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Last updated:
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NORD gratefully acknowledges Herbert Bonkovsky, MD, Adjunct Professor, Carolinas Medical Center, Cannon Research Center, and the American Porphyria Foundation, for assistance in the preparation of this report.
Summary
Variegate porphyria is a rare genetic metabolic disorder characterized by deficient function of the enzyme protoporphyrinogen oxidase (PPO or PPOX). This deficiency is caused by mutations in the PPOX gene, and leads to the accumulation of certain chemicals called porphyrins and porphyrin precursors in the body, which, in turn, can potentially result in a variety of symptoms. Specific symptoms can vary greatly from one person to another. Some affected individuals present with skin symptoms, some with neurological symptoms and some with both. Blistering and fragility of sun-exposed skin are the most common skin (cutaneous) symptoms. Common neurological symptoms include abdominal pain, nausea, vomiting, constipation, extremity pain and weakness, anxiety, restlessness and convulsions. Many different PPOX gene mutations have been identified in different families with variegate porphyria. The genetic mutation in a family is inherited as an autosomal dominant trait, but many individuals who inherit a PPOX gene mutation do not develop any symptoms (asymptomatic).
Introduction
Variegate porphyria is one of a group of disorders known as the porphyrias. The porphyrias are characterized by abnormally high levels of porphyrins or porphyrin precursors in the body. Each porphyria is due to a deficiency of a different enzyme. There are eight enzymes in the pathway for making heme, which is a part of hemoglobin and other hemoproteins. There are at least eight types of porphyria. The symptoms associated with the various types of porphyria differ, depending upon the specific enzyme that is deficient. It is important to note that people who have one type of porphyria do not develop any of the other types. Porphyrias are generally classified into two groups: the “hepatic” and “erythropoietic” types. Porphyrins and porphyrin precursors originate in excess amounts from the liver in the hepatic types, and mostly from the bone marrow in the erythropoietic types. Variegate porphyria is a hepatic form of porphyria.
Protoporphyrinogen and coproporphyrinogen accumulate in the liver in variegate porphyria because PPOX is deficient, and become oxidized to protoporphyrin and coproporphyrin, which are transported in the blood plasma and cause the skin to be sensitive to sunlight. The neurological symptoms are associated with accumulation of porphyrin precursors, namely, delta-aminolevulinic acid (ALA) and porphobilinogen (PBG).
The symptoms and severity of variegate porphyria can vary greatly from one person to another. Symptoms are rarely apparent before puberty. Affected individuals often develop skin (cutaneous) or neurological abnormalities or both. It is important to note that affected individuals may not have all of the symptoms discussed below. Affected individuals should talk to their physicians about their specific clinical situations, associated symptoms and overall prognosis.
Many individuals with variegate porphyria may not develop any notable symptoms (asymptomatic) for all or most of their lives. Other individuals can develop a variety of symptoms. Cutaneous symptoms, when they occur, are chronic and commonly last for months or years. Neurological symptoms usually occur as acute attacks lasting days or weeks and only occasionally become chronic. Acute attacks can be severe, and may occur in the absence of skin abnormalities.
Symptoms during an attack may include intense abdominal discomfort or pain, which is usually constant, lasting hours to days, but may be cramping. Nausea, vomiting, constipation (occasionally diarrhea) and trouble urinating may also occur during acute attacks. These symptoms are due to effects on the nerves of the bowel and bladder. The central nervous system is often affected with insomnia, restlessness, agitation, confusion, hallucinations and convulsions. The level of sodium in the blood may decrease and cause convulsions. The peripheral nerves are affected, leading to severe pain in the extremities, back or chest and, especially with more prolonged attacks, paralysis of muscles. This may progress to involve all extremities and the muscles that control breathing. The urine may be reddish due to increased porphyrins, and dark due to porphobilin, which is a brownish degradation product of PBG.
Increases in heart rate and blood pressure are very common on examination during attacks. Fever is usually absent or slight, because the neuropathy is not inflammatory. Reflexes may be increased initially and decreased or absent if motor neuropathy advances.
A variety of triggers are known to set off an acute attack. These include a variety of drugs, steroid hormones alcohol, decreased intake of calories or carbohydrates, and metabolic or possibly psychological stress. Women may have attacks during the second half of the menstrual cycle when progesterone levels are highest. In some cases, no trigger can be identified.
Chronic skin abnormalities result from photosensitivity, a condition in which the skin is abnormally sensitive to sunlight, causing blistering skin lesions. Symptoms include abnormally fragile skin, blisters (bullae), milia, which are tiny, white bumps or cysts, and excessive hair growth (hypertrichosis). Blisters are slow to heal and can scar leaving patches of skin that are abnormally dark (hyperpigmentation) or light (hypopigmentation). Skin symptoms may be less common in individuals who live in nontropical climates. Some individuals with variegate porphyria only develop skin abnormalities, others only develop neurological symptoms and some have both.
Individuals with variegate porphyria are at an increased risk for developing a form of liver cancer known as hepatocellular carcinoma. There is also risk of developing chronic kidney disease.
Variegate porphyria is caused by mutations of the PPOX gene. A PPOX mutation is inherited as an autosomal dominant trait within a family. Dominant genetic disorders occur when only a single copy of an altered gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the altered gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.
In some individuals, the disorder is due to a spontaneous (de novo) genetic mutation that occurs in the egg or sperm cell. In such situations, the disorder is not inherited from the parents.
The PPOX gene contains instructions for creating PPOX, one of the eight enzymes necessary for the production of heme. Heme is an iron-containing porphyrin (iron protoporphyrin) and is a part of many heme-containing proteins (hemoproteins) in the body. Hemoproteins interact with oxygen and some are involved in electron transport and energy metabolism. The best known hemoprotein is hemoglobin, which is made in the bone marrow, makes red blood cells red, and transports oxygen from the lungs to other tissues. However, the bone marrow and hemoglobin are not affected in variegate porphyria. In this condition the heme pathway in the liver, which makes heme for other important hemoproteins, is affected.
Mutations of the PPOX gene result in deficient levels of PPOX, which, in turn, disrupts the biochemical process to create heme in the liver. This disruption causes porphyrins and porphyrin precursors to accumulate in the liver and these are then transported to other parts of the body to affect the nervous system and skin.
A variety of different triggers are known to lead to attacks in individuals with variegate porphyria. Many of these triggers act by increasing heme synthesis in the liver, which makes the PPOX deficiency more significant and increases the accumulation of porphyrins and porphyrin precursors. As noted above, triggers include a variety of drugs, hormones (especially progesterone), reduced intake of calories and carbohydrate, alcohol, and stress induced by infection or other illness.
Some reports suggest that variegate porphyria affects more women than men. The incidence is estimated to occur in 1 in 100,000 individuals in the general population in European populations. The disorder occurs with the greatest frequency in South Africa in individuals of Dutch ancestry due to a founder effect. A founder effect is when a small isolated population of settlers (founders) expands over several generations leading to a high prevalence of a genetic trait. Most individuals with variegate porphyria in South Africa carry the same PPOX mutation and are descendants of a Dutch settler from the late 1600s. The incidence of variegate porphyria in South Africa among Caucasians is estimated to be 1 to 3 in 1,000 individuals.
Although, in most cases, the symptoms of variegate porphyria occur after puberty or later, very rare cases have been described where symptoms developed during infancy or childhood. Most such cases are homozygous cases who have inherited a PPOX mutation from each parent. Homozygous cases may have impaired mental development and photosensitivity, but acute attacks are not prominent.
A diagnosis of variegate porphyria is suspected based upon symptoms and examination of the skin. None of the symptoms are specific, so the diagnosis must be confirmed by biochemical testing. In the evaluation of neurological symptoms, the other acute porphyrias need to be considered. For initial screening, a spot urine sample should be obtained for measurement of PBG, ALA and total porphyrins. If none of these is elevated, acute porphyrias can be excluded as a cause of recent or concurrent symptoms. PBG measurement is most important and specific for acute porphyrias. However PBG and ALA may be less elevated and return to normal more quickly after an attack of variegate porphyria (or hereditary coproporphyria) than in acute intermittent porphyria. Therefore, measurement of total urine porphyrins is important, keeping in mind that an elevation of urine porphyrins can occur in many other medical conditions.
When blistering skin manifestations are present, porphyria cutanea tarda, hereditary coproporphyria and even congenital erythropoietic porphyria are possibilities to differentiate. Measurement of plasma and fecal porphyrins and determining the wavelength of the fluorescence peak of plasma porphyrins is useful in differentiating these conditions.
Molecular genetic testing to identify a PPOX mutation is recommended for all biochemically confirmed cases of variegate porphyria. Molecular testing is sometimes useful when symptoms have been absent for months or years and biochemical abnormalities are no longer present. Knowing the PPOX mutation is a family enables other family members to be tested reliably for the same mutation.
Treatment
The treatment of acute attacks of variegate porphyria is the same as for acute intermittent porphyria and hereditary coproporphyria. Hospitalization is usually indicated for pain control and treatment of other severe symptoms such as nausea and vomiting, electrolyte imbalances and convulsions. Monitoring for these manifestations as well and muscle weakness and respiratory embarrassment is also indicated in severe attacks. A narcotic analgesic is generally required for pain, and a phenothiazine, such as Compro (prochlorperazine) or Thorazine (chlorpromazine), or Zofran (ondansetron) for nausea and vomiting. Triggering factors should be identified and discontinued when possible. The American Porphyria Foundation’s website includes a database of safe and unsafe drugs (see Resources section of this report). Specific therapies are hemin for injection, which is available in the U.S. as Panhematin (lyophilized hematin), and glucose loading. Hemin represses the heme pathway in the liver and lowers ALA, PBG and porphyrins, and is associated with more rapid recovery from an attack. Glucose given intravenously has a similar effect, but because it is less potent is used only for mild attacks, or until hemin can be obtained from the manufacturer.
In 2019, the Food and Drug Administration (FDA) approved Givlaari (givosiran) for the treatment of acute hepatic porphyria, including variegate porphyria, in adult patients. Givlaari aims to prevent attacks from occurring.
Tagamet (cimetidine) has also been recommended based on little evidence and should not be used as a substitute for hemin or even glucose. Acute attacks are potentially life-threatening especially if not treated promptly, but most patients recover completely. Future attacks can be prevented by avoiding triggering factors. Frequent attacks that are cyclic can be prevented by administration of a GnRH analogue. Frequent noncyclic attacks are rare and can sometimes be prevented by prophylactic administration of hemin – perhaps a single dose weekly.
Chronic skin manifestations may improve if triggering factors are avoided. Hemin and glucose have not been found to be useful for this and other chronic symptoms. Treatments that are effective in porphyria cutanea tarda, namely phlebotomies and low-dose Plaquenil (hydroxychloroquine) or Aralen (chloroquine), are not useful in variegate porphyria because, even though the skin abnormalities are the same, the underlying abnormalities in the liver are very different. Avoidance of exposure to sunlight is important and may lead to gradual improvement. The use of appropriate clothing (e.g., hats, long sleeved shirts) and opaque sunscreen products can be beneficial (regular sunscreen products are generally ineffective). More specific information on these preventive measures is available from the American Porphyria Foundation (see Resources section of this report).
Individuals with variegate porphyria should carry Medic Alert bracelets or wallet cards. Individuals may also carry a list of drugs that they need to avoid, but such lists may not be up to date and it is best to refer to the American Porphyria Foundation’s website when needed. Genetic counseling may be of benefit for affected individuals and their families.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov . All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov
Some current clinical trials also are posted on the following page on the NORD website: https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, in the main, contact: www.centerwatch.com
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
Study information is also posted at the Porphyrias Consortium website:
https://rarediseasesnetwork.epi.usf.edu/porphyrias/index.htm
TEXTBOOKS
Bonkovsky HL, Hou W, Li T, Guo J-T, Narang T, Thapar M. Porphyrin and heme metabolism and the porphyrias. In Wolkoff A, Lu S, and Omary B (Eds). Comprehensive Physiology, 3:365-401, 2013. [The American Physiological Society, Bethesda, MD, Wiley and Co] [PMID: 23720291]
Phillips JD, Anderson KE. The porphyrias (Chapter 57). In: Kaushansky K, Lichtman MA, Beutler E, Kipps TJ, Seligson U, Prchal JT, eds. Williams Hematology, 8th edition. New York: McGraw-Hill 2010: 839-863.
Desnick RJ, Astrin KH, Anderson KE. Inherited porphyrias (Chapter 104). In: Rimoin DL, Conner JM, Pyeritz RE, Korf, BR, eds. Emery and Rimoin’s Principles and Practice of Medical Genetics, 5th edition. Edinburgh: Churchill Livingston, 2007, pp 2331-2358.
JOURNAL ARTICLES
Bonkovsky HL, Maddukuri V, Yazici C, Anderson K, Bissell DM, Bloomer JR, Phillips J, Peter I, Baillargeon G, Bossi K, Gandolfo L, Light C, Bishop D, Desnick RJ. Acute porphyrias in the USA: features of 108 subjects from porphyria consortium. American Am J Med. 2014 Dec;127(12):1233-41. https://www.ncbi.nlm.nih.gov/pubmed/25016127
Whatley SD, Mason NG, Woolf JR, et al. Diagnostic strategies for autosomal dominant acute porphyrias: retrospective analysis of 467 unrelated patients referred for mutational analysis of the HMBS, CPOX or PPOX gene. Clin Chem. 2009;55:1406-1414.
Anderson KE, Bloomer JR, Bonkovsky HL, Kushner JP, Pierach CA, Pimstone NR, Desnick RJ: Recommendations for the diagnosis and treatment of the acute porphyrias. Annals of Internal Medicine 2005;142:439-50.
Whatley SD, Puy H, Morgan RR, et al. Variegate porphyria in Western Europe: identification of PPOX gene mutations in 104 families, extent of allelic heterogeneity, and absence of correlation between phenotype and type of mutation. Am J Hum Genet. 1999;65:984-994.
Kirsch RE, Meissner PN, Hift RJ. Variegate porphyria. Semin Liver Dis. 1998;18:33-41.
INTERNET
Poh-Fitzpatrick MB. Variegate Porphyria.Medscape. Updated: Apr 15, 2016. Available at: https://emedicine.medscape.com/article/1103846-overview Accessed April 19, 2017.
National Digestive Diseases Clearinghouse. Porphyria. February 2014. Available at: https://digestive.niddk.nih.gov/ddiseases/pubs/porphyria/ Accessed April 19, 2017.
Deybach JC. Porphyria Variegata. Orphanet encyclopedia. February 2009. Available at: https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=79473 Accessed April 19, 2017.
McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:176200; Last Update: 08/26/2016. Available at: https://www.ncbi.nlm.nih.gov/omim/176200 Accessed April 19, 2017.
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