NORD gratefully acknowledges R.J. Desnick, PhD, MD, Professor and Chairman, and Dana O. Doheny, MS, CGC, Genetic Counselor, Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine of New York University; and Micheline M. Mathews-Roth, MD, Associate Professor of Medicine, Harvard Medical School, for assistance in the preparation of this report.
Congenital erythropoietic porphyria (CEP) is a very rare inherited metabolic disorder resulting from the deficient function of the enzyme uroporphyrinogen lll cosynthase (UROS), the fourth enzyme in the heme biosynthetic pathway. Due to the impaired function of this enzyme, excessive amounts of particular porphyrins accumulate, particularly in the bone marrow, plasma, red blood cells, urine, teeth, and bones. 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 photo-activated porphyrins in the skin cause bullae (blistering) and the fluid-filled sacs rupture, and the lesions often get infected. These infected lesions can lead to scarring, bone loss, and deformities. The hands, arms, and face are the most commonly affected areas. CEP is inherited as an autosomal recessive genetic disorder. Typically, there is no family history of the disease. Neither parent has symptoms of CEP, but each carries a defective gene that they can pass to their children. Affected offspring have two copies of the defective gene, one inherited from each parent.
CEP is one of a group of disorders known as the porphyrias. Each porphyria is characterized by abnormally high levels of particular chemicals (porphyrins) in the body due to deficiencies of certain enzymes in the step-wise synthesis of heme, the essential component of hemoglobin and various hemo-proteins. The porphyrias can be classified as cutaneous or acute depending on their respective manifestations (See www.porphyriafoundation.com). There are eight major porphyrias. The symptoms associated with the various types of porphyria differ, depending upon the specific enzyme that is deficient. People who have one type of porphyria do not develop the other types, however, rare patients have had two different porphyrias.
The most common symptom of CEP is hypersensitivity of the skin to sunlight and some types of artificial light (photosensitivity), with blistering of the skin occurring after exposure. Affected individuals may also exhibit abnormal accumulations of body fluid under affected areas (edema) and/or persistent redness or inflammation of the skin (erythema). 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. These affected areas of skin may become abnormally thick. In addition, in some cases, affected individuals may also exhibit malformations of the fingers and nails. The severity and degree of photosensitivity differ depending on the severity of the patient’s gene lesions which correlate with the deficient enzyme activity. Photosensitivity is seen from birth; however, in some cases, it may not occur until childhood, adolescence or adulthood. Patients also have erythrodontia, brownish discolored teeth, which fluoresce under ultraviolet light.
In more severe cases, other symptoms can include a low level of red blood cells (anemia), enlargement of the spleen, and increased hair growth (hypertrichosis). The anemia can be severe and such patients require periodic transformations to maintain sufficient red blood cells. In severely affected patients, anemia may be present in the fetus. Ocular problems also can occur including corneal scarring, eye inflammation, and infections.
Symptoms usually start in infancy or childhood and the diagnosis in most patients is suggested by the reddish color of the urine which stains the diapers. The diagnosis is made by finding increased levels of specific porphyrins in the urine. Diagnostic confirmation is made by measuring the specific (UROS) enzyme activity and/or by identifying the specific lesion(s) in the UROS gene which is/are responsible for the impaired enzyme.
Congenital erythropoietic porphyria is inherited as an autosomal recessive genetic condition. Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, and usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.
Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.
Mutations in the UROS gene cause CEP. The symptoms of CEP develop due to excessive levels of the specific porphyrins that accumulate in tissues of the body as a result of the markedly impaired function of the UROS enzyme.
CEP is a very rare genetic disorder that affects males and females in equal numbers. Over 200 cases have been reported worldwide.
The diagnosis of CEP may be suspected when the reddish-colored urine is noted at birth or later in life. This finding, or the occurrence of skin blisters on sun or light exposure, should lead to a thorough clinical evaluation and specialized laboratory tests. The diagnosis can be made by testing the urine for increased levels of specific porphyrins. Diagnostic confirmation requires the demonstration of the specific UROS enzyme deficiency and/or the lesion(s) in the UROS gene.
Prenatal and preimplantation genetic diagnoses are available for subsequent pregnancies in CEP families.
Avoidance of sunlight is essential to prevent the skin lesions in individuals with CEP. The use of topical sunscreens, protective clothing, long sleeves, hats, gloves, and sunglasses are strongly recommended. Individuals with CEP will 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 addition to protection from sunlight, the anemia should be treated, if present. Chronic transfusions have been useful in decreasing the bone marrow production of the phototoxic porphyrins. When successful, bone marrow transplantation has cured patients with CEP, but is accompanied by specific risks of complications and demise. For more information on this treatment, contact the American Porphyria Foundation.
Referral to an expert porphyria center is recommended for expert diagnosis, care and genetic counseling – see Resources, The Porphyrias Consortium. Genetic counseling is strongly recommended. 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
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For information about clinical trials sponsored by private sources, contact:
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Porphyrin production in the bone marrow can be reduced by red blood cell (erythrocyte) transfusions but must be used with caution due to complications associated with chronic transfusion therapy.
Successful bone marrow transplantation has been curative for patients now over 10 years post-transplantation. Hematopoietic stem cell cord blood transplantation has also been successful.
The Rare Diseases Clinical Research Network (RDCRN), funded by the National Institute of Health (NIH) and the Office for Rare Diseases Research (ORDR), is sponsoring The Porphyrias Consortium, which will focus on the inborn errors of heme biosynthesis, the Porphyrias. It is bringing together senior porphyria experts at six academic institutions, the American Porphyria Foundation (APF), and industry to carry out clinical studies and clinical trials to accelerate the development of improved diagnosis and treatment for the patients with these rare diseases.
For more information:
The Porphyrias Consortium of the Rare Diseases Clinical Research Network
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