The Italian multicenter study of Primary Hyperoxaluria (OMIM 259900 and 260000), started in 1990 to provide the biochemical and genetic diagnosis over the Country, has recently focused on the natural history of the disease and the development of predictive models that might support the key therapeutic choices. In our series of 50 type I and 2 type II patients, 70% males, aged at presentation 1 month to 49 years (median 3.0), age of ESRD 1 month to 50 years (median 13.0); in 62% diagnosis was done at ESRD or later. Vitamin B6 responsiveness as defined by comparing oxalate and glycolate levels before and after oral supplementation, was present in 12, absent in 21 and undefined in 17. In 11 patients the kidney is still functioning, 14 are on hemodialysis, 8 received isolated kidney, 2 liver and 14 combined liver/kidney transplant. AGT residual activity in liver biopsies was available for 32 subjects and showed 83% correspondence with Vitamin B6 responsiveness. Using DHPLC and DNA sequencing we identified the pathogenic mutation of 96/100 AGXT alleles (24 different from each other) and 4/4 GRHPR alleles (all R99X). The most frequent AGXT mutation G170R, causing mitochondrial mistargeting, was associated with a milder phenotype (residual enzymatic activity, late onset and responsiveness to Vitamin B6), but was also found in some patients with early progression to ESRD and oxalosis. In both the index cases and their relatives the disease penetrance and clinical course appear to be also affected by factors other than the AGXT mutation, including delayed diagnosis, diet, associated metabolic derangements, male sex and possibly other modifier genes. Disclosure of Financial Relationships: nothing to disclose
The Italian Multicenter Study of Primary Hyperoxaluria
Licia Peruzzi;ROBBIANO, Angela;MANDRILE, Giorgia;GIACHINO, Daniela Francesca;AMOROSO, Antonio;DE MARCHI, Mario
2008-01-01
Abstract
The Italian multicenter study of Primary Hyperoxaluria (OMIM 259900 and 260000), started in 1990 to provide the biochemical and genetic diagnosis over the Country, has recently focused on the natural history of the disease and the development of predictive models that might support the key therapeutic choices. In our series of 50 type I and 2 type II patients, 70% males, aged at presentation 1 month to 49 years (median 3.0), age of ESRD 1 month to 50 years (median 13.0); in 62% diagnosis was done at ESRD or later. Vitamin B6 responsiveness as defined by comparing oxalate and glycolate levels before and after oral supplementation, was present in 12, absent in 21 and undefined in 17. In 11 patients the kidney is still functioning, 14 are on hemodialysis, 8 received isolated kidney, 2 liver and 14 combined liver/kidney transplant. AGT residual activity in liver biopsies was available for 32 subjects and showed 83% correspondence with Vitamin B6 responsiveness. Using DHPLC and DNA sequencing we identified the pathogenic mutation of 96/100 AGXT alleles (24 different from each other) and 4/4 GRHPR alleles (all R99X). The most frequent AGXT mutation G170R, causing mitochondrial mistargeting, was associated with a milder phenotype (residual enzymatic activity, late onset and responsiveness to Vitamin B6), but was also found in some patients with early progression to ESRD and oxalosis. In both the index cases and their relatives the disease penetrance and clinical course appear to be also affected by factors other than the AGXT mutation, including delayed diagnosis, diet, associated metabolic derangements, male sex and possibly other modifier genes. Disclosure of Financial Relationships: nothing to disclose
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