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.

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.

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.

Genetic Testing Information

• Genetic Testing Registry: Dihydropteridine reductase deficiency
• Genetic Testing Registry: 6-Pyruvoyl-tetrahydrobiopterin synthase deficiency
• Genetic Testing Registry: Pterin-4 alpha-carbinolamine dehydratase 1 deficiency
• Genetic Testing Registry: GTP cyclohydrolase I deficiency

Genetic and Rare Diseases Information Center

• Hyperphenylalaninemia due to tetrahydrobiopterin deficiency

Patient Support and Advocacy Resources

• National Organization for Rare Disorders (NORD)

Clinical Trials

• ClinicalTrials.gov

Catalog of Genes and Diseases from OMIM

• HYPERPHENYLALANINEMIA, BH4-DEFICIENT, C; HPABH4C
• HYPERPHENYLALANINEMIA, BH4-DEFICIENT, A; HPABH4A
• HYPERPHENYLALANINEMIA, BH4-DEFICIENT, B; HPABH4B
• HYPERPHENYLALANINEMIA, BH4-DEFICIENT, D; HPABH4D

Scientific Articles on PubMed

• PubMed

• Jaggi L, Zurfluh 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. doi: 10.1016/j.ymgme.2007.10.004. Epub 2007 Dec 3. Citation on PubMed
• Liu TT, Chiang SH, Wu SJ, Hsiao KJ. Tetrahydrobiopterin-deficient hyperphenylalaninemia in the Chinese. Clin Chim Acta. 2001 Nov;313(1-2):157-69. doi: 10.1016/s0009-8981(01)00669-6. Citation on PubMed
• 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. Citation on PubMed
• Pearl PL, Taylor JL, Trzcinski S, Sokohl A. The pediatric neurotransmitter disorders. J Child Neurol. 2007 May;22(5):606-16. doi: 10.1177/0883073807302619. Citation on PubMed
• 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. doi: 10.1002/med.10055. Citation on PubMed
• Shintaku H. Disorders of tetrahydrobiopterin metabolism and their treatment. Curr Drug Metab. 2002 Apr;3(2):123-31. doi: 10.2174/1389200024605145. Citation on PubMed
• Thony B, Auerbach G, Blau N. Tetrahydrobiopterin biosynthesis, regeneration and functions. Biochem J. 2000 Apr 1;347 Pt 1(Pt 1):1-16. Citation on PubMed or Free article on PubMed Central
• Thony 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. doi: 10.1002/humu.20366. Citation on PubMed
• 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. doi: 10.1007/s10545-006-0080-y. Citation on PubMed