Primary hyperoxaluria type 1 (PH1) is caused by a deficiency of the liver peroxisomal enzyme alanine-glyoxylate and serine-pyruvate aminotransferase (AGT), which catalyzes the conversion of glyoxylate to glycine. When AGT activity is absent, glyoxylate is converted to oxalate, resulting in the formation of insoluble calcium oxalate crystals that accumulate in the kidney and eventually cause progressive renal failure. PPH1 is inherited as an autosomal recessive disorder. The majority of individuals with PH1 present in childhood or early adolescence with symptomatic nephrolithiasis and normal or reduced kidney function. The remainder of affected individuals present in adulthood with recurrent renal stones and a mild-to-moderate reduction in kidney function.
Patients with PH1 have elevated plasma oxalate, urine oxalate and urine glycolic acid concentrations. Increased urine Oxalate concentration is strongly suggestive of, but not diagnostic for PH1, since other types of inherited and secondary hyperoxaluria have elevated urine oxalate excretion rates. An elevated urine glycolate in the presence of hyperoxaluria is suggestive of PH1. Historically, the diagnosis of PH1 was confirmed by liver biopsy and AGT enzyme analysis. This test has been replaced by molecular testing.
More than 175 mutations in the AGXT gene have been reported. PH1.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. Most of the AGXT gene mutations decrease or eliminate AGT activity. Other mutations cause the enzyme to be transported to mitochondria instead of to peroxisomes. While the mitochrondrial enzyme retains activity, it cannot access glyoxylate which is in peroxisomes. The most common mistargeting mutation is G170R (gly170-to-arg). 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.
References
Milliner DS: The primary hyperoxalurias: an algorithm for diagnosis. Am J Nephrol 2005;25(2):154-160
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
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