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.
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.
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.
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McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No: 177000; Last Update: 9/3/98; Last Edit: 6/9/99.