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

• Delta-1-Pyrroline-5-Carboxylate Dehydrogenase Deficiency
• Hyperprolinemia II (HPII)
• Hyperprolinemia Type 2

What is Hyperprolinemia Type II? (Definition/Background Information)

• Hyperprolinemia is a metabolic disorder characterized by elevated levels of proline in the blood. Type I Hyperprolinemia and Type II Hyperprolinemia result from deficiencies in proline-degrading enzymes, leading to varied symptoms such as seizures and intellectual deficits
• Hyperprolinemia Type II is a metabolic disorder characterized by elevated levels of proline, an amino acid, in the blood. It is an autosomal recessive disorder caused by genetic mutations involving the ALDH4A1 gene
• This condition results from the inadequate breakdown of proline, leading to 10 to 15 times higher than normal levels in the blood, as well as elevated levels of a related compound known as pyrroline-5-carboxylate
• Clinical signs and symptoms of Hyperprolinemia Type II may include seizures, intellectual deficits, mild developmental delays, and intellectual disability. The symptoms vary in severity among affected individuals
• The management of Hyperprolinemia Type II often involves addressing symptoms. Specific treatments may include dietary adjustments and, in some cases, medical interventions to control seizures or other associated issues
• As Hyperprolinemia Type II is a genetic disorder, prevention involves genetic counseling for affected families. Early diagnosis and intervention are crucial for optimizing outcomes
• The condition is often considered benign, but the clinical course can vary. The prognosis of Hyperprolinemia Type II depends on the severity of symptoms, and while some individuals may have mild manifestations, others may experience more significant challenges

Who gets Hyperprolinemia Type II? (Age and Sex Distribution)

• Hyperprolinemia Type II is a rare congenital disorder. The exact prevalence of this condition is not known
• The presentation of symptoms may occur at any age but are known to manifest in early childhood primarily
• Both males and females may be affected
• Worldwide, individuals of all racial and ethnic groups may be affected

What are the Risk Factors for Hyperprolinemia Type II? (Predisposing Factors)

• A positive family history may be a significant risk factor since Hyperprolinemia Type II can be inherited
• The disorder may be more frequent in consanguineous pairings, where the mother and father share significant genetic similarities
• There is no known influence of external environmental or lifestyle factors that contribute to the development of Hyperprolinemia Type II

It is important to note that having a risk factor does not mean 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 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 Hyperprolinemia Type II? (Etiology)

Alterations or changes in the ALDH4A1 gene cause Hyperprolinemia Type II (HPII). The gene provides instructions for producing pyrroline-5-carboxylate dehydrogenase (P5CDH) enzyme.

• This enzyme also plays an essential role in breaking down pyrroline-5-carboxylate into the amino acid glutamate
• This conversion is required to maintain the supply of amino acids necessary for protein production and the transfer of energy
• A deficiency or shortage of this enzyme results in excess proline accumulating in the body (that can be observed through blood and urine tests), resulting in characteristic signs and symptoms, including mental retardation and seizures

HPII is an inborn genetic disorder related to amino acid metabolism inherited in an autosomal recessive pattern.

Autosomal recessive: Autosomal recessive conditions are traits or disorders that occur when two copies of an abnormal gene have been inherited on a non-sex chromosome. If both parents have an autosomal recessive condition, there is a 100% likelihood of passing on the mutated genes to their children. If only one mutant copy of the gene is inherited, the individual will be a carrier of the condition but will not be present with any symptoms. Children born to two carriers have a 25% chance of being homozygous dominant (unaffected), a 50% chance of being heterozygous (carrier), and a 25% chance of being homozygous recessive (affected).

What are the Signs and Symptoms of Hyperprolinemia Type II?

The presentation of signs and symptoms can vary, and Hyperprolinemia Type II is often considered benign. The signs and symptoms may include:

• Seizures; recurrent convulsions
• Neurological abnormalities
• Seizures
• Renal cysts
• Mild intellectual disability
• Behavioral issues

Variable severity of symptoms among affected individuals is noted.

How is Hyperprolinemia Type II Diagnosed?

A diagnosis of Hyperprolinemia Type II may involve the following tests and procedures:

• Complete physical examination with evaluation of personal and family medical history
• Blood and urine tests: Elevated proline levels in the blood and increased hydroxyl proline and glycine levels in urine may be noted
• Genetic testing that may include:
  • Molecular testing
  • Chromosomal testing
  • Biochemical genetic testing
• Diagnostic testing and scans for assessment of neurological abnormalities

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 Hyperprolinemia Type II?

Hyperprolinemia Type II can lead to the following complications:

• Severe mental retardation
• Malnutrition
• Liver disease
• Renal dysfunction
• Aminoaciduria: Presence of excess amino acids in the urine
• Psychiatric problems
• Reduced quality of life

How is Hyperprolinemia Type II Treated?

There is no cure for Hyperprolinemia Type II since it is a genetic condition. The treatment is usually given to manage the signs and symptoms effectively and any complication that develops. The treatment options may include:

• Changes and alterations in the diet: Restricting the consumption of certain substances in the diet can help prevent the building up of toxic substances in the body
• Replacing the deficit enzymes: Replacement therapy usually helps in compensating for the shortage of enzymes
• Gene therapy

How can Hyperprolinemia Type II be Prevented?

Presently, no measures are available to prevent Hyperprolinemia Type II, as it is caused by genetic factors.

• 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

What is the Prognosis of Hyperprolinemia Type II? (Outcomes/Resolutions)

The prognosis of Hyperprolinemia Type II depends on the severity of the signs and symptoms and associated complications, if any.

• It also depends on the effective treatment strategies that are employed to manage the associated signs and symptoms
• Regular medical monitoring and appropriate interventions can contribute to a better prognosis

Additional and Relevant Useful Information for Hyperprolinemia Type II:

The following DoveMed website link is a helpful resource for additional information:

https://www.dovemed.com/diseases-conditions/hyperprolinemia