Which are the causes of Primary Hyperoxaluria?

Primary Hyperoxaluria is a rare genetic disorder characterized by the overproduction of a substance called oxalate in the body. This excessive production leads to the accumulation of oxalate crystals in various organs, primarily the kidneys, which can cause severe damage and dysfunction.

The causes of Primary Hyperoxaluria are primarily genetic in nature. The disorder is typically inherited in an autosomal recessive manner, meaning that an affected individual must inherit two copies of the mutated gene, one from each parent, to develop the condition. The specific genes associated with Primary Hyperoxaluria are AGXT, GRHPR, and HOGA1.

AGXT: Mutations in the AGXT gene are responsible for the most common form of Primary Hyperoxaluria, known as Type 1. This gene provides instructions for producing an enzyme called alanine-glyoxylate aminotransferase, which is involved in the breakdown of glyoxylate, a precursor of oxalate. When the AGXT gene is mutated, the enzyme's activity is impaired, leading to the accumulation of glyoxylate and subsequent overproduction of oxalate.

GRHPR: Mutations in the GRHPR gene cause Type 2 Primary Hyperoxaluria. This gene encodes an enzyme called glyoxylate reductase/hydroxypyruvate reductase, which is involved in the conversion of glyoxylate to glycolate. When the GRHPR gene is mutated, the enzyme's function is disrupted, resulting in the buildup of glyoxylate and oxalate.

HOGA1: Type 3 Primary Hyperoxaluria is caused by mutations in the HOGA1 gene. This gene provides instructions for producing an enzyme called 4-hydroxy-2-oxoglutarate aldolase, which is involved in the breakdown of a compound called hydroxyproline. Hydroxyproline is found in collagen, a protein abundant in connective tissues. Mutations in the HOGA1 gene lead to the accumulation of hydroxyproline, which is converted to oxalate, contributing to the excessive oxalate production seen in Type 3 Primary Hyperoxaluria.

While the primary cause of Primary Hyperoxaluria is genetic, there are certain risk factors that can exacerbate the condition. These include a diet high in oxalate-rich foods, such as spinach, rhubarb, and chocolate, as well as certain medical conditions that affect the gut's ability to absorb oxalate, such as inflammatory bowel disease or gastrointestinal surgeries.

In conclusion, Primary Hyperoxaluria is primarily caused by genetic mutations in the AGXT, GRHPR, and HOGA1 genes, leading to the overproduction of oxalate. Understanding the genetic basis of this disorder is crucial for accurate diagnosis and the development of targeted treatments.