We searched Embase, Medline, Ovid, and PubMed, with no restrictions on language or dates. We used the search terms “porphyria” and “genotype”, in combination with “phenotype”, “drugs”, “precipitating factors”, “pathogenesis”, “neuropathy”, “symptoms”, “pharmacogenetics”, “CYP450”, “gene therapy”, “mouse model”, “treatment”, “iron metabolism”, and “haem” plus “enzymes”. We largely selected publications from the past 5 years, but did not exclude commonly referenced and highly regarded older
SeminarPorphyrias
Introduction
Porphyrias are a group of eight panethnic inherited metabolic disorders of haem biosynthesis. Each results from a specific enzymatic alteration in the haem biosynthesis pathway (figure 1). Specific patterns of accumulation of the haem precursors 5-aminolaevulinic acid, porphobilinogen, and porphyrins are associated with characteristic clinical features—acute neurovisceral attacks, skin lesions, or both.1, 2 Eight enzymes bring about haem synthesis from glycine and succinyl CoA. The biosynthetic pathway begins in the mitochondria and, after three cytoplasmic stages, the final steps of haem formation take place in the mitochondria (figure 1).
Although haem is synthesised in every human cell for respiratory and oxidation-reduction reactions, it is mostly produced in the erythropoietic cells for haemoglobin synthesis and the liver parenchymal cells for synthesis of cytochromes and haemoproteins. Control of haem production differs between these two tissues, mostly because of differences in rates of synthesis of 5-aminolaevulinic acid. The first enzyme, 5-aminolaevulinic acid synthase (ALAS), is coded by two genes3—one erythroid specific (ALAS2 on chromosome X) and one ubiquitous (ALAS1 on chromosome 3). ALAS1 is the rate-limiting enzyme in the production of haem in the liver and is controlled via negative-feedback regulation by the intracellular uncommitted haem pool4, 5 (figure 2).
In erythroid cells, synthesis of haem is regulated during erythroid differentiation in response to erythropoietin. In these cells, ALAS2 synthesis is induced only during active haem synthesis. The rate is limited by iron availability and is not inhibited by haem.6 Spleen and liver macrophages degrade haem and recycle iron after erythrophagocytosis through inducible haem oxygenase 1 (figure 2). Porphyrias are often classified as hepatic or erythropoietic according to the organ in which haem precursors accumulate (figure 1). However, a classification as acute porphyrias, cutaneous porphyrias, and rare recessive porphyrias based on clinical presentation is directly related to a simple biological diagnosis strategy and is more practical than are other classifications (figure 3).
Section snippets
Presentation
People with autosomal-dominant acute porphyrias—acute intermittent porphyria, variegate porphyria, and hereditary coproporphyria—can present with a sudden life-threatening crisis. These attacks are infrequent because penetrance is low and they are difficult to diagnose because they are non-specific. Acute attacks happen in all acute porphyrias. Skin lesions never develop in acute intermittent porphyria but are the only clinical manifestation in some patients with variegate porphyria (60% of
Bullous porphyrias
Variegate porphyria, hereditary coproporphyria, and porphyria cutanea tarda share the same chronic cutaneous photosensitivity. Porphyria cutanea tarda is the most frequent type of porphyria worldwide and presents with skin symptoms only. Variegate porphyria and hereditary coproporphyria can present with either cutaneous or neuropsychiatric symptoms (figure 4). Laboratory diagnosis is essential to avoid misclassification and unexpected acute attacks (figure 3 and table 1). Lesions are restricted
Congenital erythropoietic porphyria
Congenital erythropoietic porphyria (or Günther disease) is the most frequent of the rare recessive porphyrias. Inheritance is autosomal recessive, and the disorder results from a pronounced deficiency of uroporphyrinogen III synthase enzymatic activity (UROS). The enzymatic defect causes specific overproduction and excretion of the non-physiological and pathogenic isomer I of uroporphyrin and coproporphyrin (Figure 1, Figure 3).115 Molecular study116, 117 of the UROS gene in these patients has
European porphyria network
The European Porphyria Network (EPNET) is a collaborative project between European porphyria centres that was established to provide improved health care for patients and their families. It has been partly funded by the EU Commission Public Health Executive Agency (PHEA). The overall aim is to develop a common approach to diagnosis and clinical management of porphyrias so that patients, their families, and health-care professionals can benefit from access to evidence-based, consensus-agreed
Search strategy and selection criteria
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