Genotype–phenotype correlation in primary hyperoxaluria type 1: the p.Gly170Arg AGXT mutation is associated with a better outcome

• Published in: Kidney international Vol. 77; no. 5; pp. 443 - 449
• Main Authors: Harambat, Jérôme, Fargue, Sonia, Acquaviva, Cécile, Gagnadoux, Marie-France, Janssen, Françoise, Liutkus, Aurélia, Mourani, Chebl, Macher, Marie-Alice, Abramowicz, Daniel, Legendre, Christophe, Durrbach, Antoine, Tsimaratos, Michel, Nivet, Hubert, Girardin, Eric, Schott, Anne-Marie, Rolland, Marie-Odile, Cochat, Pierre
• Format: Journal Article
• Language: English
• Published: Basingstoke Elsevier Inc 01-03-2010; Nature Publishing Group; Elsevier Limited
• Subjects: Amino Acid Substitution; Arginine - metabolism; Biological and medical sciences; Child; Child, Preschool; Cohort Studies; end-stage renal disease; Errors of metabolism; genetic renal disease; Genotype; genotype–phenotype correlation; Heterozygote; Homozygote; Humans; Hyperoxaluria, Primary - diagnosis; Hyperoxaluria, Primary - genetics; Infant; Kidney Failure, Chronic - genetics; kidney stones; Medical sciences; Metabolic diseases; Miscellaneous hereditary metabolic disorders; Mutation; Nephrology. Urinary tract diseases; Nephropathies. Renovascular diseases. Renal failure; Phenotype; primary hyperoxaluria type 1; Prognosis; Renal failure; Retrospective Studies; Transaminases - genetics; genotype–phenotype correlation; end-stage renal disease; kidney stones; primary hyperoxaluria type 1; genetic renal disease; Correlation; Nephrology; Prognosis; Chronic renal failure; Oxalate; Enzymopathy; Urology; Primary; Genetics; Hyperoxaluria; Kidney disease; Urinary system disease; Typing; genotype-phenotype correlation; Metabolic diseases; Genotype; Terminal stage; Urinary stone; Genetic disease; Phenotype; Renal lithiasis; Nephropathy; Renal failure; Mutation
• ISSN: 0085-2538; 1523-1755
• DOI: 10.1038/ki.2009.435

We sought to ascertain the long-term outcome and genotype–phenotype correlations available for primary hyperoxaluria type 1 in a large retrospective cohort study. We examined the clinical history of 155 patients (129 families primarily from Western Europe, North Africa, or the Middle East) as well as the enzymatic or genetic diagnosis. The median age at first symptom was 4 years, and at diagnosis 7.7 years, at which time 43% had reached end-stage renal disease. Presentations included: (1) early nephrocalcinosis and infantile renal failure, (2) recurrent urolithiasis and progressive renal failure diagnosed during childhood, (3) late onset with occasional stone passage diagnosed in adulthood, (4) diagnosis occurring on post-transplantation recurrence, and (5) family screening. The cumulative patient survival was 95, 86, and 74% at ages 10, 30, and 50 years, respectively, with the cumulative renal survival of 81, 59, 41, and 10% at ages 10, 20, 30, and 50 years, respectively; 72 patients had undergone a total of 97 transplantations. Among the 136 patients with DNA analysis, the most common mutation was p.Gly170Arg (allelic frequency 21.5%), with a median age at end-stage renal disease of 47 years for homozygotes, 35 years for heterozygotes, and 21 years for other mutations. Our results underscore the severe prognosis of primary hyperoxaluria type 1 and the necessity for early diagnosis and treatment, as well as confirm a better prognosis of the p.Gly170Arg mutation.