First case of heteroallelic homozygous dominant acute intermittent porphyria in Argentina

PAUWELS, BELEN; GEREZ, ESTHER; BATLLE, ALCIRA; PARERA, VICTORIA; ROSSETTI, MARIA VICTORIA

Cardiff

Congreso; International Porphyrins and Porphyrias Meeting; 2011

   Acute intermittent porphyria (AIP) is an acute liver disorder caused by a deficiency of Porphobilinogen deaminase (PBG-D). It is characterized by an increase in the expression of the first enzyme of heme way, the ƒÂ-aminolevulinic acid synthase 1 (ALA-S1) and the resulting accumulation of toxic intermediate of this pathway. It is an autosomal dominant disease, however, five cases of homozygous dominant AIP (HD-AIP) in heteroallelic and homoallelic condition have been described, in one of these cases no enzymatic or molecular direct diagnostic were report. In some of them cases prominent neurological symptoms, psychomotor retardation and erythrodontia were observed.  We studied a patient with abdominal pain and neurological attacks characteristic of patients with AIP who also had mild skin symptoms and erythrodontia. The aim of this study was to analyze the biochemical and genetic patientLs studies to establish a differential diagnosis of this case of porphyria. Urine biochemical results: ALA: 3.4 mg/24 (NV: = 4mg/24h), PBG: 15.5 mg/24h (NV: = 2mg/24h), urinary porphyrins: 8459 mg/24h (NV: = 250mg/24h), Copro: 19%, Penta: 6%, Hexa: 1%, Hepta: 4%, Uro: 70% (NV: 100% Copro) blood: IPP: 5.30 at ƒÉ 619 nm (NV: = 1.30), 427 total porphyrins ƒÊg/100ml BRC (NV: 150 } 40 ƒÊg/100ml BRC), in stool: Total porphyrins: 655 mg / g dry (30-130 mg / g dry), indicated the presence of an erythropoietic component. The value of the PBG-D was 37.73 U / ml BRC (VN: 75.47 } 11.96 U / ml BRC) Genetic diagnosis was performed in peripheral blood by PCR and automatic sequencing. The results indicated the presence of two mutations in the PBG-D gene, p.G111R and p.E258G, revealing a case of heteroallelic HD-AIP. The mutation p.G111R is located on the surface of the protein, but to date the effect of the change of amino acid G by R is not known. Prokaryotic expression of the new PBG-D mutation p.E258G showed that the mutated protein have an enzyme residual activity of about 80%.  Thermal studies revealed no difference significant between the wild type and mutated  protein to 65‹C. Those patientLs symptoms uncommon to AIP cases would not be explained by our results. Moreover, her PBG-D enzyme activity would be in accordance with the absence of the more severe symptoms associated to the HD-AIP already observed in other patients described.