What are the other Names for this Condition? (Also known as/Symptoms)

• D-Glycerate Dehydrogenase Deficiency
• Glyceric Aciduria
• Peroxisomal Alanine-Glyoxylate Aminotransferase Deficiency

What is Primary Hyperoxaluria? (Definition/Background Information)

• Primary Hyperoxaluria (PH) is a group of inherited metabolic disorders. It is characterized by recurrant stones formation in the urinary tract. The onset of the condition can occur any time between birth and 40 years of age
• Primary Hyperoxaluria is categorized into types 1, 2, and 3, depending on the type of mutation involved that leads to a specific enzyme deficiency, resulting in the condition
• Primary Hyperoxaluria is caused by mutations in AGXT, GRHPR, and HOGA1 genes, which cause the types 1, 2, and 3, respectively. Normally, the gene products are involved in the breakdown of glyoxylates. The mutations cause aberrant gene products, thereby preventing the breakdown of glyoxylate
• Excess glycoxylate leads to accumulation of oxalate. The kidneys excrete the excess oxalate; the remainder in the kidneys combines with calcium to form crystals. The crystals aggregate to form kidney stones
• Since Primary Hyperoxaluria is an inherited condition, a positive family history is a major risk factor for being diagnosed with it. It is inherited in an autosomal recessive fashion
• Generally, individuals with type 1 disorder exhibit the most severe symptoms, followed by those with type 2 and type 3 disorder. The symptoms may present itself in infancy or later in life
• Symptoms in infancy may include increased concentration of oxalate in the urine, poor feeding, poor weight gain, kidney and bladder stones, blood in urine, urinary tract infections, abdominal pain, pain while passing urine, and progressive kidney malfunction
• The type 1 Primary Hyperoxaluria onset in late childhood, adolescence, or adulthood may present with kidney stones and kidney failure. The symptoms of type 2 and type 3 Primary Hyperoxaluria are similar to those of type 1, but are less severe
• In types 1 and 2, the kidneys may not be able to keep up with the excretion of excess oxalate. This may lead to kidney dysfunction and failure, which can lead to oxalate starting to accumulate in other organs, blood vessels and bones, causing further symptoms
• These include anemia, abnormally dense bones, bone fractures, enlarged liver and spleen, eye-related abnormalities, and skin problems and rashes. Type 3 Primary Hyperoxaluria has not been reported with systemic presentations
• The diagnosis of Primary Hyperoxaluria is made through a physical examination, an assessment of symptoms, an evaluation of family medical history, imaging tests to check for kidney stones, biopsy of affected kidney tissue, analysis of bladder or kidney stones to rule out other medical conditions and molecular genetic testing
• Some complications of Primary Hyperoxaluria are kidney failure and end-stage kidney disease (or ESRD). In type 1 disease, ESRD can occur any time in life; whereas in type 2, this complication typically occurs later in the life
• The treatment options for Primary Hyperoxaluria are symptomatic. If the onset is in infancy, a team of specialists may be required to help the child develop normally. Medication to treat excess oxalate, surgery or other procedures to remove kidney stones, and transplantation of liver, kidney or both for advanced disease may be required
• The prognosis is better, if Primary Hyperoxaluria is diagnosed early and treated promptly. The outcome is guarded for untreated type 1 disorder

Who gets Primary Hyperoxaluria? (Age and Sex Distribution)

• Primary Hyperoxaluria is a genetic disorder affecting individuals worldwide (all races and ethnicities)
• The exact prevalence of this condition is not known, owing to under-diagnosis or misdiagnosis. However, some estimates indicate an incident rate of 1:58,000
• Of the three types, type 1 account for the majority of cases (80%). The types 2 and 3 each account for 10% of the total number of cases
• Primary Hyperoxaluria can manifest itself at any time during an individual’s life; as early as infancy or as late as 40 years of age
• Both male and female genders are equally affected by the disorder

What are the Risk Factors for Primary Hyperoxaluria? (Predisposing Factors)

• Since Primary Hyperoxaluria is an inherited disorder, a family history of the condition is a major risk factor for developing the same
• However, the time of onset, severity of symptoms and disease progression may vary even within the same family, indicating that other genetic or environmental factors may play important roles. There is ongoing research to understand additional risk factors for Primary Hyperoxaluria

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases one's chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of Primary Hyperoxaluria? (Etiology)

Primary Hyperoxaluria is caused by mutations in the AGXT, GRHPR, or HOGA1 genes. The condition is inherited in an autosomal recessive manner.

• Under normal circumstances, the 3 genes code for enzymes that together catalyze the formation and breakdown of glyoxylates
• Mutations in the AGXT, GRHPR, or HOGA1 gene can lead to a deficiency in the respective enzymes or loss of their activity. The consequence is an accumulation of glyoxylate
• The glyoxylates are converted to oxalate. Mutations in the HOGA1 gene are reported to cause an increase in oxalate levels, although the exact mechanism of this is unclear
• The kidneys remove excess oxalate from the system. However, over time, oxalate can accumulate in the kidneys, combine with calcium and form crystals, which then aggregate to form stones
• When the kidneys are unable to cope with the excess, the oxalate compounds can also get deposited in other organs and systems, causing more damage to the body
• Primary Hyperoxaluria is classified into 3 different types
  • Mutations in AGXT gene cause type 1 disease, which accounts for 80% of all cases, and cause severe disease
  • Mutations in GRHPR gene cause type 2 disease, with moderately severe symptoms, and accounts for about 10% of the cases
  • Mutations in HOGA1 gene cause type 3 disease, the mildest of the three. This type accounts for about 10% of the reported cases

What are the Signs and Symptoms of Primary Hyperoxaluria?

The symptoms of Primary Hyperoxaluria can be present during infancy or later in life; the severity is dependent on the type of the disorder.

Type 1: It is the most severe form of Primary Hyperoxaluria.

The signs and symptoms in infants may include:

• Feeding difficulties
• Inability to gain weight
• Stones in the urinary tract
• Frequent urination; pain during urination
• Blood in urine
• Frequent urinary tract infections
• Progressive kidney dysfunction; chronic kidney disease
• Early end-stage kidney disease

The signs and symptoms in children and adolescents may include:

• Pain while passing urine
• Inability to control urination, leading to bedwetting in young children
• Progressive kidney dysfunction; chronic kidney disease
• End-stage renal disease

The signs and symptoms in adults may include:

• Recurrent kidney stone formation
• Kidney failure due to blockage with stones
• End-stage kidney disease

Note: In many cases of type 1 disease, an individual may be first diagnosed between the age of 20-40 years when he/she presents with kidney stones and/or kidney failure.

When the kidneys are unable to keep up with oxalate clearance, its functioning may decline over time. As a result, oxalate may start deposited in other organs, blood vessels and systems. This type of progression can cause symptoms such as the following:

• Increased bone density
• Bone fractures; bone pain
• Anemia that is resistant to treatment
• Damage to cranial nerve and optic nerve
• Damage to the retina
• Inflammation of heart membrane (myocarditis)
• Irregular heartbeat
• Stroke (cardioembolic)
• Enlarged spleen (splenomegaly) and enlarged liver (hepatomegaly)
• Peripheral (hands and feet) tissue death, known as peripheral gangrene
• Rashes on skin
• Problems with teeth, pain

Type 2: It is moderate at onset, but gets progressively worse with time.

• The symptoms are often similar to those seen in type 1 disease
• The severity of symptoms may be moderate to begin with, but the disease can eventually lead to end-stage renal disease, as well as oxalate accumulation in other body parts and systems

Type 3: It is the mildest of the 3 forms, with symptoms possibly being absent. Chronic and end-stage kidney disease are not reported for type 3 Primary Hyperoxaluria.

How is Primary Hyperoxaluria Diagnosed?

A diagnosis of Primary Hyperoxaluria is made based upon the following tests and exams:

• A complete physical examination and assessment of symptoms
• Evaluation of personal and family medical history
• Tests that include:
  • Urine analysis
  • Blood tests to check for elevated plasma oxalate levels in individuals with chronic or more advanced kidney disease
  • Imaging (X rays, computed tomography or CT scanning) to locate stones, structural abnormalities in kidneys
  • Biopsy of kidney tissue to assess damage
  • Biopsy of liver tissue for enzyme assays
  • Analysis of kidney stones to rule out other medical conditions with similar symptoms
  • Molecular genetic test for confirmation of genetic mutations
  • If there is a family history of the condition, molecular genetic testing of fetal cells

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the possible Complications of Primary Hyperoxaluria?

The following are some of the complications of Primary Hyperoxaluria:

• Chronic kidney disease
• End-stage kidney disease
• Cardiac arrhythmia and stroke
• Peripheral gangrene

Note: The end-stage kidney disease can occur early in type 1 disease, and later in the type 2 form.

How is Primary Hyperoxaluria Treated?

The treatment options for Primary Hyperoxalouria are generally based upon each individual’s specific signs and symptoms. A team of specialists may be required to treat the individual.

• Restricting oxalate rich food in the diet; plenty of fluid intake
• Use of pain medication
• Medications, such as potassium citrate, orthophosphates or thiazides, to help prevent the crystallization of oxalate and calcium
• Pyridoxine supplements to help reduce oxalate levels in the body
• Shock wave lithotripsy to crush stones so they can pass in urine
• Ureteroscopy, used to break kidney stones with laser
• Percutaneous nephrolithotomy, to remove stones through an incision on the back
• Urinary dialysis
• Kidney transplantation and/or liver transplantation (when necessary)

Newer medications to alter the effects of abnormal proteins using RNA interference (RNAi) and other molecular technologies are in various stages of development and commercialization. The medical provider may help with information on advancements in new treatment methods.

How can Primary Hyperoxaluria be Prevented?

• Currently, there are no specific methods or guidelines to prevent Primary Hyperoxaluria, since it is a genetic condition
• Genetic testing of the expecting parents (and related family members) and prenatal diagnosis (molecular testing of the fetus during pregnancy) may help in understanding the risks better during pregnancy
• If there is a family history of the condition, then genetic counseling will help assess risks, before planning for a child
• Active research is currently being performed to explore the possibilities for treatment and prevention of inherited and acquired genetic disorders such as Primary Hyperoxaluria

Regular medical screening at periodic intervals with tests and physical examinations are highly recommended.

• Avoiding oxalate-rich foods can help reduce build-up of oxalate in the body organs
• Drinking plenty of fluids may help flush out the kidney stones through urine

What is the Prognosis of Primary Hyperoxaluria? (Outcomes/Resolutions)

• The prognosis is generally better, if Primary Hyperoxaluria is diagnosed early and treated promptly
• However, if left untreated, the outcomes may be poor (especially in the case of type 1 disease)

Additional and Relevant Useful Information for Primary Hyperoxaluria:

Primary Hyperoxaluria is also known as ‘Peroxisomal Alanine-Glyoxylate Aminotransferase Deficiency’ and ‘D-Glycerate Dehydrogenase Deficiency’.