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Genetics Home Reference: your guide to understanding genetic conditions
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Tetrahydrobiopterin deficiency

Reviewed July 2011

What is tetrahydrobiopterin deficiency?

Tetrahydrobiopterin deficiency is a rare disorder characterized by a shortage (deficiency) of a molecule called tetrahydrobiopterin or BH4. This condition alters the levels of several substances in the body, including phenylalanine. Phenylalanine is a building block of proteins (an amino acid) that is obtained through the diet. It is found in foods that contain protein and in some artificial sweeteners. High levels of phenylalanine are present from early infancy in people with untreated tetrahydrobiopterin deficiency. This condition also alters the levels of chemicals called neurotransmitters, which transmit signals between nerve cells in the brain.

Infants with tetrahydrobiopterin deficiency appear normal at birth, but medical problems ranging from mild to severe become apparent over time. Signs and symptoms of this condition can include intellectual disability, progressive problems with development, movement disorders, difficulty swallowing, seizures, behavioral problems, and an inability to control body temperature.

How common is tetrahydrobiopterin deficiency?

This condition is rare, affecting an estimated 1 in 500,000 to 1 in 1 million newborns. In most parts of the world, tetrahydrobiopterin deficiency accounts for 1 to 3 percent of all cases of elevated phenylalanine levels. The remaining cases are caused by a similar condition called phenylketonuria (PKU). In certain countries, including Saudi Arabia, Taiwan, China, and Turkey, it is more common for elevated levels of phenylalanine to be caused by tetrahydrobiopterin deficiency than by PKU.

What genes are related to tetrahydrobiopterin deficiency?

Tetrahydrobiopterin deficiency can be caused by mutations in one of several genes, including GCH1, PCBD1, PTS, and QDPR. These genes provide instructions for making enzymes that help produce and recycle tetrahydrobiopterin in the body. Tetrahydrobiopterin normally helps process several amino acids, including phenylalanine. It is also involved in the production of neurotransmitters.

If one of the enzymes fails to function correctly because of a gene mutation, little or no tetrahydrobiopterin is available to help process phenylalanine. As a result, phenylalanine can build up in the blood and other tissues. Because nerve cells in the brain are particularly sensitive to phenylalanine levels, excessive amounts of this substance can cause brain damage. Tetrahydrobiopterin deficiency can also alter the levels of certain neurotransmitters, which disrupts normal brain function. These abnormalities underlie the intellectual disability and other characteristic features of the condition.

Related Gene(s)

Changes in these genes are associated with tetrahydrobiopterin deficiency.

  • GCH1
  • PCBD1
  • PTS
  • QDPR

How do people inherit tetrahydrobiopterin deficiency?

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

Where can I find information about diagnosis or management of tetrahydrobiopterin deficiency?

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

  • Baby's First Test: Biopterin Defect in Cofactor Biosynthesis (http://www.babysfirsttest.org/newborn-screening/conditions/biopterin-defect-in-cofactor-biosynthesis)
  • Baby's First Test: Biopterin Defect in Cofactor Regeneration (http://www.babysfirsttest.org/newborn-screening/conditions/biopterin-defect-in-cofactor-regeneration)
  • Genetic Testing Registry: 6-pyruvoyl-tetrahydropterin synthase deficiency (http://www.ncbi.nlm.nih.gov/gtr/conditions/C0878676)
  • Genetic Testing Registry: Dihydropteridine reductase deficiency (http://www.ncbi.nlm.nih.gov/gtr/conditions/C0268465)
  • Genetic Testing Registry: GTP cyclohydrolase I deficiency (http://www.ncbi.nlm.nih.gov/gtr/conditions/C0268467)
  • Genetic Testing Registry: Hyperphenylalaninemia, bh4-deficient, d (http://www.ncbi.nlm.nih.gov/gtr/conditions/C1849700)
  • MedlinePlus Encyclopedia: Serum Phenylalanine Screening (http://www.nlm.nih.gov/medlineplus/ency/article/003362.htm)

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

You may find the following resources about tetrahydrobiopterin deficiency 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 tetrahydrobiopterin deficiency?

  • BH4 deficiency
  • hyperphenylalaninemia caused by a defect in biopterin metabolism
  • hyperphenylalaninemia, non-phenylketonuric
  • non-phenylketonuric hyperphenylalaninemia

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 tetrahydrobiopterin deficiency?

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

What glossary definitions help with understanding tetrahydrobiopterin deficiency?

acids ; amino acid ; atypical ; autosomal ; autosomal recessive ; cell ; deficiency ; difficulty swallowing ; disability ; gene ; inherited ; metabolism ; molecule ; mutation ; neurotransmitters ; newborn screening ; phenylalanine ; 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

  • Jäggi L, Zurflüh MR, Schuler A, Ponzone A, Porta F, Fiori L, Giovannini M, Santer R, Hoffmann GF, Ibel H, Wendel U, Ballhausen D, Baumgartner MR, Blau N. Outcome and long-term follow-up of 36 patients with tetrahydrobiopterin deficiency. Mol Genet Metab. 2008 Mar;93(3):295-305. Epub 2007 Dec 3. (http://www.ncbi.nlm.nih.gov/pubmed/18060820?dopt=Abstract)
  • Liu TT, Chiang SH, Wu SJ, Hsiao KJ. Tetrahydrobiopterin-deficient hyperphenylalaninemia in the Chinese. Clin Chim Acta. 2001 Nov;313(1-2):157-69. (http://www.ncbi.nlm.nih.gov/pubmed/11694255?dopt=Abstract)
  • Longo N. Disorders of biopterin metabolism. J Inherit Metab Dis. 2009 Jun;32(3):333-42. doi: 10.1007/s10545-009-1067-2. Epub 2009 Feb 9. Review. Erratum in: J Inherit Metab Dis. 2009 Jun;32(3):457. (http://www.ncbi.nlm.nih.gov/pubmed/19234759?dopt=Abstract)
  • Pearl PL, Taylor JL, Trzcinski S, Sokohl A. The pediatric neurotransmitter disorders. J Child Neurol. 2007 May;22(5):606-16. Review. (http://www.ncbi.nlm.nih.gov/pubmed/17690069?dopt=Abstract)
  • Ponzone A, Spada M, Ferraris S, Dianzani I, de Sanctis L. Dihydropteridine reductase deficiency in man: from biology to treatment. Med Res Rev. 2004 Mar;24(2):127-50. Review. (http://www.ncbi.nlm.nih.gov/pubmed/14705166?dopt=Abstract)
  • Shintaku H. Disorders of tetrahydrobiopterin metabolism and their treatment. Curr Drug Metab. 2002 Apr;3(2):123-31. Review. (http://www.ncbi.nlm.nih.gov/pubmed/12003346?dopt=Abstract)
  • Thöny B, Auerbach G, Blau N. Tetrahydrobiopterin biosynthesis, regeneration and functions. Biochem J. 2000 Apr 1;347 Pt 1:1-16. Review. (http://www.ncbi.nlm.nih.gov/pubmed/10727395?dopt=Abstract)
  • Thöny B, Blau N. Mutations in the BH4-metabolizing genes GTP cyclohydrolase I, 6-pyruvoyl-tetrahydropterin synthase, sepiapterin reductase, carbinolamine-4a-dehydratase, and dihydropteridine reductase. Hum Mutat. 2006 Sep;27(9):870-8. (http://www.ncbi.nlm.nih.gov/pubmed/16917893?dopt=Abstract)
  • Wang L, Yu WM, He C, Chang M, Shen M, Zhou Z, Zhang Z, Shen S, Liu TT, Hsiao KJ. Long-term outcome and neuroradiological findings of 31 patients with 6-pyruvoyltetrahydropterin synthase deficiency. J Inherit Metab Dis. 2006 Feb;29(1):127-34. (http://www.ncbi.nlm.nih.gov/pubmed/16601879?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: July 2011
Published: October 20, 2014