Odd cases of heteroallelic compound heterozigocity in Acute Intermittent Porphyria in Argentina

PARERA V.; CERBINO G.; VARELA L.; GUOLO M.; BATLLE A.; ROSSETTI MV

Düsseldorf

Congreso; International Congress on Porphyrins and Porphyrias; 2015

ICPP

Porphyrias are metabolic diseases arising from deficiencies in the hemepathway enzymes. Acute Intermittent Porphyria (AIP), the most frequent acuteporphyria in Argentina, is a rare dominant autosomal disorder with incompletepenetrance where by overstimulation of heme biosynthesis leads to clinicalsymptoms. Because its manifestation might be forestall, identification ofmutations in the hydroxymethylbilane synthase gene (HMBS) is the bestpreventive measure. However, in most of AIP patients, genotype does notpredict phenotypic expression.As stated, AIP is a dominant autosomal unrest. Although a few homozygous ordouble heterozygous cases were described, the majority involved criticalarginine residues at the active site resulting in a greatly reduced enzyme activityand severe neurological signs.Using the long range PCR approach we found 3 families, each having twodifferent mutations on the HMBS gene. Diagnosis was made based, on theirclinical history with at least one acute attack, enhanced urinary excretion of ALAand PBG and reduced HMBS activity in RBCs. Final diagnosis, was geneticallyestablished.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 asecond (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 missensemutation (p.R321H) in exon 15. All patients had 50% reduction of PBG-Dactivity.Clinical and biochemical results in these families would indicate that unlessessential residues in both alleles were affected, when 2 mutations are presentresidual PBG-D activity, is enough to support nearly normal heme biosynthesis.These cases would behave as heterozygous cases of AIP or likely one of bothgene variants could function as a disease-modifying allele.