Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues

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Hyperoxaluria, primary, type 1 (PH1) [E74.8]

OMIM numbers: 259900, 604285 (AGXT)

Dr. rer. nat. Karin Mayer

Scientific Background

Primary hyperoxaluria type 1 is a rare autosomal recessive disease with population-dependant incidence of 1 in 100,000–250,000. The disease is most common among Arabs, Tunisians and Iranians. It manifests between the first and 25th year of life as nephrolithiasis and nephrocalcinosis caused by deposition of calcium oxalate in the urinary tract and the renal parenchyma and if untreated results in terminal kidney failure. In 10% of all patients, the diagnosis is established within the first six months of life when failure to thrive, nephrocalcinosis, anemia and metabolic acidosis occur. The cause is a deficiency in the peroxisomal enzyme alanine glyoxylate aminotransferase (AGT), which catalyzes the conversion of glyoxylate to glycine in the liver. If AGT is absent, glyoxylate is converted into oxalate, which deposits as an insoluble calcium salt in the kidneys and other organs. The ratio between oxalic acid and creatine in the urine, oxalic acid in the plasma and the activity of AGT in a liver biopsy are suggestive in laboratory findings.

The only known cause for the disease is mutations in the AGXT gene, which consists of 11 exons and occurs in 2 normal allelic states:

  • major allele (frequency approx. 80% in Caucasians)
  • minor allele (frequency of approx. 20% in Caucasians, 2% in Japanese and 3 % among the black South African population)

The two alleles differ from each other in containing three polymorphisms in the minor allele. About 50% of all affected patients also have at least one minor allele in addition to a causative mutation. So far, 150 different mutations have been described, half of which are missense mutations; others include translational stop mutations and larger genomic rearrangements. In 90% of all patients, at least one AGXT mutation can be detected. The gene product AGT is synthesized in the liver and is located in the peroxisomes. The common mutation p.Gly170Arg occurs in 25-40% of all PH1 alleles on a minor allel background. Thereby 90% of the amino transferase, which exhibits normal catalytic activity, is being falsely led into the mitochondria instead of into the peroxisomes, where it is not in contact with its substrate. About 50% of all patients display complete absence of AGT; in 20% of all cases a functional inactive enzyme is synthesized and in rare cases, an enzyme with reduced activity which has been associated with a mild course is produced. Heterozygous carriers are asymptomatic.

Regarding a differential diagnosis, primary hyperoxaluria type 2 (PH2), which is caused by a deficiency of the enzyme glyoxylate reductase (GR) should be considered. GR catalyzes the reduction of glyoxylate and hydroxypyruvate and is encoded by the GRHPR gene. PH2 is a rarer than PH1. The diagnosis of PH2 can be established by determining the enzyme activity of GR in the liver.

In 5% of patients primary hyperoxaluria type 3 (PH3) is characterized by elevated oxalate and glycolate, whereby AGT and GR both exhibit normal enzyme activity. Mutations in the HOGA1 gene, which codes for 2-keto-4-hydroxyglutarate aldolase, are causal for PH3.