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Pathogenesis, clinical manifestations, and diagnosis of acute intermittent porphyria

INTRODUCTION

Acute intermittent porphyria (AIP; also called Swedish porphyria, pyrroloporphyria, intermittent acute porphyria) is an acute neurovisceral porphyria resulting from a partial deficiency of the heme biosynthetic enzyme porphobilinogen deaminase (PBGD). It is an autosomal dominant disorder with low penetrance; development of symptoms is affected by a variety of exacerbating factors.

Despite its well characterized molecular genetics, the diagnosis of AIP is challenging. Symptoms are often vague and nonspecific; the other possible causes of neurologic findings and abdominal pain are numerous; and acute porphyria is often not considered because it is rare. Clues from the family history may also be missing, because penetrance of AIP is low and symptoms may not manifest in the majority of family members with a disease-causing mutation. Even if acute porphyria is considered, many clinicians are unfamiliar with typical findings of the disease, appropriate testing, and interpretation of test results. As a consequence, diagnosis and life-saving treatment are often delayed.

The pathogenesis, clinical manifestations, and diagnosis of AIP will be reviewed here. Management of AIP and a general overview of the porphyrias are presented separately. (See "Management and prognosis of acute intermittent porphyria" and "Porphyrias: An overview".)

PATHOGENESIS

Porphyrias are caused by alterations in the enzymes of heme biosynthesis. In addition to its essential function in the production of hemoglobin, heme is also an integral component of many other hemoproteins, including hepatic enzymes such as cytochrome P450 enzymes. The liver is the major source of overproduction of heme pathway intermediates in patients with hepatic porphyrias such as AIP; and the central, peripheral, autonomic, and enteric nervous systems are affected when levels of these intermediates are elevated in the circulation, suggesting neurotoxic effects of one or more intermediates. Some neurological manifestations may result from heme depletion in neuronal cells. (See 'Neurological dysfunction' below.)

Gene mutation — AIP is caused by heterozygosity for a mutation in the gene encoding porphobilinogen deaminase (PBGD), also called hydroxymethylbilane synthase (HMBS) and previously referred to as uroporphyrinogen I synthase. Inheritance is autosomal dominant with low penetrance. More than 300 PBGD gene mutations have been recognized in AIP, all of which lead to severe loss of PBGD enzymatic activity from the mutant allele. Virtually all remaining PBGD activity is due to expression from the unaffected allele.

                            

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Literature review current through: Oct 2014. | This topic last updated: Aug 20, 2014.
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