title: Data from a large European study indicate that the outcome of primary hyperoxaluria type 1 correlates with the AGXT mutation type.
abstract: Primary hyperoxaluria type 1 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 of which 410 have the AGXT genotype defined. We grouped mutations by the predicted effect as null, missense leading to mistargeting (G170R), and other missense, and analyzed their phenotypic correlations. Median age of end-stage renal disease increased from 9.9 for 88 homozygous null patients, 11.5 for 42 heterozygous null/missense, 16.9 for 116 homozygous missense patients, 25.1 for 61 G170R/null patients, 31.2 for 32 G170R/missense patients, and 33.9 years for 71 homozygous G170R patients. The outcome of some recurrent missense mutations (p.I244T, p.F152I, p.M195R, p.D201E, p.S81L, p.R36C) and an unprecedented number of G170R homozygotes is described in detail. Diagnosis is still delayed and actions aimed at increasing awareness of primary hyperoxaluria type 1 are recommended. Thus, in addition to G170R, other causative mutations are associated with later onset of end-stage renal disease. The OxalEurope registry will provide necessary tools for characterizing those genetic and non-genetic factors through a combination of genetic, functional, and biostatistical approaches.
authors.affiliation: 1] Medical Genetics Unit, San Luigi University Hospital, Orbassano, Torino, Italy [2] University of Torino, Department Clinical and Biological Sciences, Torino, Italy.
authors.forename: Giorgia
authors.initials: G
authors.lastname: Mandrile
authors.affiliation: Division of Nephrology, Department of Pediatrics, Emma Children's Hospital, Academic Medical Centre, Amsterdam, The Netherlands.
authors.forename: Christiaan S
authors.initials: CS
authors.lastname: van Woerden
authors.affiliation: University of Torino, Department Clinical and Biological Sciences, Torino, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Berchialla
authors.affiliation: Institute of Human Genetics, University of Cologne, Cologne, Germany.
authors.forename: Bodo B
authors.initials: BB
authors.lastname: Beck
authors.affiliation: Laboratory of Inborn Metabolic Diseases, Centre de Biologie Est, Hospices Civils de Lyon, Lyon, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Acquaviva Bourdain
authors.affiliation: Department of Nephrology, Birmingham Children's Hospital NHS Trust, Birmingham, UK.
authors.forename: Sally-Anne
authors.initials: SA
authors.lastname: Hulton
authors.affiliation: Clinical Biochemistry, UCL Hospitals, London, UK.
authors.forename: Gill
authors.initials: G
authors.lastname: Rumsby
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D002648:Child; D002675:Child, Preschool; D018389:Codon, Nonsense; D057210:Delayed Diagnosis; D005060:Europe; D005260:Female; D016368:Frameshift Mutation; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D006960:Hyperoxaluria, Primary / Q000150:complications / Q000175:diagnosis / Q000235:genetics*; D007223:Infant; D007676:Kidney Failure, Chronic / Q000209:etiology*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D020125:Mutation, Missense; D010641:Phenotype; D012189:Retrospective Studies; D015996:Survival Rate; D000637:Transaminases / Q000235:genetics*; D052878:Urolithiasis / Q000209:etiology; D055815:Young Adult
chemical_list: D018389:Codon, Nonsense; D000637:Transaminases; C019635:Alanine-glyoxylate transaminase