Hyperprolinemia is a condition which occurs when the

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha a ...

proline is not broken down properly by the enzymes proline oxidase or pyrroline-5-carboxylate dehydrogenase, causing a buildup of proline in the body.

Genetics

Mutations in the ''

ALDH4A1 Delta-1-pyrroline-5-carboxylate dehydrogenase, mitochondrial is an enzyme that in humans is encoded by the ''ALDH4A1'' gene. This protein belongs to the aldehyde dehydrogenase family of proteins. This enzyme is a mitochondrial matrix NAD-dependen ...

'' and '' PRODH'' genes cause hyperprolinemia. Hyperprolinemia type I is caused by a mutation in the ''PRODH'' gene, which codes for the enzyme proline oxidase. This enzyme begins the process of degrading proline by starting the reaction that converts it to pyrroline-5-carboxylate. Hyperprolinemia type II is caused by a mutation in the ''ALDH4A1'' gene, for the enzyme 1-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 glutamine, and the reverse reaction controlled by different enzymes, are important factors required to maintain proper metabolism and protein production. 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.Hyperprolinemia is inherited in an autosomal recessive pattern, which means two copies of the gene in each cell are altered. Most often, the parents of an individual with an autosomal recessive disorder are

heterozygous Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism. Mo ...

carriers, having only one copy of the altered gene, without having signs and symptoms of the disorder. In about one-third of cases of hyperprolinemia, individuals carrying one copy of an altered ''PRODH'' gene have moderately elevated levels of proline in their blood, but these levels do not cause any health problems. Individuals with one altered ''ALDH4A1'' gene have normal levels of proline in their blood.

Diagnosis

Types

Hyperprolinemia type I

It is difficult to determine the prevalence of hyperprolinemia type I, as many people with the condition are asymptomatic. People with hyperprolinemia type I have proline levels in their blood between 3 and 10 times the normal level. Some individuals with type I exhibit

seizure An epileptic seizure, informally known as a seizure, is a period of symptoms due to abnormally excessive or synchronous neuronal activity in the brain. Outward effects vary from uncontrolled shaking movements involving much of the body with l ...

intellectual disability Intellectual disability (ID), also known as general learning disability in the United Kingdom and formerly mental retardation, Rosa's Law, Pub. L. 111-256124 Stat. 2643(2010). is a generalized neurodevelopmental disorder characterized by signif ...

, or other neurological problems.

Hyperprolinemia type II

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 rare form of the disorder may appear benign at times, but often involves seizures, convulsions, and intellectual disability. 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, such as lactic acidemia, are likely to have elevated proline levels, because lactic acid inhibits the breakdown of proline.

Treatment

Dietary restriction of protein intake.

Research

A 2005 study on rats suggested that hyperprolininemia causes cognitive dysfunction.