NORD gratefully acknowledges R.J. Desnick, PhD, MD, Dean for Genetics and Genomic Medicine, Professor and Chairman Emeritus, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai and Angelika Erwin, MD, PhD, Medical Geneticist, Genomic Medicine Institute, Cleveland Clinic; Assistant Professor of Pediatrics, Case Western Reserve University, for preparation of this report.
Congenital erythropoietic porphyria (CEP) is a very rare inherited metabolic disorder resulting from the deficient function of the enzyme uroporphyrinogen III synthase (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, although very rarely, patients may have 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 have loss of nails and end digits of the fingers due to infection of the underlying bone. Loss of sun exposed facial features such as lips, parts of the ears, and nose can also occur. 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 often have brownish discolored teeth (erythrodontia) which fluoresce under ultraviolet light as well as increased hair growth (hypertrichosis).
In more severe cases, other symptoms can include a low level of red blood cells (anemia) and enlargement of the spleen. The anemia can be severe and such patients require periodic blood transfusions to maintain sufficient numbers of 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. One female patient with very severe CEP symptoms was found to have two lesions in the UROS gene and in addition, she also had a genetic variant in a gene called ALAS2, which is usually associated with another form of cutaneous porphyria (X-linked protoporphyria). It is assumed that this additional gene variant in the ALAS2 gene is the reason why her CEP symptoms were more severe than expected.
In very rare cases, one particular mutation in another gene called GATA1 has been found to cause CEP. So far, three CEP patients have been reported with the GATA1 mutation who do not have a mutation in the UROS gene. GATA1 is located on the X chromosome, which means that males with a CEP-causing mutation in this gene will develop CEP symptoms while female mutation carriers may remain asymptomatic or have less severe manifestations than their male relatives. This is due to the fact that males have one X chromosome whereas females have two. Inheritance of GATA1-related CEP is X-linked, which means that all daughters of an affected male will carry the GATA1 mutation but none of his sons will. If a female carries the GATA1 mutation, the risk for any of her children to inherit the mutation is 50% regardless of gender.
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 if the underlying genetic mutations are known.
Avoidance of sunlight is essential to prevent the skin lesions in individuals with CEP. The use of topical, zinc- or titanium-oxide containing 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 home. 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.
Individuals with CEP are at risk for low bone density and may therefore be more likely to experience bone fractures. Especially due to the avoidance of sun exposure, all CEP patients should therefore be taking vitamin D supplementation.
In addition to protection from sunlight, anemia should be treated if present. Chronic blood transfusions have been useful in decreasing the bone marrow production of the phototoxic porphyrins but must be used with caution due to complications associated with chronic transfusion therapy.
When successful, bone marrow or hematopoietic stem cell transplantation can cure patients with CEP, but these procedures have a risk for 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.
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The Rare Diseases Clinical Research Network (RDCRN), funded by the National Institutes of Health (NIH) and the Office for Rare Diseases Research (ORDR), is sponsoring The Porphyrias Consortium, which focuses on the Porphyrias. The Consortium brings 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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