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Hereditary coproporphyria

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Hereditary coproporphyria
Coproporphyrinogen III
SpecialtyEndocrinologyEdit this on Wikidata

Hereditary coproporphyria(HCP) is a disorder ofhemebiosynthesis, classified as an acute hepaticporphyria.[1]HCP is caused by a deficiency of the enzymecoproporphyrinogen oxidase,coded for by theCPOXgene, and is inherited in anautosomal dominantfashion, althoughhomozygousindividuals have been identified. Unlikeacute intermittent porphyria,individuals with HCP can present withcutaneousfindings similar to those found inporphyria cutanea tardain addition to the acute attacks of abdominal pain, vomiting and neurological dysfunction characteristic of acute porphyrias. Like other porphyrias, attacks of HCP can be induced by certain drugs, environmental stressors or diet changes. Biochemical and molecular testing can be used to narrow down the diagnosis of a porphyria and identify the specific genetic defect. Overall, porphyrias are rare diseases. The combined incidence for all forms of the disease has been estimated at 1:20,000. The exact incidence of HCP is difficult to determine, due to its reducedpenetrance.

Signs and symptoms[edit]

Clinically, patients affected with HCP present similarly to those with other acute porphyrias, such asacute intermittent porphyria(AIP) andvariegate porphyria(VP). Patients with HCP and VP can present with symptoms shared between the acute and cutaneous porphyrias. This includes the acute attacks of abdominal pain,nausea,vomiting,diarrhea,tachycardia,hypertensionandseizures,as well as the cutaneous findings seen inporphyria cutanea tarda(PCT), namely increased skin fragility, bullous lesions after exposure to sunlight and increased scarring.[2]

Individuals with HCP may be asymptomatic in the absence of triggering factors. Common triggers include certain drugs, alcohol, hormonal changes, and dietary changes.[1]Sunlight and other ultraviolet light can trigger the skin manifestations. Homozygous individuals forCPOXmutations can present with these findings at an earlier age thanheterozygotes.[1]

Genetics[edit]

HCP is caused by mutations inCPOX,which codes for the enzymecoproporphyrinogen oxidase.This enzyme is responsible for the sixth step in the heme biosynthetic pathway, converting coproporphyrinogen III to protoporphyrinogen IX.[3]CPOXis located at3q11.2-q12.1,[1]has 6intronsand 7exonsand produces anmRNAstrand that is 2675 bases in length.[4]It is inherited in anautosomal dominantfashion, meaning that a deficiency of 50% of the normal enzyme activity is enough to cause symptoms.[3]As reproductive fitness is not impacted,homozygousaffected individuals have been reported.[1]Along with other acute porphyrias HCP demonstrates reducedpenetrance,meaning not all individuals who carry a disease-causing mutation will express symptoms.[2]

Individuals who are homozygous for a specific mutation (K404E) or compound heterozygous with anull alleleinCPOXhave a more severe erythropoietic porphyria,harderoporphyria,[5]characterized by neonataljaundice,hyperbilirubinemia,hepatosplenomegaly and skin lesions upon exposure to ultraviolet light.[6]HCP is a rare disease, but the exact incidence is difficult to determine due to the reducedpenetranceof the acute porphyrias. Overall, the incidence of all porphyrias is estimated at 1:20,000 in the United States.[2]The incidence of harderoporphyria is even lower, with less than 10 cases reported worldwide.[1]

Diagnosis[edit]

The diagnosis of any porphyria is often delayed due to the rarity of the disease as well as the varied and non-specific findings that patients present with. Bedside measurement of urineporphobilinogenis recommended as a screening test for patients suspected of having an acute porphyria. Elevated porphobilinogen is indicative of an acute porphyria, and additional testing can be done to narrow down the specific type.[3][7]

The identification of a specific porphyria is based on the results of laboratory findings, includingblood,urineandstooltests. HCP can be distinguished from most other acute porphyrias by the cutaneous findings. VP presents similarly, but can be distinguished based on urine and stool porphyrin analysis, typically done usinghigh performance liquid chromatographywithfluorescencedetection.[8]The results of biochemical testing for porphyrias are most informative when samples are collected during an acute attack.[7]Typically, the distinguishing metabolite for HCP and VP is the presence of protoporphyrin in the plasma and feces of individuals affected with VP.[2]

Elevated coproporphyrin is a common finding in urine, known as coproporphyrinuria as it is the predominant porphyrin species in urine. This is a non-specific finding that is not necessarily due to an acute porphyria. Coproporphyrinuria can be caused by other stressors to the heme biosynthetic pathway, such as liver disease,lead poisoningand certainbone marrowdisorders.[9]

Treatment[edit]

There is no cure for HCP caused by the deficient activity of coproporphyrinogen oxidase. Treatment of the acute symptoms of HCP is the same as for other acute porphyrias. Intravenoushemin(as heme arginate or hematin) is the recommended therapy for acute attacks.[3][7]Acute attacks can be severe enough to cause death if not treated quickly and correctly. Hospitalization is typically required for administration of hemin, and appropriate drug selection is key to avoid exacerbating symptoms with drugs that interact poorly with porphyrias.[3]Proper drug selection is most difficult when it comes to treatment of the seizures that can accompany HCP, as most anti-seizure medications can make the symptoms worse.Gabapentinandlevetiracetamare two anti-seizure drugs that are thought to be safe.[3]

In patients where management of symptoms is difficult even with hemin,liver transplantis an option before the symptoms have progressed to advanced paralysis. Combined liver andkidneytransplants are sometimes undertaken in people withkidney failure.[3]

Long term treatment of acute porphyrias is centered on the avoidance of acute attacks by eliminating precipitating factors, such as drugs, dietary changes, and infections.[7]Females often have attacks coincident with their menstrual cycle, which can be managed effectively with hormonal birth control.[3]Because of the reducedpenetranceof HCP, family members of a patient may carry the same mutation without ever presenting with symptoms. Molecular analysis ofCPOXis the best way to identify these patients, as they will not express a biochemicalphenotypeon laboratory testing unless they are symptomatic. Identification of asymptomatic patients allows them to adjust their lifestyle to avoid common triggering factors.[2][7]

References[edit]

  1. ^abcdef"#121300 COPROPORPHYRIA, HEREDITARY; HCP".Johns Hopkins University.Retrieved2012-05-27.
  2. ^abcdeTortorelli, Silvia; Kloke, Karen M.; Raymond, Kimiyo M. (2010). "Disorders of Porphyrin Metabolism". In Dietzen, Dennis J; Bennett, Michael J.; Wong, Edward C. (eds.).Biochemical and Molecular Basis of Pediatric Disease(4th ed.). Washington, DC: AACC Press. pp. 307–324.ISBN978-1-59425-100-9.
  3. ^abcdefghLourenco, Charles Marquez; Lee, Chul; Anderson, Karl E. (2012). "Disorders of Haem Biosynthesis". In Saudubray, Jean-Marie; van den Berghe, Georges; Walter, John H. (eds.).Inborn Metabolic Diseases: Diagnosis and Treatment(5th ed.). New York: Springer. pp.521–532.ISBN978-3-642-15719-6.
  4. ^"Homo sapiens coproporphyrinogen oxidase, mRNA (cDNA clone MGC:19736 IMAGE:3607724), complete cds".US National Library of Medicine.Retrieved2012-05-27.
  5. ^Schmitt, C.; Gouya, L.; Malonova, E.; Lamoril, J.; Camadro, J. M.; Flamme, M.; Rose, C.; Lyoumi, S.; Da Silva, V.; Boileau, C.; Grandchamp, B.; Beaumont, C.; Deybach, J. C.; Puy, H. (2005)."Mutations in human CPO gene predict clinical expression of either hepatic hereditary coproporphyria or erythropoietic harderoporphyria".Human Molecular Genetics.14(20): 3089–3098.doi:10.1093/hmg/ddi342.PMID16159891.
  6. ^Hasanoglu, A.; Balwani, M.; Kasapkara, Ç. D. S.; Ezgü, F. S.; Okur, İ.; Tümer, L.; Cakmak, A.; Nazarenko, I.; Yu, C.; Clavero, S.; Bishop, D. F.; Desnick, R. J. (2010)."Harderoporphyria due to homozygosity for coproporphyrinogen oxidase missense mutation H327R".Journal of Inherited Metabolic Disease.34(1): 225–231.doi:10.1007/s10545-010-9237-9.PMC3091031.PMID21103937.
  7. ^abcdeAnderson, K. E.; Bloomer, J. R.; Bonkovsky, H. L.; Kushner, J. P.; Pierach, C. A.; Pimstone, N. R.; Desnick, R. J. (2005). "Recommendations for the diagnosis and treatment of the acute porphyrias".Annals of Internal Medicine.142(6): 439–450.doi:10.7326/0003-4819-142-6-200503150-00010.PMID15767622.S2CID36122555.
  8. ^Ratnaike, S.; Blake, D. (1995). "The diagnosis and follow-up of porphyria".Pathology.27(2): 142–153.doi:10.1080/00313029500169762.PMID7567142.S2CID46438357.
  9. ^"Tests for Porphyria Diagnosis".National Porphyria Foundation. Archived fromthe originalon 2014-03-20.Retrieved2012-05-28.

External links[edit]

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