Hyperoxaluria

Primary hyperoxaluria type 1 (PH1) manifests between the neonatal period and late adulthood with nephrolithiasis and nephrocalcinosis, due to deposition of calcium oxalate in the urinary tract, and renal parenchyma and leads to terminal renal failure if left untreated. In about 10% of patients, diagnosis is made within the first six months of life based on failure to thrive, nephrocalcinosis, anaemia and metabolic acidosis.

Primary hyperoxaluria type 1 has a population-dependent incidence of approximately 1:100,000–1:250,000 and occurs most commonly in Arabs, in Tunisia and in Iran.

Primary hyperoxaluria type 1 is caused by pathogenic changes in the AGXT gene, which consists of 11 exons and occurs in two normal allelic states: a major allele (frequency about 80% in Caucasians) and a minor allele (frequency about 20% in Caucasians, 2% in Japanese and 3% in black South Africans). The minor-allele haplotype contains two amino acid substitutions, p.Pro11Leu and p.Ile340Met, in addition to other polymorphic variants, and about 50% of affected individuals carry at least one minor allele together with a causative variant. More than 200 pathogenic alterations have been described, approximately half missense variants, as well as translational stop mutations and larger genomic rearrangements; AGXT variants can be detected in around 80% of primary hyperoxaluria patients.

The gene product AGT is synthesised in the liver and localised in peroxisomes, catalysing the conversion of glyoxylate to glycine. A frequent variant, p.Gly170Arg, occurs in 25–40% of primary hyperoxaluria type 1 alleles on the background of the minor allele and causes 90% of aminotransferase with normal catalytic activity to be misdirected to mitochondria rather than peroxisomes, where it has no contact with its substrate. Fifty percent of patients have a complete absence of AGT, in about 20% a functionally inactive enzyme is synthesised, and in rare cases an enzyme with reduced activity is produced that is associated with a milder course. Heterozygous carriers are asymptomatic.

Primary hyperoxaluria type 2 (PH2) is caused by deficiency of the enzyme glyoxylate reductase (GR), which catalyses the reduction of glyoxylate and hydroxypyruvate and is encoded by the GRHPR gene. Causal variants in GRHPR have been detected in up to 10% of genetically tested primary hyperoxaluria patients. PH2 occurs less frequently and is less severe than PH1.

Primary hyperoxaluria type 3 (PH3) is characterised in about 5% of patients by elevated oxalate and glycolate levels with normal AGT and GR enzyme activities, is less severe than types 1 and 2, and is caused by causative variants in the HOGA1 gene, which encodes 2-keto-4-hydroxy-glutarate aldolase. Pathogenic changes have been detected in about 10% of positive primary hyperoxaluria cases.

Laboratory diagnostics include the ratio of oxalic acid to creatinine in urine, the oxalic acid concentration in plasma, and measurement of AGT activity in a liver biopsy.

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