Undiagnosed metabolic disorders

Gene: CPOX

Green List (high evidence)

Comment on mode of inheritance: As reviewed by Sharon Whatley, variants in CPOX may cause autosomal dominant or autosomal recessive porphyria. Monoallelic variants in CPOX have very low clinical penetrance (<1%) and may be challenging to report as diagnostic. Hence, BIALLELIC, autosomal or pseudoautosomal MOI would be more appropriate.
CPOX is associated with Coproporphyria 121300 (AR and AD) and Harderoporphyria 618892 (AR) in OMIM (accessed 20th Oct 2025).

Created: 20 Oct 2025, 2:38 p.m. | Last Modified: 4 Nov 2025, 1:52 p.m.

Panel Version: 1.637

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Coproporphyria, OMIM:121300; Harderoporphyria, OMIM:618892

Publications

• 6886003
• 7757079
• 8012360
• 9454777
• 10505225
• 11074238
• 11309681
• 16159891
• 21103937
• 23236641
• 23605133
• 30828546
• 33008663
• 37540847
• 38940544
• 40296768

Green List (high evidence)

Relevant metabolic investigation: Urine porphobilinogen, plasma porphyrin fluorescence emission, faecal coproporphyrin isomer (III:I) ratio (for hereditary coproporphyria) and faecal harderoporphyrin (for harderoporphyria)

PMID: 38940544 Aarsand reports that the acute porphyrias are a group of rare inborn errors of metabolism caused by abnormal functioning of haem biosynthesis enzymes and are associated with acute neurovisceral attacks characterized by severe abdominal pain and neuropsychiatric symptoms that may require highly specialized intensive care. The acute porphyrias, acute intermittent porphyria (AIP), variegate porphyria (VP) and hereditary coproporphyria (HCP), usually become symptomatic in early adulthood.

PMID: 11309681 Lamoril reports that HCP is the least common of the autosomal dominant, acute hepatic porphyrias. It results from pathogenic variants in the CPOX gene that encodes the mitochondrial enzyme, coproporphyrinogen oxidase.

PMID: 37540847 Dickey reports that patients with acute porphyria can develop acute neurovisceral attacks often characterized by abdominal pain, nausea, vomiting, and other neurologic and psychiatric symptoms such as weakness, numbness, paraesthesia, seizures, anxiety, depression, or psychosis.

PMID: 38940544 Aarsand reports that in a patient with acute symptoms consistent with a porphyria disorder, the definitive diagnosis depends on the demonstration of increased accumulation and excretion of porphyrins and porphyrin precursors during an acute attack.

PMID: 23236641 Wang reports that HCP is classified as both an acute (hepatic) and a chronic (cutaneous) porphyria with blistering photosensitivity. The cutaneous findings in HCP resemble those in porphyria cutanea tarda (PCT) and in VP.
PMID: 11074238 Kuhnel reports that bullae and fragility of light-exposed skin occurred in only 14% of 46 patients with HCP (current or past).
PMID: 38940544 Aarsand and 23605133 Whatley report that HCP is an autosomal dominant disorder with an estimated prevalence of HCP in the UK as 1–2 in a million with a rough estimate of the clinical penetrance 0.4%. Due to this low penetrance, genetic testing alone may be misleading and cause misdiagnosis. IPNET advises that biochemical testing is used to diagnose active HCP as the penetrance is so low.
PMID: 16159891 Schmitt reports that there are two very rare, homozygous forms of hereditary coproporphyria, one of which is characterised by the faecal excretion of harderoporphyrin. Harderoporphyria has predominantly haematological manifestations such as neonatal jaundice, haemolytic anaemia and hepatosplenomegaly.

There have been 12 patients from 9 families reported with clinical details and biallelic pathogenic variants (PMID: 40296768 Kelestemur, 33008663 Fukui, 30828546 Moghe, 21103937 Hasanoglu, 16159891 Schmitt, 10505225 Doss, 9454777 Lamoril, 7757079 Lamoril, 8012360 Martasek). 10 of these 12 individuals had cutaneous symptoms. The most common manifestation was pigmentation (5 patients, 2 with adrenal insufficiency) followed by blisters (3), skin fragility (3), erythema (2), other symptoms: scarring, papules, milia and hypertrichosis were reported in single patients. Two patients had severe cutaneous photosensitivity following phototherapy (PMID: 6886003 Nordmann, 21103937 Hasanoglu).

Eight patients (from five families) with biallelic pathogenic variants had neonatal jaundice, haemolytic anaemia and hepatosplenomegaly. Of this eight, 5 patients (from 3 families) had at least one pathogenic variant located in the presumed CPOX active site (Asp400–Lys404) and harderoporprhyrin in their faecal samples leading to a diagnosis of harderoporphyria (PMID: 30828546 Moghe, 9454777 Lamoril, 7757079 Lamoril). In three patients (two families) the variants were outside this region. These homozygous hereditary coproporphyria patients were not tested for faecal harderoporphyrin (40296768 Kelestemur, 21103937 Hasanoglu).

PMID: 16159891 Schmitt reported one patient with homozygous variant p.(Lys404Glu) and harderoporphyria who was diagnosed at 39 years of age due to cutaneous symptoms with mild anaemia.

Careful consideration should be given to the reporting of a single pathogenic variant as an incidental finding in the CPOX gene, due to its low clinical penetrance (~0.4%).

Created: 11 Sep 2025, 10:05 a.m. | Last Modified: 11 Sep 2025, 10:05 a.m.

Panel Version: 1.632

Mode of inheritance
BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal

Phenotypes
121300; 618892

Publications

• 38940544
• 11309681
• 37540847
• 23236641
• 11074238
• 23605133
• 16159891
• 40296768
• 33008663
• 30828546
• 21103937
• 16159891
• 10505225
• 9454777
• 7757079
• 8012360
• 6886003

Green List (high evidence)

More than 3 unrelated cases reported. One homozygous patient repored, therefore mode of inheritance selected was 'both' to cover this. The 'treatable tag was added due to information from PMID: 12227458 in which the patient was treated with heme arginate.

Created: 23 Feb 2017, 5:13 p.m.

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Coproporphyria 121300; Harderoporphyria 121300

Publications

• 27604308
• 12227458
• 8159699
• 7987309
• 8990017