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INTRODUCTION

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The porphyrias are a group of inborn errors of metabolism resulting from enzymatic defects in heme biosynthesis. The majority of the porphyrias are inherited in an autosomal dominant manner, with most subjects retaining approximately 50% of normal enzyme activity. In most cases, this is sufficient to maintain heme biosynthesis. However, the pathway can be upregulated by precipitating factors that increase the demand for heme. Depending on which enzyme is defective, different heme pathway intermediates are overproduced, accumulate, and are excreted in urine, feces, or both. The excess amount of these intermediates gives rise to clinical manifestations which may include neurological and psychological symptoms and/or cutaneous photosensitivity. Heme pathway enzymes can also be disrupted in other disorders, by heavy metal toxicity, or by various chemicals, with the resulting clinical picture resembling a porphyria.

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HEME BIOSYNTHETIC PATHWAY

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Heme synthesis occurs in all nucleated cells, the majority being synthesized in the bone marrow and liver. Eight enzymes are required to synthesize heme, the first and last three steps in the mitochondria and the intermediate four steps occurring in the cytosol. Each step is associated with a porphyric disorder when a genetic defect, and sometimes an inhibitor, affects the enzymatic activity.

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Heme synthesis (Figure 26-1) starts in the mitochondria, where the condensation of succinyl-coenzyme A and glycine is catalyzed by aminolevulinic acid synthase (ALAS) to form aminolevulinic acid (ALA). ALAS has two different transcripts—a housekeeping gene (ALAS1) expressed in all cells, and an erythroid-specific gene (ALAS2) expressed in fetal liver and adult bone marrow. The ALAS1 enzyme is inhibited by heme, making it the rate-limiting enzyme of hepatic heme synthesis, while ALAS2 enzyme production is not affected by heme. The mechanism for the regulation of heme synthesis in the erythrocytes is more complex. As heme is required for hemoglobin synthesis, it is produced in very large amounts in the erythron and its stimulation for synthesis is accompanied by increased activity of all the pathway enzymes. To regulate the rate of synthesis, heme controls the transport of iron into reticulocytes rather than suppressing ALAS enzymatic activity as seen in the liver.1

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FIGURE 26-1.

Heme biosynthetic pathway. Heme biosynthesis consists of eight enzymatic steps, with the first and the last three steps occurring in the mitochondria and the intermediate fourth step occurring in the cytosol. If there is an enzymatic defect or inhibitor, metabolites may accumulate, resulting in expression of clinical symptoms. The disorders are listed in boxes: acute disorders as solid lines and cutaneous disorders with dashed lines. See text for additional information. ALAS1, aminolevulinic acid synthase 1, enzyme used in hepatic heme synthesis; ALAS2, aminolevulinic acid synthase 2, enzyme used in erythrocytic heme synthesis, upregulated in X-linked protoporphyria; ALAD, aminolevulinic acid dehydratase, enzyme deficient in ALAD deficiency porphyria; HMBS, hydroxymethylbilane synthase, enzyme deficient in acute intermittent porphyria; UROS, uroporphyrinogen III synthase, enzyme deficient in congenital erythropoietic ...

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