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.

Primary hyperoxaluria type 1 (PH1) is a rare genetic form of calcium oxalate kidney stone disease. It is caused by a deficiency in the liver-specific enzyme, alanine:glyoxylate aminotransferase (AGT), a pyridoxal-5′-phosphate (PLP)-dependent enzyme involved in the metabolism of glyoxylate. The excessive endogenous synthesis of oxalate that ensues leads to hyperoxaluria, and the crystallization of the poorly soluble calcium salt of oxalate is responsible for a severe kidney stone disease, which can progress to end-stage renal disease, systemic deposition of oxalate and death. Knowledge about metabolic precursors of glyoxylate and oxalate, molecular pathology of AGT and analytical methods for diagnosis and clinical assessment have allowed a better understanding of the mechanisms underlying PH1 and opened the door to new therapeutic strategies.

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