Congenital Erythropoietic Porphyria (CEP)
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 a very rare genetic disorder that affects males and females in equal numbers. Over 200 cases have been reported worldwide.
This disease is extremely rare and is autosomal recessive. Various mutations in the gene for this enzyme have been identified in different families. As is characteristic of the erythropoietic Porphyrias, symptoms begin during infancy. Sometimes CEP is recognized as a cause of anemia in a fetus before birth. In less severe cases symptoms may begin during adult life. Porphyrins are markedly increased in bone marrow, red blood cells, plasma, urine and feces. Porphyrins are also deposited in the teeth and bones.
Synonyms of Congenital Erythropoietic Porphyria
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 during heme biosynthesis.
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.
Prenatal and preimplantation genetic diagnoses are available for subsequent pregnancies in CEP families.
Signs and Symptoms
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. Skin photosensitivity may be extreme, and can lead to blistering, severe scarring and increased hair growth. Bacteria may infect the damaged skin. Facial features and fingers may be lost through phototoxic damage as well as infection. Red blood cells have a shortened life-span, and anemia often results. Synthesis of heme and hemoglobin are actually increased to compensate for the shortened red blood cell survival.
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. In the great majority of cases, photosensitivity is seen from birth; however, in some cases, it may not occur until childhood, adolescence or adulthood. Patients also have brownish discolored teeth (erythrodontia), 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 transfusions to quickly increase the amount of red blood cells and iron in the blood. In severely affected patients, anemia may be present in the fetus. Ocular problems also can occur including corneal scarring, eye inflammation, and infections.
The diagnosis of CEP may be suspected when 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 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.
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.
Blood transfusions and removing the spleen are treatments which may reduce porphyrin production by the bone marrow. Activated charcoal given by mouth is sometimes effective. Stem cell transplantation and gene therapy may also be options in the future.
Referral to an expert Porphyria center is recommended for expert diagnosis, care and genetic counseling.
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.
ALAD-Deficiency Porphyria (ADP)
ALAD Porphyria (ADP) is a very rare genetic metabolic disease characterized by almost complete deficiency of the enzyme delta-aminolevulinic acid (ALA) dehydratase. In ADP, the gene responsible is ALAD which produces the enzyme δ-aminolevulinic acid dehydratase. Deficiency of this enzyme leads to the accumulation of the toxic porphyrin precursor ALA, which can potentially result in a variety of symptoms. Symptoms vary from one person to another, but usually come from the neurological and gastrointestinal systems. This disease is inherited as an autosomal recessive disorder. ADP is more severe than the other acute Porphyrias and can present in childhood. Only ~10 cases have been reported worldwide and all reported cases have been males, in contrast to the other acute Porphyrias where more women are symptomatic.
Synonyms of ALAD Porphyria
ADP is caused by a deficiency of the enzyme δ-aminolevulinic acid dehydratase (ALAD).
The mutation is in the ALAD gene, and the disease is inherited as an autosomal recessive disorder, meaning one copy of the abnormal gene is inherited from each parent. Mutations of the ALAD gene result in deficient levels of porphobilinogen in the body, with an accumulation of ALA, which causes the symptoms associated with ALAD Porphyria.
A variety of different triggers have been identified that can precipitate an acute attack in individuals with ALAD Porphyria. These triggers include alcohol, certain drugs, physical and psychological stress, infection, fasting (reduced caloric intake) and dehydration. The use of estrogen or progesterone is also suspected of triggering an acute attack.
Signs and Symptoms
Individuals with ALAD Porphyria may have bouts where symptoms are intense, which are referred to as neurovisceral or acute attacks. An attack may last for several weeks. During an attack, affected individuals may experience severe abdominal cramping or pain accompanied by vomiting and constipation. During infancy, gastrointestinal abnormalities may cause an affected child to fail to grow and gain weight as expected.
Several other neurological symptoms can occur during an acute attack due to problems with the nerves outside the central nervous system (peripheral neuropathy), resulting in numbness or tingling in the hands and feet, burning pain, sensitivity to touch, and a lack of coordination. In severe cases, the motor nerves are involved, resulting in loss or partial impairment of the ability to use voluntary muscles. ALAD Porphyria can also be associated with psychological changes during an acute attack. In severe cases, loss of contact from reality (psychosis) has been reported.
Additional symptoms that occur during acute attacks include a rapid heartbeat (tachycardia), high blood pressure (hypertension), seizures, and breathing (respiratory) impairment.
Biochemical testing means looking for “biomarkers” in the blood or urine. To diagnose ADP, measurements of the biomarkers porphobilinogen (PBG), aminolevulinic acid (ALA), and total porphyrins in the urine should be done. Also porphyrins in the blood should be measured. The level of PBG in the body can vary so the best time to take samples is during an acute attack (e.g. when someone is having abdominal pain, etc). Slight elevations in porphyrins are not diagnostic of ADP; the levels need to be very high.
DNA testing to identify the specific mutation in an individual’s Porphyria-causing gene is the most specific and sensitive test to confirm the diagnosis of a specific Porphyria. Before requesting DNA testing, it is recommended that patients have biochemical testing (urinary, stool and/or plasma porphyrins and porphyrin precursors (ALA and PBG) and/or enzyme assays).
For the acute Porphyrias, hospitalization is often necessary for acute attacks. Medications for pain, nausea and vomiting, and close observation are generally required with monitoring of salt and water balance. Harmful drugs should be stopped. Attacks are treated with either glucose loading or intravenous administration of hemin (Panhematin®). Attacks can be prevented in many cases by avoiding harmful drugs (Safe/Unsafe Drug Database) and adverse dietary practices (Diet and Nutrition).
The treatment of ALAD Porphyria is directed toward the specific symptoms that are present in each individual. Because there have been so few cases of ALAD Porphyria, there is only limited information on treatment for the disorder.
Avoidance of triggering factors such as alcohol, certain drugs, fasting, and low carbohydrate diets is recommended for affected individuals. The specific drugs that may need to be avoided in one person can differ from the drugs that need to be avoided in another.
Two standard treatments for acute Porphyrias in general are intravenous infusions of hemin and supplementation with glucose. However, these therapies have not been universally effective in treating individuals with ALAD Porphyria.
Hemin is an orphan drug that has been approved by the Food and Drug Administration (FDA) for the treatment of acute Porphyria. The drug known as Panhematin® (hemin for injection) is usually given to treat an acute attack.
Wearing a Medic Alert bracelet or the use of a wallet card is advisable in individuals who have ADP.