Acute intermittent porphyria: novel missense mutations in the human hydroxymethylbilane synthase gene

Abstract

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-

HMBS gene mutations and hydroxymethylbilane synthase activity in acute intermittent porphyria: A systematic review

“…Finally, 15 studies were obtained for analysis. [9][10][11][12][13][14][15][16][17][18][19][20][21][22][23]…”

“…María-José et al [9] 55 25 PCR Fluorescence method Spanish Ulbrichova et al [10] 26 6 PCR Fluorescence method Israeli Yang et al [11] 24 21 PCR Fluorescence method Chinese To-Figueras et al [12] 16 10 PCR Fluorescence method Spanish Pischik et al [13] 20 9 PCR Fluorescence method Russian Solis et al [14] 3 1 PCR Fluorescence method Spanish Hessels et al [15] 3 1 PCR Fluorescence method Turkish Gregor et al [16] 20 16 DGGE Fluorescence method Polish Martinez et al [17] 14 13 DGGE Fluorescence method Italian Ramdall et al 2000 [18] 5 5 PCR Fluorescence method USA Martinez et al [19] 8 7 DGGE Fluorescence method Italian De Siervi et al [20] 22 4 PCR Fluorescence method Argentinean Maeda et al [22] 10 1 PCR Fluorescence method Japanese De Siervi et al [23] 12 5 PCR Fluorescence method Argentinean Solis et al [21] 9 8 PCR Fluorescence method Spanish DGGE = denaturing gradient gel electrophoresis, PCR = polymerase chain reaction.…”

R173W Mutation of Hydroxymethylbilane Synthetase Is Associated With Acute Intermittent Porphyria Complicated With Rhabdomyolysis

“…1,2 Mounting evidence has demonstrated the relative safety of immunosuppressives and biologics in the treatment of IBD. The management of IBD during pregnancy can provoke a great deal of anxiety in patients and physicians alike.…”

“…Compared with age-matched controls, pregnant women with IBD are more likely to have spontaneous abortions, preterm deliveries, and low fetal birth weights. 2,6,7 An important issue that has not been addressed is how to manage recurrence of IBD activity in the third trimester. 1,2 Mounting evidence has demonstrated the relative safety of immunosuppressives and biologics in the treatment of IBD.…”