NORD gratefully acknowledges Maureen Poh-Fitzpatrick, MD, Professor Emerita and Special Lecturer (Dermatology), Columbia University College of Physicians and Surgeons and Professor of Dermatology, University of Tennessee College of Medicine, for assistance in the preparation of this report.
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 scarring usually do not occur. 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 seven 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.
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. Blistering and 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, chronic 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, 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 and South Africa.
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 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, but 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 can 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. Currently, clinical trials are underway in Europe and the United States. More research is necessary to determine the long-term safety and effectiveness of this drug and whether it has a role in treating individuals with X-linked protoporphyria.
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
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;[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. 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.
Balwani M, Bloomer J, Desnick RJ. Updated:02/14/2013. X-linked Protoporphyria. In: GeneReviews at GeneTests: Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1997-2003. Available at http://www.genetests.org. Accessed on: March 20, 2013
Poh-Fitzpatrick MB. Protoporphyria. Emedicine Journal, June 20 2012. Available at: http://emedicine.medscape.com/article/1104061-overview Accessed on: March 20, 2013.
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