Tetrahydrobiopterin deficiency

Tetrahydrobiopterin deficiency is a rare disorder that increases the levels of several substances, including phenylalanine, in the blood. Phenylalanine is a building block of proteins (an amino acid) that is obtained through the diet. It is found in all proteins and in some artificial sweeteners. If tetrahydrobiopterin deficiency is not treated, phenylalanine can build up to harmful levels in the body, causing intellectual disability and other serious health problems.

High levels of phenylalanine are present from early infancy in people with untreated tetrahydrobiopterin deficiency. Infants with this condition appear normal at birth, but medical problems ranging from mild to severe become apparent over time. The 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 very rare, affecting about 1 per million newborns. In most parts of the world, tetrahydrobiopterin deficiency accounts for only 1 percent to 2 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.

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 (also known as BH4) is a molecule that helps process several amino acids, including phenylalanine. It is also involved in the production of chemicals called neurotransmitters, which transmit signals between nerve cells in the brain.

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.

Read more about the GCH1, PCBD1, PTS, and QDPR genes.

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.