Acute Intermittent Porphyria

Acute intermittent porphyria (AIP) is the most common and most clinically significant of the acute hepatic porphyrias, a group of inherited metabolic disorders caused by defects in the heme biosynthesis pathway. AIP results from an autosomal dominant mutation in the gene encoding porphobilinogen deaminase (PBG deaminase, also called hydroxymethylbilane synthase or uroporphyrinogen I synthase), the third enzyme in the heme biosynthetic pathway. This enzyme normally catalyzes the conversion of porphobilinogen (PBG) to hydroxymethylbilane. When the enzyme is deficient, porphobilinogen and its precursor delta-aminolevulinic acid (ALA) accumulate to toxic levels during acute attacks, producing the characteristic neurovisceral symptoms. The heme biosynthesis pathway consists of eight enzymatic steps, beginning with the condensation of glycine and succinyl-CoA to form delta-aminolevulinic acid (ALA) in the mitochondria (catalyzed by ALA synthase, the rate-limiting enzyme) and ending with the insertion of iron into protoporphyrin IX to form heme. Heme serves as the prosthetic group for hemoglobin, myoglobin, cytochrome P450 enzymes, and catalase. Under normal conditions, heme production is tightly regulated by negative feedback inhibition of ALA synthase -- when heme levels are adequate, ALA synthase activity...