Primary hyperoxaluria type 1 (PH1) is a rare autosomal recessive disease with a population dependent incidence of 1:100,000–1:250,000 that occurs most commonly in Arabs in Tunisia and in Iran. The disease onset is between the neonatal period and late adulthood. It manifests itself through nephrolithiasis and nephrocalcinosis due to calcium oxalate deposits in the urinary tract and renal parenchyma and leads to terminal renal failure if left untreated. In 10% of patients, the diagnosis is made within the first six months of life on the basis of failure to thrive, nephrocalcinosis, anemia and metabolic acidosis; this is the most common and most severe form of primary hyperoxaluria. It is caused by the deficiency of the peroxisomal enzyme alanine‑glyoxylate aminotransferase (AGT), which catalyses the conversion of glyoxylate to glycine in the liver. In the absence of AGT, glyoxylate is converted to oxalate, which is deposited as an insoluble calcium salt in the kidney and other organs. Diagnostic information is obtained in the laboratory from the ratio of oxalic acid to creatinine in urine, the oxalic acid concentration in plasma and the activity of AGT in a liver biopsy.
PH1 is caused by pathogenic changes in the AGXT gene, which consists of 11 exons and occurs in 2 normal allelic states:
- Major allele (frequency of about 80% in Caucasians)
- Minor allele (frequency of about 20% in Caucasians, 2% in Japanese and 3% in black South Africans)
The minor allele haplotype has two amino acid substitutions (p.Pro11Leu and p.Ile340Met) among other polymorphic variants. Half of all affected persons carry at least one minor allele in addition to a causative variant. To date, more than 200 different pathogenic alterations have been described; about half are missense variants in addition to translational stop mutations and larger genomic rearrangements. AGXT variants can be detected in approximately 80% of PH patients. The gene product AGT is synthesized in the liver and is localized in the peroxisomes. A common variant p.Gly170Arg occurs in 25-40% of all PH1 alleles against the genetic background of the minor allele. As a result, 90% of aminotransferase, which has normal catalytic activity, is misdirected into the mitochondria instead of the peroxisomes, where it has no contact with its substrate. 50% of all patients show a complete absence of AGT, in 20% a functionally inactive enzyme is synthesized, and in rare cases, an enzyme with reduced activity is produced which is associated with a mild course. Heterozygous carriers are asymptomatic.
The differential diagnosis is primary hyperoxaluria type 2 (PH2), which is less frequent and less severe than PH1. It is caused by a deficiency of the enzyme glyoxylate reductase (GR) that catalyses the reduction of glyoxylate and hydroxypyruvate and is encoded by the GRHPR gene. Causal variants in the GRHPR gene have been detected in up to 10% of genetically tested PH patients.
Primary hyperoxaluria type 3 (PH3) is seen in 5% of patients and characterized by elevated levels of oxalate and glycolate with normal AGT and GR enzyme activities. The progression is less severe than PH1 and PH2. PH3 is caused by causative variants in the HOGA1 gene, which codes for 2-keto-4-hydroxy-glutarate aldolase. Pathogenic changes have been detected in about 10% of positive PH cases.
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