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Genetics Home Reference: your guide to understanding genetic conditions
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Hyperprolinemia

Reviewed June 2007

What is hyperprolinemia?

Hyperprolinemia is 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. There are two inherited forms of hyperprolinemia, called type I and type II.

People with hyperprolinemia type I often do not show any symptoms, although they have proline levels in their blood between 3 and 10 times the normal level. Some individuals with hyperprolinemia type I exhibit seizures, intellectual disability, or other neurological or psychiatric problems.

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.

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.

How common is hyperprolinemia?

It is difficult to determine the prevalence of hyperprolinemia type I because most people with the condition do not have any symptoms. Hyperprolinemia type II is a rare condition; its prevalence is also unknown.

What genes are related to hyperprolinemia?

Mutations in the ALDH4A1 and PRODH genes cause hyperprolinemia.

Inherited hyperprolinemia is caused by deficiencies in the enzymes that break down (degrade) proline. Hyperprolinemia type I is caused by a mutation in the PRODH gene, which provides instructions for producing 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, 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.

Related Gene(s)

Changes in these genes are associated with hyperprolinemia.

  • ALDH4A1
  • PRODH

How do people inherit hyperprolinemia?

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. In about one-third of cases, 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.

Where can I find information about diagnosis or management of hyperprolinemia?

These resources address the diagnosis or management of hyperprolinemia and may include treatment providers.

  • Baby's First Test (http://www.babysfirsttest.org/newborn-screening/conditions/prolinemia)
  • Genetic Testing Registry: Deficiency of pyrroline-5-carboxylate reductase (http://www.ncbi.nlm.nih.gov/gtr/conditions/C0268530)
  • Genetic Testing Registry: Proline dehydrogenase deficiency (http://www.ncbi.nlm.nih.gov/gtr/conditions/C0268529)

You might also find information on the diagnosis or management of hyperprolinemia in Educational resources (http://www.ghr.nlm.nih.gov/condition/hyperprolinemia/show/Educational+resources) and Patient support (http://www.ghr.nlm.nih.gov/condition/hyperprolinemia/show/Patient+support).

General information about the diagnosis (http://ghr.nlm.nih.gov/handbook/consult/diagnosis) and management (http://ghr.nlm.nih.gov/handbook/consult/treatment) of genetic conditions is available in the Handbook. Read more about genetic testing (http://ghr.nlm.nih.gov/handbook/testing), particularly the difference between clinical tests and research tests (http://ghr.nlm.nih.gov/handbook/testing/researchtesting).

To locate a healthcare provider, see How can I find a genetics professional in my area? (http://ghr.nlm.nih.gov/handbook/consult/findingprofessional) in the Handbook.

Where can I find additional information about hyperprolinemia?

You may find the following resources about hyperprolinemia helpful. These materials are written for the general public.

You may also be interested in these resources, which are designed for healthcare professionals and researchers.

What other names do people use for hyperprolinemia?

  • prolinemia
  • proline oxidase deficiency
  • pyrroline-5-carboxylate dehydrogenase deficiency
  • pyrroline carboxylate dehydrogenase deficiency

For more information about naming genetic conditions, see the Genetics Home Reference Condition Naming Guidelines (http://ghr.nlm.nih.gov/ConditionNameGuide) and How are genetic conditions and genes named? (http://ghr.nlm.nih.gov/handbook/mutationsanddisorders/naming) in the Handbook.

What if I still have specific questions about hyperprolinemia?

Ask the Genetic and Rare Diseases Information Center (http://rarediseases.info.nih.gov/GARD/).

What glossary definitions help with understanding hyperprolinemia?

acids ; amino acid ; autosomal ; autosomal recessive ; breakdown ; carboxylate ; cell ; compound ; deficiency ; degrade ; dehydrogenase ; disability ; enzyme ; gene ; inherited ; lactic acid ; mutation ; neurological ; newborn screening ; oxidase ; prevalence ; proline ; protein ; recessive ; screening

You may find definitions for these and many other terms in the Genetics Home Reference Glossary (http://www.ghr.nlm.nih.gov/glossary).

References

  • Campbell HD, Webb GC, Young IG. A human homologue of the Drosophila melanogaster sluggish-A (proline oxidase) gene maps to 22q11.2, and is a candidate gene for type-I hyperprolinaemia. Hum Genet. 1997 Nov;101(1):69-74. (http://www.ncbi.nlm.nih.gov/pubmed/9385373?dopt=Abstract)
  • Geraghty MT, Vaughn D, Nicholson AJ, Lin WW, Jimenez-Sanchez G, Obie C, Flynn MP, Valle D, Hu CA. Mutations in the Delta1-pyrroline 5-carboxylate dehydrogenase gene cause type II hyperprolinemia. Hum Mol Genet. 1998 Sep;7(9):1411-5. (http://www.ncbi.nlm.nih.gov/pubmed/9700195?dopt=Abstract)
  • Humbertclaude V, Rivier F, Roubertie A, Echenne B, Bellet H, Vallat C, Morin D. Is hyperprolinemia type I actually a benign trait? Report of a case with severe neurologic involvement and vigabatrin intolerance. J Child Neurol. 2001 Aug;16(8):622-3. (http://www.ncbi.nlm.nih.gov/pubmed/11510941?dopt=Abstract)
  • OMIM: HYPERPROLINEMIA, TYPE I (http://omim.org/entry/239500)
  • OMIM: HYPERPROLINEMIA, TYPE II (http://omim.org/entry/239510)
  • Jacquet H, Berthelot J, Bonnemains C, Simard G, Saugier-Veber P, Raux G, Campion D, Bonneau D, Frebourg T. The severe form of type I hyperprolinaemia results from homozygous inactivation of the PRODH gene. J Med Genet. 2003 Jan;40(1):e7. (http://www.ncbi.nlm.nih.gov/pubmed/12525555?dopt=Abstract)
  • Shivananda, Christopher R, Kumar P. Type I hyperprolinemia. Indian J Pediatr. 2000 Jul;67(7):541-3. (http://www.ncbi.nlm.nih.gov/pubmed/10957843?dopt=Abstract)

 

The resources on this site should not be used as a substitute for professional medical care or advice. Users seeking information about a personal genetic disease, syndrome, or condition should consult with a qualified healthcare professional. See How can I find a genetics professional in my area? (http://ghr.nlm.nih.gov/handbook/consult/findingprofessional) in the Handbook.

 
Reviewed: June 2007
Published: October 20, 2014