Tetrahydrobiopterin deficiency

Tetrahydrobiopterin deficiency (also known as BH4 deficiency) is a rare disorder that increases the blood levels of phenylalanine. Phenylalanine is an amino acid 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.

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

Related genes
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.

Genetics
This condition is inherited in an autosomal recessive pattern, which means two copies of a specific gene in each cell are altered in order for the individual to be afflicted. 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.

Treatment
Treatment of BH4 deficiencies consists of BH4 supplementation (2-20 mg/kg per day) or diet to control blood phenylalanine concentration and replacement therapy with neurotransmitters precursors (L-dopa/CarbiDOPA and 5-hydroxytryptophan) and supplements of folinic acid in DHPR deficiency.