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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 and cause neurologic symptoms, photocutaneous symptoms or both. Multiple inherited mutations have been identified in all the porphyrias. However, porphyria cutanea tarda (PCT), which is caused primarily by an acquired deficiency of the fifth enzyme in the heme biosynthetic pathway, specifically in the liver, 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 has been 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, sixth, and seventh 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 acute porphyrias, and the great majority of individuals who inherit deficiencies of these enzymes remain latent through all or most of their lives. Attacks are produced 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 and hemin infusions, which repress δ-aminolevulinic acid synthase-1, the rate-limiting enzyme of the heme biosynthetic pathway in the liver.

Cutaneous porphyrias are associated with either blistering skin lesions or, in erythropoietic protoporphyria (EPP), with acute nonblistering photosensitivity. Blistering skin manifestations are identical in PCT, HCP, and VP. Similar lesions in congenital erythropoietic porphyria (CEP) are much more severe and often associated with loss of digits and facial mutilation. CEP results from a severe deficiency of the fourth enzyme in the pathway 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.

EPP is the third most common porphyria and the most common in children. It is usually caused by a deficiency of the final enzyme in the pathway. In most families, inheritance of EPP is best described as ...

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