ABSTRACT
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 over expression 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 pre symptomatic heterozygotes in
AIP families, permitting better counseling.
KEY WORDS
acute intermittent porphyria - porphobilinogen deaminase - mutations - gene - cDNA
