Hyperprolinemia type 2

Alternate names

1 alpha pyrroline-5-carboxylate dehydrogenase deficiency; Type 2 hyperprolinemia; Hyperprolinemia type 2

Definition

Hyperprolinemia type 2 results in an excess of a particular protein building block (amino acid), called proline, in the blood. This condition generally occurs when proline is not broken down properly by the body.

Hyperprolinemia can also occur with other conditions, such as malnutrition or liver disease. In particular, individuals with conditions that cause elevated levels of lactic acid in the blood (lactic acidemia) may have hyperprolinemia as well, because lactic acid inhibits the breakdown of proline.

Epidemiology

Hyperprolinemia type II is a rare condition; its prevalence is also unknown.

Cause

• Hyperprolinemia type II is caused by a mutation in the ALDH4A1 gene, which provides instructions for producing the enzyme pyrroline-5-carboxylate dehydrogenase.
• This enzyme helps to break down the pyrroline-5-carboxylate produced in the previous reaction, converting it to the amino acid glutamate.
• The conversion between proline and glutamate, and the reverse reaction controlled by different enzymes, are important in maintaining a supply of the amino acids needed for protein production, and for energy transfer within the cell.
• A deficiency of either proline oxidase or pyrroline-5-carboxylate dehydrogenase results in a buildup of proline in the body.
• A deficiency of the latter enzyme leads to higher levels of proline and a buildup of the intermediate breakdown product pyrroline-5-carboxylate, causing the signs and symptoms of hyperprolinemia type II.

Inheritance

Autosomal recessive inheritance, a 25% chance

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

Signs and symptoms

Some people with this condition develop mild intellectual disability and seizures; however, the symptoms of this disorder vary in severity among affected individuals.

Diagnosis

• Hyperprolinemia type II results in proline levels in the blood between 10 and 15 times higher than normal, and high levels of a related compound called pyrroline-5-carboxylate.
• This form of the disorder has signs and symptoms that vary in severity, and is more likely than type I to involve seizures or intellectual disability.

Treatment

There is no specific treatment for hyperprolinemia type 2, even for those individuals who experience seizures. In general, if people with hyperprolinemia type 2 have symptoms, they are usually mild and do not require treatment. If seizures are present during childhood, they tend to disappear in adulthood. Attempts to reduce the amount of proline in an affected person's diet have resulted in only modest control of proline levels in the blood and have not reduced symptoms.

Prognosis

• After an extensive search of the information resources available to us, we were not able to locate any information to suggest that people with hyperprolinemia type 2 have a shortened lifespan.
• One study of hyperprolinemia type 2 in Ireland found that most adults had normal health.
• Children Living with Inherited Metabolic Diseases (CLIMB), an advocacy organization for individuals with metabolic disorders, also notes that when patients reach adulthood, they typically appear to be symptom-free.

NIH genetic and rare disease info

• NIH info on Hyperprolinemia type 2

Hyperprolinemia type 2 is a rare disease.

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