Hereditary coproporphyria

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Hereditary coproporphyria
Coproporphyrinogen III.svg
Coproporphyrinogen III
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Hereditary coproporphyria (HCP) is a disorder of heme biosynthesis, classified as an acute hepatic porphyria. [1] HCP is caused by a deficiency of the enzyme coproporphyrinogen oxidase, coded for by the CPOX gene, and is inherited in an autosomal dominant fashion, although homozygous individuals have been identified. Unlike acute intermittent porphyria, individuals with HCP can present with cutaneous findings similar to those found in porphyria cutanea tarda in 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 reduced penetrance.

Contents

Signs and symptoms

Clinically, patients affected with HCP present similarly to those with other acute porphyrias, such as acute intermittent porphyria (AIP) and variegate 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, hypertension and seizures, as well as the cutaneous findings seen in porphyria 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 for CPOX mutations can present with these findings at an earlier age than heterozygotes. [1]

Genetics

HCP is caused by mutations in CPOX, which codes for the enzyme coproporphyrinogen oxidase. This enzyme is responsible for the sixth step in the heme biosynthetic pathway, converting coproporphyrinogen III to protoporphyrinogen IX. [3] CPOX is located at 3q11.2-q12.1, [1] has 6 introns and 7 exons and produces an mRNA strand that is 2675 bases in length. [4] It is inherited in an autosomal dominant fashion, meaning that a deficiency of 50% of the normal enzyme activity is enough to cause symptoms. [3] As reproductive fitness is not impacted, homozygous affected individuals have been reported. [1] Along with other acute porphyrias HCP demonstrates reduced penetrance, 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 a null allele in CPOX have a more severe erythropoietic porphyria, harderoporphyria, [5] characterized by neonatal jaundice, 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 reduced penetrance of 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

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 urine porphobilinogen is 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, including blood, urine and stool tests. 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 using high performance liquid chromatography with fluorescence detection. [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 poisoning and certain bone marrow disorders. [9]

Treatment

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. Intravenous hemin (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. Gabapentin and levetiracetam are two anti-seizure drugs that are thought to be safe. [3]

In patients where management of symptoms is difficult even with hemin, liver transplant is an option before the symptoms have progressed to advanced paralysis. Combined liver and kidney transplants are sometimes undertaken in people with kidney 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 reduced penetrance of HCP, family members of a patient may carry the same mutation without ever presenting with symptoms. Molecular analysis of CPOX is the best way to identify these patients, as they will not express a biochemical phenotype on laboratory testing unless they are symptomatic. Identification of asymptomatic patients allows them to adjust their lifestyle to avoid common triggering factors. [2] [7]

Related Research Articles

Porphyria Group of inherited metabolic disorders

Porphyria is a group of liver disorders in which substances called porphyrins build up in the body, negatively affecting the skin or nervous system. The types that affect the nervous system are also known as acute porphyria, as symptoms are rapid in onset and short in duration. Symptoms of an attack include abdominal pain, chest pain, vomiting, confusion, constipation, fever, high blood pressure, and high heart rate. The attacks usually last for days to weeks. Complications may include paralysis, low blood sodium levels, and seizures. Attacks may be triggered by alcohol, smoking, hormonal changes, fasting, stress, or certain medications. If the skin is affected, blisters or itching may occur with sunlight exposure.

Heme Chemical coordination complex of an iron ion chelated to a porphyrin

Heme, or haem, is a precursor to hemoglobin, which is necessary to bind oxygen in the bloodstream. Heme is biosynthesized in both the bone marrow and the liver.

Variegate porphyria Medical condition

Variegate porphyria, also known by several other names, is an autosomal dominant porphyria that can have acute symptoms along with symptoms that affect the skin. The disorder results from low levels of the enzyme responsible for the seventh step in heme production. Heme is a vital molecule for all of the body's organs. It is a component of hemoglobin, the molecule that carries oxygen in the blood.

Porphyria cutanea tarda Medical condition

Porphyria cutanea tarda is the most common subtype of porphyria. The disease is named because it is a porphyria that often presents with skin manifestations later in life. The disorder results from low levels of the enzyme responsible for the fifth step in heme production. Heme is a vital molecule for all of the body's organs. It is a component of hemoglobin, the molecule that carries oxygen in the blood.

Erythropoietic protoporphyria Medical condition

Erythropoietic protoporphyria is a form of porphyria, which varies in severity and can be very painful. It arises from a deficiency in the enzyme ferrochelatase, leading to abnormally high levels of protoporphyrin in the red blood cells (erythrocytes), plasma, skin, and liver. The severity varies significantly from individual to individual.

Iron overload Human disease

Iron overload or haemochromatosis indicates accumulation of iron in the body from any cause. The most important causes are hereditary haemochromatosis (HHC), a genetic disorder, and transfusional iron overload, which can result from repeated blood transfusions.

Aminolevulinic acid synthase Class of enzymes

Aminolevulinic acid synthase (ALA synthase, ALAS, or delta-aminolevulinic acid synthase) is an enzyme (EC 2.3.1.37) that catalyzes the synthesis of δ-aminolevulinic acid (ALA) the first common precursor in the biosynthesis of all tetrapyrroles such as hemes, cobalamins and chlorophylls. The reaction is as follows:

Dysuria refers to painful or difficult urination.

Gunther disease Medical condition

Gunther disease, is a congenital form of erythropoietic porphyria. The word porphyria originated from the Greek word porphura. Porphura actually means "purple pigment", which, in suggestion, the color that the body fluid changes when a person has Gunther's disease. It is a rare, autosomal recessive metabolic disorder affecting heme, caused by deficiency of the enzyme uroporphyrinogen cosynthetase. It is extremely rare, with a prevalence estimated at 1 in 1,000,000 or less. There have been times that prior to birth of a fetus, Gunther's disease has been shown to lead to anemia. In milder cases patients have not presented any symptoms until they have reached adulthood. In Gunther's disease, porphyrins are accumulated in the teeth and bones and an increased amount are seen in the plasma, bone marrow, feces, red blood cells, and urine.

Menkes disease X-linked recessive copper-transport disorder

Menkes disease (MNK), also known as Menkes syndrome, is an X-linked recessive disorder caused by mutations in genes coding for the copper-transport protein ATP7A, leading to copper deficiency. Characteristic findings include kinky hair, growth failure, and nervous system deterioration. Like all X-linked recessive conditions, Menkes disease is more common in males than in females. The disorder was first described by John Hans Menkes in 1962.

Inborn errors of metabolism form a large class of genetic diseases involving congenital disorders of enzyme activities. The majority are due to defects of single genes that code for enzymes that facilitate conversion of various substances (substrates) into others (products). In most of the disorders, problems arise due to accumulation of substances which are toxic or interfere with normal function, or due to the effects of reduced ability to synthesize essential compounds. Inborn errors of metabolism are now often referred to as congenital metabolic diseases or inherited metabolic disorders. To this concept it's possible to include the new term of Enzymopathy. This term was created following the study of Biodynamic Enzymology, a science based on the study of the enzymes and their derivated products. Finally, inborn errors of metabolism were studied for the first time by British physician Archibald Garrod (1857–1936), in 1908. He is known for work that prefigured the "one gene-one enzyme" hypothesis, based on his studies on the nature and inheritance of alkaptonuria. His seminal text, Inborn Errors of Metabolism, was published in 1923.

Acute intermittent porphyria Medical condition

Acute intermittent porphyria (AIP) is a rare metabolic disorder affecting the production of heme resulting from a deficiency of the porphobilinogen deaminase. It is the most common of the acute porphyrias.

Polymorphous light eruption Medical condition

Polymorphous light eruption (PLE), sometimes also called polymorphic light eruption (PMLE), is a non-life-threatening and potentially distressing skin condition that is triggered by sunlight and artificial UV exposure in a genetically susceptible person, particularly in temperate climates during the spring and early summer. Due to its many clinical appearances, it is named polymorphic or polymorphous and the terms are used interchangeably. The resulting itch can cause significant suffering.

Protoporphyrinogen oxidase

Protoporphyrinogen oxidase or protox is an enzyme that in humans is encoded by the PPOX gene.

Coproporphyrinogen III oxidase

Coproporphyrinogen-III oxidase, mitochondrial is an enzyme that in humans is encoded by the CPOX gene. A genetic defect in the enzyme results in a reduced production of heme in animals. The medical condition associated with this enzyme defect is called hereditary coproporphyria.

Hemin

Hemin is an iron-containing porphyrin with chlorine that can be formed from a heme group, such as heme B found in the hemoglobin of human blood.

Urbach–Wiethe disease Rare recessive genetic disorder

Urbach–Wiethe disease is a very rare recessive genetic disorder, with approximately 400 reported cases since its discovery. It was first officially reported in 1929 by Erich Urbach and Camillo Wiethe, although cases may be recognized dating back as early as 1908.

Aminolevulinic acid dehydratase deficiency porphyria Medical condition

Aminolevulinic acid dehydratase deficiency porphyria is a rare autosomal recessive metabolic disorder that results from inappropriately low levels of the enzyme delta-aminolevulinic acid dehydratase (ALAD), which is required for normal heme synthesis. This deficiency results in the accumulation of a toxic metabolic precursor in the heme synthesis pathway called aminolevulinic acid (ALA). Lead poisoning can also disrupt ALAD and result in elevated ALA causing the same symptoms. Heme is a component of hemoglobin which carries oxygen in red blood cells.

Harderoporphyria Medical condition

Harderoporphyria is a rare disorder of heme biosynthesis, inherited in an autosomal recessive manner caused by specific mutations in the CPOX gene. Mutations in CPOX usually cause hereditary coproporphyria, an acute hepatic porphyria, however the K404E mutation in a homozygous or compound heterozygous state with a null allele cause the more severe harderoporphyria. Harderoporphyria is the first known metabolic disorder where the disease phenotype depended on the type and location of the mutations in a gene associated with multiple disorders.

Tyrosinemia type I Medical condition

Tyrosinemia type I is a genetic disorder that disrupts the metabolism of the amino acid tyrosine, resulting in damage primarily to the liver along with the kidneys and peripheral nerves. The inability of cells to process tyrosine can lead to chronic liver damage ending in liver failure, as well as renal disease and rickets. Symptoms such as poor growth and enlarged liver are associated with the clinical presentation of the disease. Clinical manifestation of disease occurs typically within the first two years of life. The severity of the disease is correlated with the timing of onset of symptoms, earlier being more severe.

References

  1. 1 2 3 4 5 6 "#121300 COPROPORPHYRIA, HEREDITARY; HCP". Johns Hopkins University. Retrieved 2012-05-27.
  2. 1 2 3 4 5 Tortorelli, 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. ISBN   978-1-59425-100-9.
  3. 1 2 3 4 5 6 7 8 Lourenco, 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. ISBN   978-3-642-15719-6.
  4. ↑ "Homo sapiens coproporphyrinogen oxidase, mRNA (cDNA clone MGC:19736 IMAGE:3607724), complete cds". US National Library of Medicine. Retrieved 2012-05-27.
  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 . PMID   16159891.
  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. PMC   3091031 . PMID   21103937.
  7. 1 2 3 4 5 Anderson, 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. PMID   15767622. S2CID   36122555.
  8. ↑ Ratnaike, S.; Blake, D. (1995). "The diagnosis and follow-up of porphyria". Pathology. 27 (2): 142–153. doi:10.1080/00313029500169762. PMID   7567142. S2CID   46438357.
  9. ↑ "Tests for Porphyria Diagnosis". National Porphyria Foundation. Archived from the original on 2014-03-20. Retrieved 2012-05-28.
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