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Hereditary neuropathy or pain disorder v7.29 CPOX Ida Ertmanska Tag Q3_25_MOI tag was added to gene: CPOX.
Tag Q3_25_expert_review tag was added to gene: CPOX.
Hereditary neuropathy or pain disorder v7.29 CPOX Ida Ertmanska edited their review of gene: CPOX: Added comment: 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. This gene has been tagged for MOI Expert Review. CPOX is associated with Coproporphyria 121300 (AR and AD) and Harderoporphyria 618892 (AR) in OMIM (accessed 20th Oct 2025).; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v7.21 CPOX Ida Ertmanska Phenotypes for gene: CPOX were changed from Coproporphyria, 121300; Harderoporphyria, 121300; Skin photosensitivity and haemolytic anaemia. Can present acutely similar to AIP to Coproporphyria, OMIM:121300; Harderoporphyria, OMIM:618892
Publications for gene: CPOX were updated from to 8008008; 11074238; 11309681; 21103937; 24353603; 24156084; 35228944; 35584894; 38940544
Hereditary neuropathy or pain disorder v7.20 CPOX Ida Ertmanska edited their review of gene: CPOX: Changed publications to: 8008008, 11074238, 11309681, 21103937, 24353603, 24156084, 35228944, 35584894, 38940544
Hereditary neuropathy or pain disorder v7.20 CPOX Ida Ertmanska changed review comment from: Comment on list classification: Both mono- and bi- allelic variants in CPOX are known to cause hereditary coproporphyria (HCP), which may sometimes result in severe abdominal pain and progressive peripheral neuropathy. However, specific neuropathy cases are rarely reported with a genetic diagnosis - biochemical tests are a much more common diagnostic route. Since CPOX is the only gene known to cause Coproporphyria, this gene may remain Green for Hereditary neuropathy or pain disorder.; to: Comment on list classification: Both mono- and bi- allelic variants in CPOX are known to cause hereditary coproporphyria (HCP), which may result in severe abdominal pain and progressive peripheral neuropathy. However, specific neuropathy cases are rarely reported with a genetic diagnosis - only 1 individual with peripheral neuropathy and a heterozygous CPOX variant is included in this review (PMID: 35228944 Upchurch et al., 2025). Biochemical testing of faecal coproporphyrin is a much more common diagnostic route. Since CPOX is the only gene known to cause Coproporphyria, this gene may remain Green for Hereditary neuropathy or pain disorder.
Hereditary neuropathy or pain disorder v7.20 CPOX Ida Ertmanska changed review comment from: HCP patients may present with acute neurovisceral attacks, characterised by severe abdominal pain and neuropsychiatric symptoms - often provoked by drugs, alcohol, or endocrine factors. Diagnosis of HCP is established based on increased faecal coproporphyrin III:I ratio when VP has been excluded by the plasma fluorescence scan wavelength (PMID: 11309681 Lamoril et al., 2001; 38940544 Aarsand et al., 2022). Acute episodes can progress to include seizures, peripheral motor neuropathy and posterior reversible encephalopathy syndrome if left untreated (PMID: 35584894 Schulenburg-Brand et al., 2022)

PMID: 11074238 Kuhnel et al., 2000
53 patients with HCP. Phenotype: abdominal pain (89% of the cohort), neurologic (33%), psychiatric (28%), cardiovascular (25%), and skin symptoms (14%).

PMID: 21103937 Hasanoglu 2011
Male infant from a Turkish consanguineous family presented with the Harderoporphyria phenotype: neonatal hyperbilirubinemia, hemolytic anemia, hepatosplenomegaly, and skin lesions when exposed to UV light. Heterozygous for c.980A>G (p.His327Arg) The patient died at 5 months old due to an apparent acute neurologic porphyric attack. Structural studies predicted that p.H327R interacts with residue W399 in the CPOX active site.

CPOX is associated with Coproporphyria 121300 (AR and AD) and Harderoporphyria 618892 (AR) in OMIM (accessed 21st Oct 2025).; to: HCP patients may present with acute neurovisceral attacks, characterised by severe abdominal pain and neuropsychiatric symptoms - often provoked by drugs, alcohol, or endocrine factors. Diagnosis of HCP is established based on increased faecal coproporphyrin III:I ratio when VP has been excluded by the plasma fluorescence scan wavelength (PMID: 11309681 Lamoril et al., 2001; 38940544 Aarsand et al., 2022). Acute episodes can progress to include seizures, peripheral motor neuropathy and posterior reversible encephalopathy syndrome if left untreated (PMID: 35584894 Schulenburg-Brand et al., 2022)

PMID: 8008008 Barohn et al. 1994
A 23-year-old man with no genetic diagnosis. Presented with epilepsy and a past history of abdominal pain. Electrophysiologic studies demonstrated a peripheral neuropathy with features of axonal degeneration and demyelination.

PMID: 11074238 Kuhnel et al., 2000
53 patients with HCP. Phenotype: abdominal pain (89% of the cohort), neurologic (33%), psychiatric (28%), cardiovascular (25%), and skin symptoms (14%).

PMID: 21103937 Hasanoglu 2011
Male infant from a Turkish consanguineous family presented with the Harderoporphyria phenotype: neonatal hyperbilirubinemia, hemolytic anemia, hepatosplenomegaly, and skin lesions when exposed to UV light. Heterozygous for c.980A>G (p.His327Arg) The patient died at 5 months old due to an apparent acute neurologic porphyric attack. Structural studies predicted that p.H327R interacts with residue W399 in the CPOX active site.

PMID: 24353603 Chen et al., 2013
46yo Chinese woman with a biochemical diagnosis of HCP. Phenotype: acute abdominal pain and progressive bilateral weakness and pain in the limbs. She also experienced significant muscle atrophy and decreased strength. Nerve conduction potential study revealed motor-sensory polyneuropathy. Successfully treated with hemin.

PMID: 24156084 Jiménez-Jiménez et al., 2013
44-year-old patient presenting clinically with acute ataxia who was diagnosed with HCP. Heterozygous for p.Q306X.

PMID: 35228944 Upchurch et al., 2025
26-year-old female with HCP who presented with acute ascending flaccid paralysis and respiratory failure after COVID-19 infection and was initially misdiagnosed and treated for Guillain-Barré syndrome. Patient developed progressively worsening abdominal pain; symmetric, distal-predominant, and ascending weakness developed four weeks later, associated with severe headaches and complex visual hallucinosis. Electrodiagnostic testing: profound axonal sensorimotor peripheral polyneuropathy affecting all extremities. No abnormalities on brain MRI. Successfully treated with hemin. Heterozygous for c.1070G>A (p.Cys357Tyr) - rare in gnomAD v4, Revel score = 0.9. Seq method: unknown.

CPOX is associated with Coproporphyria 121300 (AR and AD) and Harderoporphyria 618892 (AR) in OMIM (accessed 21st Oct 2025).
Hereditary neuropathy or pain disorder v7.20 CPOX Ida Ertmanska changed review comment from: Comment on list classification: Both mono- and bi- allelic variants in CPOX are known to cause hereditary coproporphyria, which may sometimes result in severe abdominal pain and progressive peripheral neuropathy. However, specific neuropathy cases are rarely reported with a genetic diagnosis - biochemical tests are a much more common diagnostic route. Since CPOX is the only gene known to cause Coproporphyria, this gene may remain Green for Hereditary neuropathy or pain disorder.; to: Comment on list classification: Both mono- and bi- allelic variants in CPOX are known to cause hereditary coproporphyria (HCP), which may sometimes result in severe abdominal pain and progressive peripheral neuropathy. However, specific neuropathy cases are rarely reported with a genetic diagnosis - biochemical tests are a much more common diagnostic route. Since CPOX is the only gene known to cause Coproporphyria, this gene may remain Green for Hereditary neuropathy or pain disorder.
Hereditary neuropathy or pain disorder v7.20 CPOX Ida Ertmanska edited their review of gene: CPOX: Changed publications to: 11074238, 11309681, 21103937, 35584894, 38940544
Hereditary neuropathy or pain disorder v7.20 CPOX Ida Ertmanska changed review comment from: Comment on list classification: Both mono- and bi- allelic variants in CPOX are known to cause hereditary coproporphyria, which may sometimes result in severe abdominal pain and progressive peripheral neuropathy. However, specific neuropathy cases are not reported with a genetic diagnosis - biochemical tests are a much more common diagnostic route. Since CPOX is the only gene known to cause Coproporphyria, this gene may remain Green for Hereditary neuropathy or pain disorder.; to: Comment on list classification: Both mono- and bi- allelic variants in CPOX are known to cause hereditary coproporphyria, which may sometimes result in severe abdominal pain and progressive peripheral neuropathy. However, specific neuropathy cases are rarely reported with a genetic diagnosis - biochemical tests are a much more common diagnostic route. Since CPOX is the only gene known to cause Coproporphyria, this gene may remain Green for Hereditary neuropathy or pain disorder.
Hereditary neuropathy or pain disorder v7.20 CPOX Ida Ertmanska changed review comment from: HCP patients may present with acute neurovisceral attacks, characterised by severe abdominal pain and neuropsychiatric symptoms - often provoked by drugs, alcohol, or endocrine factors. Diagnosis of HCP is established based on increased faecal coproporphyrin III:I ratio when VP has been excluded by the plasma fluorescence scan wavelength (PMID: 11309681 Lamoril et al., 2001; 38940544 Aarsand et al., 2022). Acute episodes can progress to include seizures, peripheral motor neuropathy and posterior reversible encephalopathy syndrome if left untreated (PMID: 35584894 Schulenburg-Brand et al., 2022)

PMID: 11074238 Kuhnel et al., 2000
53 patients with HCP. Phenotype: abdominal pain (89% of the cohort), neurologic (33%), psychiatric (28%), cardiovascular (25%), and skin symptoms (14%).

CPOX is associated with Coproporphyria 121300 (AR and AD) and Harderoporphyria 618892 (AR) in OMIM (accessed 21st Oct 2025).; to: HCP patients may present with acute neurovisceral attacks, characterised by severe abdominal pain and neuropsychiatric symptoms - often provoked by drugs, alcohol, or endocrine factors. Diagnosis of HCP is established based on increased faecal coproporphyrin III:I ratio when VP has been excluded by the plasma fluorescence scan wavelength (PMID: 11309681 Lamoril et al., 2001; 38940544 Aarsand et al., 2022). Acute episodes can progress to include seizures, peripheral motor neuropathy and posterior reversible encephalopathy syndrome if left untreated (PMID: 35584894 Schulenburg-Brand et al., 2022)

PMID: 11074238 Kuhnel et al., 2000
53 patients with HCP. Phenotype: abdominal pain (89% of the cohort), neurologic (33%), psychiatric (28%), cardiovascular (25%), and skin symptoms (14%).

PMID: 21103937 Hasanoglu 2011
Male infant from a Turkish consanguineous family presented with the Harderoporphyria phenotype: neonatal hyperbilirubinemia, hemolytic anemia, hepatosplenomegaly, and skin lesions when exposed to UV light. Heterozygous for c.980A>G (p.His327Arg) The patient died at 5 months old due to an apparent acute neurologic porphyric attack. Structural studies predicted that p.H327R interacts with residue W399 in the CPOX active site.

CPOX is associated with Coproporphyria 121300 (AR and AD) and Harderoporphyria 618892 (AR) in OMIM (accessed 21st Oct 2025).
Hereditary neuropathy or pain disorder v7.20 CPOX Ida Ertmanska edited their review of gene: CPOX: Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v7.20 CPOX Ida Ertmanska edited their review of gene: CPOX: Changed publications to: 11074238, 11309681, 35584894, 38940544
Hereditary neuropathy or pain disorder v7.20 CPOX Ida Ertmanska commented on gene: CPOX: Comment on list classification: Both mono- and bi- allelic variants in CPOX are known to cause hereditary coproporphyria, which may sometimes result in severe abdominal pain and progressive peripheral neuropathy. However, specific neuropathy cases are not reported with a genetic diagnosis - biochemical tests are a much more common diagnostic route. Since CPOX is the only gene known to cause Coproporphyria, this gene may remain Green for Hereditary neuropathy or pain disorder.
Hereditary neuropathy or pain disorder v7.20 CPOX Ida Ertmanska reviewed gene: CPOX: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Coproporphyria, OMIM:121300, Harderoporphyria, OMIM:618892; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v7.8 CPOX Sharon Whatley changed review comment from: Relevant metabolic investigation: Urine porphobilinogen

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: 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 of 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: 35584894 Schulenburg-Brand reviews the neuropathy that may occur in the acute porphyrias. Weakness and altered sensation are typically mild in an acute attack and improve as the pain resolves. In a small number of cases, severe, progressive peripheral neuropathy develops. Neuropathy can worsen, even after the acute pain resolves, with a Guillain-Barré like picture. Proximal muscle weakness occurs in the upper limbs and can progress to involve the legs and cause respiratory failure. Cranial nerves can be involved, with the facial, vagus and hypoglossal nerves most often affected, causing swallowing difficulties. Sensory neuropathy is less common, but can cause numbness over the torso and thighs, sometimes with severe pain. Cases gradually resolve with respiratory support, and some patients may need prolonged mechanical ventilation. After recovery, some degree of peripheral neuropathy can persist, with foot drop and wrist drop being fairly typical.

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%).; to: Relevant metabolic investigation: Urine porphobilinogen

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: 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 of 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: 35584894 Schulenburg-Brand reviews the neuropathy that may occur in the acute porphyrias. Weakness and altered sensation are typically mild in an acute attack and improve as the pain resolves. In a small number of cases, severe, progressive peripheral neuropathy develops. Neuropathy can worsen, even after the acute pain resolves, with a Guillain-Barré like picture. Proximal muscle weakness occurs in the upper limbs and can progress to involve the legs and cause respiratory failure. Cranial nerves can be involved, with the facial, vagus and hypoglossal nerves most often affected, causing swallowing difficulties. Sensory neuropathy is less common, but can cause numbness over the torso and thighs, sometimes with severe pain. Cases gradually resolve with respiratory support, and some patients may need prolonged mechanical ventilation. After recovery, some degree of peripheral neuropathy can persist, with foot drop and wrist drop being fairly typical.

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%).
Hereditary neuropathy or pain disorder v7.8 CPOX Sharon Whatley reviewed gene: CPOX: Rating: GREEN; Mode of pathogenicity: None; Publications: 38940544, 11309681, 23605133, 35584894; Phenotypes: 121300, 618892; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v2.18 CPOX Mafalda Gomes Tag Q4_21_MOI was removed from gene: CPOX.
Hereditary neuropathy or pain disorder v2.18 CPOX Eleanor Williams commented on gene: CPOX
Hereditary neuropathy or pain disorder v2.17 CPOX Mafalda Gomes Mode of inheritance for gene CPOX was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v1.64 CPOX Ivone Leong Tag Q4_21_MOI tag was added to gene: CPOX.
Hereditary neuropathy or pain disorder v1.64 CPOX Ivone Leong reviewed gene: CPOX: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v0.74 PPOX Louise Daugherty commented on gene: PPOX: Gene rated Green : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart). Extension of panel scope - syndrome with non-neurological features / Broader phenotype: variegate porphyria. As per CPOX usually presents more acutely but management implications. Promote to Green as management implications
Hereditary neuropathy or pain disorder v0.73 HMBS Louise Daugherty commented on gene: HMBS: Gene rated Green : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart). Extension of panel scope - syndrome with non-neurological features / Broader phenotype - acute intermittent porphyria As per CPOX usually presents more acutely but management implications. Promote to Green as management implications
Hereditary neuropathy or pain disorder v0.73 CPOX Louise Daugherty changed review comment from: Gene rated Green : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart). Extension of panel scope - syndrome with non-neurological features / Broader phenotype - porphyria, can present similar to AIP according to Alex Promote to Green as management implications; to: Gene rated Green : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart). Extension of panel scope - syndrome with non-neurological features / Broader phenotype - porphyria, can present similar to AIP according to Alex Rossor. Promote to Green as management implications
Hereditary neuropathy or pain disorder v0.43 CPOX Louise Daugherty Classified gene: CPOX as Green List (high evidence)
Hereditary neuropathy or pain disorder v0.43 CPOX Louise Daugherty Gene: cpox has been classified as Green List (High Evidence).
Hereditary neuropathy or pain disorder v0.42 CPOX Louise Daugherty edited their review of gene: CPOX: Added comment: Gene rated Green : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart). Extension of panel scope - syndrome with non-neurological features / Broader phenotype - porphyria, can present similar to AIP according to Alex Promote to Green as management implications; Changed rating: GREEN
Hereditary neuropathy or pain disorder v0.42 CPOX Louise Daugherty Classified gene: CPOX as Amber List (moderate evidence)
Hereditary neuropathy or pain disorder v0.42 CPOX Louise Daugherty Added comment: Comment on list classification: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
Hereditary neuropathy or pain disorder v0.42 CPOX Louise Daugherty Gene: cpox has been classified as Amber List (Moderate Evidence).
Hereditary neuropathy or pain disorder v0.1 CPOX Ellen McDonagh gene: CPOX was added
gene: CPOX was added to Hereditary neuropathy NOT PMP22 copy number. Sources: NHS GMS,London North GLH
Mode of inheritance for gene: CPOX was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: CPOX were set to Coproporphyria, 121300; Harderoporphyria, 121300; Skin photosensitivity and haemolytic anaemia. Can present acutely similar to AIP