Erythropoietic Protoporphyria (EPP) or Protoporphyria
Erythropoietic Protoporphyria is characterized by abnormally elevated levels of protoporphyrin IX in erythrocytes (red blood cells) and plasma (the fluid portion of circulating blood), and by sensitivity to visible light that is usually noticed in early childhood and occurs throughout life. EPP can result either from mutations of the ferrochelatase gene (FECH), or less commonly the delta-aminolevulinic acid synthase-2 gene (ALAS2). When EPP is due to an ALAS2 mutation it is termed X-linked protoporphyria (XLP), because that gene is found on the X chromosome.
Protoporphyrin accumulates first in the bone marrow in EPP, and then in red blood cells, plasma and sometimes the liver. Protoporphyrin is excreted by the liver into the bile, after which it enters the intestine and is excreted in the feces. It is not soluble in water so is not excreted in the urine.
EPP is the third most common type of porphyria, and the most common in childhood. It causes very painful photosensitivity and can greatly impair quality of life. Delay in diagnosis is greater than with any other type of porphyria.
Swelling, burning, itching, and redness of the skin may appear during or after exposure to sunlight, including sunlight that passes through window glass. This can cause mild to severe burning pain on sun-exposed areas of the skin. Usually, these symptoms subside in 12 to 24 hours and heal without significant scarring. Blistering and scarring are characteristic of other types of cutaneous porphyria but are unusual in EPP. Skin manifestations generally begin early childhood and are more severe in the summer.
There is an increased risk of gallstones, which contain protoporphyrin. Excess protoporphyrin can also cause liver damage. Less than 5% of EPP patients’ severe liver damage and a condition caused protoporphyric hepatopathy that sometimes requires liver transplantation.
Diagnosis and Genetic Counseling
EPP should be suspected in anyone with non-blistering photosensitivity especially when it is prolonged and beginning in childhood. It is easy to make a diagnosis, or rule it out, once it is suspected.
The diagnosis of EPP is established by finding an abnormally high level of total erythrocyte protoporphyrin, and showing that this increase is mostly free protoporphyrin rather than zinc protoporphyrin. There is considerable confusion about which test to order. Sometimes laboratories have measured only zinc protoporphyrin and reported results incorrectly as “protoporphyrin” or “free erythrocyte protoporphyrin (FEP)”. Laboratories that measure total erythrocyte protoporphyrin, free protoporphyrin and zinc protoporphyrin and report results reliably are:
- Porphyria Laboratory and Center, University of Texas Medical Branch at Galveston, 1-409-772-4661
- Mayo Medical Laboratories, 1-800-533-1710
Porphyrins are almost always elevated in plasma in EPP, but may be normal in mild cases. Fecal porphyrins may be normal or increased.
An experienced biochemical laboratory can usually distinguish between patients with EPP and XLP, because the former have much less zinc protoporphyrin in their erythrocytes. This can be explained because in the marrow the enzyme ferrochelatase not only normally makes heme (iron protoporphyrin) from protoporphyrin and iron, but can also make zinc protoporphyrin, especially when excess protoporphyrin is present or iron is deficient. However, this does not replace DNA studies.
Rarely, EPP develops in adults in the presence of a bone marrow disorder such as polycythemia vera, and is due to expansion of a clone of red blood cell precursors in the marrow that is deficient in ferrochelase.
DNA studies are important for confirming the diagnosis of EPP and XLP and for genetic counseling. This should be completed first in a person known to have the disease, and the information about the mutations in that individual used to guide testing of family members.
When EPP is due to a FECH mutation the inheritance is described as autosomal recessive. It is most common to find that one severe mutation is inherited from one parent and another weak mutation inherited from the other parent. The weak mutation is quite common in normal Caucasians, rare in Blacks and even more common in Japanese and Chinese populations. This mutation is sometime referred to as “hypomorphic” because it results in formation of a less than normal amount of ferrochelatase. But is does not cause EPP unless it is paired with a severe mutation. The severe mutation is characteristic for an EPP family and is present in all affected individuals. “Carriers” of the severe mutation are not affected because they do not have the weak mutation. Affected individuals and unaffected carriers can transmit the severe mutation to the next generation. Some of their children will have EPP if the other parent has a copy of the weak mutation. Rarely, the weak mutation is absent in an EPP family and two severe mutations are found, with at least one producing some ferrochelatase.
In XLP, mutations of the ALAS2 gene, which is found on the X chromosome, causes an increase in the production of the enzyme ALAS2 in the bone marrow. Several of these “gain of function” mutations have been described in different XLP families. In XLP protoporphyrin production exceeds that needed for heme and hemoglobin formation. Like hemophilia and other X linked genetic diseases, XLP is more common in men. Women have two X chromosomes and are usually not affected because they have a normal as well as a mutated ALAS2 gene. Men have only one X chromosome and will be affected if they inherit an ALAS2 mutation. Women with an ALAS2 mutation will, on average, pass that mutation to half of their daughters (who will usually be unaffected carriers) and to half of their sons (who will be affected).
Treatment and Management
1. Sunlight protection
Protection from sunlight is the mainstay of management of EPP, and this is necessary throughout life. Disease severity and porphyrin levels in erythrocytes and plasma probably remain high and relatively constant throughout life in EPP. However, this has been little studied and more longitudinal observations are needed. Life style, employment, travel and recreation require adjustment in order to avoid painful reactions to sunlight and even from exposure to fluorescent lighting. For these reasons EPP can substantially affect quality of life.
Protective clothing, including broad-brimmed hats, long sleeves, gloves and trousers (rather than shorts), is beneficial. Several manufacturers specialize on clothing made of closely woven fabrics for people with photosensitivity.
2. Other considerations
In an occasional patient, protoporphyrin causes liver problems, so monitoring liver function is important. EPP patients should also not use any drug or anesthetic which causes cholestasis (slowing down bile flow), and should also avoid alcohol. Women should avoid medications containing estrogen (birth-control pills, hormone replacement therapy), and men should avoid testosterone supplements, as these substances can also have deleterious effects on the liver of a person with EPP.
Consult a specialist. Because EPP is a rare condition, most physicians are not knowledgeable about it. Contact The American Porphyria Foundation, 713-266-9617 for contact with an expert and to provide further information. A Medic Alert bracelet with instructions to contact a specialist if needed is a worthwhile precaution.
Yearly monitoring. Testing to include erythrocyte total protoporphyrin, plasma porphyrin, complete blood counts, ferritin and liver function tests should be done yearly. Porphyry levels are expected to be stable and liver tests to remain normal. EPP patients may have evidence of iron deficiency, and an iron supplement may be advisable if the serum ferritin is below about 20 ng/mL.
Vitamin D. Because they avoid sunlight, EPP patients are likely to be deficient in vitamin D. A vitamin D supplement with calcium is recommended for bone health.
Liver protection. It is important to avoid other causes of liver disease that might promote the development of liver complications from EPP. Patients should avoid alcohol and other substances that might damage the liver, including many herbal preparations, and be vaccinated for hepatitis A and B.
Surgical lights. Strong operating room lights can cause photosensitivity of the skin and even surfaces of internal organs. Flexible membrane filters, such as CL5-200-X from Madico Co., are available to cover surgical lights and offer some protection. This is especially important in EPP patients with liver failure, which causes even greater increases in protoporphyrin levels and photosensitivity.
Drugs. Drugs that are harmful in other porphyrias are not known to make EPP worse, but are best avoided as a precaution. This may include estrogens and other drugs that might reduce bile formation. A short course of a non-steroidal anti-inflammatory drug can provide some pain relief after an episode of photosensitivity, but can cause ulcerations of the digestive track especially with prolonged use.
Laser treatment. According to Dr. Roth, laser treatments for hair removal or eye surgery have not been a problem in EPP people. But the doctor should be made aware of the diagnosis, and that laser output between 400 and 650 nanometers might be harmful. Before hair removal treatment, the doctor may irradiate a small area of the skin to be treated for the length of time it will take to do the hair removal to ascertain if the patient would react within the period of time that a reaction to sunlight would be expected in that patient.
Children with EPP. Avoiding sunlight can be difficult for children with EPP who have less sunlight tolerance than their friends. Camp Discovery is an option for such children. It provides a week-long summer camping experience of fishing, boating, swimming, water skiing, arts and crafts, and just plain fun for young people with skin disorders, and is sponsored by the American Academy of Dermatology. Full scholarships, including transportation, are provided by the American Academy of Dermatology through generous donations of their members and other organizations. Members of the Academy are asked to recommend candidates for Camp Discovery, so ask your child's doctor about sending your child to Camp Discovery.
Disneyland and Disney World are responsive to people with sun sensitivity. They will provide a pass to enable you to enter attractions without waiting in line in the sun.
Go to "Town Hall" and explain your problem with photosensitivity. You should bring a physician's letter with you as well as an APF brochure explaining the type of Porphyria you have. The staff will ask you some questions about your limitations (e.g., whether or not you can climb stairs) and how many are in your group. Next time you return, be sure to bring the old card with you, as it will only take about half as long to go through the process on your next trip.
Proceed to the "Guest Relations" office at any park (Magic Kingdom, EPCOT, etc.) and request the Special Assistance Pass.
Remember to bring a doctor's note and explanation of your condition, because it is not necessarily visible. People on duty may not be familiar with light sensitivity and its consequences.
Patients with EPP and XLP can participate in the research through the Porphyrias Consortium. The American Porphyria Foundation has information on what research protocols are currently open.
The Porphyrias Consortium is conducting a Longitudinal Study to better define the natural history of the disease. This study is currently open for enrollment of new patients.
The Porphyrias Consortium will be starting a pilot study soon on a drug that may lower porphyrin levels in EPP.
Clinuvel Pharmaceuticals is developing afamelanotide (Scenesse®) for the treatment of EPP. This drug is given by injection and increases skin pigmentation. Another study of this drug is expected to open within the next year.
All patients with porphyria are encouraged to enter the Porphyrias Registry at the Porphyrias Consortium website. A link to this website is found on the website of the American Porphyria Foundation. Registration demonstrates to NIH that patients and their families think that research on porphyrias is important. You can also ask that one of the 6 porphyria center in the Consortium contact you.
Additional Reading about EPP and below that is more info on XLP:
NORD gratefully acknowledges Micheline M. Mathews-Roth, MD, Associate Professor of Medicine, Harvard Medical School, for assistance in the preparation of this report.
Synonyms of Erythropoietic Protoporphyria
- Erythrohepatic Protoporphyria
Erythropoietic protoporphyria (EPP) is a rare inherited metabolic disorder characterized by a deficiency of the enzyme ferrochelatase (FECH). Due to abnormally low levels of this enzyme, excessive amounts of protoporphyrin accumulate in the bone marrow, blood plasma, and red blood cells. The major symptom of this disorder is hypersensitivity of the skin to sunlight and some types of artificial light, such as fluorescent lights (photosensitivity). After exposure to light, the skin may become itchy and red. Affected individuals may also experience a burning sensation on their skin. The hands, arms, and face are the most commonly affected areas. Some people with erythropoietic protoporphyria may also have complications related to liver and gallbladder function. Erythropoietic protoporphyria is inherited as an autosomal dominant genetic trait with poor penetrance.
Erythropoietic protoporphyria is one of a group of disorders known as the porphyrias. The porphyrias are all characterized by abnormally high levels of particular chemicals (porphyrins) in the body due to deficiencies of certain enzymes essential to the synthesis of hemoglobin. There are at least seven 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.
Signs & Symptoms
The most common symptom of erythropoietic protoporphyria is hypersensitivity of the skin to sunlight and some types of artificial light (photosensitivity), with pain, itching, and/or burning of the skin occurring after exposure to sunlight and occasionally to fluorescent light. Affected individuals may also exhibit abnormal accumulations of body fluid under affected areas (edema) and/or persistent redness or inflammation of the skin (erythema). In rare cases, affected areas of the skin may develop sac-like lesions (vesicles or bullae), scar, and/or become discolored (hyperpigmentation) if exposure to sunlight is prolonged. However, scarring and/or discoloring of the skin is uncommon and rarely severe. These affected areas of skin may become abnormally thick. In addition, in some cases, affected individuals may also exhibit malformations of the nails. The severity and degree of photosensitivity is different from case to case. Photosensitivity is often seen during infancy; however, in some cases, it may not occur until adolescence or adulthood.
In some affected individuals, the flow of bile through the gallbladder and bile ducts (biliary system) may be interrupted (cholestasis) causing gallstones (cholelithiasis) to form. In turn, such stones can cause obstruction and/or inflammation of the gallbladder (cholecystitis). Rarely, affected individuals may also develop liver damage that, in very severe cases, may lead to liver failure requiring transplantation.
Symptoms usually start in childhood but diagnosis is often delayed since blistering is not common and, because the porphyrins are insoluble, they usually escape detection on urinanalysis. The diagnosis is made upon finding increased levels of the protoporphyrin in the plasma or red blood cells.
Erythropoietic protoporphyria is a rare disorder inherited as an autosomal dominant genetic trait with poor penetrance. Human traits, including the classic genetic diseases, are the product of the interaction of two genes, one received from the father and one from the mother.
In dominant disorders, a single copy of the disease gene (received from either the mother or father) will be expressed “dominating” the other normal gene and resulting in the appearance of the disease. The risk of transmitting the disorder from affected parent to offspring is 50 percent for each pregnancy regardless of the sex of the resulting child. The risk is the same for each pregnancy.
The symptoms of erythropoietic protoporphyria develop due to excessive levels of a chemical called protoporphyrin that accumulates in certain tissues of the body (i.e., the plasma, red blood cells, and the liver). Excessive protoporphyrin levels occur as the result of abnormally low levels of the enzyme ferrochelatase (FECH).
There are several different allelic variants of erythropoietic protoporphyria. An allele is any of a series of two or more genes that may occupy the same position (locus) on a specific chromosome. Symptoms of these allelic variants of erythropoietic protoporphyria are predominantly the same; however, one type may be inherited as an autosomal recessive genetic trait.
The gene that is responsible for regulating the production of the enzyme ferrochelatase (FECH) has been located on the long arm of chromosome 18 (18q21.3). Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males, and two X chromosomes for females. Each chromosome has a short arm designated as “p” and a long arm identified by the letter “q”.
Some people who have inherited this defective gene may have slightly elevated levels of protoporphyrin in the body but will not exhibit the symptoms of erythropoietic protoporphyria.
Erythropoietic protoporphyria is a very rare inherited disorder that affects males and females in equal numbers. It is estimated that the disorder occurs in about 1 in about 74,300 individuals. The onset of symptoms affecting the skin usually occurs in infancy; however, in some cases, onset may not occur until adolescence or adulthood. More than 300 cases of EPP have been reported in the medical literature.
Symptoms of the following disorders can be similar to those of EPP. Comparisons may be useful for a differential diagnosis:
There are several other types of porphyrias, all of which involve deficiencies of specific enzymes. Most of the symptoms of these porphyrias are not similar to the symptoms found in erythropoietic protoporphyria. Individuals with porphyria cutanea tarda and congenital erythropoietic porphyria may develop skin lesions; however, these lesions do not resemble the skin lesions found in EPP. It is important to note that individuals with one type of porphyria do not develop any of the other types. In addition, there are skin disorders characterized by hypersensitivity to artificial light and sunlight besides EPP, such as xeroderma pigmentosum and epidermolysis bullosa. The skin lesions in these disorders do not resemble the skin lesions in EPP. (For more information on these disorders, choose “Porphyria and Epidermolysis Bullosa” as your search terms in the Rare Disease Database.)
Xeroderma pigmentosum (XP) is a group of rare inherited skin disorders characterized by hypersensitivity of sunlight and some types of artificial light, with skin blistering occurring after such exposure. In some cases, pain and blistering may occur immediately after contact with sunlight or artificial light. Acute sunburn and persistent redness or inflammation of the skin (erythema) are also early symptoms of xeroderma pigmentosum. In most cases, these symptoms may be apparent immediately after birth or occur within the next three years. Other skin symptoms of xeroderma pigmentosum may include discolorations of the skin, weak and fragile skin, and/or scarring of the skin. Xeroderma pigmentosum also affects the eyes; the most common symptom being an extreme intolerance to light (photophobia). Additional symptoms may include some neurological impairments, short stature, an increased susceptibility to some forms of cancer (e.g., skin cancer). There are several types of xeroderma pigmentosum; in most cases, XP is inherited as an autosomal recessive genetic trait. (For more information on this disorder, choose “Xeroderma Pigmentosum” as your search terms in the Rare Disease Database).
The diagnosis of erythropoietic protoporphyria (EPP) may be made by a thorough clinical evaluation, characteristic physical findings, and specialized laboratory tests. EPP is usually diagnosed during infancy or early childhood, due to characteristic skin symptoms. The diagnosis may be confirmed by testing the red blood cells (erythrocytes) for increased levels of protoporphyrin.
Avoidance of sunlight will be of benefit to individuals with erythropoietic protoporphyria. The use of topical sunscreens, double layers of clothing, long sleeves, hats, and sunglasses will also benefit photosensitive individuals. Individuals with EPP may also benefit from window tinting or using vinyls or films to cover the windows in their car or house. Before tinting or shading car windows, affected individuals should check with their local Registry of Motor Vehicles to ensure that such measures do not violate any local codes.
In erythropoietic protoporphyria, a high potency form of oral beta-carotene (Lumitene, Tishcon) may be given to improve an affected individual's tolerance of sunlight. For more information on this treatment, contact the organizations listed at the end of this report (i.e., American Porphyria Foundation and the EPPREF) and Mr. George McShane of the Tishcon Corp. (1-800-848-8442). In some cases, the drug cholestyramine may be given to alleviate skin symptoms and lower the protoporphyrin levels in the body.
When iron deficiency is present, iron supplements may be given. A type of bile acid (chenodeoxycholic acid) may be prescribed to help the liver dispose of excess protoporphyrin, and activated charcoal or cholestyramine may be used to interrupt the circulation of protoporphyrin through the liver and intestines.
Estrogens and drugs that can impair bile flow should be given cautiously under the supervision of a physician. In addition, individuals with high levels of protoporphyrin in the plasma and red blood cells should be observed closely by a physician for possible liver malfunction that could eventually lead to liver failure.
Genetic counseling will be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.
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:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
For information about clinical trials sponsored by private sources, contact:
The orphan product L-Cysteine is being tested for the prevention and reduction of photosensitivity in erythropoietic protoporphyria. More research is needed to determine the long-term safety and effectiveness of this drug for the treatment EPP. For more information, contact:
Micheline M. Mathews-Roth, M.D.
Harvard Medical School
181 Longwood Ave
Boston, MA 02115-5804
Red blood cell transfusions have also been used to treat some people with EPP. In some affected individuals with severe liver disease, liver transplantations have been performed. Extreme caution should be used by physicians considering these treatment options; each particular case should be evaluated on its own merits.
NORD gratefully acknowledges Maureen Poh-Fitzpatrick, MD, Professor Emerita and Special Lecturer (Dermatology), Columbia University College of Physicians and Surgeons, for assistance in the preparation of this report.
Synonyms of X-Linked Protoporphyria
- X-linked dominant protoporphyria
X-linked protoporphyria is an extremely rare genetic disorder characterized by an abnormal sensitivity to the sun (photosensitivity) that can cause severe pain, burning, and itching of sun-exposed skin. Symptoms may occur immediately or shortly after exposure to the sun, including direct exposure or indirect exposure such as sunlight that passes through window glass or that is reflected off water or sand. Redness and swelling of affected areas can also occur. Blistering and severe scarring occur infrequently. Chronic episodes of photosensitivity may lead to changes in the skin of sun-exposed areas. Some individuals eventually develop potentially severe liver disease. X-linked protoporphyria is caused by mutations of the ALAS2 gene and is inherited as an X-linked dominant trait. Males often develop a severe form of the disorder while females may not develop any symptoms (asymptomatic) or can develop a form as severe as that seen in males.
X-linked protoporphyria belongs to a group of disorders known as the porphyrias. This group of at least eight disorders is characterized by abnormally high levels of porphyrins and porphyrin precursors due to deficiency of certain enzymes essential to the creation (synthesis) of heme, a part of hemoglobin and other hemoproteins. There are eight enzymes in the pathway for making heme and at least eight different forms of porphyria. The symptoms associated with the various forms of porphyria differ. 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 and related substances originate in excess amounts chiefly from the liver in the hepatic types and mostly from the bone marrow in the erythropoietic types. Porphyrias with skin manifestations are sometimes referred to as "cutaneous porphyrias." The term "acute porphyria" is used to describe porphyrias that can be associated with sudden attacks of pain and other neurological symptoms.
X-linked protoporphyria is an erythropoietic form of porphyria and is extremely similar clinically to erythropoietic protoporphyria (EPP). X-linked protoporphyria was first described in the medical literature in 2008.
Signs & Symptoms
Hypersensitivity of the skin to sunlight is the characteristic finding of X-linked protoporphyria. Affected individuals develop pain, itching, and burning of the skin after exposure to sunlight. Sometimes these symptoms are accompanied by swelling and redness (erythema) of the affected areas. Large blisters and severe scarring, which are common to other forms of cutaneous porphyria, usually do not occur in individuals with X-linked protoporphyria. Symptoms may be noticed as quickly as a few minutes after exposure to the sun. Although most symptoms usually subside within 24-48 hours, pain and a red or purple discoloration of the skin may persist for several days after the initial incident. Pain is disproportionately severe in relation to the visible skin lesions. Pain associated with X-linked protoporphyria can be excruciating and is often resistant to pain medications, even narcotics.
Repeated episodes of photosensitivity may eventually causes changes in the skin of affected individuals. Such changes include thickening and hardening of the skin, development of a rough or leathery texture, small facial pock-like pits, and grooving around the lips.
Some individuals with X-linked protoporphyria develop liver disease, which can range from mild liver abnormalities to liver failure. Information on liver disease is limited, but the risk of liver disease is believed to be higher in X-linked protoporphyria than in EPP. Affected individuals may experience back pain and severe abdominal pain especially in the upper right area of the abdomen. In some affected individuals, the flow of bile through the gallbladder and bile ducts may be interrupted (cholestasis) leading to gallstones. These stones can cause obstruction and inflammation of the gallbladder (cholecystitis). Scarring of the liver (cirrhosis) may also develop and some individuals may eventually develop end stage liver failure.
Additional symptoms have been reported in individuals with X-linked protoporphyria including mild anemia (low levels of circulating red blood cells) and iron deficiency.
X-linked protoporphyria is caused by gain-of-function mutations to the ALAS2 gene and is inherited as an X-linked dominant disorder. In contrast to most X-linked disorders, which are recessive, X-linked dominant disorders are evident in a female with one normal X chromosome and one affected X chromosome.
The ALAS2 gene is located on the short arm (p) of the X chromosome (Xp11.21)*. The gene encodes a protein known as erythroid specific 5-aminolevulinate synthase 2. Mutations of the ALAS2 gene lead to the overproduction of this enzyme, which, in turn, results in elevated levels of a chemical called protoporphyrin. Protoporphyrin abnormally accumulates in certain tissues of the body, especially the blood, liver, and skin. The symptoms of X-linked protoporphyria develop because of this abnormal accumulation of protoporphyrin. For example, when protoporphyrins absorb energy from sunlight, they enter an excited state (photoactivation) and this abnormal activation results in the characteristic damage to the skin. Accumulation of protoporphyrins in the liver causes toxic damage to the liver and may contribute to the formation of gallstones. Protoporphyrin is formed within red blood cells in the bone marrow and then enters the blood plasma, which carries it to the skin where it can be photoactivated by sunlight and cause damage. The liver removes protoporphyrin from the blood plasma and secretes it into the bile.
* [Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males and two X chromosomes for females. Each chromosome has a short arm designated as “p” and a long arm identified by the letter “q”. Chromosomes are further subdivided into bands that are numbered. For example, “chromosome Xp22.2-22.1” refers to bands 22.2 through 22.1 on the short arm of chromosome X.]
X-linked protoporphyria affects males and females. However, males usually develop a severe form of the disorder while females with an ALAS2 mutation may range from having no symptoms (asymptomatic) to developing a severe form of the disorder. The exact incidence or prevalence of X-linked protoporphyria is unknown. The disorder has only been reported in the medical literature in a handful of families in Europe, South Africa and Japan.
Symptoms of the following disorders can be similar to those of X-linked protoporphyria. Comparisons may be useful for a differential diagnosis.
Erythropoietic protoporphyria (EPP) is a rare inherited metabolic disorder characterized by a deficiency of the enzyme ferrochelatase (FECH). Due to abnormally low activity of this enzyme, excessive amounts of protoporphyrin accumulate in the bone marrow, blood plasma, and red blood cells. The major symptom of this disorder is hypersensitivity of the skin to sunlight and some types of artificial light, such as fluorescent lights (photosensitivity). After exposure to light, the skin may become itchy or painful, and red or swollen. The hands, arms, and face are the most commonly affected areas. Some people with erythropoietic protoporphyria may also have complications related to liver and gallbladder function. (For more information on this disorder, choose “erythropoietic protoporphyria” as your search term in the Rare Disease Database.)
There are other conditions that may cause signs and symptoms that are similar to those seen in X-linked protoporphyria. Such conditions include other cutaneous porphyrias such as variegate porphyria, drug-induced photosensitivity, various forms of lupus, and solar urticaria. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
A diagnosis of X-linked protoporphyria is based upon identification of characteristic symptoms (e.g., non-blistering photosensitivity), a detailed patient history, a thorough clinical evaluation, and a variety of specialized tests.
Clinical Testing and Workup
A diagnosis of X-linked protoporphyria may be made through blood tests that can detect markedly increased levels of metal-free and zinc-bound protoporphyrins within red blood cells (erythrocytes). A higher ratio of zinc-bound protoporphyrin to metal-free protoporphyrin can differentiate X-linked protoporphyria from EPP.
Molecular genetic testing can confirm a diagnosis of X-linked protoporphyria by detecting mutations in the ALAS2 gene (the only gene known to cause this disorder).
Additional tests may be performed such as blood tests to evaluate anemia and iron stores in the body and vitamin D levels, or an abdominal sonogram to detect and evaluate liver disease potentially associated with X-linked protoporphyria.
The treatment of X-linked protoporphyria is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, hematologists, dermatologists, hepatologists, and other healthcare professionals may need to systematically and comprehensively plan an affected child’s treatment. Genetic counseling may benefit affected individuals and their families.
There is no specific, FDA-approved therapy for individuals with X-linked protoporphyria. Because the disorder is so rare, most treatment information is based on EPP, which is clinically similar to X-linked protoporphyria.
Avoidance of sunlight will benefit affected individuals and can include the use of clothing styles with long sleeves and pant legs, made with double layers of fabric or of light-exclusive fabrics, wide brimmed hats, gloves, and sunglasses. Topical sunscreens are generally ineffective, unless they contain light-reflective ingredients. Certain tanning products with ingredients that increase pigmentation may be helpful. Affected individuals may also benefit from window tinting and the use of vinyl or films to cover the windows of their homes and cars.
Avoidance of sunlight can potentially cause vitamin D deficiency and some individuals may require supplemental vitamin D.
A high potency form of oral beta-carotene (Lumitene) may be given to improve an affected individual’s tolerance of sunlight. This drug causes skin discoloration and may improve tolerance to sunlight. For more information on this treatment, contact the organizations listed at the end of this report (i.e. American Porphyria Foundation and the EPPREF). Another drug sometimes used to improve tolerance to sunlight is cysteine.
In some cases, the drug cholestyramine may be given. Cholestyramine absorbs porphyrin. The drug may interrupt the recirculation of protoporphyrin secreted into the bile back into the liver and promote its excretion through the feces. Other drugs that absorb porphyrins such as activated charcoal have also been used to treat affected individuals. These drugs may lead to improvement of liver disease.
Individuals with any form of protoporphyria should avoid substances associated with cholestasis including alcohol and certain drugs such as estrogens. Immunizations for hepatitis A and B are recommended as well.
Plasmapheresis and red blood cell transfusions have been used to treat people with EPP. In individuals with severe liver disease, a liver transplantation may be required. Extreme caution should be used by physicians considering these treatment options for individuals with X-linked protoporphyria (or EPP). Each individual case should be evaluated on its own merits.
Iron supplementation may be considered in individuals with anemia and abnormal iron metabolism. Such therapy requires strict monitoring by physicians. In EPP, iron supplementation has resulted in clinical improvement, but also carries a risk of increased photosensitivity.
Afamelanotide, an alpha-melanocyte-stimulating hormone analogue, is being studied as a protective agent against sunlight in individuals with EPP. This drug increases the production of melanin in the skin. Afamelanotide is available to patients in Europe and is under consideration by the United States Food and Drug Administration (2016). The long-term safety and effectiveness of this drug and its role in treating individuals with X-linked protoporphyria remain under investigation.
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
For information about clinical trials sponsored by private sources, in the main, contact:
For more information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/ The Porphyrias Consortium is a joint endeavor including five of the leading porphyria centers in the United States. Staff includes physicians, researchers, research coordinators, and technical laboratory staff. The Consortium aims to expand the knowledge about porphyrias to benefit patients and families. Study information regarding porphyrias is also posted at the Porphyrias Consortium website: http://rarediseasesnetwork.epi.usf.edu/porphyrias/index.htm
Ninomiya Y, Kokunai Y, Tanizaki H, Akasaka E, Nakano H, Moriwaki S. X-linked dominant protoporphyria: The first reported Japanese case. J Dermatol. 2015:[Epub ahead of print]. http://www.ncbi.nlm.nih.gov/pubmed/26387792
Landefeld C, Kentouche K, Gruhn B, Stauch T, Rößler S, Schuppan D, Whatley SD, Beck JF, Stölzel U. X-linked protoporphyria: Iron supplementation improves protoporphyrin overload, liver damage and anaemia. Br J Haematol. 2015 [Epub ahead of print]. http://www.ncbi.nlm.nih.gov/pubmed/?term=X-linked+protoporphyria+Landefeld+2015
Balwani M, Doheny D, Bishop DF, et al. Loss-of-funtion ferrochelatase and gain-of-function erythroid 5-aminolevulinate synthase mutations causing erythropoietic protoporphyria and X-linked protoporphyria in North American patients reveal novel mutations and a high prevalence of X-linked protoporphyria. Mol Med. 2013;19(1): 26–35; [Epub ahead of print]: http://www.ncbi.nlm.nih.gov/pubmed/23364466
Bishop DF, Tchaikovskii V, Nazarenko I, Desnick RJ. Molecular expression and characterization of erythroid-specific 5-aminolevulinate synthase gain-of-function mutations causing X-linked protoporphyria. Mol Med. 2013;19:18-25.http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3592931/
Balwani M, Desnick RJ. The porphyrias: advances in diagnosis and treatment. Blood. 2012;120:4496-4504. http://www.ncbi.nlm.nih.gov/pubmed/22791288
Late-onset of X-linked dominant protoporphyria: an etiology of photosensitivity in the elderly. J Invest Dermatol. 2013;133:1688-90. 2012:[Epub ahead of print].http://www.ncbi.nlm.nih.gov/pubmed/23223129
Whatley SD, Ducamp S, Gouya L, et al. C-Terminal deletions in the ALAS2 gene lead to gain of function and cause X-linked dominant protoporphyria without anemia or iron overload. Am J Hum Genet. 2008;83:408-414. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2556430/
Balwani M, Bloomer J, Desnick R; Porphyrias Consortium of the NIH-Sponsored Rare Diseases Clinical Research Network. X-Linked Protoporphyria. 2013 Feb 14. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2016.Available from:http://www.ncbi.nlm.nih.gov/books/NBK121284/ Accessed April 4, 2016.
Poh-Fitzpatrick MB. Protoporphyria. Medscape, Last Update: February 24, 2014. Available at: http://emedicine.medscape.com/article/1104061 Accessed April 4, 2016.
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