Primary hyperoxaluria type 1 (PH1)

Pathology caused by a defect in the enzyme L-alanine:glyoxylate aminotransferase that transforms glyoxylate into oxalate. When this enzyme does not function correctly, the accumulation of calcium oxalate crystals occurs, especially in the kidneys, causing renal dysfunction.

Primary hyperoxaluria (PH) belongs to the group of metabolic disorders characterized by the accumulation of oxalate in the kidneys and other tissues. It is caused by alterations that mainly occur in three genes and define the three types of primary hyperoxaluria known as PH1, PH2 and PH3.

The most frequent and severe type of hyperoxaluria is PH1, which is due to mutations in the AGXT gene. The prevalence of PH1 is less than 3 cases per million population, with a higher incidence in North African and Middle Eastern countries.

Symptoms

There is significant heterogeneity in the symptoms and onset of PH1. The infantile form of the disease manifests in the first months of life and causes growth retardation, accumulation of calcium oxalate crystals in the kidneys and/or stones in the kidneys and urinary tract. There is a second, less severe form, which appears in childhood and adolescence, and causes recurrent kidney and urinary tract stones.

Sometimes it is not until adulthood that symptoms appear. Occasionally or recurrently, patients accumulate oxalate kidney stones, which, in some cases, can lead to renal failure due to the obstruction they cause in the kidneys. If oxalate levels reach very high levels in the blood, other organs may be affected, leading, for example, to cardiac disturbances and an increased risk of broken bones.

Disease management

Early and intense treatment is essential to maintain renal function, which involves minimizing calcium oxalate deposits. Abundant diuresis, administration of vitamin B6 (pyridoxine) and treatment with calcium-oxalate crystallization inhibitors (citrate, pyrophosphate, and magnesium) are used. When patients progress to renal failure, the option of kidney and liver transplantation is considered.

Lumasiran is an RNA interference or RNAi-based drug that was approved in 2020 by both the EMA (European Medicines Agency) and the FDA (United States Food and Drug Administration) for the specific treatment of PH1 for its ability to reduce oxalate production. Its efficacy in preserving long-term renal function is still under study.

Genes analyzed

AGXT

Bibliography

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