GRHPR Gene, Known Mutation
Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test
Primary hyperoxaluria type 2 (PH2) is a hereditary disorder of glyoxylate metabolism caused by deficiency of the hepatic enzyme glyoxylate reductase/hydroxypyruvate reductase (GRHPR). Absence of GRHPR activity results in excess oxalate and usually L-glycerate excreted in the urine leading to nephrolithiasis (kidney stones) and sometimes renal failure.
Onset of PH2 is typically in childhood or adolescence with symptoms related to kidney stones. In some cases, kidney failure may be the initial presenting feature. Nephrocalcinosis, as seen by renal ultrasound, is observed less frequently in individuals with PH2 than primary hyperoxaluria type 1 (PH1). End-stage renal disease (ESRD) is also less common and of later onset than PH1; however, once ESRD develops, oxalate deposition in other organs such as bone, retina, and myocardium can occur.
While the exact prevalence and incidence of PH2 are not known, it is thought that PH2 is less common than PH1, which has an estimated prevalence rate of 1 to 3 per million population and an incidence of 0.1 per million/year.
Biochemical testing is indicated in patients with possible primary hyperoxaluria. Measurement of urinary oxalate in a timed, 24-hour urine collection is strongly preferred, with correction to adult body surface area in pediatric patients (HYOX/86213 Hyperoxaluria Panel, Urine; OXU/8669 Oxalate, Urine). In very young children (incapable of performing a timed collection), random urine oxalate to creatinine ratios may be used for determination of oxalate excretion. In patients with reduced kidney function, POXA/81408 Oxalate, Plasma is also recommended. Urinary excretion of oxalate of >1.0 mmol/1.73 m(2)/24 hours is strongly suggestive of, but not diagnostic for, primary hyperoxaluria as there are other forms of inherited (PH1 and non-PH1/PH2) hyperoxaluria and secondary hyperoxaluria that may result in similarly elevated urine oxalate excretion rates. An elevated urine glycerate in the presence of hyperoxaluria is suggestive of PH2. Caution is warranted in interpretation of urine oxalate excretion in patients with reduced kidney function as urine oxalate concentrations may be lower due to reduced glomerular filtration rate. Historically, the diagnosis of PH2 was confirmed by GRHPR enzyme analysis performed on liver biopsy; however, this has been replaced by molecular testing, which forms the basis of confirmatory or carrier testing in most cases.
PH2 is inherited as an autosomal recessive disorder caused by mutations in the GRHPR gene, which encodes the enzyme GRHPR. Two common GRHPR mutations have been identified: c.103delG and c.403_404+2delAAGT. These mutations account for about one third of the mutant alleles described in the Northern European Caucasian population and about 15% in the Asian population.
Carrier testing of individuals with a family history of primary hyperoxaluria type 2 (PH2)
Diagnostic confirmation of PH2 when familial mutations in the GRHPR gene have been previously identified
Prenatal testing when 2 familial mutations in the GRHPR gene have been previously identified in an affected family member
All detected alterations will be evaluated according to American College of Medical Genetics and Genomics (ACMG) recommendations.(1) Variants will be classified based on known, predicted, or possible pathogenicity, and reported with interpretive comments detailing their potential or known significance.
Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances
The identification of disease-causing mutations in an affected family member is necessary before predictive testing for other family members can be offered. If a familial mutation has not been previously identified, order GRHMS/50037 GRHPR Gene, Full Gene Analysis.
Analysis is performed for the familial mutation provided only. This assay does not rule out the presence of other mutations within this gene or within other genes that may be associated with primary hyperoxaluria type 2.
Test results should be interpreted in the context of clinical findings, family history, and other laboratory data. Any error in the diagnosis or in the pedigree provided to us, including false-paternity, could lead to erroneous interpretation of results.
A previous bone marrow transplant from an allogenic donor will interfere with testing. Call Mayo Medical Laboratories for instructions for testing patients who have received a bone marrow transplant.
In addition to disease-related probes, this test utilizes probes localized to other chromosomal regions as internal controls. In certain circumstances, these control probes may detect other diseases or conditions for which this test was not specifically intended. Results of the control probes are not normally reported. However, in cases where clinically relevant information is identified, the ordering physician will be informed of the result and provided with recommendations for any appropriate follow-up testing.
Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.
An interpretive report will be provided.
Clinical References Provides recommendations for further in-depth reading of a clinical nature
1. Richards CS, Bale S, Bellissimo DB, et al: ACMG recommendations for standards of interpretation and reporting of sequence variations: revisions 2007. Genet Med 2008;10(4):294-300
2. Primary Hyperoxaluria Type 2-GeneReviews-NCBI Bookshelf. Available from URL: http://www.ncbi.nlm.nih.gov/books/NBK2692/, accessed 8-7-2012
3. Rumsby G, Williams E, Coulter-Mackie M: Evaluation of mutation screening as a first line test for the diagnosis of the primary hyperoxalurias. Kidney Int 2004;66(3):959-963
4. Cregeen DP, Williams EL, Hulton S, Rumsby G: Molecular analysis of the glyoxylate reductase (GRHPR) gene and description of mutations underlying primary hyperoxaluria type 2. Hum Mutat 2003;22(6):497
5. Laboratory and molecular diagnosis of primary hyperoxaluria and oxalosis. Mayo Medical Laboratories' Communique, April 2007