ALA dehydratase porphyria
- Karl E Anderson, MD, FACP
Karl E Anderson, MD, FACP
- The University of Texas Medical Branch
The porphyrias are metabolic disorders caused by altered activity of enzymes within the heme biosynthetic pathway. Delta-aminolevulinic acid (ALA) dehydratase (ALAD) porphyria (ADP; OMIM 612740, also called Doss porphyria and plumboporphyria) is the rarest of the inherited porphyrias, with only six documented cases reported worldwide.
ADP is an acute hepatic porphyria. It is an autosomal recessive disorder resulting from severe deficiency of ALAD, the second enzyme in the pathway of heme synthesis (figure 1). The incidence, pathophysiology, diagnosis, and treatment of ADP will be reviewed here. An overview of porphyrias is presented separately. (See "Porphyrias: An overview".)
DEFINITION AND HISTORY
Delta-aminolevulinic acid (ALA) dehydratase (ALAD) porphyria (ADP) is an acute porphyria resulting from severe ALAD deficiency that is caused by a genetic defect. The first two cases  and the fifth  were identified in Germany by Doss, and therefore the disease is referred to as Doss porphyria. It has also been termed plumboporphyria because ALAD is inhibited by lead, and lead poisoning can mimic the clinical and biochemical findings of ADP.
Enzymology — Heme synthesis defects can cause accumulation of pathogenic intermediates in red blood cell precursor and hepatic cells that leak into the plasma and cause toxicity to a variety of tissues. ALA dehydratase porphyria (ADP) is caused by severe reduction in the activity of the second enzyme in the heme biosynthetic pathway, delta-aminolevulinic acid (ALA) dehydratase (ALAD, also called porphobilinogen synthase [PBGS]; EC 18.104.22.168) (figure 1). ALAD catalyzes the formation of the monopyrrole porphobilinogen (PBG) from two molecules of ALA (figure 2), the obligate heme precursor.
Relative to activities of other enzymes in the heme biosynthetic pathway, ALAD is present in vast abundance in mammalian cells. In the liver, for example, the activity of ALAD is 80- to 100-fold that of ALA synthase, the first enzyme in the heme biosynthetic pathway and the rate-limiting enzyme in the liver (figure 1 and table 1) . This physiologic abundance of ALAD helps to explain why heterozygotes with half-normal ALAD activity are asymptomatic.
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