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Last updated: 9/17/2024
Years published: 1987, 1988, 1990, 1991, 1993, 1996, 1997, 2001, 2010, 2013, 2017, 2024
NORD gratefully acknowledges Gioconda Alyea, MD (FMG), MS, National Organization for Rare Disorders and 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 changes (variants) 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 have 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 variants have been identified in different families with variegate porphyria. The gene variant in a family is inherited in an autosomal dominant pattern, but many individuals who inherit a PPOX gene variant do not develop any symptoms (asymptomatic).
Introduction
Variegate porphyria is one of a group of disorders known as 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 โhepaticโ and โerythropoieticโ 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).
Acute attacks of variegate porphyria often require hospitalization for managing symptoms like severe pain, nausea, and vomiting. Strong pain medications and drugs to control nausea are commonly used. Doctors also monitor for muscle weakness and breathing issues. Identifying and stopping any triggers, like unsafe medications, is important for recovery.
The symptoms and severity of variegate porphyria can vary greatly between affected people. It is important to understand that not everyone with this condition will experience all the symptoms listed below. Some people may remain symptom-free for most of their lives, while others may develop a combination of skin and neurological issues. Symptoms are rare before puberty. Here is a breakdown of the potential symptoms:
Many people with variegate porphyria never develop noticeable symptoms throughout their lives.
Symptoms can affect the skin (chronic) or the nervous system (acute), or both.
Acute neurological attacks
These attacks can be severe and occur without skin symptoms. Common symptoms during an attack include:
Several factors can trigger acute attacks, including:
In some people, no specific trigger can be identified.
Chronic skin symptoms
These are due to photosensitivity, where the skin is overly sensitive to sunlight. Symptoms include:
Skin symptoms may be less common in individuals living in non-tropical climates.
People affected with variegate porphyria have an increased risk of developing:
Variegate porphyria is caused by changes (pathogenic variants) of the PPOX gene. The PPOX gene contains instructions for creating PPOX, one of the eight enzymes necessary to produce 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, 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.
Variants 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 factors 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.
A PPOX variant is inherited in an autosomal dominant pattern within a family. Dominant genetic disorders occur when only a single copy of a disease-causing gene variant is necessary to cause the disease. The gene variant can be inherited from either parent or can be the result of a new (de novo) changed gene in the affected individual that is not inherited. The risk of passing the gene variant from an affected parent to a child is 50% for each pregnancy. The risk is the same for males and females.
Some reports suggest that variegate porphyria affects more females than males. 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 variant 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.
According to the American Porphyria Foundation, taken together, all forms of Porphyria afflict fewer than 200,000 people in the United States.
Although, in most cases, the symptoms of variegate porphyria occur after puberty or later, very rare patients have been described where symptoms developed during infancy or childhood. Most such patients inherited a PPOX variant from each parent. These patients 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 variant 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 variant is a family enables other family members to be tested reliably for the same variant.
Treatment
Treatment is specific to the type of porphyria; however, the basic defect cannot presently be treated, but significant effort is being directed toward treating the underlying mechanisms that cause symptoms. The acute attacks in variegate porphyria are treated like the acute attacks seen in other forms of porphyria. When experiencing an acute porphyria attack, itโs important to start with conservative (non-invasive) treatment before moving to more aggressive options like heme infusion (adding heme or glucose directly into a vein). It works by blocking the formation of aminolevulinic acid synthase, which limits the formation of porphyrin in the liver and marrow. The duration of this first-line treatment depends on the condition and how well the affected person is responding. If the symptoms worsen, immediate treatment with a heme infusion is necessary to prevent nerve damage.
The first steps of the treatment are:
If these steps donโt help, an intravenous (IV) heme infusion, like Panhematin, is recommended for 3-14 days. Heme infusions are important because they prevent porphyria attacks from worsening and causing permanent nerve damage. In the U.S., Panhematin is the FDA approved treatment, but a similar medication, heme arginate (Normosang), is used in Europe and South Africa.
While receiving heme treatment, doctors may monitor certain chemicals in the urine (such as ALA, PBG and porphyrins) to see if the treatment is working.
Itโs crucial that the doctor follows the right dosage guidelines, as giving too much heme in a single dose can cause temporary kidney problems, though normal doses are generally safe.
If seizures occur during an attack, controlling them can be complicated because many anti-seizure medications are processed by the liver and can make the attack worse. The following treatments are generally safe for seizures during porphyria:
Doctors will also check for any imbalances in the bodyโs electrolytes, which can cause or worsen seizures.
For long-term seizure control, medications like gabapentin may be preferred because they are not metabolized by the liver.
In 2019, the FDA approved Givlaari (givosiran), a medication designed to prevent porphyria attacks. Givlaari works by reducing levels of a liver enzyme that triggers these attacks and has been shown to reduce the frequency of attacks by 74% in clinical trials.
Hospitalization is often necessary for managing severe symptoms of an acute attack, such as:
If the attack is mild, IV glucose may help, as it works similarly to heme but is less potent. However, glucose is only a temporary solution until heme can be administered.
After an acute attack, itโs important to avoid anything that might trigger future episodes. Common triggers include certain medications, stress, or fasting. The American Porphyria Foundation provides a list of drugs that are safe or unsafe for individuals with porphyria. Itโs a good idea for patients to wear a Medic Alert bracelet or carry a wallet card that lists the condition and any medications you need to avoid.
For those who have frequent attacks, there are preventive treatments:
People with variegate porphyria who have chronic skin symptoms should avoid exposure to sunlight to help prevent flare-ups. Wearing protective clothing (like hats and long-sleeved shirts) and using opaque sunscreen can reduce skin damage. Traditional sunscreens may not be effective, so itโs important to choose products specifically designed for porphyria patients. Iron supplementation is likely to cause a skin flare-up and should preferably be administered in the vein.
Since porphyria is hereditary, genetic counseling can help the patient and their families to understand the condition and how it may affect future generations.
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: [email protected]
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
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
National Digestive Diseases Clearinghouse. Porphyria. July 2020. Available at: https://www.niddk.nih.gov/health-information/liver-disease/porphyria Accessed Sept 16, 2024.
Deybach JC. Porphyria Variegata. Orphanet. March 2024. Available at: https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=79473 Accessed Sept 16, 2024.
McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:176200; Last Update: 09/11/2023. Available at: https://www.ncbi.nlm.nih.gov/omim/176200 Accessed Sept 16, 2024.
Fyre RE. Acute Porphyria Treatment & Management. Medscape Reference. August 17, 2022. https://emedicine.medscape.com/article/957604-treatment Accessed Sept 16, 2024.
About Porphyria. For Patients. American Porphyria Foundation. https://porphyriafoundation.org/for-patients/about-porphyria/ Accessed Sept 16, 2024.
NORD strives to open new assistance programs as funding allows. If we donโt have a program for you now, please continue to check back with us.
NORD and MedicAlert Foundation have teamed up on a new program to provide protection to rare disease patients in emergency situations.
Learn more https://rarediseases.org/patient-assistance-programs/medicalert-assistance-program/Ensuring that patients and caregivers are armed with the tools they need to live their best lives while managing their rare condition is a vital part of NORDโs mission.
Learn more https://rarediseases.org/patient-assistance-programs/rare-disease-educational-support/This first-of-its-kind assistance program is designed for caregivers of a child or adult diagnosed with a rare disorder.
Learn more https://rarediseases.org/patient-assistance-programs/caregiver-respite/The information provided on this page is for informational purposes only. The National Organization for Rare Disorders (NORD) does not endorse the information presented. The content has been gathered in partnership with the MONDO Disease Ontology. Please consult with a healthcare professional for medical advice and treatment.
The Genetic and Rare Diseases Information Center (GARD) has information and resources for patients, caregivers, and families that may be helpful before and after diagnosis of this condition. GARD is a program of the National Center for Advancing Translational Sciences (NCATS), part of the National Institutes of Health (NIH).
View reportOrphanet has a summary about this condition that may include information on the diagnosis, care, and treatment as well as other resources. Some of the information and resources are available in languages other than English. The summary may include medical terms, so we encourage you to share and discuss this information with your doctor. Orphanet is the French National Institute for Health and Medical Research and the Health Programme of the European Union.
View reportOnline Mendelian Inheritance In Man (OMIM) has a summary of published research about this condition and includes references from the medical literature. The summary contains medical and scientific terms, so we encourage you to share and discuss this information with your doctor. OMIM is authored and edited at the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine.
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