Primary hyperoxaluria Type 1 is a rare autosomal recessive inborn error of glyoxylate metabolism, caused by a deficiency of the liver-specific enzyme alanine:glyoxylate aminotransferase. The disorder results in overproduction and excessive urinary excretion of oxalate, causing recurrent urolithiasis and nephrocalcinosis. As glomerular filtration rate declines due to progressive renal involvement, oxalate accumulates leading to systemic oxalosis. The diagnosis is based on clinical and sonographic findings, urine oxalate assessment, enzymology and/or DNA analysis. Early initiation of conservative treatment (high fluid intake, pyridoxine, inhibitors of calcium oxalate crystallization) aims at maintaining renal function. In chronic kidney disease Stages 4 and 5, the best outcomes to date were achieved with combined liver-kidney transplantation.

Although more than one-half of the PH1 patients have symptoms under the age of 10 years, PH1 can present at any age. In adults, PH1 presents predominantly with ESRD, which may be due to misinterpretation of early symptoms. Although nephrocalcinosis is correlated with development of renal insufficiency, the latter can occur even in the absence of nephrocalcinosis. Pyridoxine sensitivity is associated with better outcome in PH1.

Early detection of Gly170Arg and Phe152Ile mutations in PH1 has important clinical implications because of their association with pyridoxine responsiveness and clinical outcome. The association of a homozygous 33insC mutation with severe infantile ESRD, resulting in early deaths in 2 out of 3 cases, warrants a choice for prenatal diagnostics in affected families.

Acknowledgments:We are grateful to patients and their families and to all the contributing clinicians in each country (see list). BBB acknowledges funding from a Koeln GM acknowledges Telethon foundation (grant GGP10092) Running title AGXT mutations classes and outcome AbstractPrimary hyperoxaluria type 1 (PH1) displays a heterogeneous phenotype, likely to be affected by genetic and non genetic factors, including timeliness of diagnosis and quality of care. As previous genotype-phenotype studies were hampered by limited patient numbers the European OxalEurope Consortium was constituted. This preliminary retrospective report is based on 526 patients (410 with AGXT genotype). We grouped mutations by the predicted effect as null (N), missense leading to mistargeting (G170R) and other missense (M) and analyzed their phenotypic correlations. Median age of End-stage Renal Disease increased from 9.9 to 11.5, 16.9, 25.1, 31.2 and 33.9 years for the NN (n=88), MN (n=42), MM(n=116), G170RN(n=61), G170R/M(n=32) and G170R/G170R(n=71) respectively. The effect of individual missense mutations was estimated by ranking patient carrying the same mutation according to median ages at onset and at renal failure. The outcome of some recurrent missense mutations and an unprecedented number of G170R homozygotes is described in detail.Diagnosis of PH1 is still delayed and actions aimed at increasing knowledge and screening of kidney stones is recommended. Our analysis indicates that, in addition to G170R, other causative mutations are associated with later onset of ESRD. The OxalEurope registry will provide tools necessary for characterizing those genetic and nongenetic factors through a combination of future innovative genetic, functional, and biostatistical approaches.