ACUTE INTERMITTENT PORPHYRIA IN FINLAND - 19 MUTATIONS IN THE PORPHOBILINOGEN DEAMINASE GENE

The sensitivity of single-strand conformation polymorphism (SSCP) analysis for the detection of mutations in the porphobilinogen deaminase (PBGD) gene among Finnish patients with acute intermittent porphyria (AIP) was studied. 13 novel mutations including one de novo event, and six previously characterized mutations were identified among AIP patients. The 19 mutations reported here for 28 families cover 72% of all the AIP families in the Finnish population of five million. When compared to direct sequencing, SSCP-analysis detected 17 (89%) of the 19 mutations when a combination of various electrophoretic conditions were used. The most informative electrophoretic condition was a gel run without glycerol in the coldroom (11/18 mutations). 86% of mutations were identified from amplified fragments greater than 300 bp and detection was dependent on both the amount of glycerol in the gel and the running temperature, but seemed to be independent of the size of the analyzed fragment or the type of mutation. The diagnostic efficiency of biochemical assays versus mutation screening in the PBGD gene was studied in three large AIP families, each representing different GRIM subtypes of AIP. The results demonstrated that using assays of erythrocyte PBGD activity, the majority (82%) of family members (n = 51) were diagnosed correctly. Of a total of 81 family members, 30 of whom had deficiency of PBGD confined to non-erythroid tissues, diagnosis at the asymptomatic stage of disease in 11 individuals (14%) required the application of mutation screening.