MOLECULAR EPIDEMIOLOGY AND DIAGNOSIS OF PBG DEAMINASE GENE DEFECTS INACUTE INTERMITTENT PORPHYRIA

Acute intermittent porphyria (AIP) is the major autosomal dominant for m of acute hepatic porphyrias. The disease is due to mutations in the gene encoding for porphobilinogen (PEG) deaminase and is characterized by life-threatening neurovisceral attacks, often precipitated by drug s, fasting, cyclical hormonal changes, or infectious diseases. This re port describes a prospective study on the molecular epidemiology of PE G deaminase gene defects in AIP. It uses a sensitive, reliable, and ea sy-to-handle method for routine AIP molecular diagnosis and family stu dy based on an exon-by-exon denaturing gradient gel electrophoresis (D GGE) strategy followed by direct sequencing. Fifteen genomic DNA fragm ents, including all the coding sequence and covering 3.35 kb of the PE G deaminase gene, were investigated in 405 subjects from 121 unrelated French Caucasian AIP families who had not been screened previously at the DNA level. PEG deaminase gene mutations were identified in 109 fa milies, but only 78 were of different type, and each of them had a pre valence rate <5%. Among these mutations, 33 had not been published pre viously. Sixty percent of these 78 mutations were located in only thre e exons (exons 10, 12, and 14), 44% were missense, 18% were splice def ect, 13% were frameshift, and 16% were nonsense. In addition, two de n ovo mutational events were characterized. The evaluation of the effici ency of the standard PEG deaminase enzymatic screening method for gene -carrier detection indicated 95% of con-cordancy with the molecular-ba sed diagnosis.