The porphyrias are classified as acute or nonacute (cutaneous) according to their clinical and biochemical features (Table 1).

Table1. Classification of Porphyrias

Each of the different types of porphyria is linked to a reduced activity or deficiency of a specific enzyme in the heme biosynthetic pathway, with the exception of X-linked dominant erythropoietic protoporphyria, which results from inheritance of a gain-of function mutation in the ALAS2 gene (see Fig. 1). When porphyria is caused by a loss-of-function mutation, the resulting enzyme deficiency impairs the production of the end-product heme, and there is overproduction and increased excretion of the heme precursors formed by the steps before the enzyme defect. There is also a compensatory increase in activity of the initial and rate-controlling enzyme ALAS. In the acute porphyrias, there is overproduction of all the porphyrins and porphyrin precursors (e.g., ALA, PBG) formed proximal to the enzyme defect. The increased excretion of porphyrin precursors in the acute porphyrias is caused by decreased activity of PBGD in these conditions. The decrease can be caused by genetic mutation of the enzyme (in AIP) or by inhibition of PBGD by protoporphyrinogen and coproporphyrinogen in variegate porphyria and hereditary coproporphyria, respectively.

Fig1. PATHWAY OF HEME BIOSYNTHESIS IN MAMMALIAN CELLS. The first step in the pathway is catalyzed by aminolevulinate synthase (ALAS) and occurs within the mitochondrion using pyridoxal 5′-phosphate as a cofactor. 5-Aminolevulinate (ALA) then leaves the mitochondrion and is converted by ALA dehydratase to give a monopyrrole, porphobilinogen. Four molecules of this compound are converted by porphobilinogen deaminase to a linear tetrapyrrole, hydroxymethylbilane. This molecule is then cyclized by uroporphyrinogen III synthase to uroporphyrinogen III, which is decarboxylated to coproporphyrinogen III. This molecule enters the mitochondrion and is oxidized in succession by coproporphyrinogen III oxidase and protoporphyrinogen oxidase. The product is protoporphyrin IX, a substrate for ferrochelatase, which catalyzes the insertion of Fe2+ to form heme. A mitochondrial heme exporter has been identified as feline leukemia virus subgroup C receptor 1b. The defective steps associated with specific porphyrias and X-linked hereditary sideroblastic anemia are shown.

In the nonacute porphyrias, there is overproduction of all porphyrins formed before the enzyme defect but no overproduction of porphyrin precursors. The cause of this lack of overproduction of porphyrin precursors in the nonacute porphyrias is unclear, but it may result from a compensatory increase in the activity of the enzyme PBGD in addition to increased activity of ALAS and site-specific heme synthesis.33 The pattern of overproduction and excretion of porphyrins and porphyrin precursors in the various porphyrias is shown in Table 2. A consequence is that each of the different porphyrias is characterized by a different excretion pattern. Quantitative studies of the different porphyrins and precursors in the urine and feces usually identify the particular type of porphyria. The porphyrin precursors ALA and PBG and the more water-soluble porphyrins (with multiple carboxyl groups) are excreted mainly in the urine. Other porphyrins are mainly excreted in the feces by way of bile.

Table2. Changes in Porphyrins and Their Precursors in the Porphyrias, Porphyrinurias, and Hereditary Sideroblastic Anemia

The clinical manifestations of an acute attack of porphyria can be explained by dysfunction of the central, peripheral, and autonomic nervous systems. The mechanism by which altered heme synthesis results in dysfunction is unknown, although porphyrin-induced protein aggregation may be a mechanism for both external and internal tissue dam age in porphyrias that involve fluorescent porphyrin accumulation.

Perhaps the most likely hypothesis is that the neurologic and muscular manifestations of acute porphyria arise as a result of heme deficiency within the nerve cells, which causes dysfunction of the energy-dependent Na+/K+ ATPase. The proposal that axonal dysfunction results from impaired energy metabolism is supported by the findings of axonal membrane depolarization during acute attacks of porphyric neuropathy and reduction in inward rectification between episodes. However, this does not exclude the possibility that ALA may also act as a pharmacologic agent in these diseases, compounding the effects of heme deficiency. ALA has a pro-oxidant effect on rat brain tissues and generates free radical species during its auto-oxidation, and this oxidant stress has been proposed to directly damage myelination by Schwann cells. The concept of auto-oxidation or oxidative stress is supported by the hypothesis that manganese excess could contribute to induction of superoxide dis mutase and increased indicators of such stress in lead exposure. There is evidence that ALA enters cells by a pathway common to it and γ-aminobutyric acid (GABA).

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