Hyperprolinaemia (Type I and Type II)

What else is it called?

  • Proline oxidase deficiency 
  • Prolinaemia 
  • Pyrroline-5-carboxylate dehydrogenase deficiency 
  • Pyrroline carboxylate dehydrogenase deficiency 
  • HP-I 
  • HP-II 

Get in touch

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What causes it?

Hyperprolinaemia is caused by mutations (changes) in the PRODH or ALDH4A1 gene. 

Hyperprolinaemia type I is caused by a mutation in the PRODH gene which provides instructions for producing the enzyme proline oxidase. The enzyme starts degrading proline by a reaction that converts proline to pyrroline-5-carboxylate.  

Hyperprolinaemia type II is caused by a mutation in the ALDH4A1 gene which provides instructions for producing the enzyme pyrroline-5-carboxylate dehydrogenase. This enzyme breaks down the pyrroline-5-carboxylate produced in the previous reaction, converting it into amino acid glutamate. This conversion which is controlled by different enzymes is important in preserving a supply of the amino acids necessary for protein production and energy transfer in the cells of the body.  

A lack of either proline oxidase or pyrroline-5-carboxylate dehydrogenase causes a build-up of proline in the body. A lack of pyrroline-5-carboxylate dehydrogenase causes higher levels of proline and a build-up of the breakdown product pyrroline-5-carboxylate which causes the signs and symptoms of Hyperprolinaemia type II. 

How common is it?

The prevalence of Hyperprolinaemia Type I is difficult to determine as most people with the condition do not show any symptoms.  

 Hyperprolinaemia Type II is very rare, and the prevalence is unknown.  

What are the signs and symptoms?

Individuals with Hyperprolinaemia type I usually do not show any symptoms. However, their proline levels in their blood are between 3 and 10 times higher than the normal level. Some individuals with this condition may show symptoms. These symptoms may include:  

  • Seizures 
  • Intellectual disability  
  • Neurological problems  
  • Psychiatric problems  

Individuals with Hyperprolinaemia type II have blood levels in their blood between 10 and 15 times high than normal and high levels of pyrroline-5-carboxylate. Type II of this condition has symptoms that vary in severity. Individuals with type II are more likely than individuals with type I to have symptoms including: 

  • Seizures  
  • Intellectual disability  

How is it diagnosed?

Hyperprolinaemia type I is diagnosed through a specialized blood test. The disorder is identified by raised blood proline levels (the normal level is around 450 units, whereas HP-I patients may have levels of 1900 to 2000 units). A diagnosis is usually made by exclusion after not being able to make a diagnosis and then ordering a blood proline level test. The results of this test confirm the diagnosis. 

Hyperprolinaemia type II is diagnosed through a specialized blood and urine test which will detect raised blood proline levels and raised P-5-C levels in the urine. Normal blood proline levels are around 450 units, patients with HP-II may reach 1900-2000 units.  

Can it be treated?

There is no specific treatment for Hyperprolinaemia. Attempts to control blood proline levels by restrictive diets has not been successful.  

Patients with childhood neurological problems usually grow out of the pattern of fevers and seizures. Adult life with this condition has been shown to be symptom-free. 



Do my family need to be tested?

Hyperprolinaemia is an inherited condition. Humans have chromosomes made up of DNA. Genes are pieces of DNA that carry the genetic information. Each chromosome may have several thousand genes. We inherit chromosomes from the egg of the mother and sperm of the father. The genes on those chromosomes carry the instructions that determine a person’s characteristics, which are a combination of the parents. 

The pattern of inheritance of Hyperprolinaemia is autosomal recessive. This means that carriers of the condition do not have the disorder because the other gene of this pair is working normally. Parents of children with Hyperprolinaemia are carriers.  

When both parents are carriers, the risk to the baby in each pregnancy is 

  • 25% chance (1 in 4) of developing the condition 
  • 50% chance (1 in 2) for the baby to be a carrier of the condition 
  • 25% chance (1 in 4) for the baby to have two working genes and neither have the condition nor be a carrier 

Genetic counselling can be requested to get a full explanation.  

Relevant Organisations


References are available on request. Please contact Helen Morris by phoning 0845 241 2173 or emailing helen@metabolicsupportuk.org [Resource Library No: AAP002]. 

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