Molecular analysis of acute intermittent porphyria: mutation screening in 20 patients in Germany reveals 11 novel mutations

Acute intermittent porphyria (AIP) is a very rare autosomal dominant disorder with low penetrance. Mutations in the gene of the porphobilinogen deaminase (PBG-D), also called hydroxymethylbilane synthase (HMBS), cause a partial deficiency of this enzyme of the heme biosynthetic pathway. Overstimulation of heme biosynthesis causes clinical symptoms. Because of the variability of the symptoms, diagnosis is often delayed. Using two approaches for genetic analysis, first in a stepwise manner, then sequencing extensive parts of the gene, the screening of the DNA of 20 unrelated individuals revealed 20 different mutations, 11 of which had not been reported previously. The novel mutations affected intron 1 (33 + 2 T→C), exon 5 (181 G→C), intron 6 (267–61 del 8 bp), intron 7 (345–1 G→C), intron 9 (498 + 15 G→T and 499–13 Δ-14 bp indel TGA), intron 13 (825 + 1 G→C and 825 + 2 T→C), exon 15 (962 G-A, 1067 del A and 1067–1068 ins 5 bp). The other nine mutations detected affected intron 14, exons 6, 7, 8, 9, 10 (3×) and 12. In the majority of AIP patients, the genotype does not predict phenotypic expression. Since the sudden manifestation of the disease maybe prevented by early diagnosis, identification of AIP gene carriers is the best preventive measure. This was performed in five families, revealing 10 additional AIP gene carriers.