Hyperprolinemia

Hyperprolinemia is a metabolic condition characterized by elevated levels of the amino acid proline in the blood, often resulting from a deficiency in the enzymes required to break it down.

Overview

Hyperprolinemia is an excess of the amino acid proline in the blood. It is categorized into two types based on the specific enzyme deficiency and the severity of symptoms. The condition can also occur secondary to other issues, such as malnutrition, liver disease, or lactic acidosis.

Types

Hyperprolinemia Type I

Individuals with type I often show no symptoms, though they may have proline levels 3 to 10 times higher than normal. Some may experience seizures, intellectual disability, or other neurological and psychiatric problems.

Hyperprolinemia Type II

Type II results in proline levels 10 to 15 times higher than normal, along with high levels of a related compound called pyrroline-5-carboxylate. This form is more likely to involve seizures or intellectual disability of varying severity.

Causes

Hyperprolinemia is caused by variants in the PRODH or ALDH4A1 genes:

• Type I: Caused by variants in the PRODH gene, which provides instructions for the enzyme proline dehydrogenase. This enzyme initiates the breakdown of proline.
• Type II: Caused by variants in the ALDH4A1 gene, which provides instructions for the enzyme pyrroline-5-carboxylate dehydrogenase. This enzyme breaks down the product of the previous reaction into glutamate.

When these enzymes do not function correctly, proline accumulates in the body.

Inheritance

This condition is inherited in an autosomal recessive pattern, meaning both copies of the gene in each cell have variants. Parents of an affected individual typically carry one copy of the altered gene without showing symptoms. In some cases, carriers of a PRODH variant may have moderately elevated proline levels that do not cause health problems.