AGXT Gene, Known Mutation
Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test
Primary hyperoxaluria type 1 (PH1) is a hereditary disorder of glyoxylate metabolism caused by deficiency of alanine:glyoxylate-aminotransferase (AGT), a hepatic enzyme that converts glyoxylate to glycine. Absence of AGT activity results in conversion of glyoxylate to oxalate, which is not capable of being degraded. Therefore, excess oxalate is excreted in the urine, causing kidney stones (urolithiasis), nephrocalcinosis, and kidney failure. As kidney function declines, blood levels of oxalate increase markedly, and oxalate combines with calcium to form calcium oxalate deposits in the kidney, eyes, heart, bones, and other organs, resulting in systemic disease. Pyridoxine (vitamin B6), a cofactor of AGT, is effective in reducing urine oxalate excretion in some PH1 patients.
Presenting symptoms of PH1 include nephrolithiasis, nephrocalcinosis, or end-stage kidney disease with or without a history of urolithiasis. Age of symptom onset is variable; however, most individuals present in childhood or adolescence with symptoms related to kidney stones. In some infants with a more severe phenotype, kidney failure may be the initial presenting feature. Less frequently, affected individuals present in adulthood with recurrent kidney stones or kidney failure. End-stage kidney failure is most often seen in the third decade of life, but can occur at any age.
The exact prevalence and incidence of PH1 are not known, but prevalence rates of 1 to 3 per million population and incidences of 0.1 per million/year have been estimated from population surveys.
Biochemical testing is indicated in patients with possible primary hyperoxaluria, and can be performed prior to molecular testing. 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 / Hyperoxaluria Panel, Urine; OXU / Oxalate, Urine). In very young children (incapable of performing a timed collection), random urine oxalate to creatinine ratios may be used to determine oxalate excretion. In patients with reduced kidney function, POXA / 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, this disorder, as there are other forms of inherited (type 2 and non-PH1/PH2) hyperoxaluria and secondary hyperoxaluria that may result in similarly elevated urine oxalate excretion rates. An elevated urine glycolate in the presence of hyperoxaluria is suggestive of PH1. 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 (GFR). The plasma oxalate concentration may also be helpful in supporting the diagnosis in patients with reduced kidney function, with values >50 micromol/L highly suggestive of PH1 when GFR is <20 mL/min/1.73 m(2). Historically, the diagnosis of PH1 was confirmed by AGT enzyme analysis performed on liver biopsy; however, this has since been replaced by molecular testing, which forms the basis of confirmatory or carrier testing in most cases.
PH1 is inherited as an autosomal recessive disorder caused by mutations in the AGXT gene, which encodes the enzyme AGT. Several common AGXT mutations have been identified including c.33dupC, p.Gly170Arg (c.508G->A), and p.Ile244Thr (c.731T->C). These mutations account for at least 1 of the 2 affected alleles in approximately 70% of individuals with PH1. Direct sequencing of the AGXT gene is predicted to identify 99% of alleles in individuals who are known by enzyme analysis to be affected with PH1.
While age of onset and severity of disease is variable and not necessarily predictable by genotype, a correlation between pyridoxine responsiveness and homozygosity for the p.Gly170Arg mutation has been observed. (Note: molecular testing is available as AGXMS / AGXT Gene, Full Gene Analysis and, for the p.Gly170Arg mutation only, as AGXT / Alanine:Glyoxylate Aminotransferase [AGXT] Mutation Analysis [G170R], Blood). Pyridoxine (vitamin B6) is a known cofactor of AGT and is effective in reducing urine oxalate excretion in some PH1 patients treated with pharmacologic doses. Individuals with 2 copies of the p.Gly170Arg mutation have been shown to normalize their urine oxalate when treated with pharmacologic doses of pyridoxine and those with a single copy of the mutation show reduction in urine oxalate. This is valuable because not all patients have been shown to be responsive to pyridoxine, and strategies that help to identify the individuals most likely to benefit from such targeted therapies are desirable.
Site-specific (known mutation) testing for mutations that have already been identified in an affected patient is useful for confirming a suspected diagnosis in a family member. It is also useful for determining whether at-risk individuals are carriers of the disease and, subsequently, at risk for having a child with PH1 deficiency.
Carrier testing of individuals with a family history of primary hyperoxaluria type 1
Diagnostic confirmation of primary hyperoxaluria type 1 deficiency when familial mutations have been previously identified
Prenatal testing when 2 familial mutations have been previously identified in an affected family member
An interpretative report will indicate if results are diagnostic for primary hyperoxaluria type 1 (2 mutations identified), if the patient is a carrier for primary hyperoxaluria type 1 (1 mutation identified), or if no mutations are identified.
Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances
The identification of a disease-causing mutation 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 AGXMS / AGXT Gene, Full Gene Analysis.
Analysis is performed for the familial mutation(s) 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 PH1.
We strongly recommend that patients undergoing predictive testing receive genetic counseling both prior to testing and after results are available.
Predictive testing of an asymptomatic child is not recommended.
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.
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. Milliner DS: The primary hyperoxalurias: an algorithm for diagnosis. Am J Nephrol 2005;25(2):154-160
2. Monico CG, Rossetti S, Olson JB, Milliner DS: Pyridoxine effect in type I primary hyperoxaluria is associated with the most common mutant allele. Kidney Int 2005;67(5):1704-1709
3. Monico CG, Rossetti S, Schwanz HA, et al: Comprehensive mutation screening in 55 probands with type 1 primary hyperoxaluria shows feasibility of a gene-based diagnosis. J Am Soc Nephrol 2007;18:1905-1914
4. 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
5. Williams EL, Acquaviva C, Amoroso, A, et al: Primary hyperoxaluria type I: update and additional mutation analysis of the AGXT gene. Hum Mutat 2009;30:910-917
6. Williams E, Rumsby G: Selected exonic sequencing of the AGXT gene provides a genetic diagnosis in 50% of patients with primary hyperoxaluria type 1. Clin Chem 2007;53(7):1216-1221
7. Communique April 2007: Laboratory and Molecular Diagnosis of Primary Hyperoxaluria and Oxalosis