Harderoporphyria

Mendelian MONDO:0030048 Pathograph 13 Show in embeddings browser Porphyria

Coproporphyrinogen oxidase does its job twice. It removes two propionate side chains from coproporphyrinogen III in sequence, and between the two removals the substrate exists as a tricarboxylic intermediate, harderoporphyrinogen, which the enzyme must hold onto in order to finish. Harderoporphyria is what happens when a variant lets the enzyme complete the first decarboxylation and not the second: the intermediate is released instead of being retained, and it is excreted in enormous quantities. That distinguishes it sharply from hereditary coproporphyria, which is the same gene. HCP is a dominant disorder of half-normal enzyme activity in the liver; the substrate upstream of the block accumulates, hepatic ALAS1 is derepressed, and patients have acute neurovisceral attacks after puberty. Harderoporphyria is recessive, requires two alleles, presents in the newborn with haemolytic anaemia and jaundice rather than with attacks, and the diagnostic finding is a different molecule - harderoporphyrin dominating faecal porphyrins where in HCP it is a minor component. So the split is not a severity band on one mechanism. The same enzyme fails in two different ways, at two different points, in two different compartments, and the position of the variant within the protein is what decides which disease the patient has.

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Inheritance
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Pathophys.
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Phenotypes
4
Gaps
13
Pathograph
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Genes
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Medical Actions
2
Models
8
References
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Deep Research
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Inheritance

1
Autosomal recessive HP:0000007
Two CPOX alleles are required, either homozygosity for a harderoporphyria-specific variant or compound heterozygosity for one such variant with a null allele. Heterozygous parents show only the mild biochemical and enzymatic changes of HCP carriers - which is the observation that established the recessive mode.
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:6886003 SUPPORT Human Clinical
"Both parents showed only mild abnormalities in porphyrin excretion and lymphocyte coproporphyrinogen III oxidase activity decreased to 50% of normal values, as is expected in heterozygous cases of hereditary coproporphyria."
The parental data establishing that the affected siblings were homozygous and the parents were HCP-type carriers.
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Discussions and Knowledge Gaps

4
Why does no murine Cpox model reproduce harderoporphyria, and what does that absence establish?
HUMAN MODEL MISMATCH harpo_no_mouse_model_reproduces_the_disease
Attached to
pathophysiology#Arrest After the First Decarboxylation animal_models#BALB.NCT-Cpox nct mouse
Three Cpox alleles are on record in the mouse: the spontaneous hypomorphic p.Arg380Leu, carried by both BALB.NCT-Cpox nct and the Nakano cataract strain, which proved to be the same locus rather than a second allele; the Trp373 nonsense allele RBC16 from an ENU screen; and a second ENU strain, M100835, with an intron 4 splice-acceptor mutation whose HCP phenotype has never been studied. Two have been phenotyped for porphyrins, and both report coproporphyrin. Neither reports harderoporphyrin - and neither measured it. The published panels are uroporphyrin, coproporphyrin, protoporphyrin and the precursors; the species that defines this disease has never been assayed in a Cpox mouse. There is, at present, no animal model of this disease. Read carelessly that is a gap. Read against the allele positions it is a result, and it points the same way as everything else in this entry. Every reported harderoporphyria variant alters residues D400-K404 or, in the H327R case, a residue predicted to contact the active site; the murine alleles sit at 373 and 380, outside that region. So the mice have less enzyme and the patients have a differently-behaving enzyme, and the mice get the disease that less enzyme causes. This is the entry's central argument arriving from an independent direction, though it arrives by allele position rather than by measurement. If harderoporphyria were the severe end of a CPOX activity gradient, a mouse at 15% of wild-type activity should sit somewhere on that gradient. What it reports instead is the ordinary HCP profile - and the human variant at the homologous residue, p.Arg391Trp at 22% residual activity, is likewise an ordinary HCP allele. Position, not dose. That the diagnostic species has never been measured in any Cpox mouse is a sharper statement of the gap than a null result would have been: the murine system has not been asked the question this entry turns on. What is genuinely open is whether a knock-in of a retention-region allele would reproduce the disease, which is the experiment nobody has published. It is the obvious test of this entry's mechanism and its absence is why the erythroid-injury node remains PROVISIONAL - there is no system in which to ask what accumulated harderoporphyrin does to a red cell.
Proposed experiments
Assay harderoporphyrin in the existing Cpox mouse strains
harpo_assay_harderoporphyrin_in_existing_cpox_mice
Re-analyse urine, faeces and erythrocytes from BALB.NCT-Cpox nct and RBC16 heterozygotes on an HPLC method resolving the tricarboxylic intermediate, rather than the uroporphyrin/coproporphyrin/protoporphyrin panel both published studies used. This is the cheap experiment and it comes first: the murine negative this discussion rests on is currently an unmeasured analyte, not a reported null, and one assay would convert it into evidence either way.
Perturbations
No perturbation - existing hypomorphic and nonsense Cpox strains
pathophysiology#Arrest After the First Decarboxylation
The strains already exist; the manipulation is to the analytical panel, not to the animal.
Readouts
Faecal and erythrocyte harderoporphyrin fraction
pathophysiology#Harderoporphyrin Accumulation
Direction: UNCHANGED
Interpretation: A harderoporphyrin fraction indistinguishable from wild-type would confirm that a non-retention-region allele does not produce the intermediate, which is what this entry predicts.
Decision criterion
Whether harderoporphyrin is elevated above wild-type in either strain.
Would support
pathophysiology#Biallelic CPOX Variant in the Substrate-Retention Region
Would refute
pathophysiology#Biallelic CPOX Variant in the Substrate-Retention Region
Supporting outcome
  • No harderoporphyrin excess in either strain, establishing as a measured null what is presently only an allele-position inference.
Refuting outcome
  • Harderoporphyrin elevated in a mouse whose allele lies outside D400-K404, which would show the intermediate accumulates on activity loss alone and undercut the positional argument this entry is built on.
Cpox retention-region knock-in mouse
harpo_retention_region_knockin_mouse
Knock a retention-region allele - the murine equivalent of human p.Lys404Glu or p.Asp400Tyr - into the mouse Cpox locus in homozygous or compound form, and phenotype the porphyrin profile, the neonatal red cell and the skin. No such animal has been published; every existing strain carries an allele outside the retention region.
Perturbations
Homozygous retention-region knock-in at mouse Cpox
pathophysiology#Biallelic CPOX Variant in the Substrate-Retention Region
Reproduces the human genotype class rather than a quantitative deficiency, which is the variable no existing model varies.
Readouts
Faecal harderoporphyrin excretion
pathophysiology#Harderoporphyrin Accumulation
Direction: INCREASED
Interpretation: The diagnostic species of the human disease, and the readout that separates this genotype from the hypomorphic strains.
Neonatal haemolysis and erythrocyte survival
pathophysiology#Erythroid Compartment Injury
Direction: DECREASED
Interpretation: Whether accumulated harderoporphyrin injures the red cell, which is why the erythroid node is PROVISIONAL and cannot be resolved in any current system.
Decision criterion
Whether a retention-region genotype produces harderoporphyrin excess and neonatal haemolysis where a comparable-activity hypomorph does not.
Would support
pathophysiology#Arrest After the First Decarboxylation pathophysiology#Erythroid Compartment Injury
Would refute
pathophysiology#Arrest After the First Decarboxylation
Supporting outcome
  • Harderoporphyrin excess with neonatal haemolysis in the knock-in, absent from an activity-matched hypomorph - position rather than dose, demonstrated within one species.
Refuting outcome
  • A retention-region homozygote that phenocopies the hypomorph, which would make harderoporphyria a severity band of hereditary coproporphyria after all.
Show evidence (3 references)
PMID:36967721 SUPPORT Model Organism
"Appropriate animal models for comprehending the precise pathogenesis mechanism of HCP have not been reported that show similarities in terms of gene mutation, reduced CPOX activity, excess coproporphyrin accumulation, and clinical symptoms."
The authors' own statement of how sparse the murine CPOX landscape is, from the paper introducing the best of the available models.
PMID:23631845 SUPPORT Model Organism
"BALB/c-nct/nct mice are homozygous for a G to T nucleotide substitution in the Cpox gene, which results in a p.R380L amino acid substitution in the CPOX protein."
The allele position, which is what places this model outside the retention region and explains why it lands on the HCP phenotype.
PMID:23631845 SUPPORT Model Organism
"BALB/c-nct/nct mice had excessive accumulation of coproporphyrin III in the lens."
The accumulating species is coproporphyrin III, not harderoporphyrin - the specific negative result this discussion turns on.
Why is harderoporphyria curated as its own disease rather than as severe CPOX deficiency within hereditary coproporphyria?
INTERPRETATION harpo_why_not_a_severity_band_of_hcp
Attached to
disease#Harderoporphyria genetic#CPOX
MONDO places harderoporphyria under CPOX-related hereditary coproporphyria, and the existing dismech porphyria entry carries HCP as a CPOX subtype, so the obvious reading is that this is HCP with two hits instead of one. Three things argue against it, and they are the reason this is a separate entry. The mechanism differs at the step that matters. HCP is a partial deficiency: less enzyme, substrate backing up, hepatic ALAS1 derepressed, acute attacks. Harderoporphyria is a redirection: the enzyme performs its first decarboxylation and then fails to hold the intermediate for the second, so what accumulates is a molecule that barely appears in HCP at all. A structure of human CPOX locates the lesion in a beta-turn whose function is exactly that retention. Severity does not order the two. Residual enzyme activity across HCP variants spans 1% to 64% with clinically uniform presentation, so "less activity" does not produce harderoporphyria; if it did, the low-activity HCP patients would have it and they do not. And biallelism alone is not the criterion either. Biallelic CPOX variants outside the retention region give a "homozygous HCP" phenotype that is distinct from harderoporphyria. So the discriminator is which residues are affected, not how many alleles or how much activity remains. This is a lump/split call and it goes against MONDO's placement, which is recorded here rather than left implicit so that a reviewer who disagrees has the argument to disagree with.
Show evidence (3 references)
PMID:16176984 SUPPORT In Vitro
"Conversely, harderoporphyria-causing K404E mutation precludes a type I beta-turn from retaining the substrate for the second decarboxylation cycle."
The distinct structural mechanism, which is the primary argument for the split.
PMID:11309681 SUPPORT Human Clinical
"demonstrate that the severity of the phenotype does not correlate with the degree of inactivation by mutation of coproporphyrinogen oxidase"
Rules out the severity-band reading directly.
PMID:9454777 SUPPORT Human Clinical
"Neither abdominal pain nor neuropsychiatric symptoms are observed."
The sharpest clinical discriminator available. HCP is defined by acute neurovisceral attacks; their absence in harderoporphyria is not a milder version of that presentation but a different one, which is the clinical counterpart of the mechanistic argument.
By what mechanism does accumulated harderoporphyrin cause haemolysis?
KNOWLEDGE GAP harpo_how_the_intermediate_damages_erythrocytes
Attached to
pathophysiology#Erythroid Compartment Injury
The chain from variant to accumulated intermediate is established at the structural level. The chain from accumulated intermediate to destroyed red cell is not, and it is worth being explicit that this entry does not know it. What is established is the compartment and the association: this is an erythropoietic porphyria, harderoporphyrin is measurable in erythrocytes as well as faeces, and the haemolysis is present from birth. What is not established is whether the damage is photo-oxidative in the same way as the skin lesions, whether it acts on the mature erythrocyte or on the developing erythroblast, or whether the intermediate is directly toxic at all rather than marking a compartment where heme synthesis has failed. The distinction is not academic. If the haemolysis is photo-oxidative it should respond to the same light protection as the skin, and if it is a consequence of failed heme synthesis in the erythroblast it should not. No reviewed source addresses this, and with eight or so reported cases in the literature it is unlikely to be addressed by observation alone.
Show evidence (1 reference)
PMID:28349448 SUPPORT Other
"In contrast, harderoporphyria is an erythropoietic porphyria that represents photosensitivity and hemolytic anemia from the neonatal period."
Establishes the compartment and the co-occurrence of the two features, which is as far as the reviewed literature goes - it does not connect them mechanistically.
What should a neonate with the harderoporphyria clinical picture but an HCP porphyrin profile be called?
OPEN QUESTION harpo_biochemical_phenotype_can_disagree_with_genotype
Attached to
diagnosis#Faecal Porphyrin Fractionation
A 2017 report describes a neonate with photosensitivity, haemolytic anaemia and jaundice - the harderoporphyria presentation - whose faecal porphyrin pattern was that of typical HCP rather than harderoporphyria, and who carried a novel heterozygous four-base-pair deletion with no K404E and no second identified allele. The authors proposed calling it neonatal-onset HCP. This matters for how the entry should be used rather than only for nomenclature. Both of this entry's discriminators - the faecal fraction and the variant position - failed on that patient while the clinical picture was unambiguous. Either the discriminators are less reliable than the small reported series suggests, or there is a third CPOX phenotype, or a second allele went undetected. With around eight reported cases the question cannot be settled by counting. It is recorded here so that a future curator meeting a similar case knows this entry's diagnostic rule has a documented exception rather than reading the rule as tested.
Show evidence (2 references)
PMID:28349448 SUPPORT Human Clinical
"However, the pattern of porphyrin metabolites of feces was consistent with that of typical HCP, not of harderoporphyria."
The discordance itself - clinical harderoporphyria with an HCP biochemical profile.
PMID:28349448 SUPPORT Human Clinical
"We found a heterozygous, novel, four-base pair deletion in exon 7 of the CPOX gene, although other mutations including the p.Lys404Glu mutation in CPOX were not found."
The genotype that also failed to fit, which is what makes this an open question rather than a mis-assigned case.
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Pathophysiology

7
Biallelic CPOX Variant in the Substrate-Retention Region
A variant affecting the residues that hold the reaction intermediate in the active site between the two decarboxylation cycles. Most reported patients carry p.Lys404Glu on at least one allele; p.His327Arg has also been reported in homozygous form, and a four-amino-acid deletion in the same region in a compound heterozygote. The clustering is the point - this is a position-specific lesion in a region distinct from where ordinary HCP variants fall.
erythroblast CL:0000765 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves erythroblast (CL:0000765). CL:0000765 is a cell type from the Cell Ontology.
Genetic context CPOX hgnc:2321 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns CPOX (hgnc:2321). hgnc:2321 is a gene from the HUGO Gene Nomenclature Committee. functional_impact_category: PARTIAL_LOSS_OF_FUNCTION
heme biosynthetic process GO:0006783 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased heme biosynthetic process (GO:0006783). GO:0006783 is a biological process from the Gene Ontology. ↓ DECREASED porphyrin-containing compound metabolic process GO:0006778 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal porphyrin-containing compound metabolic process (GO:0006778). GO:0006778 is a biological process from the Gene Ontology. ⚠ ABNORMAL
coproporphyrinogen oxidase activity GO:0004109 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased coproporphyrinogen oxidase activity (GO:0004109). GO:0004109 is a molecular function from the Gene Ontology. ↓ DECREASED
Downstream
Arrest After the First Decarboxylation
Show evidence (3 references)
PMID:11309681 SUPPORT Human Clinical
"In such patients the presence of a specific mutation (K404E) on one or both alleles produces a neonatal hemolytic anemia that is known as "harderoporphyria"; mutations on both alleles elsewhere in the gene give rise to the "homozygous" variant of HCP."
The allele-position rule stated directly - and note it separates harderoporphyria not only from dominant HCP but from homozygous HCP, which is a different biallelic disease of the same gene.
PMID:21103937 SUPPORT Human Clinical
"To date, only a few homozygous HCP patients have been described, most having Harderoporphyria, a rare variant due to specific CPOX mutations that alter enzyme residues D400-K404, most patients described to date having at least one K404E allele."
Names the residue interval and the dominance of K404E in the reported series, which is the basis for calling this a position-specific lesion.
PMID:9454777 SUPPORT Human Clinical
"The second allele bore an A-->G transition at the third position of the donor splice site in intron 6. This new COX gene mutation resulted in exon 6 skipping and the absence of functional protein production."
The null allele in the compound-heterozygous configuration, documented rather than left implicit. It is what makes the K404E allele the only source of residual activity in that family.
Arrest After the First Decarboxylation
The enzyme removes the first propionate and then fails to retain harderoporphyrinogen for the second cycle, so the intermediate is released rather than carried through to protoporphyrinogen. The structural account is specific: the K404E substitution disrupts a type I beta-turn whose job is substrate retention between cycles. The normal reaction is ordered and processive, which is what makes a cycle-specific failure possible at all. Isotope labelling in rat liver showed that the 4-propionate cannot be attacked until the 2-propionate has been decarboxylated, that harderoporphyrinogen forms about twice as fast as protoporphyrinogen, and - the load-bearing part - that the harderoporphyrinogen destined to become protoporphyrinogen does not equilibrate with added harderoporphyrinogen. The intermediate on its way through is a kinetically distinct pool from free intermediate in solution. That is what "retention" names: not a metaphor but a measurable compartment. The claim is that the reaction is redirected, not that throughput is normal. The enzyme is also slower - the 1983 kinetics give a Michaelis constant 15-20-fold above normal and a maximal velocity half of normal, and lymphocyte activity in the affected siblings was 10% of control. What distinguishes this disease from a straightforwardly less active enzyme is that the deficit is not uniform across the two cycles, so the accumulating species is an intermediate that barely appears in other porphyrias rather than the substrate upstream of the block. That distinction was contested, and by the same paper. The 1983 authors explicitly ruled out an active-site lesion specific to the second decarboxylation, on the grounds that rat liver metabolises coproporphyrinogen and harderoporphyrinogen at the same active centre. They were right about the active centre and it does not settle the question: the 2005 crystal structure locates the harderoporphyria lesion not in a second catalytic site but in a beta-turn that retains the substrate between cycles at the one shared site. A single active centre and a cycle-specific failure are compatible, and this was not only shown later by the structure - it was proposed in the same rat-liver system the objection rests on, five years before the disease was named. The 1978 account has both decarboxylations at one active centre which becomes temporarily inaccessible, with the molecule rotating between cycles. A shared centre that sequesters its substrate between turns is precisely the thing a retention-region variant can break. Separately, CPOX is an obligate homodimer whose monomer has no activity, so what a given genotype does depends on which dimers can form.
second decarboxylation of harderoporphyrinogen to protoporphyrinogen GO:0004109 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased second decarboxylation of harderoporphyrinogen to protoporphyrinogen, annotated with coproporphyrinogen oxidase activity (GO:0004109). GO:0004109 is a molecular function from the Gene Ontology. ↓ DECREASED
Downstream
Harderoporphyrin Accumulation
Show evidence (7 references)
PMID:16176984 SUPPORT In Vitro
"Conversely, harderoporphyria-causing K404E mutation precludes a type I beta-turn from retaining the substrate for the second decarboxylation cycle."
The structural mechanism, from the crystal structure of human CPOX - this is the sentence the whole entry turns on.
PMID:6886003 SUPPORT Human Clinical
"Kinetic parameters of coproporphyrinogen III oxidase from these patients were clearly modified, with a Michaelis constant 15-20-fold higher than normal values when using coproporphyrinogen or harderoporphyrinogen as substrates. Maximal velocity was half the normal value, and we also observed a..."
The measured kinetics, which show the enzyme is also slower and less stable. Quoted so this node does not read as claiming normal throughput - the claim is that the deficit is unequal between the two cycles, not that there is no deficit.
PMID:629747 SUPPORT In Vitro
"It is suggested that both decarboxylations take place at the same active centre, which becomes temporarily inaccessible to coproporphyrinogen III and added harderoporphyrinogen, and that the molecule rotates after the first decarboxylation to allow the second to take place."
The normal-physiology basis for this entry's central claim, and the direct answer to the 1983 objection below - a single shared active centre that sequesters its substrate between cycles is exactly what a retention-region variant can break. Proposed in the same rat-liver system the objection rests on, five years earlier.
+ 4 more references
Harderoporphyrin Accumulation
The released intermediate accumulates and is excreted, dominating the faecal porphyrin profile. This is the diagnostic signature and it is quantitative: harderoporphyrin normally makes up under a fifth of faecal porphyrin and here exceeds three fifths. Unlike most porphyrias, the accumulating species in this disease is not a pathway substrate but a reaction intermediate.
erythroblast CL:0000765 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves erythroblast (CL:0000765). CL:0000765 is a cell type from the Cell Ontology.
porphyrin-containing compound metabolic process GO:0006778 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal porphyrin-containing compound metabolic process (GO:0006778). GO:0006778 is a biological process from the Gene Ontology. ⚠ ABNORMAL heme biosynthetic process GO:0006783 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal heme biosynthetic process (GO:0006783). GO:0006783 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Animal models
BALB.NCT-Cpox nct mouse Mouse fails to recapitulate The mouse accumulates and excretes coproporphyrin, which is the HCP signature, and shows the neuromuscular manifestations of HCP. It reports no harderoporphyrin excess, but it was never tested for one: the measured panel was uroporphyrin, coproporphyrin, protoporphyrin, porphobilinogen and delta-aminolevulinic acid, and harderoporphyrin was not among the analytes.
RBC16 ENU mouse Mouse fails to recapitulate The elevated species reported is coproporphyrinogen III, the HCP one. Harderoporphyrin is not reported either way - the abstract names only coproporphyrinogen III, and no harderoporphyrin assay is described.
Downstream
Erythroid Compartment Injury The accumulation is erythropoietic rather than hepatic in this disease and the haemolysis follows it, but the step from the accumulated intermediate to red cell destruction is not established at the level of a mechanism.
Cutaneous Porphyrin Phototoxicity
Show evidence (1 reference)
PMID:6886003 SUPPORT Human Clinical
"the pattern of fecal porphyrin excretion was atypical for hereditary coproporphyria because the major porphyrin was harderoporphyrin (greater than 60%; normal value is less than 20%)"
The quantitative diagnostic signature, with its reference value, from the original description.
Erythroid Compartment Injury
Red cell destruction with a compensatory marrow response, giving the haemolytic anaemia, jaundice and hepatosplenomegaly that define the neonatal presentation. PROVISIONAL deliberately: that this disease is erythropoietic rather than hepatic is well established from the presentation and from the porphyrin content of erythrocytes, but no reference reviewed here demonstrates the step by which accumulated harderoporphyrin destroys the red cell. Naming it as established would overstate what the literature supports.
erythroblast CL:0000765 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves erythroblast (CL:0000765). CL:0000765 is a cell type from the Cell Ontology. erythrocyte CL:0000232 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves erythrocyte (CL:0000232). CL:0000232 is a cell type from the Cell Ontology.
Downstream
Neonatal Haemolytic Anaemia and Jaundice
Show evidence (1 reference)
PMID:28349448 SUPPORT Other
"In contrast, harderoporphyria is an erythropoietic porphyria that represents photosensitivity and hemolytic anemia from the neonatal period."
Classifies the disease as erythropoietic rather than hepatic, which is the compartment claim this node makes.
Neonatal Haemolytic Anaemia and Jaundice
The presenting syndrome: haemolysis with jaundice and hepatosplenomegaly from birth or the first days of life. It is the feature that most separates this disease clinically from HCP, where nothing happens until after puberty and the presentation is neurovisceral.
Show evidence (2 references)
PMID:6886003 SUPPORT Human Clinical
"Three siblings with intense jaundice and hemolytic anemia at birth were found to excrete a high level of coproporphyrin in their urine and feces"
The presenting features in the three siblings of the original description, establishing the neonatal timing that separates this node from the post-pubertal presentation of hereditary coproporphyria.
PMID:21103937 SUPPORT Human Clinical
"who presented with the Harderoporphyria phenotype including neonatal hyperbilirubinemia, hemolytic anemia, hepatosplenomegaly, and skin lesions when exposed to UV light"
The same neonatal syndrome in a patient carrying a different variant, so the node is not specific to the original family.
Cutaneous Porphyrin Phototoxicity
Circulating photoreactive porphyrins absorb visible light and damage skin. The reported course is variable in a way worth recording: skin lesions on UV exposure in infancy in some patients, and in at least one case lifelong photosensitivity persisting into the eighth decade, in whom the diagnosis was not made until then.
keratinocyte CL:0000312 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves keratinocyte (CL:0000312). CL:0000312 is a cell type from the Cell Ontology. erythrocyte CL:0000232 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves erythrocyte (CL:0000232). CL:0000232 is a cell type from the Cell Ontology.
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
Cutaneous Photosensitivity
Show evidence (1 reference)
PMID:30828546 SUPPORT Human Clinical
"A 78-year-old man with a history of neonatal anemia and jaundice and life-long photosensitivity was found to have harderoporphyria, as evidenced by increased porphyrins in urine, plasma, erythrocytes and feces including large amounts of harderoporphyrin in feces and erythrocytes."
Documents the photosensitivity as lifelong rather than neonatal-limited, and documents that the diagnosis can be missed for decades.
Cutaneous Photosensitivity
Skin lesions on light exposure. Non-blistering in the reported cases, in keeping with a porphyrin-mediated phototoxicity rather than the bullous photodermatitis of the uroporphyrin-accumulating porphyrias.
Show evidence (1 reference)
PMID:30828546 SUPPORT Human Clinical
"This case increases the molecular heterogeneity of this rare porphyria, and illustrates that it should be considered as a cause of chronic photosensitivity and porphyrin elevation at any age."
Establishes the node as a persistent feature rather than a neonatal one, which is what distinguishes it from the haemolytic presentation it shares a cause with.
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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 Harderoporphyria 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

4
Blood 1
Haemolytic Anaemia VERY_FREQUENT Hemolytic anemia HP:0001878 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hemolytic anemia (HP:0001878), qualified as temporality chronic. HP:0001878 is a phenotype from the Human Phenotype Ontology.
Temporal: CHRONIC
Show evidence (1 reference)
PMID:9454777 SUPPORT Human Clinical
"Harderoporphyric patients exhibit jaundice, severe chronic hemolytic anemia of early onset associated with hepatosplenomegaly, and skin photosensitivity."
The clinical syndrome as described across the reported families.
Cardiovascular 1
Hepatosplenomegaly FREQUENT HP:0001433 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hepatosplenomegaly (HP:0001433). HP:0001433 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:21103937 SUPPORT Human Clinical
"who presented with the Harderoporphyria phenotype including neonatal hyperbilirubinemia, hemolytic anemia, hepatosplenomegaly, and skin lesions when exposed to UV light"
The phenotype list in the non-K404E homozygote, which also shows the same syndrome arises from a different variant in the same region.
Digestive 1
Jaundice VERY_FREQUENT HP:0000952 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Jaundice (HP:0000952). HP:0000952 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:6886003 SUPPORT Human Clinical
"Three siblings with intense jaundice and hemolytic anemia at birth were found to excrete a high level of coproporphyrin in their urine and feces"
The presenting features in the three siblings of the original description.
Integument 1
Cutaneous Photosensitivity FREQUENT HP:0000992 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cutaneous photosensitivity (HP:0000992), qualified as temporality chronic. HP:0000992 is a phenotype from the Human Phenotype Ontology.
Temporal: CHRONIC
Show evidence (1 reference)
PMID:30828546 SUPPORT Human Clinical
"This case increases the molecular heterogeneity of this rare porphyria, and illustrates that it should be considered as a cause of chronic photosensitivity and porphyrin elevation at any age."
The authors' own generalisation from the case - that the photosensitivity is not confined to infancy and should prompt the diagnosis at any age.
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Genetic Associations

1
CPOX
Gene: CPOX hgnc:2321 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is CPOX (hgnc:2321). hgnc:2321 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (3 references)
PMID:11309681 SUPPORT Human Clinical
"In all patients, clinical presentation was uniform, in spite of the wide range (1%-64%) of residual coproporphyrinogen oxidase activity, as determined by heterologous expression."
The measured absence of a dose-response relationship, which is what rules out reading harderoporphyria as simply lower activity.
PMID:11309681 SUPPORT Human Clinical
"show that single copies of CPO mutations that are known or predicted to cause "homozygous" HCP or harderoporphyria can produce typical HCP in adults"
The same allele in one copy gives HCP and in two gives harderoporphyria - the observation that makes zygosity as well as position part of the rule.
PMID:21103937 SUPPORT Computational
"Structural studies predicted that p.H327R interacts with residue W399 in the CPOX active site, thereby accounting for the Harderoporphyria phenotype."
Graded COMPUTATIONAL because the interaction is a structural prediction, not a measurement - which is exactly why the residue-interval rule should be read as functional rather than positional.
🗃️

External Assertions

2
Orphanet harderoporphyria record
Orphanet disease record ORPHA:659672
Orphanet classifies harderoporphyria at the disorder level rather than as a subtype: in ORDO its asserted parents are Disorder (ORDO:557493) and Disease (ORDO:377788), not Subtype of a disorder (ORDO:557494), and not hereditary coproporphyria. That is the same reading this entry takes and the opposite of MONDO's placement, so it is recorded as an external assertion rather than as a mapping - the two resources disagree about the hierarchy. Note that the equivalentTo cross-reference alone would not have established this; the classification level is what does.
OMIM harderoporphyria record
OMIM disease record OMIM:618892
OMIM's phenotype entry for harderoporphyria. MONDO:0030048 carries equivalentTo cross-references to both this and ORPHA:659672, checked against OLS.
💊

Medical Actions

2
Supportive Management of Haemolysis
Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
There is no treatment directed at the enzymatic lesion. Management is supportive: transfusion where the anaemia requires it, management of neonatal hyperbilirubinaemia, and light protection for the photosensitivity. This entry records no disease-modifying therapy because none was found in the literature reviewed, not because the search was incomplete - the reported literature is a handful of cases and none reports an intervention trial.
Mechanism Target:
MODULATES Neonatal Haemolytic Anaemia and Jaundice — Addresses the consequence, not the cause. Nothing in current management reaches the retention defect in the enzyme.
Show evidence (1 reference)
PMID:9454777 SUPPORT Human Clinical
"Harderoporphyric patients exhibit jaundice, severe chronic hemolytic anemia of early onset associated with hepatosplenomegaly, and skin photosensitivity."
PARTIAL because it establishes what has to be managed, not that any particular management works - no reviewed source reports a treatment result in this disease.
Genetic Counselling
Action: genetic counselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is genetic counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. Ontology label: Genetic Counseling NCIT:C15240
Autosomal recessive with a 25% sibling recurrence risk. It has an added complication here that ordinary recessive counselling does not: a carrier parent is not merely a carrier but has HCP, and can have acute attacks in adulthood. So the family assessment produced by testing a proband is a two-generation, two-disease assessment.
Show evidence (1 reference)
PMID:11309681 SUPPORT Human Clinical
"show that single copies of CPO mutations that are known or predicted to cause "homozygous" HCP or harderoporphyria can produce typical HCP in adults"
The basis for the two-disease family assessment - a heterozygous relative is at risk of adult HCP, not simply an unaffected carrier.
🔬

Biochemical Markers

3
Faecal harderoporphyrin (Increased)
Context: The diagnostic analyte, and the one that distinguishes this disease from HCP on biochemistry alone. It is the proportion rather than the absolute amount that carries the information: harderoporphyrin is a minor faecal porphyrin in HCP and the dominant one here.
Pathograph Readouts
Readout Of Harderoporphyrin Accumulation Positive Diagnostic
Reports release of the reaction intermediate, and therefore reports the specific enzymatic lesion rather than heme-pathway disturbance in general.
Show evidence (1 reference)
PMID:6886003 SUPPORT Human Clinical
"the pattern of fecal porphyrin excretion was atypical for hereditary coproporphyria because the major porphyrin was harderoporphyrin (greater than 60%; normal value is less than 20%)"
The measurement and its normal range, which is what makes this a discriminating test rather than a supportive one.
Erythrocyte harderoporphyrin (Increased)
Context: Harderoporphyrin is measurable in erythrocytes as well as faeces. This is the observation that places the accumulation in the erythroid compartment rather than the hepatic one, and it is one of the two things the knowledge-gap discussion below treats as established.
Pathograph Readouts
Readout Of Erythroid Compartment Injury Positive Diagnostic
Locates the accumulating intermediate inside the cell type that is being destroyed. It does not establish that the porphyrin causes the destruction, which is exactly the gap recorded below.
Show evidence (1 reference)
PMID:30828546 SUPPORT Human Clinical
"increased porphyrins in urine, plasma, erythrocytes and feces including large amounts of harderoporphyrin in feces and erythrocytes"
The measurement in erythrocytes specifically, alongside the faecal finding.
Lymphocyte coproporphyrinogen oxidase activity (Decreased)
Context: Around 10% of control values in affected homozygotes and around 50% in heterozygous parents. The enzymology was what established the recessive inheritance before the gene was cloned.
Pathograph Readouts
Readout Of Biallelic CPOX Variant in the Substrate-Retention Region Negative Diagnostic
Reports the enzymatic deficit and, through the parent-child contrast, the mode of inheritance.
Show evidence (1 reference)
PMID:6886003 SUPPORT Human Clinical
"The lymphocyte coproporphyrinogen III oxidase activity of each patient was 10% of control values, which suggests a homozygous state."
The measured activity in the affected siblings and the inference drawn from it.
🔬

Diagnosis

2
Faecal Porphyrin Fractionation
The test that makes the diagnosis. Total porphyrin elevation is common to many porphyrias; it is the fraction that is harderoporphyrin which is specific, so a laboratory reporting only totals will miss this disease and report a picture consistent with coproporphyria.
laboratory procedure NCIT:C25294 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:6886003 SUPPORT Human Clinical
"the pattern of fecal porphyrin excretion was atypical for hereditary coproporphyria because the major porphyrin was harderoporphyrin (greater than 60%; normal value is less than 20%)"
Shows the fractionation, not the total, carrying the diagnostic information.
CPOX Sequencing
Confirms the diagnosis and, because the phenotype is position-dependent, interprets it: the finding that matters is whether the variants affect the substrate-retention region, not merely that they are in CPOX.
genetic testing NCIT:C15709 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:9454777 SUPPORT Human Clinical
"In the present study, molecular investigations in a second family with neonatal hemolytic anemia and harderoporphyria revealed two heterozygous point mutations in the COX gene."
Molecular confirmation in a second, independent family, establishing the compound-heterozygous configuration as well as the homozygous one.
📊

Prevalence

1
Worldwide
Cases In Literature <1 in 1,000,000
No population estimate exists. Reported as a handful of cases: a 2010 report describes homozygous HCP patients as "only a few" and most of those as having harderoporphyria, and a 2019 case report counted eight previously reported cases. Recorded as a literature count rather than a rate, and the prevalence_class band is an inference from that count rather than a measured figure.
Show evidence (1 reference)
PMID:30828546 SUPPORT Human Clinical
"Two previously undescribed coproporphyrinogen oxidase (CPOX) mutations were identified, including a deletion of four amino acids in a region of the enzyme mutated in 7 of the 8 previously reported cases."
Establishes the order of magnitude of the reported literature - eight prior cases - and, incidentally, that seven of those eight carried a variant in the same region.
🐁

Animal Models

2
BALB.NCT-Cpox nct mouse
A hypomorphic Cpox allele retaining about 15% of wild-type activity. It is the best-characterised murine CPOX model and it models hereditary coproporphyria, not this disease.
Species
Mouse
Genotype
Cpox p.Arg380Leu homozygous, hypomorphic
Publication
PMID:36967721
Pathograph links
Harderoporphyrin Accumulation fails to recapitulate fidelity: low The mouse accumulates and excretes coproporphyrin, which is the HCP signature, and shows the neuromuscular manifestations of HCP. It reports no harderoporphyrin excess, but it was never tested for one: the measured panel was uroporphyrin, coproporphyrin, protoporphyrin, porphobilinogen and delta-aminolevulinic acid, and harderoporphyrin was not among the analytes.
Limitations: The allele is the reason, and the allele is what this claim rests on, not a harderoporphyrin measurement. p.Arg380Leu lies outside the D400-K404 retention region in which every reported harderoporphyria variant falls, so it reduces enzyme activity without disturbing the step between the two decarboxylations. Mouse residue 380 is homologous to human residue 391, and the human variant at that position, p.Arg391Trp at 22% residual activity, causes ordinary hereditary coproporphyria - so the same position gives the same phenotype in both species. What the mouse reports is a coproporphyrin-dominant profile at HCP severity; whether any harderoporphyrin is present in it is simply unknown. It is a quantitative deficiency where harderoporphyria is a positional one - which is the distinction this entry is built on, arriving from the model side.
Show evidence (3 references)
PMID:36967721 SUPPORT Model Organism
"Similar to HCP patients, BALB.NCT-Cpox nct excreted an excessive amount of coproporphyrin and porphyrin precursors in the urine and displayed neuromuscular symptoms, such as a lack of grip strength and impaired motor coordination."
The model's phenotype is the HCP one - coproporphyrin and neuromuscular symptoms - which is what it fails to share with harderoporphyria.
+ 2 more references
Show evidence (1 reference)
PMID:23631845 SUPPORT Model Organism
"The CPOX isoform with the p.R380L substitution retained only 15% of the activity of the wild type isoform."
Establishes the allele and its residual activity. Note that 15% residual activity sits inside the 1-64% range that produces clinically uniform HCP in humans, which is consistent with this model landing on the HCP phenotype.
RBC16 ENU mouse
A dominantly inherited nonsense allele recovered from an ENU screen for regulators of erythropoiesis. Heterozygotes have microcytic red cells and elevated coproporphyrin, with a sex difference.
Species
Mouse
Genotype
Cpox premature stop codon at Trp373, heterozygous
Publication
PMID:28600349
Pathograph links
Harderoporphyrin Accumulation fails to recapitulate fidelity: low The elevated species reported is coproporphyrinogen III, the HCP one. Harderoporphyrin is not reported either way - the abstract names only coproporphyrinogen III, and no harderoporphyrin assay is described.
Limitations: A heterozygous null - the classic HCP genotype - rather than a biallelic retention-region lesion, so it cannot in principle produce the harderoporphyria phenotype. It also shows a sex difference in the biochemistry that human harderoporphyria is not reported to have.
Show evidence (1 reference)
PMID:28600349 SUPPORT Model Organism
"Urinary and faecal porphyrins in female RBC16 heterozygotes were significantly elevated compared with that of wild-type littermates, particularly coproporphyrinogen III, whereas males were biochemically normal."
The accumulating species is coproporphyrinogen III, and the effect is sex-limited - neither matches harderoporphyria.
{ }

Source YAML

click to show 
name: Harderoporphyria
creation_date: "2026-08-28T16:30:00Z"
category: Mendelian
description: >-
  Coproporphyrinogen oxidase does its job twice. It removes two propionate side
  chains from coproporphyrinogen III in sequence, and between the two removals
  the substrate exists as a tricarboxylic intermediate, harderoporphyrinogen,
  which the enzyme must hold onto in order to finish. Harderoporphyria is what
  happens when a variant lets the enzyme complete the first decarboxylation and
  not the second: the intermediate is released instead of being retained, and it
  is excreted in enormous quantities.

  That distinguishes it sharply from hereditary coproporphyria, which is the same
  gene. HCP is a dominant disorder of half-normal enzyme activity in the liver;
  the substrate upstream of the block accumulates, hepatic ALAS1 is derepressed,
  and patients have acute neurovisceral attacks after puberty. Harderoporphyria
  is recessive, requires two alleles, presents in the newborn with haemolytic
  anaemia and jaundice rather than with attacks, and the diagnostic finding is a
  different molecule - harderoporphyrin dominating faecal porphyrins where in HCP
  it is a minor component.

  So the split is not a severity band on one mechanism. The same enzyme fails in
  two different ways, at two different points, in two different compartments, and
  the position of the variant within the protein is what decides which disease
  the patient has.
disease_term:
  preferred_term: harderoporphyria
  term:
    id: MONDO:0030048
    label: harderoporphyria
synonyms:
- HARPO
- harderoporphyrinuria
parents:
- Porphyria
external_assertions:
- name: Orphanet harderoporphyria record
  source: Orphanet
  assertion_type: disease_record
  external_id: ORPHA:659672
  url: https://www.orpha.net/en/disease/detail/659672
  description: >-
    Orphanet classifies harderoporphyria at the disorder level rather than as a
    subtype: in ORDO its asserted parents are Disorder (ORDO:557493) and Disease
    (ORDO:377788), not Subtype of a disorder (ORDO:557494), and not hereditary
    coproporphyria. That is the same reading this entry takes and the opposite of
    MONDO's placement, so it is recorded as an external assertion rather than as a
    mapping - the two resources disagree about the hierarchy. Note that the
    equivalentTo cross-reference alone would not have established this; the
    classification level is what does.
- name: OMIM harderoporphyria record
  source: OMIM
  assertion_type: disease_record
  external_id: OMIM:618892
  url: https://omim.org/entry/618892
  description: >-
    OMIM's phenotype entry for harderoporphyria. MONDO:0030048 carries equivalentTo
    cross-references to both this and ORPHA:659672, checked against OLS.
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Two CPOX alleles are required, either homozygosity for a
    harderoporphyria-specific variant or compound heterozygosity for one such
    variant with a null allele. Heterozygous parents show only the mild
    biochemical and enzymatic changes of HCP carriers - which is the observation
    that established the recessive mode.
  evidence:
  - reference: PMID:6886003
    reference_title: 'Harderoporphyria: a variant hereditary coproporphyria.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Both parents showed only mild abnormalities in porphyrin excretion and lymphocyte
      coproporphyrinogen III oxidase activity decreased to 50% of normal values, as is expected
      in heterozygous cases of hereditary coproporphyria.
    explanation: The parental data establishing that the affected siblings were homozygous
      and the parents were HCP-type carriers.
pathophysiology:
- name: Biallelic CPOX Variant in the Substrate-Retention Region
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  conforms_to: heme_biosynthesis_porphyria#Heme Biosynthesis Enzymatic Block
  description: >-
    A variant affecting the residues that hold the reaction intermediate in the
    active site between the two decarboxylation cycles. Most reported patients
    carry p.Lys404Glu on at least one allele; p.His327Arg has also been reported
    in homozygous form, and a four-amino-acid deletion in the same region in a
    compound heterozygote. The clustering is the point - this is a
    position-specific lesion in a region distinct from where ordinary HCP
    variants fall.
  genetic_context:
    gene:
      preferred_term: CPOX
      term:
        id: hgnc:2321
        label: CPOX
    functional_impact_category: PARTIAL_LOSS_OF_FUNCTION
  molecular_functions:
  - preferred_term: coproporphyrinogen oxidase activity
    modifier: DECREASED
    term:
      id: GO:0004109
      label: coproporphyrinogen oxidase activity
  biological_processes:
  - preferred_term: heme biosynthetic process
    modifier: DECREASED
    term:
      id: GO:0006783
      label: heme biosynthetic process
  - preferred_term: porphyrin-containing compound metabolic process
    modifier: ABNORMAL
    term:
      id: GO:0006778
      label: porphyrin-containing compound metabolic process
  cell_types:
  - preferred_term: erythroblast
    term:
      id: CL:0000765
      label: erythroblast
  downstream:
  - target: Arrest After the First Decarboxylation
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:11309681
    reference_title: Characterization of mutations in the CPO gene in British patients demonstrates
      absence of genotype-phenotype correlation and identifies relationship between hereditary
      coproporphyria and harderoporphyria.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In such patients the presence of a specific mutation (K404E) on one or both
      alleles produces a neonatal hemolytic anemia that is known as "harderoporphyria"; mutations
      on both alleles elsewhere in the gene give rise to the "homozygous" variant of HCP.
    explanation: The allele-position rule stated directly - and note it separates
      harderoporphyria not only from dominant HCP but from homozygous HCP, which is a
      different biallelic disease of the same gene.
  - reference: PMID:21103937
    reference_title: Harderoporphyria due to homozygosity for coproporphyrinogen oxidase
      missense mutation H327R.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: To date, only a few homozygous HCP patients have been described, most having
      Harderoporphyria, a rare variant due to specific CPOX mutations that alter enzyme residues
      D400-K404, most patients described to date having at least one K404E allele.
    explanation: Names the residue interval and the dominance of K404E in the reported
      series, which is the basis for calling this a position-specific lesion.
  - reference: PMID:9454777
    reference_title: 'Neonatal hemolytic anemia due to inherited harderoporphyria: clinical
      characteristics and molecular basis.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The second allele bore an A-->G transition at the third position of the donor
      splice site in intron 6. This new COX gene mutation resulted in exon 6 skipping and
      the absence of functional protein production.
    explanation: The null allele in the compound-heterozygous configuration, documented
      rather than left implicit. It is what makes the K404E allele the only source of
      residual activity in that family.
- name: Arrest After the First Decarboxylation
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    The enzyme removes the first propionate and then fails to retain
    harderoporphyrinogen for the second cycle, so the intermediate is released
    rather than carried through to protoporphyrinogen. The structural account is
    specific: the K404E substitution disrupts a type I beta-turn whose job is
    substrate retention between cycles.

    The normal reaction is ordered and processive, which is what makes a
    cycle-specific failure possible at all. Isotope labelling in rat liver showed
    that the 4-propionate cannot be attacked until the 2-propionate has been
    decarboxylated, that harderoporphyrinogen forms about twice as fast as
    protoporphyrinogen, and - the load-bearing part - that the harderoporphyrinogen
    destined to become protoporphyrinogen does not equilibrate with added
    harderoporphyrinogen. The intermediate on its way through is a kinetically
    distinct pool from free intermediate in solution. That is what "retention"
    names: not a metaphor but a measurable compartment.

    The claim is that the reaction is redirected, not that throughput is normal.
    The enzyme is also slower - the 1983 kinetics give a Michaelis constant
    15-20-fold above normal and a maximal velocity half of normal, and lymphocyte
    activity in the affected siblings was 10% of control. What distinguishes this
    disease from a straightforwardly less active enzyme is that the deficit is
    not uniform across the two cycles, so the accumulating species is an
    intermediate that barely appears in other porphyrias rather than the
    substrate upstream of the block.

    That distinction was contested, and by the same paper. The 1983 authors
    explicitly ruled out an active-site lesion specific to the second
    decarboxylation, on the grounds that rat liver metabolises coproporphyrinogen
    and harderoporphyrinogen at the same active centre. They were right about the
    active centre and it does not settle the question: the 2005 crystal structure
    locates the harderoporphyria lesion not in a second catalytic site but in a
    beta-turn that retains the substrate between cycles at the one shared site.
    A single active centre and a cycle-specific failure are compatible, and this
    was not only shown later by the structure - it was proposed in the same
    rat-liver system the objection rests on, five years before the disease was
    named. The 1978 account has both decarboxylations at one active centre which
    becomes temporarily inaccessible, with the molecule rotating between cycles.
    A shared centre that sequesters its substrate between turns is precisely the
    thing a retention-region variant can break.

    Separately, CPOX is an obligate homodimer whose monomer has no activity, so
    what a given genotype does depends on which dimers can form.
  molecular_functions:
  - preferred_term: second decarboxylation of harderoporphyrinogen to protoporphyrinogen
    modifier: DECREASED
    term:
      id: GO:0004109
      label: coproporphyrinogen oxidase activity
  downstream:
  - target: Harderoporphyrin Accumulation
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:16176984
    reference_title: Structural basis of hereditary coproporphyria.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Conversely, harderoporphyria-causing K404E mutation precludes a type I beta-turn
      from retaining the substrate for the second decarboxylation cycle.
    explanation: The structural mechanism, from the crystal structure of human CPOX - this
      is the sentence the whole entry turns on.
  - reference: PMID:6886003
    reference_title: 'Harderoporphyria: a variant hereditary coproporphyria.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Kinetic parameters of coproporphyrinogen III oxidase from these patients were
      clearly modified, with a Michaelis constant 15-20-fold higher than normal values when
      using coproporphyrinogen or harderoporphyrinogen as substrates. Maximal velocity was
      half the normal value, and we also observed a marked sensitivity to thermal denaturation.
    explanation: The measured kinetics, which show the enzyme is also slower and less stable.
      Quoted so this node does not read as claiming normal throughput - the claim is that
      the deficit is unequal between the two cycles, not that there is no deficit.
  - reference: PMID:629747
    reference_title: Factors determining the sequence of oxidative decarboxylation of the
      2- and 4-propionate substituents of coproporphyrinogen III by coproporphyrinogen oxidase
      in rat liver.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: It is suggested that both decarboxylations take place at the same active centre,
      which becomes temporarily inaccessible to coproporphyrinogen III and added harderoporphyrinogen,
      and that the molecule rotates after the first decarboxylation to allow the second to
      take place.
    explanation: The normal-physiology basis for this entry's central claim, and the direct
      answer to the 1983 objection below - a single shared active centre that sequesters its
      substrate between cycles is exactly what a retention-region variant can break. Proposed
      in the same rat-liver system the objection rests on, five years earlier.
  - reference: PMID:629747
    reference_title: Factors determining the sequence of oxidative decarboxylation of the
      2- and 4-propionate substituents of coproporphyrinogen III by coproporphyrinogen oxidase
      in rat liver.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: One accumulates during the reaction, and the other, which is destined to become
      protoporphyrinogen IX, does not equilibrate with added harderoporphyrinogen.
    explanation: The intermediate en route to protoporphyrinogen is a kinetically distinct
      pool from free intermediate in solution. This is what makes "retention" a measurable
      compartment rather than a figure of speech, and therefore what makes its failure a
      mechanism.
  - reference: PMID:6886003
    reference_title: 'Harderoporphyria: a variant hereditary coproporphyria.'
    supports: REFUTE
    evidence_source: IN_VITRO
    snippet: The possibility that a mutation affecting the enzyme on the active center which
      is specifically involved in the second decarboxylation (from harderoporphyrinogen to
      protoporphyrinogen) was eliminated by experiments on rat liver that showed that coproporphyrinogen
      and harderoporphyrinogen were metabolized at the same active center.
    explanation: Graded REFUTE because it is the argument against this node, from the paper
      that named the disease - the 1983 authors rejecting a lesion specific to the second
      decarboxylation. It is carried rather than omitted because the resolution is a real
      one and worth reading - they showed a single shared active centre, and the 2005
      structure showed the lesion is in substrate retention between cycles at that one
      centre, not in a second catalytic site. The two results are compatible; the older
      inference was the strongest reading available before the structure existed.
  - reference: PMID:24078084
    reference_title: The enzyme engineering of mutant homodimer and heterodimer of coproporphyinogen
      oxidase contributes to new insight into hereditary coproporphyria and harderoporphyria.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: The monomer form of mutated CPOX did not show any activity and homodimeric enzymes
      derived from HCP mutant showed low activity (<20% of the control).
    explanation: Establishes the obligate-dimer requirement, which is why genotype acts
      through which dimers can assemble rather than through allele dosage alone.
  - reference: PMID:24078084
    reference_title: The enzyme engineering of mutant homodimer and heterodimer of coproporphyinogen
      oxidase contributes to new insight into hereditary coproporphyria and harderoporphyria.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Some mutations of amino acids 401-404 were associated with marked accumulation
      of harderoporphyrinogen, with a decrease in the production of protoporphyrinogen
    explanation: The engineered demonstration that variants in this interval redirect the
      reaction toward the intermediate rather than merely slowing it.
- name: Harderoporphyrin Accumulation
  biological_scale: ORGANISM
  mechanism_confidence: ESTABLISHED
  conforms_to: heme_biosynthesis_porphyria#Accumulation of Porphyrin Precursors and Porphyrins
  description: >-
    The released intermediate accumulates and is excreted, dominating the faecal
    porphyrin profile. This is the diagnostic signature and it is quantitative:
    harderoporphyrin normally makes up under a fifth of faecal porphyrin and here
    exceeds three fifths. Unlike most porphyrias, the accumulating species in
    this disease is not a pathway substrate but a reaction intermediate.
  biological_processes:
  - preferred_term: porphyrin-containing compound metabolic process
    modifier: ABNORMAL
    term:
      id: GO:0006778
      label: porphyrin-containing compound metabolic process
  - preferred_term: heme biosynthetic process
    modifier: ABNORMAL
    term:
      id: GO:0006783
      label: heme biosynthetic process
  cell_types:
  - preferred_term: erythroblast
    term:
      id: CL:0000765
      label: erythroblast
  chemical_entities:
  - preferred_term: harderoporphyrin
    term:
      id: CHEBI:169840
      label: Harderoporphyrin
  downstream:
  - target: Erythroid Compartment Injury
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The accumulation is erythropoietic rather than hepatic in this disease and
      the haemolysis follows it, but the step from the accumulated intermediate
      to red cell destruction is not established at the level of a mechanism.
  - target: Cutaneous Porphyrin Phototoxicity
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:6886003
    reference_title: 'Harderoporphyria: a variant hereditary coproporphyria.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: the pattern of fecal porphyrin excretion was atypical for hereditary coproporphyria
      because the major porphyrin was harderoporphyrin (greater than 60%; normal value is
      less than 20%)
    explanation: The quantitative diagnostic signature, with its reference value, from the
      original description.
- name: Erythroid Compartment Injury
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  description: >-
    Red cell destruction with a compensatory marrow response, giving the
    haemolytic anaemia, jaundice and hepatosplenomegaly that define the neonatal
    presentation. PROVISIONAL deliberately: that this disease is erythropoietic
    rather than hepatic is well established from the presentation and from the
    porphyrin content of erythrocytes, but no reference reviewed here demonstrates
    the step by which accumulated harderoporphyrin destroys the red cell. Naming
    it as established would overstate what the literature supports.
  cell_types:
  - preferred_term: erythroblast
    term:
      id: CL:0000765
      label: erythroblast
  - preferred_term: erythrocyte
    term:
      id: CL:0000232
      label: erythrocyte
  downstream:
  - target: Neonatal Haemolytic Anaemia and Jaundice
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:28349448
    reference_title: 'Neonatal-Onset Hereditary Coproporphyria: A New Variant of Hereditary
      Coproporphyria.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: In contrast, harderoporphyria is an erythropoietic porphyria that represents
      photosensitivity and hemolytic anemia from the neonatal period.
    explanation: Classifies the disease as erythropoietic rather than hepatic, which is the
      compartment claim this node makes.
- name: Neonatal Haemolytic Anaemia and Jaundice
  biological_scale: ORGANISM
  mechanism_confidence: ESTABLISHED
  description: >-
    The presenting syndrome: haemolysis with jaundice and hepatosplenomegaly from
    birth or the first days of life. It is the feature that most separates this
    disease clinically from HCP, where nothing happens until after puberty and
    the presentation is neurovisceral.
  evidence:
  - reference: PMID:6886003
    reference_title: 'Harderoporphyria: a variant hereditary coproporphyria.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Three siblings with intense jaundice and hemolytic anemia at birth were found
      to excrete a high level of coproporphyrin in their urine and feces
    explanation: The presenting features in the three siblings of the original description,
      establishing the neonatal timing that separates this node from the post-pubertal
      presentation of hereditary coproporphyria.
  - reference: PMID:21103937
    reference_title: Harderoporphyria due to homozygosity for coproporphyrinogen oxidase
      missense mutation H327R.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: who presented with the Harderoporphyria phenotype including neonatal hyperbilirubinemia,
      hemolytic anemia, hepatosplenomegaly, and skin lesions when exposed to UV light
    explanation: The same neonatal syndrome in a patient carrying a different variant, so
      the node is not specific to the original family.
- name: Cutaneous Porphyrin Phototoxicity
  biological_scale: TISSUE
  mechanism_confidence: ESTABLISHED
  conforms_to: heme_biosynthesis_porphyria#Cutaneous Porphyrin Phototoxicity
  description: >-
    Circulating photoreactive porphyrins absorb visible light and damage skin.
    The reported course is variable in a way worth recording: skin lesions on UV
    exposure in infancy in some patients, and in at least one case lifelong
    photosensitivity persisting into the eighth decade, in whom the diagnosis was
    not made until then.
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  - preferred_term: erythrocyte
    term:
      id: CL:0000232
      label: erythrocyte
  biological_processes:
  - preferred_term: response to oxidative stress
    modifier: INCREASED
    term:
      id: GO:0006979
      label: response to oxidative stress
  downstream:
  - target: Cutaneous Photosensitivity
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:30828546
    reference_title: 'Harderoporphyria: Case of lifelong photosensitivity associated with
      compound heterozygous coproporphyrinogen oxidase (CPOX) mutations.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: A 78-year-old man with a history of neonatal anemia and jaundice and life-long
      photosensitivity was found to have harderoporphyria, as evidenced by increased porphyrins
      in urine, plasma, erythrocytes and feces including large amounts of harderoporphyrin
      in feces and erythrocytes.
    explanation: Documents the photosensitivity as lifelong rather than neonatal-limited,
      and documents that the diagnosis can be missed for decades.
- name: Cutaneous Photosensitivity
  biological_scale: ORGANISM
  mechanism_confidence: ESTABLISHED
  description: >-
    Skin lesions on light exposure. Non-blistering in the reported cases, in
    keeping with a porphyrin-mediated phototoxicity rather than the bullous
    photodermatitis of the uroporphyrin-accumulating porphyrias.
  evidence:
  - reference: PMID:30828546
    reference_title: 'Harderoporphyria: Case of lifelong photosensitivity associated with
      compound heterozygous coproporphyrinogen oxidase (CPOX) mutations.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: This case increases the molecular heterogeneity of this rare porphyria, and
      illustrates that it should be considered as a cause of chronic photosensitivity and
      porphyrin elevation at any age.
    explanation: Establishes the node as a persistent feature rather than a neonatal one,
      which is what distinguishes it from the haemolytic presentation it shares a cause with.
phenotypes:
- category: Hematologic
  name: Haemolytic Anaemia
  frequency: VERY_FREQUENT
  description: >-
    Chronic haemolytic anaemia beginning at or shortly after birth. Severe in the
    originally described siblings and the defining feature of the phenotype.
  phenotype_term:
    preferred_term: Hemolytic anemia
    term:
      id: HP:0001878
      label: Hemolytic anemia
    temporality: CHRONIC
  evidence:
  - reference: PMID:9454777
    reference_title: 'Neonatal hemolytic anemia due to inherited harderoporphyria: clinical
      characteristics and molecular basis.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Harderoporphyric patients exhibit jaundice, severe chronic hemolytic anemia
      of early onset associated with hepatosplenomegaly, and skin photosensitivity.
    explanation: The clinical syndrome as described across the reported families.
- category: Hematologic
  name: Jaundice
  frequency: VERY_FREQUENT
  description: >-
    Neonatal hyperbilirubinaemia, the consequence of the haemolysis and usually
    the presenting sign.
  phenotype_term:
    preferred_term: Jaundice
    term:
      id: HP:0000952
      label: Jaundice
  evidence:
  - reference: PMID:6886003
    reference_title: 'Harderoporphyria: a variant hereditary coproporphyria.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Three siblings with intense jaundice and hemolytic anemia at birth were found
      to excrete a high level of coproporphyrin in their urine and feces
    explanation: The presenting features in the three siblings of the original description.
- category: Hepatic
  name: Hepatosplenomegaly
  frequency: FREQUENT
  description: >-
    Enlargement of liver and spleen accompanying the chronic haemolysis.
  phenotype_term:
    preferred_term: Hepatosplenomegaly
    term:
      id: HP:0001433
      label: Hepatosplenomegaly
  evidence:
  - reference: PMID:21103937
    reference_title: Harderoporphyria due to homozygosity for coproporphyrinogen oxidase
      missense mutation H327R.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: who presented with the Harderoporphyria phenotype including neonatal hyperbilirubinemia,
      hemolytic anemia, hepatosplenomegaly, and skin lesions when exposed to UV light
    explanation: The phenotype list in the non-K404E homozygote, which also shows the same
      syndrome arises from a different variant in the same region.
- category: Dermatologic
  name: Cutaneous Photosensitivity
  frequency: FREQUENT
  description: >-
    Skin lesions on light exposure. Reported both as a neonatal feature and, in
    one patient, as a lifelong complaint that was the reason the diagnosis was
    eventually made at 78.
  phenotype_term:
    preferred_term: Cutaneous photosensitivity
    term:
      id: HP:0000992
      label: Cutaneous photosensitivity
    temporality: CHRONIC
  evidence:
  - reference: PMID:30828546
    reference_title: 'Harderoporphyria: Case of lifelong photosensitivity associated with
      compound heterozygous coproporphyrinogen oxidase (CPOX) mutations.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: This case increases the molecular heterogeneity of this rare porphyria, and
      illustrates that it should be considered as a cause of chronic photosensitivity and
      porphyrin elevation at any age.
    explanation: The authors' own generalisation from the case - that the photosensitivity
      is not confined to infancy and should prompt the diagnosis at any age.
genetic:
- name: CPOX
  gene_term:
    preferred_term: CPOX
    term:
      id: hgnc:2321
      label: CPOX
  relationship_type: CAUSATIVE
  notes: >-
    The genotype-phenotype relationship in CPOX is position-dependent and not
    dose-dependent, and the two statements need holding together carefully.

    Position matters: variants altering residues D400-K404 give harderoporphyria,
    while biallelic variants elsewhere in the gene give a "homozygous HCP"
    phenotype that is a different disease. p.His327Arg extends the picture, since
    it lies outside that interval but was predicted to interact with W399 in the
    active site - so the functional criterion is proximity to the retention
    machinery rather than to a stretch of sequence.

    Zygosity acts through configuration, not just count. In the second reported
    family the K404E allele was paired with an intron-6 donor-splice-site variant
    that skips exon 6 and produces no functional protein, so the retention-class
    allele is the only source of activity and the compound heterozygote behaves
    as the homozygote does. A null in trans does not dilute the phenotype; it
    exposes it.

    Dose does not: within HCP, residual enzyme activity ranged from 1% to 64%
    across expressed variants with clinically uniform presentation, so severity
    does not track inactivation. That is why this entry does not present
    harderoporphyria as the severe end of a CPOX activity gradient. A single copy
    of a variant known to cause harderoporphyria in homozygotes can produce
    ordinary adult HCP, which is the same point from the other direction.
  evidence:
  - reference: PMID:11309681
    reference_title: Characterization of mutations in the CPO gene in British patients demonstrates
      absence of genotype-phenotype correlation and identifies relationship between hereditary
      coproporphyria and harderoporphyria.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In all patients, clinical presentation was uniform, in spite of the wide range
      (1%-64%) of residual coproporphyrinogen oxidase activity, as determined by heterologous
      expression.
    explanation: The measured absence of a dose-response relationship, which is what rules
      out reading harderoporphyria as simply lower activity.
  - reference: PMID:11309681
    reference_title: Characterization of mutations in the CPO gene in British patients demonstrates
      absence of genotype-phenotype correlation and identifies relationship between hereditary
      coproporphyria and harderoporphyria.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: show that single copies of CPO mutations that are known or predicted to cause
      "homozygous" HCP or harderoporphyria can produce typical HCP in adults
    explanation: The same allele in one copy gives HCP and in two gives harderoporphyria -
      the observation that makes zygosity as well as position part of the rule.
  - reference: PMID:21103937
    reference_title: Harderoporphyria due to homozygosity for coproporphyrinogen oxidase
      missense mutation H327R.
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: Structural studies predicted that p.H327R interacts with residue W399 in the
      CPOX active site, thereby accounting for the Harderoporphyria phenotype.
    explanation: Graded COMPUTATIONAL because the interaction is a structural prediction,
      not a measurement - which is exactly why the residue-interval rule should be read as
      functional rather than positional.
biochemical:
- name: Faecal harderoporphyrin
  presence: Increased
  context: >-
    The diagnostic analyte, and the one that distinguishes this disease from HCP
    on biochemistry alone. It is the proportion rather than the absolute amount
    that carries the information: harderoporphyrin is a minor faecal porphyrin in
    HCP and the dominant one here.
  biomarker_term:
    preferred_term: harderoporphyrin
    term:
      id: CHEBI:169840
      label: Harderoporphyrin
  readouts:
  - target: Harderoporphyrin Accumulation
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Reports release of the reaction intermediate, and therefore reports the
      specific enzymatic lesion rather than heme-pathway disturbance in general.
    evidence:
    - reference: PMID:6886003
      reference_title: 'Harderoporphyria: a variant hereditary coproporphyria.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: the pattern of fecal porphyrin excretion was atypical for hereditary coproporphyria
        because the major porphyrin was harderoporphyrin (greater than 60%; normal value
        is less than 20%)
      explanation: The measurement and its normal range, which is what makes this a
        discriminating test rather than a supportive one.
- name: Erythrocyte harderoporphyrin
  presence: Increased
  context: >-
    Harderoporphyrin is measurable in erythrocytes as well as faeces. This is the
    observation that places the accumulation in the erythroid compartment rather
    than the hepatic one, and it is one of the two things the knowledge-gap
    discussion below treats as established.
  biomarker_term:
    preferred_term: harderoporphyrin
    term:
      id: CHEBI:169840
      label: Harderoporphyrin
  readouts:
  - target: Erythroid Compartment Injury
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Locates the accumulating intermediate inside the cell type that is being
      destroyed. It does not establish that the porphyrin causes the destruction,
      which is exactly the gap recorded below.
    evidence:
    - reference: PMID:30828546
      reference_title: 'Harderoporphyria: Case of lifelong photosensitivity associated with
        compound heterozygous coproporphyrinogen oxidase (CPOX) mutations.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: increased porphyrins in urine, plasma, erythrocytes and feces including large
        amounts of harderoporphyrin in feces and erythrocytes
      explanation: The measurement in erythrocytes specifically, alongside the faecal finding.
- name: Lymphocyte coproporphyrinogen oxidase activity
  presence: Decreased
  context: >-
    Around 10% of control values in affected homozygotes and around 50% in
    heterozygous parents. The enzymology was what established the recessive
    inheritance before the gene was cloned.
  biomarker_term:
    preferred_term: coproporphyrinogen oxidase activity
    term:
      id: GO:0004109
      label: coproporphyrinogen oxidase activity
  readouts:
  - target: Biallelic CPOX Variant in the Substrate-Retention Region
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Reports the enzymatic deficit and, through the parent-child contrast, the
      mode of inheritance.
    evidence:
    - reference: PMID:6886003
      reference_title: 'Harderoporphyria: a variant hereditary coproporphyria.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The lymphocyte coproporphyrinogen III oxidase activity of each patient was
        10% of control values, which suggests a homozygous state.
      explanation: The measured activity in the affected siblings and the inference drawn
        from it.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: BELOW_1_IN_1000000
  notes: >-
    No population estimate exists. Reported as a handful of cases: a 2010 report
    describes homozygous HCP patients as "only a few" and most of those as having
    harderoporphyria, and a 2019 case report counted eight previously reported
    cases. Recorded as a literature count rather than a rate, and the
    prevalence_class band is an inference from that count rather than a measured
    figure.
  evidence:
  - reference: PMID:30828546
    reference_title: 'Harderoporphyria: Case of lifelong photosensitivity associated with
      compound heterozygous coproporphyrinogen oxidase (CPOX) mutations.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Two previously undescribed coproporphyrinogen oxidase (CPOX) mutations were
      identified, including a deletion of four amino acids in a region of the enzyme mutated
      in 7 of the 8 previously reported cases.
    explanation: Establishes the order of magnitude of the reported literature - eight prior
      cases - and, incidentally, that seven of those eight carried a variant in the same
      region.
diagnosis:
- name: Faecal Porphyrin Fractionation
  description: >-
    The test that makes the diagnosis. Total porphyrin elevation is common to
    many porphyrias; it is the fraction that is harderoporphyrin which is
    specific, so a laboratory reporting only totals will miss this disease and
    report a picture consistent with coproporphyria.
  diagnosis_term:
    preferred_term: laboratory procedure
    term:
      id: NCIT:C25294
      label: Laboratory Procedure
  evidence:
  - reference: PMID:6886003
    reference_title: 'Harderoporphyria: a variant hereditary coproporphyria.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: the pattern of fecal porphyrin excretion was atypical for hereditary coproporphyria
      because the major porphyrin was harderoporphyrin (greater than 60%; normal value is
      less than 20%)
    explanation: Shows the fractionation, not the total, carrying the diagnostic
      information.
- name: CPOX Sequencing
  description: >-
    Confirms the diagnosis and, because the phenotype is position-dependent,
    interprets it: the finding that matters is whether the variants affect the
    substrate-retention region, not merely that they are in CPOX.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:9454777
    reference_title: 'Neonatal hemolytic anemia due to inherited harderoporphyria: clinical
      characteristics and molecular basis.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In the present study, molecular investigations in a second family with neonatal
      hemolytic anemia and harderoporphyria revealed two heterozygous point mutations in
      the COX gene.
    explanation: Molecular confirmation in a second, independent family, establishing the
      compound-heterozygous configuration as well as the homozygous one.
treatments:
- name: Supportive Management of Haemolysis
  therapeutic_modality: OTHER
  description: >-
    There is no treatment directed at the enzymatic lesion. Management is
    supportive: transfusion where the anaemia requires it, management of neonatal
    hyperbilirubinaemia, and light protection for the photosensitivity. This
    entry records no disease-modifying therapy because none was found in the
    literature reviewed, not because the search was incomplete - the reported
    literature is a handful of cases and none reports an intervention trial.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_mechanisms:
  - target: Neonatal Haemolytic Anaemia and Jaundice
    treatment_effect: MODULATES
    description: >-
      Addresses the consequence, not the cause. Nothing in current management
      reaches the retention defect in the enzyme.
  evidence:
  - reference: PMID:9454777
    reference_title: 'Neonatal hemolytic anemia due to inherited harderoporphyria: clinical
      characteristics and molecular basis.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Harderoporphyric patients exhibit jaundice, severe chronic hemolytic anemia
      of early onset associated with hepatosplenomegaly, and skin photosensitivity.
    explanation: PARTIAL because it establishes what has to be managed, not that any
      particular management works - no reviewed source reports a treatment result in this
      disease.
- name: Genetic Counselling
  therapeutic_modality: BEHAVIORAL
  description: >-
    Autosomal recessive with a 25% sibling recurrence risk. It has an added
    complication here that ordinary recessive counselling does not: a carrier
    parent is not merely a carrier but has HCP, and can have acute attacks in
    adulthood. So the family assessment produced by testing a proband is a
    two-generation, two-disease assessment.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:11309681
    reference_title: Characterization of mutations in the CPO gene in British patients demonstrates
      absence of genotype-phenotype correlation and identifies relationship between hereditary
      coproporphyria and harderoporphyria.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: show that single copies of CPO mutations that are known or predicted to cause
      "homozygous" HCP or harderoporphyria can produce typical HCP in adults
    explanation: The basis for the two-disease family assessment - a heterozygous relative
      is at risk of adult HCP, not simply an unaffected carrier.
animal_models:
- name: BALB.NCT-Cpox nct mouse
  species: Mouse
  genotype: Cpox p.Arg380Leu homozygous, hypomorphic
  publication: PMID:36967721
  description: >-
    A hypomorphic Cpox allele retaining about 15% of wild-type activity. It is the
    best-characterised murine CPOX model and it models hereditary coproporphyria,
    not this disease.
  modeled_mechanisms:
  - target: Harderoporphyrin Accumulation
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    description: >-
      The mouse accumulates and excretes coproporphyrin, which is the HCP
      signature, and shows the neuromuscular manifestations of HCP. It reports no
      harderoporphyrin excess, but it was never tested for one: the measured panel
      was uroporphyrin, coproporphyrin, protoporphyrin, porphobilinogen and
      delta-aminolevulinic acid, and harderoporphyrin was not among the analytes.
    limitations: >-
      The allele is the reason, and the allele is what this claim rests on, not a
      harderoporphyrin measurement. p.Arg380Leu lies outside the D400-K404 retention
      region in which every reported harderoporphyria variant falls, so it reduces
      enzyme activity without disturbing the step between the two decarboxylations.
      Mouse residue 380 is homologous to human residue 391, and the human variant at
      that position, p.Arg391Trp at 22% residual activity, causes ordinary hereditary
      coproporphyria - so the same position gives the same phenotype in both species.
      What the mouse reports is a coproporphyrin-dominant profile at HCP severity;
      whether any harderoporphyrin is present in it is simply unknown. It is a
      quantitative deficiency where harderoporphyria is a positional one -
      which is the distinction this entry is built on, arriving from the model side.
    evidence:
    - reference: PMID:36967721
      reference_title: BALB.NCT-Cpox (nct) is a unique mouse model of hereditary coproporphyria.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Similar to HCP patients, BALB.NCT-Cpox nct excreted an excessive amount of
        coproporphyrin and porphyrin precursors in the urine and displayed neuromuscular symptoms,
        such as a lack of grip strength and impaired motor coordination.
      explanation: The model's phenotype is the HCP one - coproporphyrin and neuromuscular
        symptoms - which is what it fails to share with harderoporphyria.
    - reference: PMID:36967721
      reference_title: BALB.NCT-Cpox (nct) is a unique mouse model of hereditary coproporphyria.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: A patient with HCP heterozygous for the R391W amino acid substitution at the
        homologous position of the R380L substitution in BALB.NCT-Cpoxnct was reported
      explanation: Establishes that mouse residue 380 corresponds to human residue 391, so
        the murine allele can be compared directly with a reported human one.
    - reference: PMID:36967721
      reference_title: BALB.NCT-Cpox (nct) is a unique mouse model of hereditary coproporphyria.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: The mutant CPOX-R391W was approximately 22% as active as the wild type.
      explanation: The human variant at the homologous position causes ordinary hereditary
        coproporphyria at 22% residual activity, which is why the murine phenotype at this
        position is the expected one rather than a failure of the model.
  evidence:
  - reference: PMID:23631845
    reference_title: 'Hereditary cataract of the Nakano mouse: Involvement of a hypomorphic
      mutation in the coproporphyrinogen oxidase gene.'
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: The CPOX isoform with the p.R380L substitution retained only 15% of the activity
      of the wild type isoform.
    explanation: Establishes the allele and its residual activity. Note that 15% residual
      activity sits inside the 1-64% range that produces clinically uniform HCP in humans,
      which is consistent with this model landing on the HCP phenotype.
- name: RBC16 ENU mouse
  species: Mouse
  genotype: Cpox premature stop codon at Trp373, heterozygous
  publication: PMID:28600349
  description: >-
    A dominantly inherited nonsense allele recovered from an ENU screen for
    regulators of erythropoiesis. Heterozygotes have microcytic red cells and
    elevated coproporphyrin, with a sex difference.
  modeled_mechanisms:
  - target: Harderoporphyrin Accumulation
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    description: >-
      The elevated species reported is coproporphyrinogen III, the HCP one.
      Harderoporphyrin is not reported either way - the abstract names only
      coproporphyrinogen III, and no harderoporphyrin assay is described.
    limitations: >-
      A heterozygous null - the classic HCP genotype - rather than a biallelic
      retention-region lesion, so it cannot in principle produce the harderoporphyria
      phenotype. It also shows a sex difference in the biochemistry that human
      harderoporphyria is not reported to have.
    evidence:
    - reference: PMID:28600349
      reference_title: A mouse model of hereditary coproporphyria identified in an ENU mutagenesis
        screen.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Urinary and faecal porphyrins in female RBC16 heterozygotes were significantly
        elevated compared with that of wild-type littermates, particularly coproporphyrinogen
        III, whereas males were biochemically normal.
      explanation: The accumulating species is coproporphyrinogen III, and the effect is
        sex-limited - neither matches harderoporphyria.
discussions:
- discussion_id: harpo_no_mouse_model_reproduces_the_disease
  kind: HUMAN_MODEL_MISMATCH
  attaches_to:
  - pathophysiology#Arrest After the First Decarboxylation
  - animal_models#BALB.NCT-Cpox nct mouse
  prompt: Why does no murine Cpox model reproduce harderoporphyria, and what does that
    absence establish?
  rationale: >-
    Three Cpox alleles are on record in the mouse: the spontaneous hypomorphic
    p.Arg380Leu, carried by both BALB.NCT-Cpox nct and the Nakano cataract strain,
    which proved to be the same locus rather than a second allele; the Trp373
    nonsense allele RBC16 from an ENU screen; and a second ENU strain, M100835,
    with an intron 4 splice-acceptor mutation whose HCP phenotype has never been
    studied. Two have been phenotyped for porphyrins, and both report
    coproporphyrin. Neither reports harderoporphyrin - and neither measured it.
    The published panels are uroporphyrin, coproporphyrin, protoporphyrin and the
    precursors; the species that defines this disease has never been assayed in a
    Cpox mouse. There is, at present, no animal model of this disease.

    Read carelessly that is a gap. Read against the allele positions it is a
    result, and it points the same way as everything else in this entry. Every
    reported harderoporphyria variant alters residues D400-K404 or, in the H327R
    case, a residue predicted to contact the active site; the murine alleles sit
    at 373 and 380, outside that region. So the mice have less enzyme and the
    patients have a differently-behaving enzyme, and the mice get the disease that
    less enzyme causes.

    This is the entry's central argument arriving from an independent direction,
    though it arrives by allele position rather than by measurement. If
    harderoporphyria were the severe end of a CPOX activity gradient, a mouse at
    15% of wild-type activity should sit somewhere on that gradient. What it
    reports instead is the ordinary HCP profile - and the human variant at the
    homologous residue, p.Arg391Trp at 22% residual activity, is likewise an
    ordinary HCP allele. Position, not dose. That the diagnostic species has
    never been measured in any Cpox mouse is a sharper statement of the gap than
    a null result would have been: the murine system has not been asked the
    question this entry turns on.

    What is genuinely open is whether a knock-in of a retention-region allele
    would reproduce the disease, which is the experiment nobody has published. It
    is the obvious test of this entry's mechanism and its absence is why the
    erythroid-injury node remains PROVISIONAL - there is no system in which to
    ask what accumulated harderoporphyrin does to a red cell.
  proposed_experiments:
  - experiment_id: harpo_assay_harderoporphyrin_in_existing_cpox_mice
    name: Assay harderoporphyrin in the existing Cpox mouse strains
    description: >-
      Re-analyse urine, faeces and erythrocytes from BALB.NCT-Cpox nct and RBC16
      heterozygotes on an HPLC method resolving the tricarboxylic intermediate,
      rather than the uroporphyrin/coproporphyrin/protoporphyrin panel both
      published studies used. This is the cheap experiment and it comes first:
      the murine negative this discussion rests on is currently an unmeasured
      analyte, not a reported null, and one assay would convert it into evidence
      either way.
    perturbations:
    - name: No perturbation - existing hypomorphic and nonsense Cpox strains
      target: pathophysiology#Arrest After the First Decarboxylation
      description: >-
        The strains already exist; the manipulation is to the analytical panel,
        not to the animal.
    readouts:
    - name: Faecal and erythrocyte harderoporphyrin fraction
      target: pathophysiology#Harderoporphyrin Accumulation
      direction: UNCHANGED
      interpretation: >-
        A harderoporphyrin fraction indistinguishable from wild-type would confirm
        that a non-retention-region allele does not produce the intermediate, which
        is what this entry predicts.
    decision_criterion: >-
      Whether harderoporphyrin is elevated above wild-type in either strain.
    would_support:
    - pathophysiology#Biallelic CPOX Variant in the Substrate-Retention Region
    supporting_outcome:
    - >-
        No harderoporphyrin excess in either strain, establishing as a measured null
        what is presently only an allele-position inference.
    would_refute:
    - pathophysiology#Biallelic CPOX Variant in the Substrate-Retention Region
    refuting_outcome:
    - >-
        Harderoporphyrin elevated in a mouse whose allele lies outside D400-K404,
        which would show the intermediate accumulates on activity loss alone and
        undercut the positional argument this entry is built on.
  - experiment_id: harpo_retention_region_knockin_mouse
    name: Cpox retention-region knock-in mouse
    description: >-
      Knock a retention-region allele - the murine equivalent of human p.Lys404Glu
      or p.Asp400Tyr - into the mouse Cpox locus in homozygous or compound form,
      and phenotype the porphyrin profile, the neonatal red cell and the skin. No
      such animal has been published; every existing strain carries an allele
      outside the retention region.
    perturbations:
    - name: Homozygous retention-region knock-in at mouse Cpox
      target: pathophysiology#Biallelic CPOX Variant in the Substrate-Retention Region
      description: >-
        Reproduces the human genotype class rather than a quantitative deficiency,
        which is the variable no existing model varies.
    readouts:
    - name: Faecal harderoporphyrin excretion
      target: pathophysiology#Harderoporphyrin Accumulation
      direction: INCREASED
      interpretation: >-
        The diagnostic species of the human disease, and the readout that separates
        this genotype from the hypomorphic strains.
    - name: Neonatal haemolysis and erythrocyte survival
      target: pathophysiology#Erythroid Compartment Injury
      direction: DECREASED
      interpretation: >-
        Whether accumulated harderoporphyrin injures the red cell, which is why the
        erythroid node is PROVISIONAL and cannot be resolved in any current system.
    decision_criterion: >-
      Whether a retention-region genotype produces harderoporphyrin excess and
      neonatal haemolysis where a comparable-activity hypomorph does not.
    would_support:
    - pathophysiology#Arrest After the First Decarboxylation
    - pathophysiology#Erythroid Compartment Injury
    supporting_outcome:
    - >-
        Harderoporphyrin excess with neonatal haemolysis in the knock-in, absent from
        an activity-matched hypomorph - position rather than dose, demonstrated within
        one species.
    would_refute:
    - pathophysiology#Arrest After the First Decarboxylation
    refuting_outcome:
    - >-
        A retention-region homozygote that phenocopies the hypomorph, which would make
        harderoporphyria a severity band of hereditary coproporphyria after all.
  evidence:
  - reference: PMID:36967721
    reference_title: BALB.NCT-Cpox (nct) is a unique mouse model of hereditary coproporphyria.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Appropriate animal models for comprehending the precise pathogenesis mechanism
      of HCP have not been reported that show similarities in terms of gene mutation, reduced
      CPOX activity, excess coproporphyrin accumulation, and clinical symptoms.
    explanation: The authors' own statement of how sparse the murine CPOX landscape is,
      from the paper introducing the best of the available models.
  - reference: PMID:23631845
    reference_title: 'Hereditary cataract of the Nakano mouse: Involvement of a hypomorphic
      mutation in the coproporphyrinogen oxidase gene.'
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: BALB/c-nct/nct mice are homozygous for a G to T nucleotide substitution in the
      Cpox gene, which results in a p.R380L amino acid substitution in the CPOX protein.
    explanation: The allele position, which is what places this model outside the
      retention region and explains why it lands on the HCP phenotype.
  - reference: PMID:23631845
    reference_title: 'Hereditary cataract of the Nakano mouse: Involvement of a hypomorphic
      mutation in the coproporphyrinogen oxidase gene.'
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: BALB/c-nct/nct mice had excessive accumulation of coproporphyrin III in the lens.
    explanation: The accumulating species is coproporphyrin III, not harderoporphyrin - the
      specific negative result this discussion turns on.
- discussion_id: harpo_why_not_a_severity_band_of_hcp
  kind: INTERPRETATION
  attaches_to:
  - disease#Harderoporphyria
  - genetic#CPOX
  prompt: Why is harderoporphyria curated as its own disease rather than as severe CPOX
    deficiency within hereditary coproporphyria?
  rationale: >-
    MONDO places harderoporphyria under CPOX-related hereditary coproporphyria,
    and the existing dismech porphyria entry carries HCP as a CPOX subtype, so
    the obvious reading is that this is HCP with two hits instead of one. Three
    things argue against it, and they are the reason this is a separate entry.

    The mechanism differs at the step that matters. HCP is a partial deficiency:
    less enzyme, substrate backing up, hepatic ALAS1 derepressed, acute attacks.
    Harderoporphyria is a redirection: the enzyme performs its first
    decarboxylation and then fails to hold the intermediate for the second, so
    what accumulates is a molecule that barely appears in HCP at all. A structure
    of human CPOX locates the lesion in a beta-turn whose function is exactly that
    retention.

    Severity does not order the two. Residual enzyme activity across HCP variants
    spans 1% to 64% with clinically uniform presentation, so "less activity" does
    not produce harderoporphyria; if it did, the low-activity HCP patients would
    have it and they do not.

    And biallelism alone is not the criterion either. Biallelic CPOX variants
    outside the retention region give a "homozygous HCP" phenotype that is
    distinct from harderoporphyria. So the discriminator is which residues are
    affected, not how many alleles or how much activity remains.

    This is a lump/split call and it goes against MONDO's placement, which is
    recorded here rather than left implicit so that a reviewer who disagrees has
    the argument to disagree with.
  evidence:
  - reference: PMID:16176984
    reference_title: Structural basis of hereditary coproporphyria.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Conversely, harderoporphyria-causing K404E mutation precludes a type I beta-turn
      from retaining the substrate for the second decarboxylation cycle.
    explanation: The distinct structural mechanism, which is the primary argument for the
      split.
  - reference: PMID:11309681
    reference_title: Characterization of mutations in the CPO gene in British patients demonstrates
      absence of genotype-phenotype correlation and identifies relationship between hereditary
      coproporphyria and harderoporphyria.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: demonstrate that the severity of the phenotype does not correlate with the degree
      of inactivation by mutation of coproporphyrinogen oxidase
    explanation: Rules out the severity-band reading directly.
  - reference: PMID:9454777
    reference_title: 'Neonatal hemolytic anemia due to inherited harderoporphyria: clinical
      characteristics and molecular basis.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Neither abdominal pain nor neuropsychiatric symptoms are observed.
    explanation: The sharpest clinical discriminator available. HCP is defined by acute
      neurovisceral attacks; their absence in harderoporphyria is not a milder version of
      that presentation but a different one, which is the clinical counterpart of the
      mechanistic argument.
- discussion_id: harpo_how_the_intermediate_damages_erythrocytes
  kind: KNOWLEDGE_GAP
  attaches_to:
  - pathophysiology#Erythroid Compartment Injury
  prompt: By what mechanism does accumulated harderoporphyrin cause haemolysis?
  rationale: >-
    The chain from variant to accumulated intermediate is established at the
    structural level. The chain from accumulated intermediate to destroyed red
    cell is not, and it is worth being explicit that this entry does not know it.

    What is established is the compartment and the association: this is an
    erythropoietic porphyria, harderoporphyrin is measurable in erythrocytes as
    well as faeces, and the haemolysis is present from birth. What is not
    established is whether the damage is photo-oxidative in the same way as the
    skin lesions, whether it acts on the mature erythrocyte or on the developing
    erythroblast, or whether the intermediate is directly toxic at all rather than
    marking a compartment where heme synthesis has failed.

    The distinction is not academic. If the haemolysis is photo-oxidative it
    should respond to the same light protection as the skin, and if it is a
    consequence of failed heme synthesis in the erythroblast it should not. No
    reviewed source addresses this, and with eight or so reported cases in the
    literature it is unlikely to be addressed by observation alone.
  evidence:
  - reference: PMID:28349448
    reference_title: 'Neonatal-Onset Hereditary Coproporphyria: A New Variant of Hereditary
      Coproporphyria.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: In contrast, harderoporphyria is an erythropoietic porphyria that represents
      photosensitivity and hemolytic anemia from the neonatal period.
    explanation: Establishes the compartment and the co-occurrence of the two features,
      which is as far as the reviewed literature goes - it does not connect them
      mechanistically.
- discussion_id: harpo_biochemical_phenotype_can_disagree_with_genotype
  kind: OPEN_QUESTION
  attaches_to:
  - diagnosis#Faecal Porphyrin Fractionation
  prompt: What should a neonate with the harderoporphyria clinical picture but an HCP
    porphyrin profile be called?
  rationale: >-
    A 2017 report describes a neonate with photosensitivity, haemolytic anaemia
    and jaundice - the harderoporphyria presentation - whose faecal porphyrin
    pattern was that of typical HCP rather than harderoporphyria, and who carried
    a novel heterozygous four-base-pair deletion with no K404E and no second
    identified allele. The authors proposed calling it neonatal-onset HCP.

    This matters for how the entry should be used rather than only for
    nomenclature. Both of this entry's discriminators - the faecal fraction and
    the variant position - failed on that patient while the clinical picture was
    unambiguous. Either the discriminators are less reliable than the small
    reported series suggests, or there is a third CPOX phenotype, or a second
    allele went undetected.

    With around eight reported cases the question cannot be settled by counting.
    It is recorded here so that a future curator meeting a similar case knows this
    entry's diagnostic rule has a documented exception rather than reading the
    rule as tested.
  evidence:
  - reference: PMID:28349448
    reference_title: 'Neonatal-Onset Hereditary Coproporphyria: A New Variant of Hereditary
      Coproporphyria.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: However, the pattern of porphyrin metabolites of feces was consistent with that
      of typical HCP, not of harderoporphyria.
    explanation: The discordance itself - clinical harderoporphyria with an HCP biochemical
      profile.
  - reference: PMID:28349448
    reference_title: 'Neonatal-Onset Hereditary Coproporphyria: A New Variant of Hereditary
      Coproporphyria.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We found a heterozygous, novel, four-base pair deletion in exon 7 of the CPOX
      gene, although other mutations including the p.Lys404Glu mutation in CPOX were not
      found.
    explanation: The genotype that also failed to fit, which is what makes this an open
      question rather than a mis-assigned case.
references:
- reference: PMID:6886003
  title: 'Harderoporphyria: a variant hereditary coproporphyria.'
- reference: PMID:9454777
  title: 'Neonatal hemolytic anemia due to inherited harderoporphyria: clinical characteristics
    and molecular basis.'
- reference: PMID:11309681
  title: Characterization of mutations in the CPO gene in British patients demonstrates
    absence of genotype-phenotype correlation and identifies relationship between hereditary
    coproporphyria and harderoporphyria.
- reference: PMID:16176984
  title: Structural basis of hereditary coproporphyria.
- reference: PMID:21103937
  title: Harderoporphyria due to homozygosity for coproporphyrinogen oxidase missense mutation
    H327R.
- reference: PMID:24078084
  title: The enzyme engineering of mutant homodimer and heterodimer of coproporphyinogen
    oxidase contributes to new insight into hereditary coproporphyria and harderoporphyria.
- reference: PMID:28349448
  title: 'Neonatal-Onset Hereditary Coproporphyria: A New Variant of Hereditary Coproporphyria.'
- reference: PMID:30828546
  title: 'Harderoporphyria: Case of lifelong photosensitivity associated with compound heterozygous
    coproporphyrinogen oxidase (CPOX) mutations.'
notes: >-
  Scope, and a disagreement with MONDO. MONDO places harderoporphyria under
  CPOX-related hereditary coproporphyria. This entry treats it as its own
  disease, and the reasoning is curated as a discussion rather than buried here:
  the mechanism is a redirection of the reaction rather than a partial loss of
  it, severity does not order the two phenotypes, and biallelic CPOX variants
  outside the retention region give a third phenotype again. The existing
  Inherited_Porphyria entry carries HCP as a CPOX subtype and is not modified by
  this PR; a reviewer who prefers to see harderoporphyria as a subtype there
  should say so and it can be moved.

  Module conformance. Three nodes declare conforms_to against
  heme_biosynthesis_porphyria. The enzymatic block and the cutaneous phototoxicity
  conform closely. The accumulation node conforms in structure while differing in
  substance in a way worth flagging: the module describes accumulation of
  pathway precursors and porphyrins upstream of a block, whereas what accumulates
  here is a reaction intermediate released mid-catalysis. The conformance is
  still correct - it is the same node in the causal chain - but the module's
  description does not currently cover this case.

  Prevalence. Recorded as CASES_IN_LITERATURE with no rate, because no population
  estimate exists. The prevalence_class band is an inference from a reported
  count of roughly eight cases, not a measured figure, and the notes field says
  so.

  Erythroid injury. The node linking harderoporphyrin accumulation to haemolysis
  is graded PROVISIONAL and its incoming edge is
  INDIRECT_UNKNOWN_INTERMEDIATES. The compartment is established; the mechanism
  of red cell destruction is not, and a knowledge-gap discussion records what
  specifically is unknown and why it would matter.

  Deep research. Two runs. The openscientist run commissioned for this entry
  timed out at 3600s and was cancelled by the client, so no report existed when
  the entry was written and every reference here was located independently
  through PubMed. A claude_code run was then commissioned during PR review and is
  committed alongside this entry.

  What the report changed. An earlier version of this note said it "supplied no
  citable content the entry lacked". That was wrong, and wrong in the same way
  the entry's first draft was wrong: the claim was made without reading the
  reference caches the run had fetched. Three of the nine contained content this
  entry needed, and PR review found them.

  PMID:629747 is the one that mattered. It establishes, in the same rat-liver
  system the 1983 objection rests on, that both decarboxylations occur at one
  active centre which becomes temporarily inaccessible, and that the intermediate
  en route to protoporphyrinogen does not equilibrate with free
  harderoporphyrinogen. That is the normal physiology this entry's whole argument
  presupposes, and the direct answer to the objection the REFUTE item carries -
  which had been argued in prose alone. The other two were the murine models now
  curated in animal_models.

  What the report did corroborate: the prevalence handling, which it independently
  describes as "fewer than 10 cases reported worldwide", consistent with the
  CASES_IN_LITERATURE record above.

  The lesson is narrower and more useful than "read the report". A deep-research
  run leaves two artifacts - the narrative and the reference caches it fetched to
  validate itself - and the second is not a by-product. Reading the narrative and
  concluding "adds nothing" while nine unread caches sit in the same commit is
  the same error as the original under-consumption, committed while writing a
  note congratulating this entry for recording a null result honestly.

  Its own term-validation section flags two identifiers it names wrongly, and
  they are the now-familiar pattern: HP:0032263, which it calls
  "Coproporphyrinuria" and which HPO calls Increased blood pressure, and
  UBERON:0001155, which it calls "liver" and which UBERON calls colon. Both
  resolve, so nothing but the name check catches them. Neither is used here.
📚

References & Deep Research

References

8
PMID:6886003
Harderoporphyria: a variant hereditary coproporphyria.
No top-level findings curated for this source.
PMID:9454777
Neonatal hemolytic anemia due to inherited harderoporphyria: clinical characteristics and molecular basis.
No top-level findings curated for this source.
PMID:11309681
Characterization of mutations in the CPO gene in British patients demonstrates absence of genotype-phenotype correlation and identifies relationship between hereditary coproporphyria and harderoporphyria.
No top-level findings curated for this source.
PMID:16176984
Structural basis of hereditary coproporphyria.
No top-level findings curated for this source.
PMID:21103937
Harderoporphyria due to homozygosity for coproporphyrinogen oxidase missense mutation H327R.
No top-level findings curated for this source.
PMID:24078084
The enzyme engineering of mutant homodimer and heterodimer of coproporphyinogen oxidase contributes to new insight into hereditary coproporphyria and harderoporphyria.
No top-level findings curated for this source.
PMID:28349448
Neonatal-Onset Hereditary Coproporphyria: A New Variant of Hereditary Coproporphyria.
No top-level findings curated for this source.
PMID:30828546
Harderoporphyria: Case of lifelong photosensitivity associated with compound heterozygous coproporphyrinogen oxidase (CPOX) mutations.
No top-level findings curated for this source.

Deep Research

1
Claude Code ▸
Harderoporphyria: Comprehensive Research Report
claude-haiku-4-5-20251001, claude-sonnet-5 25 citations 2026-08-28T17:55:22.714914

Harderoporphyria: Comprehensive Research Report

1. Disease Information

Overview. Harderoporphyria (HARPO) is an extremely rare, autosomal recessive, erythropoietic (hematologically dominant) variant of hereditary coproporphyria (HCP). It is caused by biallelic (homozygous or compound heterozygous) pathogenic variants in CPOX, the gene encoding coproporphyrinogen oxidase (coproporphyrinogen-III oxidase, CPOX/CPO), the sixth enzyme of the heme biosynthetic pathway. Unlike classic heterozygous HCP — an autosomal dominant acute hepatic porphyria with neurovisceral attacks — harderoporphyria presents in the neonatal period with severe hemolytic anemia, jaundice, hepatosplenomegaly, and cutaneous photosensitivity, and is biochemically defined by massive fecal excretion of the tricarboxylic porphyrin harderoporphyrin, an intermediate normally present only in trace amounts (Wikipedia; OMIM #618892; Nordmann et al. 1983, PMID pending/JCI).

Key identifiers: | Resource | ID | |---|---| | OMIM (disease) | #618892 — Harderoporphyria; HARPO | | OMIM (related, allelic disorder) | #121300 — Coproporphyria, Hereditary (HCP) | | OMIM (gene) | 612732 — Coproporphyrinogen Oxidase; CPOX | | Orphanet | ORPHA:659672 (Harderoporphyria); gene page Orphanet CPOX | | MeSH | C562816 | | SNOMED CT | 238056003 | | ICD-10-CM | E80.29 (Other porphyria) — no disease-specific code exists; harderoporphyria and HCP are both subsumed under the "other porphyria" E80.2x block (ICD10Data) | | Gene (HGNC) | CPOX, HGNC:2321, chromosome 3q11.2* (some sources cite 3q12) | | MONDO | Not yet independently confirmed in this search pass — flag for direct MONDO lookup during curation |

Synonyms: Harderoporphyria; Homozygous hereditary coproporphyria (a related but non-identical term, since not all homozygous/biallelic CPOX genotypes produce the harderoporphyrin-excess phenotype); erythropoietic variant of hereditary coproporphyria.

Evidence basis: All published knowledge derives from individual case reports and small case series (fewer than a dozen kindreds described worldwide since 1983) rather than large aggregated cohorts or registries — a defining feature of this ultra-rare disorder that should be reflected in curation confidence levels.

Sources: Wikipedia: Harderoporphyria; OMIM #618892; OMIM *612732; Orphanet CPOX gene page

2. Etiology

2a. Disease Causal Factors — Genetic

Harderoporphyria is caused exclusively by biallelic loss-of-function/altered-function variants in CPOX. It is a purely monogenic, enzymopathic disorder — there is no known environmental or infectious primary cause, although environmental porphyrinogenic triggers modulate expressivity (see below).

2b. Genetic Risk Factors

  • The defining genotype-phenotype rule: Missense variants restricted to five amino acid residues encoded by exon 6, positions D400–K404 of CPOX, when present in the homozygous state or compound heterozygous with a "null" (loss-of-function) allele, produce the harderoporphyria phenotype rather than classic acute HCP. This is described in the literature as "the first known metabolic disorder in which the clinical expression of disease (acute hepatic vs. erythropoietic) depended on the location and type of mutation within the same gene" (Schmitt et al. 2005, Hum Mol Genet 14:3089–3098; summarized via OMIM #618892).
  • K404E (c.1210A>G, p.Lys404Glu; rs121917868) is the most recurrently reported harderoporphyria-associated allele: all five patients from three families in the founding literature carried K404E in homozygosity or compound heterozygosity with a null CPOX allele. Enzymatic expression studies (K404E mutant CPOX expressed in E. coli) showed the Michaelis constant (Km) for the mutant enzyme was ~10-fold higher than wild type, implicating Lys404 in substrate binding, together with reduced catalytic activity and premature release of the harderoporphyrinogen intermediate (search synthesis of Schmitt et al. 2005; Nordmann et al. 1983, JCI).
  • H327R — a second, distinct missense variant reported causing harderoporphyria via homozygosity, described in "Harderoporphyria due to homozygosity for coproporphyrinogen oxidase missense mutation H327R" (PubMed 21103937; also indexed at Springer/JIMD).
  • A four-amino-acid in-frame deletion in the same D400–K404 hot-region has also been reported, again "a region of the enzyme mutated in 7 of the 8 previously reported cases" of harderoporphyria, in a patient with compound heterozygous CPOX mutations and lifelong photosensitivity (Frank/ScienceDirect case report, PMID 30828546).
  • Population frequency of K404E: reported in gnomAD at an allele frequency of approximately 0.009%, consistent with extreme rarity of the harderoporphyria phenotype (which requires two hits) even though heterozygous carriers of K404E are essentially asymptomatic HCP carriers.
  • Contrast with typical HCP variants: heterozygous pathogenic variants distributed across all seven CPOX exons cause classic autosomal-dominant HCP with reduced penetrance; missense, nonsense, splice-site, and small deletion/insertion variants are all represented (GeneReviews: Hereditary Coproporphyria, citing Lamoril et al. 2001, PMID 11309681, "no genotype-phenotype correlation exists" for classic HCP severity — in contrast to the sharp genotype-phenotype rule that specifically produces harderoporphyria).
  • Consanguinity / homozygosity mechanism: Because two hits are needed, harderoporphyria arises typically in the setting of (a) parental consanguinity producing true homozygosity for a hot-region allele, or (b) compound heterozygosity for a hot-region missense allele plus an unrelated null allele inherited from the other, typically unaffected or mildly HCP-affected, parent. In the founding Nordmann family, both parents showed only mild biochemical abnormalities (lymphocyte CPOX activity ~50% of normal, consistent with heterozygous HCP carrier status), while the three affected children had lymphocyte CPOX activity reduced to ~10% of control.

2c. Environmental / Modifying Risk Factors

As in all hepatic porphyrias, porphyrinogenic triggers exacerbate biochemical and clinical expression, although the literature specific to harderoporphyria emphasizes that neither abdominal pain nor neuropsychiatric acute attacks are typically observed in the classic neonatal harderoporphyria presentation (unlike HCP). Recognized triggers relevant to the broader HCP/CPOX-deficiency spectrum (applicable especially to heterozygous relatives and to milder harderoporphyria variants) include: - Cytochrome P450-inducing/porphyrinogenic drugs (barbiturates, certain anticonvulsants, sulfonamides, estrogens/progestogens) - Fasting/caloric restriction - Alcohol - Intercurrent infection and physiological stress - Hormonal factors (menstrual cycle, pregnancy) in the classic-HCP spectrum - Light exposure, specifically the Soret-band (~400–410 nm) and near-visible wavelengths that photoactivate accumulated porphyrins in skin and red cells, driving the photosensitivity and hemolysis; avoidance of light <510 nm has been reported to reduce cutaneous manifestations, anemia, and splenomegaly in erythropoietic porphyrias generally.

2d. Protective Factors

No specific genetic or environmental protective factors for harderoporphyria are described in the literature; this reflects both its rarity and its being a loss-of-function enzymopathy rather than a susceptibility trait. Reduced penetrance of the underlying heterozygous HCP genotype (documented in classic HCP) is presumed but not specifically quantified for the harderoporphyria compound state.

2e. Gene-Environment Interaction

The core gene-environment relationship is that heme-pathway-inducing drugs and metabolic stress amplify hepatic ALAS1 activity and pathway flux through the partially deficient CPOX enzyme, increasing intermediate accumulation (harderoporphyrinogen/harderoporphyrin, coproporphyrinogen) in both hepatic (classic HCP-like) and erythroid (harderoporphyria-specific) compartments; light then photoactivates the accumulated erythroid/cutaneous porphyrins to produce hemolysis and skin damage.

Sources: OMIM #618892; Nordmann et al. 1983; PubMed 21103937; GeneReviews HCP; ScienceDirect case report

3. Phenotypes

Phenotype Type Onset Frequency/Notes Suggested HPO term
Severe hemolytic anemia Laboratory abnormality / hematologic sign Neonatal Core, near-universal feature across reported cases HP:0001878 (Hemolytic anemia); consider HP:0004804 (early-onset) qualifier
Neonatal jaundice Clinical sign Birth / first days of life Presenting feature in essentially all reported neonates HP:0000952 (Jaundice)
Hepatosplenomegaly Physical sign Neonatal/infantile, chronic Reported consistently, secondary to chronic hemolysis and extramedullary erythropoiesis HP:0001433 (Hepatosplenomegaly)
Cutaneous photosensitivity Symptom/sign Can present neonatally or emerge later; described as lifelong in at least one case Skin fragility/blistering in light-exposed areas, similar to other cutaneous porphyrias HP:0000992 (Cutaneous photosensitivity)
Bullae / skin fragility Physical sign Variable Overlaps with the ~20% of classic HCP patients who develop bullous photosensitivity HP:0000988 (Skin lesion) / HP:0032169 (bullae, if separately modeled)
Elevated erythrocyte protoporphyrin Laboratory abnormality Present from neonatal period Reported increased in erythrocytes in the founding cases HP:0025230 (or closest available porphyrin-elevation term; verify against enum)
Markedly elevated fecal harderoporphyrin Laboratory abnormality Present from birth Pathognomonic biochemical signature — >60% of total fecal porphyrin in affected homozygotes vs. <20% in unaffected/heterozygous carriers No dedicated HPO term identified; capture as biochemical marker rather than HPO phenotype
Elevated urinary coproporphyrin Laboratory abnormality Present from birth Large amount of coproporphyrin found in urine in addition to fecal harderoporphyrin HP:0032263 (Coproporphyrinuria) if present in enum, else free text
Markedly decreased lymphocyte/erythrocyte CPOX activity Laboratory abnormality Constitutional ~10% of normal in affected homozygotes (vs. ~50% in heterozygous HCP carriers/parents) No direct HPO enzyme-activity term; model as biochemical finding

Absence of classic acute HCP features: A clinically important negative finding repeatedly emphasized in the literature is that harderoporphyria patients do not exhibit the abdominal pain or neuropsychiatric/neurovisceral attacks characteristic of classic acute hepatic HCP, distinguishing the erythropoietic/hematologic clinical gestalt of harderoporphyria from its allelic, dominantly inherited counterpart.

Severity/progression: Severity is described as variable but generally significant enough to require close neonatal hematologic monitoring; some patients require red cell transfusion support for hemolytic anemia (inferred by analogy with related erythropoietic porphyrias — see Treatment section; direct harderoporphyria-specific transfusion data were not found in this pass and should be verified against the primary case reports before citation).

Quality of life impact: Not separately quantified in available literature (no disease-specific EQ-5D/SF-36 data identified); QoL burden can be inferred as substantial in the neonatal/infantile period due to anemia and photosensitivity, but this should be flagged as an evidence gap rather than asserted numerically.

Sources: Wikipedia: Harderoporphyria; Nordmann et al. 1983; case-report synthesis of "Neonatal Hemolytic Anemia Due to Inherited Harderoporphyria" (ASH Blood 91:1453, 1998; PubMed 9454777)

4. Genetic/Molecular Information

  • Causal gene: CPOX (coproporphyrinogen oxidase), HGNC:2321, OMIM *612732, chromosome 3q11.2 (also cited as 3q12 in some resources — reconcile against Ensembl/NCBI Gene during curation).
  • Protein: Coproporphyrinogen-III oxidase (CPOX/CPO), a homodimeric, oxygen-dependent mitochondrial intermembrane-space enzyme (EC 1.3.3.3).
  • Enzymatic reaction: CPOX catalyzes the sequential oxidative decarboxylation of the 2- and 4-propionate side chains of coproporphyrinogen III to vinyl groups, producing protoporphyrinogen IX. The reaction proceeds via an obligate tricarboxylic intermediate, harderoporphyrinogen (2-vinyl-4,6,7-tripropionate porphyrinogen): the 4-propionate group cannot be attacked until the 2-propionate group has already been decarboxylated. Mechanistic studies suggest both decarboxylations occur at the same active site, which becomes transiently inaccessible after the first decarboxylation, requiring substrate/intermediate rotation before the second decarboxylation can proceed (summarized from enzymology literature, e.g. PubMed 629747; ScienceDirect topic overview).
  • Structural basis of the harderoporphyria mutations: Crystal structures of CPOX orthologs (human and yeast Hem13p) show a central seven-stranded antiparallel β-sheet flanked by helices, with a deep, conserved active-site cleft that adopts open and closed conformations via an ~8 Å helix movement upon substrate binding — closing over the substrate to protect the reactive intermediate from inappropriate oxidation and to position it for the second decarboxylation step. Harderoporphyria-associated missense variants (K404E, H327R, and the D400–K404 hot-region deletion) are proposed to destabilize this closed conformation or the substrate-binding geometry specifically at the point where harderoporphyrinogen would normally be retained for its second decarboxylation — causing premature release of harderoporphyrinogen/harderoporphyrin rather than complete conversion to protoporphyrinogen IX. This structural hypothesis explains why only this narrow residue window produces the erythropoietic/harderoporphyrin-excess phenotype rather than simple loss of total enzyme activity (synthesis of Schmitt et al. 2005 and CPOX crystallography literature, e.g. PubMed 14633981; JBC Hem13p structure).
  • Variant classification (ACMG/ClinVar): K404E (c.1210A>G / rs121917868) is classified Pathogenic in ClinVar, with functional/enzymatic data (elevated Km, reduced Vmax) supporting pathogenicity. H327R and the D400–K404 in-frame deletion are reported pathogenic missense/deletion variants specific to harderoporphyria case reports.
  • Zygosity requirement: Harderoporphyria requires homozygosity or compound heterozygosity for a hot-region (D400–K404) missense allele, generally paired with a null (loss-of-function) allele on the other chromosome — i.e., biallelic CPOX involvement, contrasted with the single heterozygous hit sufficient for classic dominant HCP.
  • Modifier genes: None specifically documented for harderoporphyria. In the broader porphyria literature, digenic/oligogenic interactions (e.g., co-inheritance of CPOX with ALAD or PPOX variants) have been described to modulate phenotype severity in HCP generally (GeneReviews, citing Hasegawa et al. 2017, PMID 28349448), but no harderoporphyria-specific digenic modifier has been reported in this search pass.
  • Epigenetics: No disease-specific epigenetic (DNA methylation/histone) data were identified for harderoporphyria or CPOX deficiency.
  • Chromosomal abnormalities: None reported; harderoporphyria is caused by point mutations/small indels, not large structural chromosomal rearrangements.
  • Somatic vs. germline: Exclusively germline; harderoporphyria is a congenital, constitutional Mendelian disorder.

Suggested ontology terms: Gene: hgnc:2321 (CPOX); relevant GO molecular function: GO:0004109 (coproporphyrinogen oxidase activity); relevant GO biological process: GO:0006783 (heme biosynthetic process) / GO:0033013 (tetrapyrrole metabolic process).

Sources: OMIM *612732; GeneReviews HCP; ClinVar VCV000000453; PubMed 14633981

5. Environmental Information

Harderoporphyria has no independent environmental, infectious, or lifestyle causal factor — it is a purely monogenic disorder — but disease expression is environmentally modulated:

  • Light exposure is the dominant environmental modifier, driving the cutaneous photosensitivity component and likely contributing to porphyrin-mediated hemolysis via phototoxic damage to circulating erythrocytes carrying excess porphyrin. Avoidance of visible light in the ~400–510 nm range is the mainstay non-pharmacologic intervention across the erythropoietic porphyria spectrum.
  • Porphyrinogenic drugs/xenobiotics (CYP450 inducers such as certain barbiturates, sulfonamide antibiotics, and hormonal agents) can, by analogy with classic HCP, increase hepatic heme-pathway flux and porphyrin precursor/intermediate accumulation, though harderoporphyria's dominant lesion is erythroid rather than hepatic and direct harderoporphyria-specific drug-trigger case data were not identified in this pass.
  • Fasting/caloric restriction and intercurrent illness are recognized triggers for acute exacerbation in the broader HCP disease family.
  • No infectious agent is implicated in pathogenesis.

Sources: General porphyria trigger literature via GeneReviews HCP; erythropoietic porphyria light-avoidance data via general erythropoietic protoporphyria/CEP literature (How I treat EPP/XLP, ASH Blood 141:2921)

6. Mechanism / Pathophysiology

Causal chain (upstream → downstream)

  1. Molecular trigger (upstream): Biallelic CPOX variants concentrated in exon 6 residues D400–K404 (e.g., K404E, H327R) impair the enzyme's ability to complete the second oxidative decarboxylation step of coproporphyrinogen III metabolism, and/or destabilize the closed, substrate-protective active-site conformation.
  2. Enzymatic consequence: The reaction stalls after the first decarboxylation, and the intermediate harderoporphyrinogen is released prematurely from the active site rather than undergoing the second decarboxylation to protoporphyrinogen IX. Kinetic studies show markedly increased Km (reduced substrate affinity) and reduced Vmax for mutant enzyme.
  3. Biochemical accumulation: Harderoporphyrinogen (and its oxidized product, harderoporphyrin) plus coproporphyrinogen/coproporphyrin accumulate — disproportionately in the erythroid compartment, where high heme-pathway flux during erythropoiesis exposes the partially defective enzyme to saturating substrate concentrations, in contrast to the lower flux in hepatocytes of classic (heterozygous) HCP. This tissue-specific flux difference is the proposed mechanistic explanation for why the harderoporphyria genotype manifests primarily as an erythropoietic/hematologic disease rather than a hepatic/neurovisceral one.
  4. Cellular consequence — hemolysis: Accumulated porphyrins in developing and circulating erythrocytes are photoreactive; upon light exposure they generate reactive oxygen species that damage the erythrocyte membrane, producing chronic hemolysis, jaundice, and compensatory extramedullary erythropoiesis (hepatosplenomegaly).
  5. Cellular/tissue consequence — cutaneous photosensitivity: The same photoactivation mechanism operating in dermal capillaries and skin-resident porphyrin deposits produces the light-triggered skin fragility/blistering phenotype, analogous to (but biochemically distinct from) other cutaneous porphyrias such as congenital erythropoietic porphyria and erythropoietic protoporphyria.
  6. Organismal outcome: Chronic hemolytic anemia with neonatal jaundice, hepatosplenomegaly from extramedullary hematopoiesis and reticuloendothelial porphyrin/hemolysis burden, and lifelong photosensitivity, generally without the acute neurovisceral (abdominal pain, neuropathy, psychiatric) attacks that define classic hepatic HCP — reflecting the relatively preserved hepatic ALA/PBG handling in harderoporphyria compared to the erythroid-dominant porphyrin burden.

Molecular pathway

Heme biosynthesis (KEGG hsa00860 / Reactome heme biosynthesis pathway): Glycine + succinyl-CoA → ALA (ALAS1/ALAS2) → PBG (ALAD) → hydroxymethylbilane (HMBS) → uroporphyrinogen III (UROS) → coproporphyrinogen III (UROD) → [CPOX, defective step] → protoporphyrinogen IX → protoporphyrin IX (PPOX) → heme (FECH, with iron insertion).

Cell types and tissues involved

  • Erythroid precursors / developing erythrocytes (primary site of pathological porphyrin accumulation) — consider CL:0000038 (erythroid progenitor cell) / CL:0000232 (erythrocyte)
  • Hepatocytes (secondary/lesser contribution relative to classic HCP) — UBERON:0001155 liver structures
  • Reticuloendothelial system / spleen macrophages (hemolysis clearance, splenomegaly) — UBERON:0002106 spleen
  • Skin (keratinocytes, dermal vasculature) — site of phototoxic injury — UBERON:0002097 skin

Suggested GO terms

  • GO:0004109 coproporphyrinogen oxidase activity (molecular function, defective)
  • GO:0006783 heme biosynthetic process (biological process, disrupted)
  • GO:0006979 response to oxidative stress (downstream, in phototoxic hemolysis)
  • GO:0006915 apoptotic process / GO:0070265 necrotic cell death (candidate downstream erythrocyte injury processes, not yet specifically documented for harderoporphyria)

Omics / advanced technologies

No transcriptomic, proteomic, metabolomic, single-cell, or spatial data specific to harderoporphyria patients or models were identified in this search — an evidence gap typical of an ultra-rare Mendelian disease with fewer than a dozen published cases. Metabolomic characterization is effectively limited to targeted porphyrin fractionation (fecal harderoporphyrin, urinary coproporphyrin, erythrocyte protoporphyrin) reported in the founding case series.

Sources: Nordmann et al. 1983; Schmitt et al. 2005 (Hum Mol Genet 14:3089–3098, summarized via OMIM #618892); PubMed 629747 (decarboxylation sequence mechanism); PubMed 14633981 (crystal structure)

7. Anatomical Structures Affected

Organ level: - Primary: Bone marrow/erythroid tissue (site of porphyrin overproduction), skin (photosensitivity), liver and spleen (secondary — hepatosplenomegaly from hemolysis and extramedullary erythropoiesis) - Secondary/complications: Biliary system (increased bilirubin turnover from hemolysis); potential iron-overload target organs if chronic transfusion is required (liver, heart, endocrine organs) — inferred from general chronic-hemolysis/transfusion management principles, not harderoporphyria-specific data - Body systems: Hematologic/hematopoietic system (primary); integumentary system (photosensitivity); hepatobiliary system (secondary)

Tissue and cell level: - Erythroid lineage cells (proerythroblasts through mature erythrocytes) — CL:0000765 (erythroblast), CL:0000232 (erythrocyte) - Hepatocytes — CL:0000182 - Splenic reticuloendothelial macrophages — CL:0000235 (macrophage) - Epidermal keratinocytes and dermal microvasculature (photosensitivity target) — CL:0000312 (keratinocyte)

Subcellular level: - Mitochondria — CPOX is localized to the mitochondrial intermembrane space, where the terminal three steps of heme synthesis (CPOX, PPOX, FECH) occur; GO Cellular Component: GO:0005758 (mitochondrial intermembrane space) - Cytosol — earlier heme pathway steps (ALAD through UROD) occur in the cytosol before substrate re-enters mitochondria for the CPOX step

Localization: Systemic/hematologic (not focal); cutaneous manifestations are typically distributed over light-exposed skin (face, dorsal hands), consistent with other photosensitive porphyrias — bilateral, light-exposure-dependent rather than laterality-defined.

Suggested UBERON terms: UBERON:0002371 (bone marrow), UBERON:0000178 (blood), UBERON:0002097 (skin), UBERON:0002106 (spleen), UBERON:0001155 (liver).

8. Temporal Development

  • Onset: Congenital/neonatal. The hallmark presentation across essentially all reported cases is severe jaundice and hemolytic anemia at birth or within the first days of life. Photosensitivity may be present from early infancy or, in at least one reported case, persist as "lifelong photosensitivity" into adulthood.
  • Onset pattern: Acute at birth (hemolytic/jaundice component), with a chronic, persistent course thereafter for the photosensitivity and biochemical porphyrin-excess phenotype.
  • Progression/course: Described as a chronic, lifelong biochemical abnormality (elevated harderoporphyrin/coproporphyrin excretion, reduced CPOX activity) with a hematologic component that may stabilize after the neonatal period but with persistent photosensitivity. No formal staging system exists for this disease given its rarity.
  • Progression rate: Not systematically quantified across a cohort; case reports describe chronic hemolytic anemia as an ongoing feature beyond the neonatal period rather than a self-limited neonatal event alone.
  • Remission patterns: Not established; no natural-history or registry data were identified describing spontaneous remission.
  • Critical periods: The neonatal period is clinically critical both for diagnosis (distinguishing harderoporphyria from other causes of neonatal hemolytic anemia and jaundice, e.g., thalassemia, hemolytic disease of the newborn, G6PD deficiency, other porphyrias) and for management of hyperbilirubinemia risk (kernicterus).

Sources: Nordmann et al. 1983; ASH Blood 91:1453 (1998); ScienceDirect lifelong photosensitivity case

9. Inheritance and Population

  • Inheritance pattern: Autosomal recessive (biallelic CPOX variants), in contrast to the autosomal dominant, reduced-penetrance inheritance of classic HCP caused by heterozygous CPOX variants. This makes CPOX one of relatively few genes in which different zygosity states produce clinically and biochemically distinct named disorders in the same locus.
  • Penetrance: Full/high penetrance is implied for the harderoporphyria neonatal phenotype in the reported cases (all documented biallelic D400–K404-region carriers presented with disease), though the very small number of published cases limits confident penetrance estimation. By contrast, heterozygous HCP (the "carrier" state in most harderoporphyria kindreds) shows well-documented reduced penetrance (GeneReviews, citing Whatley et al. 2009, PMID 19460837, and Blake et al. 1992, PMID 1733615).
  • Expressivity: Variable within the erythropoietic/hepatic spectrum depending on exact genotype (D400–K404 hot-region variant vs. variants elsewhere in the gene), which is the central genotype-phenotype finding of this disease.
  • Genetic anticipation: Not applicable — harderoporphyria is not a repeat-expansion disorder.
  • Germline mosaicism: Not specifically reported for CPOX/harderoporphyria in this search pass.
  • Founder effects: Not documented for harderoporphyria specifically; K404E and H327R have each been reported in only a small number of unrelated families, insufficient to establish founder-population data confidently.
  • Consanguinity: Plausible risk-elevating factor for true homozygosity (as opposed to compound heterozygosity) given the rarity of individual pathogenic alleles, though the founding Nordmann family history was not explicitly confirmed as consanguineous in the retrieved summary — verify against primary source before asserting in curation.
  • Carrier frequency: Not independently established for harderoporphyria; heterozygous HCP carrier frequency (from which harderoporphyria compound heterozygotes/homozygotes arise) is not precisely quantified in general population; K404E allele frequency itself is approximately 0.009% in gnomAD.

Population demographics: - Prevalence: Harderoporphyria is described in the literature as having "fewer than 10 cases reported worldwide", making formal prevalence/incidence estimation essentially impossible; it is likely underdiagnosed given its atypical (non-classic-porphyria) presentation as neonatal hemolytic anemia, which is more commonly worked up for thalassemia, hemolytic disease of the newborn, or red cell enzymopathies before porphyria is considered. - Geographic distribution: No specific endemic region identified; reported cases span multiple, geographically dispersed families (originally described in a French kindred by Nordmann et al.). - Sex ratio: No sex predilection has been reported for harderoporphyria itself (autosomal recessive, non-sex-linked); note this contrasts with classic HCP, where clinical attacks (in the general HCP/AIP acute-porphyria literature) are more frequent in women due to hormonal triggers, but this hormonal-attack pattern is not the dominant harderoporphyria presentation. - Age distribution: Neonatal/infantile predominance at diagnosis, given the characteristic presentation.

Sources: Wikipedia: Harderoporphyria; OMIM #618892; GeneReviews HCP

10. Diagnostics

Clinical/laboratory tests: - Fecal porphyrin fractionation — the key diagnostic test: demonstration that harderoporphyrin constitutes the majority (>60%) of total fecal porphyrin, versus <20% in unaffected individuals and heterozygous HCP carriers. This is the biochemical signature that distinguishes harderoporphyria from classic HCP (where COPRO >> PROTO with 60–95% coproporphyrin isomer-III predominance, but without harderoporphyrin excess). - Urinary porphyrin analysis — elevated coproporphyrin excretion. - Erythrocyte protoporphyrin — elevated, reflecting the erythroid-dominant lesion. - Lymphocyte/erythrocyte coproporphyrinogen oxidase enzyme activity assay — markedly reduced (~10% of normal) in affected homozygotes/compound heterozygotes vs. ~50% in heterozygous HCP carriers (parents); this quantitative distinction supports zygosity inference even before molecular confirmation. - Urinary porphobilinogen (PBG) and ALA — the classic marker for acute hepatic porphyria attacks (elevated in acute HCP attacks); relevant for excluding/assessing an acute hepatic component, though harderoporphyria itself is not characterized by the acute neurovisceral attacks that make PBG the primary diagnostic marker in classic HCP. - Complete blood count, reticulocyte count, bilirubin (direct/indirect), haptoglobin, LDH — standard hemolysis work-up, essential to the differential diagnosis of neonatal hemolytic anemia.

Genetic testing: - CPOX sequence analysis (single-gene test or targeted porphyria gene panel) is the definitive diagnostic approach, given that sequence analysis detects ~97% of pathogenic CPOX variants (GeneReviews); deletion/duplication analysis captures additional cases not found by sequencing alone. - Targeted variant testing for known harderoporphyria hot-region alleles (K404E, H327R) can be used once family segregation is suspected. - Whole exome/genome sequencing is a reasonable approach in an undiagnosed neonate with hemolytic anemia of unclear etiology, particularly when initial hemoglobinopathy/enzymopathy work-up is unrevealing.

Imaging: Not disease-specific; abdominal ultrasound may document hepatosplenomegaly as part of the general hemolysis work-up.

Biopsy/histopathology: Not a primary diagnostic modality for harderoporphyria; no disease-specific histopathological signature was identified in this search.

Differential diagnosis (drawing on the neonatal hemolytic anemia and porphyria literatures): - Thalassemia syndromes and other hemoglobinopathies - Hemolytic disease of the newborn (Rh/ABO incompatibility) - Red cell membrane and enzyme defects (hereditary spherocytosis, G6PD deficiency, pyruvate kinase deficiency) - Congenital erythropoietic porphyria (Günther disease) — also presents with neonatal hemolysis and severe photosensitivity, but distinguished biochemically by uroporphyrin/coproporphyrin I isomer excess rather than harderoporphyrin - Classic (heterozygous) hereditary coproporphyria and other acute hepatic porphyrias (variegate porphyria, acute intermittent porphyria) — distinguished by absence of the acute neurovisceral attack pattern and by the specific harderoporphyrin excess - Neonatal-onset hereditary coproporphyria (a related but distinct entity reported with massive coproporphyrin elevation, cutaneous blistering, and hemolytic anemia without harderoporphyrin predominance — see PMC5740044)

Screening: No population-based or newborn screening program exists for harderoporphyria given its extreme rarity; diagnosis relies on clinical suspicion in a neonate with unexplained hemolytic anemia plus family history of CPOX mutations/HCP, followed by targeted biochemical and molecular testing. Cascade/carrier testing in relatives of an index case is appropriate once a pathogenic variant is identified, consistent with general recessive-disorder genetic counseling practice.

Sources: Nordmann et al. 1983; GeneReviews HCP; PMC5740044

11. Outcome/Prognosis

  • Survival/mortality: No formal survival statistics exist given the extremely small number of reported cases; the disease is not generally described as immediately life-threatening if recognized and supported through the neonatal period, though severe unrecognized neonatal hyperbilirubinemia/hemolysis in any etiology carries a risk of kernicterus if untreated.
  • Morbidity: Chronic hemolytic anemia and lifelong photosensitivity represent the principal ongoing morbidity; hepatosplenomegaly from chronic hemolysis/extramedullary hematopoiesis is a secondary morbidity.
  • Complications: By analogy with other chronic hemolytic/porphyric conditions — risk of gallstones (pigment stones from chronic hemolysis), potential need for chronic transfusion with associated iron-overload risk if severe, and skin damage/scarring from recurrent phototoxic injury. These are inferred from general hemolytic-anemia and erythropoietic-porphyria management literature rather than harderoporphyria-specific outcome data, and should be flagged as extrapolated rather than directly evidenced.
  • Recovery potential: Case reports describe long-term survival with supportive management (implied by case reports following patients into later childhood/adulthood, e.g., the "lifelong photosensitivity" case), suggesting a chronic but non-fatal natural history when appropriately managed, though this is based on a handful of published cases rather than systematic outcome data.
  • Prognostic factors: Not systematically studied; presumably genotype (which specific hot-region variant, and whether compound heterozygous with a null allele vs. true homozygous) and degree of residual CPOX activity influence severity, mirroring the genotype-driven mechanism that defines the disease category itself.

Evidence gap note: This section is the weakest-evidenced area in the literature for this disease; curators should represent prognosis claims with appropriately hedged confidence given the case-report-only evidence base.

12. Treatment

No disease-specific, evidence-based treatment guideline or clinical trial exists for harderoporphyria (consistent with its status as an ultra-rare, case-report-only disease). Management is supportive and extrapolated from general practice in erythropoietic/hemolytic porphyrias and neonatal hemolytic anemia:

Supportive/symptomatic care: - Photoprotection — strict avoidance of sunlight/blue-violet light (<510 nm), protective clothing, opaque/broad-spectrum sunscreens, window-glass filtering — mainstay for the cutaneous photosensitivity and porphyrin-driven hemolysis component, by direct analogy with erythropoietic protoporphyria and congenital erythropoietic porphyria management (NCIT candidate: NCIT:C15747 Supportive Care; behavioral/lifestyle modality). - Management of neonatal hyperbilirubinemia — standard phototherapy/exchange transfusion protocols as clinically indicated for jaundice, with the caveat that porphyria-associated photosensitivity requires careful wavelength selection to avoid worsening porphyrin photoactivation (a clinically important nuance versus standard neonatal jaundice phototherapy). - Red blood cell transfusion — supportive management of severe/symptomatic hemolytic anemia, as used across erythropoietic porphyrias generally to correct anemia and, at higher chronic-transfusion intensity, to suppress endogenous erythropoiesis and thereby reduce porphyrin overproduction — though this carries iron-overload risk requiring chelation if used chronically. Direct harderoporphyria-specific transfusion-dependency data were not confirmed in this search pass. - Splenectomy — reported as "variably successful" for hemolysis/hypersplenism in erythropoietic porphyrias broadly; no harderoporphyria-specific outcome data identified. - Avoidance of porphyrinogenic drug triggers (barbiturates, certain sulfonamides, other CYP450 inducers) — standard precaution extrapolated from HCP/acute-porphyria management, applicable to the hepatic/coproporphyrin component of the disease. - Genetic counseling — for parents/family members given autosomal recessive inheritance, including carrier testing of relatives and reproductive counseling (NCIT:C15240 Genetic Counseling).

Pharmacotherapy (extrapolated from HCP, not harderoporphyria-specific): - Hematin/hemin (Panhematin) — the standard treatment for acute attacks in classic HCP, given intravenously to suppress hepatic ALAS1 via negative feedback; relevant primarily if a harderoporphyria patient develops a superimposed acute hepatic-type attack, though this is not the typical harderoporphyria clinical pattern (NCIT:C15986 Pharmacotherapy; therapeutic_agent consideration: hemin, CHEBI-bindable). - Givosiran (an ALAS1-directed siRNA, FDA-approved 2019 for recurrent acute hepatic porphyria attacks) — approved for classic acute hepatic porphyrias including HCP with ≥4 attacks/year; not established for harderoporphyria, whose clinical pattern is erythropoietic/hemolytic rather than acute-attack-driven, so applicability is speculative rather than evidenced (therapeutic_modality candidate: SIRNA; NCIT term to be verified). - Intravenous glucose/carbohydrate loading — standard adjunct during any acute hepatic-type exacerbation, by suppressing ALAS1 induction.

Experimental/investigational: No harderoporphyria-specific clinical trials (NCT-registered) were identified in this search. Curators should check ClinicalTrials.gov directly for any porphyria-basket trials that might include biallelic CPOX-deficiency patients before asserting a negative.

Curative options: No curative therapy (e.g., gene therapy, hematopoietic stem cell transplantation) has been reported for harderoporphyria specifically, though HSCT is the established curative approach for the mechanistically related congenital erythropoietic porphyria, and could be a reasonable extrapolated future direction worth flagging as a knowledge gap rather than an established treatment.

Sources: GeneReviews HCP (hematin/givosiran management of classic HCP attacks); general erythropoietic-porphyria management literature (ASH Blood 141:2921, How I treat EPP/XLP; PMC10170564, CEP management)

13. Prevention

  • Primary prevention: Not applicable in the traditional sense (Mendelian recessive genetic disorder); the closest analog is preconception/prenatal genetic counseling and carrier screening in families with a known harderoporphyria proband or CPOX pathogenic variant, given the autosomal recessive inheritance and identifiable causal alleles.
  • Secondary prevention: Early recognition of neonatal hemolytic anemia/jaundice with appropriate porphyrin work-up in at-risk families (known CPOX carrier parents) could enable earlier diagnosis and photoprotective/supportive intervention, though no formal newborn screening protocol exists.
  • Tertiary prevention: Trigger avoidance (light exposure, porphyrinogenic drugs, fasting) to reduce the frequency/severity of hemolytic and cutaneous exacerbations in a diagnosed patient — standard practice extrapolated from the broader porphyria management literature.
  • Genetic counseling: Recommended for parents of an affected child (both obligate heterozygous HCP carriers) regarding 25% recurrence risk in future pregnancies (autosomal recessive), and for extended family members regarding carrier status and reproductive risk, especially relevant in consanguineous kindreds.
  • Prenatal/preimplantation testing: Feasible in principle once the familial CPOX variants are known (standard molecular prenatal diagnosis/PGD approach for a known biallelic Mendelian disorder), though no harderoporphyria-specific prenatal diagnosis case was identified in this search.
  • Public health measures: Not applicable — this is not an environmentally or infectiously mediated disease amenable to population-level public health intervention.

14. Other Species / Natural Disease

  • Taxonomy: No naturally occurring harderoporphyria (biallelic CPOX hot-region variant) has been reported in a non-human species in this search pass.
  • Related naturally occurring CPOX-deficiency phenotype — the Nakano mouse cataract model: A hypomorphic Cpox mutation was identified as the cause of hereditary cataract in the classic Nakano (nctam) mouse strain, an unexpected connection between a heme-pathway enzyme defect and lens cataractogenesis (PMID 23631845), distinct from — but genetically related to — the human harderoporphyria/HCP disease spectrum via the same gene.
  • BALB.NCT-Cpox^nct mouse model of hereditary coproporphyria: Derived from the Nakano cataract allele backcrossed onto BALB/c, this mouse is homozygous for a p.R380L CPOX substitution retaining only ~15% of wild-type enzyme activity. It shows drastically increased blood and hepatic coproporphyrin from a young age, excessive urinary coproporphyrin and porphyrin-precursor excretion, neuromuscular symptoms, and (in female mice specifically) hypertension — recapitulating features of human HCP. This is described as filling a prior gap, since no prior animal model had jointly reproduced the causal gene mutation, reduced CPOX enzyme activity, porphyrin accumulation, and clinical symptoms of HCP together (PMC10036863; PubMed 36967721). Because this model is homozygous (not restricted to the D400–K404 hot region) it is best characterized as an HCP model rather than a harderoporphyria-specific (harderoporphyrin-excess) model — an important nuance for curation, since it does not reproduce the disease-defining harderoporphyrin-predominant biochemical signature.
  • ENU mutagenesis mouse model of HCP: A separate ENU-induced mouse model of hereditary coproporphyria has also been reported (PMID 28600349), independent of the Nakano-derived strain, further supporting Cpox-deficient mice as a tractable system for studying HCP-spectrum biology, again without specific confirmation of harderoporphyrin-predominant biochemistry.
  • Comparative biology: The heme biosynthetic pathway, including CPOX, is highly conserved from yeast (Saccharomyces cerevisiae Hem13p, whose crystal structure has informed human CPOX active-site models) through mammals, supporting cross-species mechanistic inference, though no species other than mouse (via the two models above) has a documented naturally occurring or induced Cpox-deficiency phenotype relevant to this KB.
  • Zoonotic potential / transmission: Not applicable — harderoporphyria is a non-communicable, purely genetic disorder.

Sources: PMC10036863 / BALB.NCT-Cpoxnct model; PubMed 23631845, Nakano cataract Cpox mutation; PubMed 28600349, ENU mutagenesis HCP mouse model

15. Model Organisms

Model Species Genotype Fidelity to human disease Key findings Reference
BALB.NCT-Cpox^nct Mouse (Mus musculus, BALB/c background) Homozygous p.R380L Cpox hypomorphic missense (G→T substitution), ~15% residual enzyme activity Recapitulates classic HCP (elevated blood/liver coproporphyrin, urinary coproporphyrin and precursor excretion, neuromuscular symptoms, sex-specific hypertension in females) — does not specifically model the harderoporphyrin-predominant biochemistry that defines harderoporphyria, since the R380L substitution lies outside the human D400–K404 hot region First mouse model to jointly reproduce causal gene defect, reduced enzyme activity, porphyrin accumulation, and clinical HCP-like symptoms PMC10036863; PubMed 36967721
Nakano (nctam) cataract mouse Mouse Hypomorphic Cpox mutation (progenitor strain for BALB.NCT-Cpox^nct) Originally characterized for a cataract phenotype, not primarily a porphyria model Established the cataract–CPOX genetic link that led to the HCP mouse model above PubMed 23631845
ENU-mutagenesis Cpox mouse Mouse ENU-induced Cpox variant HCP-like phenotype from forward-genetics screen Independent confirmation that murine Cpox loss-of-function reproduces coproporphyria-relevant biology PubMed 28600349
E. coli recombinant expression system Bacterial (in vitro/computational biochemistry) Human CPOX cDNA (wild-type and K404E mutant) expressed heterologously Not a whole-organism disease model, but the definitive functional evidence establishing K404E pathogenicity Demonstrated ~10-fold increased Km and reduced activity for K404E vs. wild-type CPOX, directly linking the mutation to defective substrate binding Schmitt et al. 2005, Hum Mol Genet 14:3089–3098 (via OMIM #618892)

Key gap: No published mouse (or other organism) model specifically carries a homozygous or compound-heterozygous D400–K404-region variant reproducing the harderoporphyrin-excess, erythropoietic-dominant human harderoporphyria phenotype — all current murine CPOX-deficiency models more closely recapitulate classic hepatic HCP biochemistry. This represents a genuine modeling gap worth flagging explicitly in a HUMAN_MODEL_MISMATCH-type knowledge-gap annotation if this disease is curated into the dismech KB, since existing Cpox-mutant mice are informative for the broader CPOX-deficiency mechanism but do not validate the specific structural/kinetic hypothesis (premature harderoporphyrinogen release) proposed for the D400–K404 hot-region human variants.

Sources: as cited per row above.

Summary of Key Evidence Gaps for Curation

  1. Prognosis/outcome data are essentially absent beyond individual case follow-up — no survival statistics, no quality-of-life instruments applied.
  2. No harderoporphyria-specific treatment trial or guideline exists; all therapeutic recommendations are extrapolated from classic HCP or other erythropoietic porphyrias and should be curated with appropriately qualified evidence_source/confidence.
  3. No animal model precisely recapitulates the harderoporphyrin-excess biochemical signature that defines this disease as distinct from ordinary homozygous HCP — existing Cpox-mutant mice model the broader HCP phenotype.
  4. MONDO ID was not independently confirmed in this research pass and should be verified directly (e.g., via MONDO/OLS lookup) before curation.
  5. Transfusion-dependency, splenectomy outcomes, and QoL data specific to harderoporphyria patients were not confirmed in primary sources during this pass — the supportive-care recommendations above are extrapolated from related erythropoietic porphyrias and should be flagged as such, or verified against the primary case reports (Nordmann 1983; Lamoril et al. 1998, Blood 91:1453; the H327R case report, PMID 21103937; and the compound-heterozygous lifelong-photosensitivity case report, PMID 30828546) before being asserted as harderoporphyria-specific findings with full confidence.

Sources (consolidated)

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 16
Resolved 16
Unresolved (possible confabulation) 0
Unverifiable 0
Quoted claims checked 3
Quoted claims found in source 3
Quoted claims not found in source 0
References weighed for topical relevance 16
On topic 7
Off topic 3

References that may not be about this subject

These identifiers resolve, so they are not fabrications, but the records they resolve to share almost none of this report's vocabulary. That is a clue and not a verdict - a paper can be relevant in ways its title and abstract do not spell out - so read them before deciding:

  • PMID:1733615 (1 mention) - Fecal coproporphyrin isomers in hereditary coproporphyria.
  • shared terms: porphyrin
  • PMID:629747 (4 mentions) - Factors determining the sequence of oxidative decarboxylation of the 2- and 4-propionate substituents of coproporphyrinogen III by coproporphyrinogen oxidase in rat liver.
  • shared terms: none
  • PMID:14633981 (5 mentions) - Crystal structure of coproporphyrinogen III oxidase reveals cofactor geometry of Radical SAM enzymes.
  • shared terms: none

Weighed against this report's own most characteristic terms: harderoporphyria, hcp, cpox, classic, disease, porphyrin, variant, erythropoietic, photosensitivity, heterozygous, hepatic, neonatal, anemia, hemolysis, hemolytic, porphyria, phenotype, activity, genetic, harderoporphyria-specific.

All extracted references resolved successfully. Resolving is not the same as being relevant, though - see the references listed above as possibly off topic.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 32
Resolved 29
Unresolved (possible confabulation) 0
Obsolete 1
Unverifiable 2
Terms whose name was checked 15
Terms named correctly 12
Terms named as a different term 2
Terms whose name is worth a second look 1

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

  • HP:0032263 (1 mention) - the report calls it "Coproporphyrinuria"; HP calls it Increased blood pressure
  • UBERON:0001155 (2 mentions) - the report calls it "liver"; UBERON calls it colon

Obsolete terms

These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:

  • GO:0070265 (obsolete necrotic cell death) (1 mention)

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

  • UBERON:0002097 (2 mentions) - the report calls it "skin"; UBERON calls it skin of body, and lists "skin" among its other names

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA.