Tetrahydrobiopterin Deficiency

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What is tetrahydrobiopterin deficiency?

Tetrahydrobiopterin (also known as BH4) deficiency is a rare disorder that increases the blood levels of a substance called phenylalanine. Phenylalanine is an amino acid (a building block of proteins) obtained through the diet. It is found in all proteins and in some artificial sweeteners. If tetrahydrobiopterin deficiency is not treated, excess phenylalanine can build up to harmful levels in the body, causing mental retardation and other serious health problems.

High levels of phenylalanine are present from infancy in people with untreated tetrahydrobiopterin deficiency. The resulting signs and symptoms range from mild to severe. Mild complications may include temporary low muscle tone. Severe complications include mental retardation, movement disorders, difficulty swallowing, seizures, behavioral problems, progressive problems with development, and an inability to control body temperature.

How common is tetrahydrobiopterin deficiency?

This condition is very rare; approximately 450 cases have been reported worldwide. In most parts of the world, only 1 percent to 2 percent of all infants with high phenylalanine levels have this disorder. In China, about 30 percent of newborns with elevated levels of phenylalanine have a deficiency of tetrahydrobiopterin.

What genes are related to tetrahydrobiopterin deficiency?

Mutations in the GCH1, PCBD1, PTS, and QDPR genes cause tetrahydrobiopterin deficiency.

Tetrahydrobiopterin is a compound that helps convert several amino acids, including phenylalanine, to other essential molecules in the body. It is also involved in the production of chemicals called neurotransmitters that transmit signals between nerve cells in the brain. Tetrahydrobiopterin deficiency can be caused by mutations in one of several genes, including GCH1, PCBD1, PTS, and QDPR. These genes make enzymes that are critical for producing and recycling tetrahydrobiopterin. If one of the enzymes fails to function correctly because of a gene mutation, little or no tetrahydrobiopterin is produced. As a result, phenylalanine from the diet builds up in the bloodstream and other tissues and can damage nerve cells in the brain. Tetrahydrobiopterin deficiency also disrupts the levels of certain neurotransmitters in the brain, which affects the function of the central nervous system.

How do people inherit tetrahydrobiopterin deficiency?

This condition is inherited in an autosomal recessive pattern, which means two copies of a specific gene in each cell are altered. Most often, the parents of an individual with an autosomal recessive disorder are carriers of one copy of the altered gene but do not show signs and symptoms of the disorder.

Source: National Institutes of Health

New vascular disease research from University of Oklahoma outlined

"Here, we demonstrate that diabetes reduced BH4 by increasing 26S proteasome-dependent degradation of guanosine 5'-triphosphate cyclohydrolase I (GTPCH), a rate-limiting enzyme in the synthesis of BH4, in parallel with increased formation of both superoxide and peroxynitrite (ONOO-)Exposure of human umbilical vein endothelial cells to high glucose concentrations (30 mmol/L D-glucose) but not to high osmotic conditions (25 mmol/L L-glucose plus 5 mmol/L D-glucose) significantly lowered the levels of both GTPCH protein and BH4. In addition, high glucose increased both the 26S proteasome activity and the ubiquitination of GTPCH. Inhibition of the 26S proteasome with either MG132 or PR-11 prevented the high glucose - triggered reduction of GTPCH and BH4. Exposure of human umbilical vein endothelial cells to exogenous ONOO- increased proteasome activity and 3-nitrotyrosine in 26S proteasome. Furthermore, adenoviral overexpression of superoxide dismutase and inhibition of endothelial nitric oxide synthase with N-G-nitro-L-arginine methyl ester significantly attenuated the high glucose - induced activation of 26S proteasome and the reduction of GTPCH," wrote J. Xu and colleagues, University of Oklahoma.

The researchers concluded: "Finally, administration of MG132 or a superoxide dismutase mimetic, tempol, reversed the diabetes mellitus - induced reduction of GTPCH and BH4 and endothelial dysfunction in streptozotocin-induced diabetes mellitusWe conclude that diabetes mellitus triggers BH4 deficiency by increasing proteasome-dependent degradation of GTPCH."

Xu and colleagues published their study in Circulation (Proteasome-dependent degradation of guanosine 5'-triphosphate cyclohydrolase I causes tetrahydrobiopterin deficiency in diabetes mellitus. Circulation, 2007;116(8):944-953).

Additional information can be obtained by contacting M.H. Zou, University of Oklahoma, Health Science Center, Dept. of Medical, Division Endocrinol & Diabetes, BSEB 325, 941 Stanton L Young Blvd., Oklahoma City, OK 73104, USA.

The publisher of the journal Circulation can be contacted at: Lippincott Williams & Wilkins, 530 Walnut St., Philadelphia, PA 19106-3621, USA.

Keywords: United States, Oklahoma City, Vascular Disease, University of Oklahoma.

This article was prepared by Hematology Week editors from staff and other reports. Copyright 2007, Hematology Week via NewsRx.com.