ACUTE INTERMITTENT PORPHYRIA: THE FIRST "OVERPRODUCTION DISEASE" LOCALIZED TO A SPECIFIC ENZYME.

Abstract

Acute intermittent porphyria is an inborn error of metabolism characterized chemically by the excretion in the urine of excessive amounts of porphyrin precursors [6-aminolevulinic acid (ALA) and porphobilinogen (PBG) ]-6 and clinically by neurologic dysfunction. It is transmitted as an autosomal dominant disorder with an incidence of about 1.5 per 100,000 in most areas.7 Chemical manifestations which resemble those of acute intermittent porphyria can be produced in animals by administration of any one of several compounds.8 9 The increased excretion of porphyrin precursors seen in experimental porphyria produced by at least one of these compounds (allylisopropylacetamide) is now thought to result from the induction in liver of a-aminolevulinic acid synthetase (ALA synthetase), the ratecontrolling enzyme of porphyrin biosynthesis.l0-'2 The enzyme occurs exclusively in mitochondria.0, 12 The induction of this enzyme can be inhibited by carbohydrate administration,l2 a phenomenon previously demonstrated with certain other inducible enzymes and termed the glucose effect. The inhibition of induction of hepatic ALA synthetase by carbohydrate explains the observation that the ability to produce experimental porphyria is reciprocally related to the intake of carbohydrate in the diet.l3 The fact that changes in diet in the human genetically determined disease produced similar effects on porphyrin precursor excretion to those seen in experimental porphyria suggested that ALA synthetase was induced in the livers of patients with the disease and that the induction in man was subject to the glucose effect.l4 Using a new method for the measurement of ALA syn