HMB-synthase; formerly known as porphobilinogen deaminase or utoporphyrinogen I synthase). Clinical onset of AIP typically occurs during or after puberty and is characterized by acute attacks of neurologic dysfunction. These attacks include abdominal pain, hypertension, tachycardia, and various peripheral and central nervous system manifestations. The attacks are precipitated by environmental (e.g., certain drugs, dieting, or starvation), metabolic (e.g., alcohol), and hormonal (e.g., certain steroids) factors that induce hepatic S-aminolevulinic acid synthase activity, the first and rate-limiting enzyme of heme bi0synthesis.l-' With increased activity of this enzyme, levels of the porphpin precursors, 5-aminolevulinic acid (ALA) and porphobilinogen (PBG} increase, and the halfnormal level of hepatic EIMB-synthase activity in AIP patients is insufficient to prevent pathologic accumulation of these compounds, and acute, life-threatening neurologic symptoms. Presyrnptornatic identification of heterozygotes in affected families, and counseling regarding the avoidance of the precipitating factors is crucial in the management of this disease. Symptomatic heterozygotes, who excrete increased urinary levels of A m and PBG, are easily identified, provided that the diagnosis is considered. In contrast, the diagnosis of asymptomatic heterozygotes (-80% of heterozygous individuals), who usually have normal levels of urinary A M and PBG, has been problematic primarily due to the significant overlap between high heterozygote and low normal values of HMBsynthase activity in Therefore, efforts have been directed to identify the specific HMB-synthase mutations in each family, particularly because most mutations have been "private," i.e., limited to a single or few families.HMB-synthase is a monomeric enzyme that catalyzes the head to tail condensation of four molecules of PBG to form the linear tetrapyrrole hydroxymethylbilane.l.2 HMB-synthase is encoded by a single 1 1-kb gene that contains 15 exons and 2 distinct promoters that generate housekeeping and erythroidspecific transcripts by alternative spli~irig.'~-'~ The housekeeping promoter is in the 5' flanking region and its transcript contains exons 1 and 3-1 5, whereas the erythroid-specific promoter is in intron 1 and its transcript is encoded by exons 2-15. The hausekeeping and erythroid-specific transcripts encode isozymes of 42 and 40 m a , respectively.ll In classic RIP (-95% of the AIP families), both the housekeeping and erythroid-specific isozymes have half-normal activities, whereas in variant AIP (representing -5% of AIP families), the house-
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