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Porphyrias are diseases that result from derangements of specific enzymes in the heme biosynthetic pathway that lead to overproduction and accumulation of pathway intermediates that cause neurologic symptoms, photocutaneous symptoms, or both. Inherited mutations within the genes encoding the eight committed steps in heme synthesis have been identified in each of the porphyrias. An acquired form of porphyria cutanea tarda (PCT) is caused by an inhibitor of the fifth enzyme in the heme biosynthetic pathway, specifically in the liver, and is usually not associated with a mutation of this enzyme.

Porphyrias can be classified as either hepatic or erythropoietic, depending on the principal site of initial accumulation of excess pathway intermediates. Erythropoietic porphyrias are characterized by childhood onset and a generally stable clinical course. Hepatic porphyrias almost always develop during adult life, and are more variable because of multiple influences of drugs, hormones, and nutritional factors on the heme biosynthetic pathway in the liver.

Porphyrias are also classified as acute or cutaneous. The four acute porphyrias are associated with neurologic manifestations that usually occur as acute attacks. δ-Aminolevulinate dehydratase porphyria (ADP) is an autosomal recessive disorder caused by a deficiency of the second enzyme in the pathway and is the rarest type of porphyria. ADP is classified as hepatic, but also has erythropoietic features. The three other acute porphyrias, namely acute intermittent porphyria (AIP), hereditary coproporphyria (HCP), and variegate porphyria (VP), are autosomal dominant hepatic porphyrias, and result from deficiencies of the third (porphobilinogen deaminase [PBGD]), sixth (coproporphyrinogen oxidase [CPO]), and seventh (protoporphyrinogen oxidase [PPO]) enzymes in the pathway, respectively. HCP and VP are also classified as cutaneous, because photocutaneous lesions may develop, especially in VP. AIP is the most common acute porphyria and the second most common porphyria. Disease expression is highly variable in the acute hepatic porphyrias, and the great majority of individuals who inherit mutations of these enzymes remain latent through all or most of their lives. Attacks are precipitated by factors that increase hepatic heme synthesis, including certain drugs, sex steroid hormones and their metabolites, and restriction of dietary calories and carbohydrate. Treatment of acute porphyrias includes glucose loading, hemin infusions, and RNA interference, all of which target δ-aminolevulinic acid synthase-1 (ALAS1), the rate-limiting enzyme of the heme biosynthetic pathway in the liver.

Cutaneous porphyrias are associated with either blistering skin lesions or, in the protoporphyrias, with acute nonblistering photosensitivity. Blistering skin manifestations are nearly identical in PCT, HCP, and VP. In congenital erythropoietic porphyria (CEP), the cutaneous manifestations are much more severe and are often associated with loss of digits and facial mutilation. CEP results from a severe deficiency of the fourth enzyme in the pathway, uroporphyrinogen III synthase (UROS), and is inherited in an autosomal recessive fashion. Hemolytic anemia is common, and severe cases may be transfusion dependent, and may even present in utero with fetal hydrops. Hematopoietic stem cell transplantation in early childhood is the most effective treatment.

Erythropoietic protoporphyria (EPP) is the ...

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