Primary Hyperoxaluria (PH) is a rare autosomal recessive disease with impaired hepatic detoxification of glyoxylate, due to AGT (PHI) or GRHPR (PHII) enzyme deficiency. Oxalate overproduction in turn causes nephrolithiasis, end-stage renal failure, systemic oxalosis and multi-tissue damage. In responsive subjects an early biochemical and genetic diagnosis can address to treatment with vitamin B6 (the AGT cofactor). In many cases liver or combined liver/kidney transplant is necessary to correct the metabolic defect. In a cohort of 47 PHI and 2 PHII Italian patients we identified the pathogenic mutation of 90/94 PHI and 4/4 PHII alleles (96% mutation detection) using DHPLC and DNA sequencing. Age at presentation varied from 1 month to 49 years (median 6 y). AGT residual activity in liver biopsies is available for 34 subjects. In 33 it was possible to define B6 responsiveness by comparing plasma oxalate before and after oral supplementation. 23 different mutations were found (6 unpublished); missense mutations affect evolutionary conserved residues and are absent in 160 chromosomes of healthy ethnically matched controls. Genotype-phenotype correlations show an important role of non-genetic factors as diet or delayed diagnosis, and confirm in our population that the most frequent mutation G170R, causing mitochondrial mistargeting, is associated with a mild phenotype (residual enzymatic activity, late onset and responsiveness to B6). For missense (G116R) and insdel inframe (c.283dupGAG) mutations we presume an antimorphic effect as they were found only in patients with a severe phenotype despite the presence of a mild mutation on the other allele.
Primary hyperoxaluria in Italy
ROBBIANO, Angela;MANDRILE, Giorgia;GIACHINO, Daniela Francesca;AMOROSO, Antonio;DE MARCHI, Mario
2008-01-01
Abstract
Primary Hyperoxaluria (PH) is a rare autosomal recessive disease with impaired hepatic detoxification of glyoxylate, due to AGT (PHI) or GRHPR (PHII) enzyme deficiency. Oxalate overproduction in turn causes nephrolithiasis, end-stage renal failure, systemic oxalosis and multi-tissue damage. In responsive subjects an early biochemical and genetic diagnosis can address to treatment with vitamin B6 (the AGT cofactor). In many cases liver or combined liver/kidney transplant is necessary to correct the metabolic defect. In a cohort of 47 PHI and 2 PHII Italian patients we identified the pathogenic mutation of 90/94 PHI and 4/4 PHII alleles (96% mutation detection) using DHPLC and DNA sequencing. Age at presentation varied from 1 month to 49 years (median 6 y). AGT residual activity in liver biopsies is available for 34 subjects. In 33 it was possible to define B6 responsiveness by comparing plasma oxalate before and after oral supplementation. 23 different mutations were found (6 unpublished); missense mutations affect evolutionary conserved residues and are absent in 160 chromosomes of healthy ethnically matched controls. Genotype-phenotype correlations show an important role of non-genetic factors as diet or delayed diagnosis, and confirm in our population that the most frequent mutation G170R, causing mitochondrial mistargeting, is associated with a mild phenotype (residual enzymatic activity, late onset and responsiveness to B6). For missense (G116R) and insdel inframe (c.283dupGAG) mutations we presume an antimorphic effect as they were found only in patients with a severe phenotype despite the presence of a mild mutation on the other allele.
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