Acute intermittent porphyria

Acute intermittent porphyria (AIP) is transmitted as an autosomal dominant disorder with incomplete penetrance. Recent population studies suggest that the prevalence of asymptomatic heterozygotes for a mutant AIP gene may be in the range of 1 in 2,000. Clinical manifestations include abdominal pain and neurological dysfunctions. These symptoms occur during acute attacks, which are often precipitated by drugs, alcohol, low caloric intake, or infections. Biochemical abnormalities are thought to result from primary defects of porphobilinogen deaminase (PBGD; also called hydroxymethyl bilane synthase), the third enzyme of the heme synthesis pathway, and consecutive hepatic overexpression of the first enzyme of the pathway, 5-aminolevulinate synthase. As a result of these enzymatic disturbances, heme precursors are synthesized in excess in the liver, and massive amounts of compounds upstream of the enzymatic block are excreted in urine. Although the pathophysiology of the disease has not yet been fully elucidated, a specific treatment of acute attacks with heme has improved the prognosis. The cDNAs and the gene encoding PBGD have been isolated, permitting identification of mutations that account for the corresponding enzymatic deficiencies. Consequently, DNA analysis improves the accuracy of detection of presymptomatic heterozygotes in AIP families, permitting better counseling.