Hyperprolinemia is a condition which occurs when the amino acid

proline Proline (symbol Pro or P) is an organic acid classed as a proteinogenic amino acid (used in the biosynthesis of proteins), although it does not contain the amino group but is rather a secondary amine. The secondary amine nitrogen is in the prot ...

is not broken down properly by the enzymes

proline oxidase Proline dehydrogenase, mitochondrial is an enzyme that in humans is encoded by the ''PRODH'' gene. The protein encoded by this gene is a mitochondrial proline dehydrogenase which catalyzes the first step in proline catabolism. Deletion of this gen ...

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 Proline dehydrogenase, mitochondrial is an enzyme that in humans is encoded by the ''PRODH'' gene. The protein encoded by this gene is a mitochondrial proline dehydrogenase which catalyzes the first step in proline catabolism. Deletion of this gen ...

'' genes cause hyperprolinemia. Hyperprolinemia type I is caused by a mutation in the ''PRODH'' gene, which codes for the enzyme

. 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 In enzymology, a 1-pyrroline-5-carboxylate dehydrogenase () is an enzyme that catalyzes the chemical reaction : (S)-1-pyrroline-5-carboxylate + NAD+ + 2 H2O \rightleftharpoons L-glutamate + NADH + H+ The three substrates of this enzyme are ( ...

. This enzyme helps to break down the pyrroline-5-carboxylate produced in the previous reaction, converting it to the amino acid

glutamate Glutamic acid (symbol Glu or E; the ionic form is known as glutamate) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a non-essential nutrient for humans, meaning that the human body can syn ...

. 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 In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...

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 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 In medicine, any disease is classified asymptomatic if a patient tests as carrier for a disease or infection but experiences no symptoms. Whenever a medical condition fails to show noticeable symptoms after a diagnosis it might be considered asy ...

. People with hyperprolinemia type I have

levels in their blood between 3 and 10 times the normal level. Some individuals with type I exhibit seizures, intellectual disability, 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 1-Pyrroline-5-carboxylic acid (systematic name 3,4-dihydro-2H-pyrrole-2-carboxylic acid) is a cyclic imino acid. Its conjugate base and anion is 1-pyrroline-5-carboxylate (P5C). In solution, P5C is in spontaneous equilibrium with glutamate-5-se ...

. 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

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.