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Chapter 28: The Porphyrias

INTRODUCTION

  • The porphyrias are inherited or acquired disorders in which the activity of an enzyme in the heme biosynthetic pathway is altered. Metabolic intermediates are produced in excess, initially either in the marrow or the liver, and result in neurologic and/or photocutaneous symptoms and signs.

CLASSIFICATION

  • See Table 28–1.

  • The two organs most active in heme biosynthesis are the marrow and the liver. Photosensitivity (indicated below with the following symbols as either blistering* or nonblistering†) and/or (indicated below with the following symbol as) neurovisceral symptoms‡ may be part of the porphyria phenotype. Therefore, porphyrias are classified as erythropoietic or hepatic and as cutaneous or acute.

TABLE 28–1HUMAN PORPHYRIAS: SPECIFIC ENZYMES AFFECTED BY MUTATIONS, MODES OF INHERITANCE, CLASSIFICATION, AND MAJOR CLINICAL FEATURES OF EACH OF THE HUMAN PORPHYRIAS
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TABLE 28–1 HUMAN PORPHYRIAS: SPECIFIC ENZYMES AFFECTED BY MUTATIONS, MODES OF INHERITANCE, CLASSIFICATION, AND MAJOR CLINICAL FEATURES OF EACH OF THE HUMAN PORPHYRIAS
Porphyriaa Affected Enzyme Known Mutations Inheritance Classification Principal Clinical Features
X-linked protoporhyria (XLP) δ-Aminolevulinic acid (ALA) synthase erythroid-specific form (ALAS2) 4 (gain of function) Sex-linked recessive Erythropoietic Nonblistering photosensitivity
δ-Aminolevulinic acid dehydratase porphyria (ADP) ALA dehydratase (ALAD) 10 Autosomal recessive Hepaticb Neurovisceral
Acute intermittent porphyria (AIP) PBG deaminase (PBGD) 273 Autosomal dominant Hepatic Neurovisceral
Congenital erythropoietic porphyria (CEP) Uroporphyrinogen III synthase (UROS) 36 Autosomal recessive Erythropoietic Neurovisceral
Porphyria cutanea tarda (PCT) Uroporphyrinogen decarboxylase (UROD) 70 (includes HEP) Autosomal dominantc Hepatic Blistering photosensitivity
Hepatoerythropoietic porphyria (HEP) UROD — Autosomal recessive Hepaticb Blistering photosensitivity
Hereditary coproporphyria (HCP) Coproporphyrinogen oxidase (CPO) 42 Autosomal dominant Hepatic Neurovisceral; blistering photosensitivity (uncommon)
Variegate porphyria (VP) Protoporphyrinogen oxidase (PPO) 130 Autosomal dominant Hepatic Neurovisceral; blistering photosensitivity (common)
EPP – classic form Ferrochelatase (FECH) 90 Autosomal recessived Erythropoietic Nonblistering photosensitivity

aPorphyrias are listed in the order of the affected enzyme in the heme biosynthetic pathway.

bThese porphyrias also have erythropoietic features, including increases in erythrocyte zinc protoporphyrin.

cHeterozygous UROD mutations are present in familial (type 2) but not in the more common sporadic (type 1) PCT. In all cases, an acquired inhibition of hepatic UROD reduces the enzyme activity to less than ~20% of normal.

dBecause both alleles are abnormal in affected individuals (in most cases with a severe FECH mutation trans to a hypomorphic FECH allele), EPP is now regarded as recessive at the molecular level.

Source: Williams Hematology, 9th ed, Chap. 58, Table 58–1.

Erythropoietic Porphyrias

  • Principal site of initial accumulation of pathway intermediates: the erythroblast

  • Congenital erythropoietic porphyria (CEP)*

  • Erythropoietic protoporphyria (EPP)†

  • X-linked protoporphyria (XLP)†

Hepatic Porphyrias

  • Principal site of initial accumulation of pathway intermediates: the liver

  • δ-Aminolevulinic acid dehydratase porphyria (ADP)‡

  • Acute intermittent porphyria (AIP)‡

  • Hereditary coproporphyria (HCP)*‡

  • Variegate ...

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