CONICET | Buscador de Institutos y Recursos Humanos

Porphyrias are metabolic diseases arising from deficiencies in the heme pathway enzymes. Acute Intermittent Porphyria (AIP), the most frequent acute porphyria in Argentina, is a rare dominant autosomal disorder with incomplete penetrance where by overstimulation of heme biosynthesis leads to clinical symptoms. Because its manifestation might be forestall, identification of mutations in the hydroxymethylbilane synthase gene (HMBS) is the best preventive measure. However, in most of AIP patients, genotype does not predict phenotypic expression.As stated, AIP is a dominant autosomal unrest. Although a few homozygous or double heterozygous cases were described, the majority involved critical arginine residues at the active site resulting in a greatly reduced enzyme activity and severe neurological signs. Using the long range PCR approach we found 3 families, each having two different mutations on the HMBS gene. Diagnosis was made based, on their clinical history with at least one acute attack, enhanced urinary excretion of ALA and PBG and reduced HMBS activity in RBCs. Final diagnosis, was genetically established.Two unrelated families showed the same genetic variant in IVS6 c.267-61del8bp (gaaggggt), a deletion leading to the loss of exon 7. Each family has a second (trans) missense mutation: the first is p.G111R and the other is p.R26C, both already described as causing AIP. The 3rd family carries a splicing defect (c.772-1 G>A) leading to exon 13 skipping and on the other allele a missense mutation (p.R321H) in exon 15. All patients had 50% reduction of PBG-D activity. Clinical and biochemical results in these families would indicate that unless essential residues in both alleles were affected, when 2 mutations are present residual PBG-D activity, is enough to support nearly normal heme biosynthesis. These cases would behave as heterozygous cases of AIP or likely one of both gene variants could function as a disease-modifying allele