nicole Weisschuh, Susanne Kohl, Klaus Rüther, Peter Michael Kroisel, Tobias Brockmann, Steffi Knappe, Ulrich Kellner, Wolf Lagrèze, Pascale Mazzola, Tobias B Haack, Bernd Wissinger, and Felix Tonagel. dnajc30 disease-causing gene variants in a large central european cohort of patients with suspected leber’s hereditary optic neuropathy and optic atrophy. Journal of Medical Genetics, 59(10):1027-1034, Jan 2022. URL: https://doi.org/10.1136/jmedgenet-2021-108235, doi:10.1136/jmedgenet-2021-108235. This article has 35 citations and is from a domain leading peer-reviewed journal.

  9. (kieninger2022dnajc30diseasecausinggene pages 5-6): Sinja Kieninger, Ting Xiao, Nicole Weisschuh, Susanne Kohl, Klaus Rüther, Peter Michael Kroisel, Tobias Brockmann, Steffi Knappe, Ulrich Kellner, Wolf Lagrèze, Pascale Mazzola, Tobias B Haack, Bernd Wissinger, and Felix Tonagel. dnajc30 disease-causing gene variants in a large central european cohort of patients with suspected leber’s hereditary optic neuropathy and optic atrophy. Journal of Medical Genetics, 59(10):1027-1034, Jan 2022. URL: https://doi.org/10.1136/jmedgenet-2021-108235, doi:10.1136/jmedgenet-2021-108235. This article has 35 citations and is from a domain leading peer-reviewed journal.

  10. (skorczykwerner2023dnajc30genevariants pages 10-11): Anna Skorczyk-Werner, Katarzyna Tońska, Aleksandra Maciejczuk, Katarzyna Nowomiejska, Magdalena Korwin, Monika Ołdak, Anna Wawrocka, and Maciej R. Krawczyński. Dnajc30 gene variants are a frequent cause of a rare disease: leber hereditary optic neuropathy in polish patients. Dec 2023. URL: https://doi.org/10.3390/ijms242417496, doi:10.3390/ijms242417496. This article has 8 citations.

  11. (kieninger2022dnajc30diseasecausinggene pages 3-4): Sinja Kieninger, Ting Xiao, Nicole Weisschuh, Susanne Kohl, Klaus Rüther, Peter Michael Kroisel, Tobias Brockmann, Steffi Knappe, Ulrich Kellner, Wolf Lagrèze, Pascale Mazzola, Tobias B Haack, Bernd Wissinger, and Felix Tonagel. dnajc30 disease-causing gene variants in a large central european cohort of patients with suspected leber’s hereditary optic neuropathy and optic atrophy. Journal of Medical Genetics, 59(10):1027-1034, Jan 2022. URL: https://doi.org/10.1136/jmedgenet-2021-108235, doi:10.1136/jmedgenet-2021-108235. This article has 35 citations and is from a domain leading peer-reviewed journal.

  12. (wiggs2021dnajc30biallelicmutations pages 2-3): Janey L. Wiggs. Dnajc30 biallelic mutations extend mitochondrial complex i–deficient phenotypes to include recessive leber’s hereditary optic neuropathy. Journal of Clinical Investigation, Mar 2021. URL: https://doi.org/10.1172/jci147734, doi:10.1172/jci147734. This article has 22 citations and is from a highest quality peer-reviewed journal.

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