Wiederholt T1, Poblete Gutiérrez P1, Gardlo K2, Bolsen K2, Merk HF3, Frank J4
1Department of Dermatology and Allergology and Porphyria Center and Interdisciplinary Center for Clinical Research, University Clinic of the RWTH Aachen, Aachen, 2Department of Dermatology, Heinrich Heine University Düsseldorf, Düsseldorf, 3Department of Dermatology and Allergology, University Clinic of the RWTH Aachen, Aachen, 4Department of Dermatology and Allergology and Porphyria Center, University Clinic of the RWTH Aachen, Aachen, Germany
The porphyrias are a group of metabolic disorders arising from catalytic deficiencies of specific enzymes along the heme biosynthetic pathway. Acute intermittent porphyria (AIP) is the most frequent type of acute porphyria worldwide and results from a decreased activity of porphobilinogen deaminase (PBGD), the third enzyme in heme biosynthesis. Clinically, the disease is characterized by life-threatening acute neurological attacks that can be provoked by porphyrinogenic drugs. AIP is transmitted as an autosomal trait with incomplete penetrance and, to date, several disease causing mutations have been reported. In an effort to characterize the molecular basis of AIP in Germany, we identified seven different mutations in ten AIP families by PCR, heteroduplex analysis, automated sequencing, and restriction enzyme digestion. Interestingly, a mutation located at the donor splice site of exon 1 was found in four unrelated families of German origin thus raising the possibility that this mutation might represent a mutational hotspot or a novel founder mutation in the PBGD gene. Our data emphasize the molecular heterogeneity in AIP and confirm the advantages of DNA analysis as a diagnostic tool and for the detection of clinically asymptomatic mutation carriers within AIP families.