Acute intermittent porphyria (referred to as AIP in this GeneReview) results from half-normal activity of the enzyme hydroxymethylbilane synthase (HMBS). It is characterized clinically by life-threatening acute neurovisceral attacks of severe abdominal pain without peritoneal signs, often accompanied by nausea, vomiting, tachycardia, and hypertension. Attacks may be complicated by neurologic findings (mental changes, convulsions, and peripheral neuropathy that may progress to respiratory paralysis), and hyponatremia. Acute attacks, which may be provoked by certain drugs, alcoholic beverages, endocrine factors, calorie restriction, stress, and infections, usually resolve within two weeks. Most individuals with AIP have one or a few attacks; about 5% (mainly women) have recurrent attacks (defined as >4 attacks/year) that may persist for years. Other long-term complications are chronic renal failure, hepatocellular carcinoma (HCC), and hypertension. Attacks, which are very rare before puberty, are more common in women than men. All individuals with a genetic change in the gene HMBS that predisposes to AIP are at risk of developing acute attacks; however, most never have symptoms and are said to have latent (or presymptomatic) AIP.
With one exception (5-aminolevulinate dehydratase deficiency [ALAD]), acute attacks of porphyria are associated with an increased urinary concentration of porphobilinogen (PBG). Demonstration that an increased PBG concentration is caused by AIP requires exclusion of other acute porphyrias by analysis of porphyrins in stool and plasma. Molecular genetic testing is used in a symptomatic individual to identify a mutation that can then be used to identify AIP in relatives of the proband. Assay of erythrocyte HMBS enzyme activity may be useful in families in which an HMBS mutation cannot be identified or when molecular testing is not available.
AIP is inherited in an autosomal dominant manner. About 1% of probands may have a de novo mutation. Sibs and offspring of individuals with an HMBS mutation are at 50% risk of inheriting the HMBS mutation; however, because penetrance is low the likelihood of an individual with an inherited HMBS mutation having an acute attack is small. Prenatal testing is possible but is rarely requested because of the low clinical penetrance and favorable clinical outcome for the great majority of symptomatic adults.