ALA dehydratase deficiency

ALA dehydratase deficiency (hepatic) (MIM 125270) Acute intermittent porphyria (hepatic) (MIM 176000) Congenital erythropoietic (erythropoietic) (MIM 263700)... 

The acute porphyrias include ALA dehydratase deficiency porphyria (ADP), AIP, VP, and HCP. These disorders are autosomal dominant except for ADP, which is autosomal recessive. 

Figure 44-3. Heme biosynthetic pathway and characteristics associated with specific enzyme-deficiency porphyrias. ADP = ALA dehydratase deficiency porphyria AIP = acute intermittent porphyria CEP = congenital erythropoietic porphyria PCT = porphyria cutanea tarda HEP = hepatoerythropoietic porphyria HCP = hereditary coproporphyria VP = variegate porphyria EPP = erythropoietic protoporphyria.

The first disease manifestion is rarely before puberty, the first maximum is in the young adults and a second in senescence. Females are 5-10 times more often symptomatic than males and often show spontaneous symptomatology in the premenstrual days. The rare autosomal recessive acute porphyria (ALA-dehydratase deficiency, 31.1) may become symptomatic shortly after birth in the neonatal period or late after puberty with the same symptoms as other acute porphyrias (Table 31.2). 

ALA-dehydratase deficiency Acute attacks Neonatal periode Very rare... 

The reaction mechanism consists of Schiff base formation by the keto group of one molecule of ALA with the e-amino group of a lysyl residue of the enzyme, followed by nucleophilic attack by the enzyme-ALA anion on the carbonyl group of a second ALA molecule with elimination of water. Then, a proton is transferred from the amino group of the second ALA molecule to the e-amino group of the lysyl residue with formation of PBG. Lead is a potent inhibitor of ALA dehydratase, presumably by displacement of zinc by lead because the lead-inhibited enzyme can be reactivated by the addition of zinc. ALA dehydratase is inhibited competitively by suc-cinyl acetone (HOOC-CH2-CH2-CO-CH2-CO-CH3), which occurs in urine and blood in hereditary tyrosinemia (Chapter 17). Genetic deficiency of ALA dehydratase is known to occur. 

C. An increase in urine/serum ALA without concomitant increase in PBG indicates disrupted activity of ALA dehydratase. ALA alone can cause the same neurovisceral symptoms as ALA and PBG together cause in AIP. ALAD-deficiency porphyria is an extremely rare autosomal recessive disorder. 

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