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PORPHYRIAS DESCRIPTION |
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Biosynthesis of heme is a multistep
process that starts with simple molecules and ends with a large,
complex heme molecule. Each step of the biosynthesis pathway is
directed by its own task-specific protein, called an enzyme. As a
heme precursor molecule moves through each step, an enzyme modifies
it in some way. If the precursor is not modified, it cannot proceed
to the next step. This situation is the main characteristic of the porphyrias. Owing to a defect in one of the enzymes of the heme biosynthesis pathway, protoporphyrins or porphyrin (heme precursors) are prevented from proceeding further along the pathway. Instead, precursors accumulate at the stage of the enzyme defect and cause an array of physical symptoms in the affected person. Specific symptoms depend on the point at which heme biosynthesis is blocked and which precursors accumulate. In general, the porphyrias primarily affect the skin and the nervous system. Symptoms can be debilitating or life threatening in some cases. Porphyria is an inherited condition, but it may be acquired after exposure to poisonous substances. Heme Heme is produced in several tissues in the body, but its primary biosynthesis sites are the liver and the bone marrow. Heme synthesis for immature red blood cells, namely the erythroblasts and the reticulocytes, occurs in the bone marrow. Although production is concentrated in the liver and bone marrow, heme is utilized in various capacities in virtually every tissue in the body. In most cells, it is a key building block in the construction of factors that oversee metabolism as well as transport of oxygen and energy. In the liver, heme is used in several vital enzymes, particularly cytochrome P450. This enzyme is involved in the metabolism of chemicals, vitamins, fatty acids, and hormones; it is very important in transforming toxic substances into easily excretable materials. In immature red blood cells, heme is a the featured component of hemoglobin. Hemoglobin is the red pigment that gives red blood cells the ability to transport oxygen--which is essential for life--as well as their characteristic color. Heme biosynthesis The heme molecule is composed of porphyrin and an iron atom. Much of the heme biosynthesis pathway is dedicated to constructing the porphyrin molecule. Porphyrin is a large molecule shaped like a four-leaf clover. An iron atom is placed at its center point during the last step of heme biosynthesis. The production of heme may be compared to a factory assembly line. At the start of the line, raw materials are fed into the process. At specific points along the line, an addition or adjustment is made to further development. Once additions and adjustments are complete, the final product roles off the end of the line. The heme "assembly line" is an eight-step process, requiring eight different--and properly functioning--enzymes: Step 1: delta-aminolevulinic acid synthase Step 2: delta-aminolevulinic acid dehydratase Step 3: porphobilogen deaminase Step 4: uroporphyrinogen III cosynthase Step 5: uroporphyrinogen decarboxylase Step 6: coproporphyrinogen oxidase Step 7: protoporphyrinogen oxidase Step 8: ferrochelatase. The control of heme biosynthesis is complex. There are various chemical signals that can trigger increased or decreased production. These signals can affect the enzymes themselves or their production, starting at the genetic level. For example, one point at which heme biosynthesis may be controlled is at the first step. When heme levels are low, greater quantities of delta-aminolevulinic acid (ALA) synthase are produced. As a result, larger quantities of heme precursors are fed into the biosynthesis pathway to step up heme production. Porphyrias Under normal circumstances, when heme concentrations are at an appropriate level, precursor production decreases. However, a glitch in the biosynthesis pathway--represented by a defective enzyme--means that heme biosynthesis does not reach completion. Because heme levels remain low, the synthesis pathway continues to churn out precursor molecules in an attempt to make up the deficit. The net effect of this continued production is an abnormal accumulation of precursor molecules and development of some type of porphyria. Each type of porphyria corresponds with a specific enzyme defect and an accumulation of the associated precursor. Although there are eight steps in heme biosynthesis, there are only seven types of porphyrias; a defect in ALA synthase activity does not have a corresponding porphyria. The porphyrias are divided into two general categories, depending on the location of the deficient enzyme. Porphyrias that affect heme biosynthesis in the liver are called hepatic porphyrias. The porphyrias that affect heme biosynthesis in immature red blood cells are called erythropoietic porphyrias (erythropoiesis is the process through which red blood cells are produced). Enzymes involved in heme biosynthesis have subtle, tissue-specific variations; therefore, heme biosynthesis may be impeded in the liver, but normal in the immature red blood cells, or vice versa. Incidence of porphyria varies widely between types and occasionally by geographic location. Although certain porphyrias are more common than others, their greater frequency is only relative to other types; all porphyrias are considered rare disorders. The hepatic porphyrias, and the heme biosynthesis steps at which enzyme defects occur, are: ALA dehydratase deficiency porphyria (step 2). This porphyria type is extraordinarily rare; only six cases have ever been reported in the medical literature. The inheritance pattern seems to be autosomal recessive, which means a defective enzyme gene must be inherited from both parents for the disorder to occur. Acute intermittent porphyria (step 3). Acute intermittent porphyria (AIP) is also known as Swedish porphyria, pyrroloporphyria, and intermittent acute porphyria. AIP is inherited as an autosomal dominant trait, which means only one copy of the defective gene needs to be present for the disorder to occur. However, simply inheriting this gene does not necessarily mean that a person will develop the disease. Approximately 5-10 per 100,000 persons in the United States carry the gene, but only10% of them ever develop AIP symptoms. Porphyria cutanea tarda (step 5). Porphyria cutanea tarda (PCT) is also called symptomatic porphyria, porphyria cutanea symptomatica, and idiosyncratic porphyria. PCT may be acquired, typically as a result of disease (especially hepatitis C), drug or excess alcohol use, or exposure to certain poisons. PCT may also be inherited as an autosomal dominant disorder, but most people remain latent--that is, symptoms never develop. It is the most common of the porphyrias, but the incidence is not well defined. Hereditary coproporphyria (step 6). Hereditary coproporphyria (HCP) is inherited in an autosomal dominant manner. As with all porphyrias, it is an uncommon ailment. By 1977, only 111 cases were recorded; in Denmark, the estimated incidence is 2 in 1 million people. Variegate porphyria (step 7). Variegate porphyria (VP) is also known as porphyria variegata, protocoproporphyria, South African genetic porphyria, and Royal malady (supposedly King George III of England and Mary, Queen of Scots, suffered from VP). VP is inherited in an autosomal dominant manner and is especially prominent in South Africans of Dutch descent. Among that population, the incidence is approximately 3 in 1,000 persons and it is estimated that there are 10,000 cases of VP in South Africa. Interestingly, it seems that the affected South Africans are descendants of two Dutch settlers who came to South Africa in 1680. Elsewhere, the incidence is estimated to be 1-2 cases per 100,000 persons. The erythropoietic porphyrias, and the steps of heme biosynthesis at which they occur, are: Congenital erythropoietic porphyria (step 4). Congenital erythropoietic porphyria (CEP) is also called Gunther's disease, erythropoietic porphyria, congenital porphyria, congenital hematoporphyria, and erythropoietic uroporphyria. CEP is inherited in an autosomal recessive manner and occurs very rarely. As of 1992, only 200 cases had been reported. Onset of symptoms usually occurs in infancy, but may hold off until adulthood. Erythropoietic protoporphyria (step 8). Also known as protoporphyria and erythrohepatic protoporphyria, erythropoietic protoporphyria (EPP) is more common than CEP; more than 300 cases have been reported. In these cases, onset of symptoms typically occurred in childhood. In addition to the above types of porphyria, there is a very rare type, called hepatoerythopoietic porphyria (HEP), that affects heme biosynthesis in both the liver and the bone marrow. HEP results from a defect in uroporphyrinogen decarboxylase activity (step 5), but strongly resembles congenital erythropoietic porphyria. Only 20 cases of HEP have been reported worldwide; it seems to be inherited in an autosomal recessive manner. |
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