First case of heteroallelic homozigous dominant acute intermittent porphyria in Argentina

PIÑEIRO PAUWELS, MARÍA; GEREZ, ESTHER; BATLLE, ALCIRA; PARERA, VICTORIA; ROSSETTI, MARIA VICTORIA

Cardiff

Congreso; International Porphyrins and Porphyrias Meeting; 2011

British Association of Dermatologists

Acute intermittent porphyria (AIP) is an acute liver disorder caused by a deficiency of porphobilinogen (PBG) deaminase (PBGD). It is characterized by an increase in the expression of the first enzyme of the haem biosynthesis pathway, d-aminolaevulinic acid (ALA) synthase 1 (ALAS1), and the resulting accumulation of toxic intermediates of this pathway. It is an autosomal dominant disease; however, five cases of homozygous dominant AIP (HD-AIP) in heteroallelic and homoallelic conditions have been described, and in one of these cases no enzymatic or direct molecular diagnostics were reported. In some cases prominent neurological symptoms, psychomotor retardation and erythrodontia were observed. We studied a patient with abdominal pain and neurological attacks characteristic of AIP who also had mild skin symptoms and erythrodontia. The aim of this study was to perform biochemical and genetic analysis in this patient to establish a differential diagnosis of this case of porphyria. Biochemical results were as follows. Urine: ALA 3Æ4 mg per 24 h (normal 4); PBG 15Æ5 mg per 24 h (normal 2); urinary porphyrins 8459 mg per 24 h (normal 250); copro 19%, penta 6%, hexa 1%, hepta 4%, uro 70% (normal 100% copro); blood: plasma prophyrin index 5Æ30 at k 619 nm (normal 1Æ30); total porphyrins 427 lg per 100 mL red blood cells (normal 150 ± 40); stool: total porphyrins: 655 mg g)1 dry weight (normal 30?130). Results indicated the presence of an erythropoietic component. The PBGD value was 37Æ73 U mL)1 red blood cells (normal 75Æ47 ± 11Æ96). Genetic diagnosis was performed in peripheral blood by polymerase chain reaction and automatic sequencing. The results indicated the presence of two mutations in the PBGD 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 PBGD mutation p.E258G showed that the mutated protein has an residual enzyme activity of about 80%. Thermal studies revealed no significant difference between the wild-type and mutated protein to 65 C. C. C. C. Our patient?s symptoms, uncommon in AIP, would not be explained by our results. Moreover, her PBGD enzyme activity would be in accordance with the absence of the more severe symptoms associated with HD-AIP observed previously in other patients described.