Primary hyperoxaluria is a rare condition characterized by recurrent kidney and bladder stones. The condition often results in end stage renal disease (ESRD), which is a life-threatening condition that prevents the kidneys from filtering fluids and waste products from the body effectively.

Primary hyperoxaluria results from the overproduction of a substance called oxalate. Oxalate is filtered through the kidneys and excreted as a waste product in urine, leading to abnormally high levels of this substance in urine (hyperoxaluria). During its excretion, oxalate can combine with calcium to form calcium oxalate, a hard compound that is the main component of kidney and bladder stones. Deposits of calcium oxalate can damage the kidneys and other organs and lead to blood in the urine (hematuria), urinary tract infections, kidney damage, ESRD, and injury to other organs. Over time, kidney function decreases such that the kidneys can no longer excrete as much oxalate as they receive. As a result oxalate levels in the blood rise, and the substance gets deposited in tissues throughout the body (systemic oxalosis), particularly in bones and the walls of blood vessels. Oxalosis in bones can cause fractures.

There are three types of primary hyperoxaluria that differ in their severity and genetic cause. In primary hyperoxaluria type 1, kidney stones typically begin to appear anytime from childhood to early adulthood, and ESRD can develop at any age. Primary hyperoxaluria type 2 is similar to type 1, but ESRD develops later in life. In primary hyperoxaluria type 3, affected individuals often develop kidney stones in early childhood, but few cases of this type have been described so additional signs and symptoms of this type are unclear.

Mutations in the AGXT, GRHPR, and HOGA1 genes cause primary hyperoxaluria types 1, 2, and 3, respectively. These genes provide instructions for making enzymes that are involved in the breakdown and processing of protein building blocks (amino acids) and other compounds. The enzyme produced from the HOGA1 gene is involved in the breakdown of an amino acid, which results in the formation of a compound called glyoxylate. This compound is further broken down by the enzymes produced from the AGXT and GRHPR genes.

Mutations in the AGXT, GRHPR, or HOGA1 gene lead to a decrease in production or activity of the respective proteins, which prevents the normal breakdown of glyoxylate. AGXT and GRHPR gene mutations result in an accumulation of glyoxylate, which is then converted to oxalate for removal from the body as a waste product. HOGA1 gene mutations also result in excess oxalate, although researchers are unsure as to how this occurs. Oxalate that is not excreted from the body combines with calcium to form calcium oxalate deposits, which can damage the kidneys and other organs.

Normal Function

The AGXT gene provides instructions for making an enzyme called alanine-glyoxylate aminotransferase. This enzyme is found in liver cells, specifically within cell structures called peroxisomes. These structures are important for several cellular activities, such as ridding the cell of toxic substances and helping to break down certain fats. In the peroxisome, alanine-glyoxylate aminotransferase converts a compound called glyoxylate to the protein building block (amino acid) glycine.

Health Conditions Related to Genetic Changes

Primary hyperoxaluria

More than 175 mutations in the AGXT gene have been found to cause primary hyperoxaluria type 1. This condition is caused by the overproduction of a substance called oxalate. Excess amounts of this substance lead to kidney and bladder stones, which can begin anytime from childhood to early adulthood with kidney disease developing at any age. Deposition of oxalate in multiple other tissues throughout the body (systemic oxalosis) can cause additional health problems.

Most of the AGXT gene mutations decrease or eliminate alanine-glyoxylate aminotransferase activity, which impairs the conversion of glyoxylate to glycine. Other mutations cause the enzyme to be misplaced in cells, transporting it to structures called mitochondria instead of to peroxisomes. While the enzyme in the mitochondria retains activity, it cannot access glyoxylate, which is in peroxisomes. All AGXT gene mutations result in the accumulation of glyoxylate, which is converted to oxalate instead of glycine. The oxalate is filtered through the kidneys and is either excreted in urine as a waste product or combines with calcium to form calcium oxalate, a hard compound that is the main component of kidney and bladder stones. Increased oxalate levels in the blood can lead to systemic oxalosis, particularly affecting bones and the walls of blood vessels in people with primary hyperoxaluria type 1.

Other Names for This Gene

• AGT
• AGT1
• AGXT1
• alanine glyoxylate aminotransferase
• alanine-glyoxylate aminotransferase
• alanine-glyoxylate aminotransferase (oxalosis I; hyperoxaluria I; glycolicaciduria; serine-pyruvate aminotransferase)
• alanine-glyoxylate transaminase
• L-alanine: glyoxylate aminotransferase 1
• pyruvate (glyoxylate) aminotransferase
• serine-pyruvate aminotransferase
• serine:pyruvate aminotransferase
• SPAT
• SPT

Genomic Location

Normal Function

The GRHPR gene provides instructions for making an enzyme called glyoxylate and hydroxypyruvate reductase. This enzyme plays a role in preventing the buildup of a potentially harmful substance called glyoxylate by converting it to a substance called glycolate, which is easily excreted from the body. Additionally, this enzyme can convert a compound called hydroxypyruvate to D-glycerate, which is eventually converted to the simple sugar glucose (by other enzymes) and used for energy.

Health Conditions Related to Genetic Changes

Primary hyperoxaluria

More than 25 mutations in the GRHPR gene have been found to cause primary hyperoxaluria type 2. This condition is caused by the overproduction of a substance called oxalate. Excess amounts of this substance lead to kidney and bladder stones, which begin in childhood and often result in kidney disease by early adulthood. Deposition of oxalate in multiple other tissues throughout the body (systemic oxalosis) can cause additional health problems.

GRHPR gene mutations either disrupt production of the glyoxylate and hydroxypyruvate reductase enzyme or alter its structure. As a result, enzyme activity is absent or severely reduced and the conversion of glyoxylate to glycolate is impaired. Glyoxylate builds up and is converted to a compound called oxalate. The oxalate is filtered through the kidneys and is either excreted in urine as a waste product or combines with calcium to form calcium oxalate, a hard compound that is the main component of kidney and bladder stones. Increased oxalate levels in the blood can lead to systemic oxalosis, particularly affecting bones and the walls of blood vessels in people with primary hyperoxaluria type 2.

Other Names for This Gene

• D-glycerate dehydrogenase
• GLXR
• glyoxylate reductase/hydroxypyruvate reductase
• GRHPR_HUMAN
• PH2

Genomic Location

Normal Function

The HOGA1 gene provides instructions for making the 4-hydroxy-2-oxoglutarate aldolase (HOGA) enzyme. This enzyme is found in liver and kidney cells, specifically within structures called mitochondria, which are the energy-producing centers in cells. The HOGA enzyme is involved in breaking down a protein building block (amino acid) called hydroxyproline. Specifically, during the breakdown process, HOGA cuts (cleaves) a substance called 4-hydroxy-2-oxoglutarate to produce two smaller substances called pyruvate and glyoxylate. In mitochondria, pyruvate is likely involved in energy production, but the function of glyoxylate is unclear.

Health Conditions Related to Genetic Changes

Primary hyperoxaluria

At least 24 mutations in the HOGA1 gene have been found to cause primary hyperoxaluria type 3. This condition is caused by the overproduction of a substance called oxalate. Excess amounts of this substance lead to kidney and bladder stones, which begin in early childhood and often result in blood in the urine (hematuria) and urinary tract infections. A specific mutation that alters the way the gene's instructions are used to make the enzyme (written as 700+5G>T) is present in about half of affected individuals. As a result of HOGA1 gene mutations, the HOGA enzyme cannot break down 4-hydroxy-2-oxoglutarate, which leads to a buildup of this substance in the mitochondria of liver cells.

It is unclear how an accumulation of 4-hydroxy-2-oxoglutarate leads to an overproduction of oxalate in people with primary hyperoxaluria type 3. Some researchers think that the accumulation of 4-hydroxy-2-oxoglutarate interferes with the activity of other enzymes, which lead to the accumulation of substances that get converted into oxalate. Other researchers think that excess 4-hydroxy-2-oxoglutarate in mitochondria may leak out into liver cells. Enzymes within these cells would then convert 4-hydroxy-2-oxoglutarate to glyoxylate, and then convert glyoxylate into oxalate. In individuals with primary hyperoxaluria type 3, the oxalate is filtered through the kidneys and is either excreted in urine as a waste product or combines with calcium to form calcium oxalate, a hard compound that is the main component of kidney and bladder stones.

Other Names for This Gene

• DHDPS2
• DHDPSL
• dihydrodipicolinate synthase-like, mitochondrial
• dihydrodipicolinate synthetase homolog 2

Genomic Location

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Primary hyperoxaluria is estimated to affect 1 in 58,000 individuals worldwide. Type 1 is the most common form, accounting for approximately 80 percent of cases. Types 2 and 3 each account for about 10 percent of cases.