Tetrahydrobiopterin deficiency (Tetrahydrobiopterin deficiency) - Genes GCH1, PCBD1, PTS, and QDPR.
Tetrahydrobiopterin deficiency is a rare disorder characterized by a deficiency of a molecule called tetrahydrobiopterin or BH4. This condition alters the concentrations of various substances in the body, including phenylalanine. High levels of phenylalanine are present since early childhood in people with untreated tetrahydrobiopterin deficiency. This disease also alters neurotransmitter concentrations. Children with tetrahydrobiopterin deficiency appear normal at birth but, over time, demonstrate medical problems ranging from mild to severe. Signs and symptoms may include mental retardation, developmental problems progressive, movement disorders, difficulty swallowing, convulsions, behavioral problems and inability to control body temperature.
This may be due to mutations in one of several genes, including GCH1, PCBD1, PTS, and QDPR genes. These genes encode 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. Specifically, tetrahydrobiopterin is involved in the production of dopamine and serotonin. Among its many functions, the dopamine transmits signals within the brain to produce smooth physical movement, while serotonin regulates mood, emotion, sleep and appetite. If one of the enzymes does not work properly due to a genetic mutation, phenylalanine can accumulate in the blood and other tissues. As nerve cells in the brain are particularly sensitive to the concentration of phenylalanine, excessive amounts of this substance can cause brain damage. Tetrahydrobiopterin deficiency may also alter the concentrations of certain neurotransmitters, which disrupts normal brain function. These abnormalities are the basis of intellectual disability and other features of the disease.
The GCH1 gene, located on the long arm of chromosome 14 (14q22.1-q22.2) encoding GTP cyclohydrolase 1. This enzyme is involved in the first three steps in the production of tetrahydrobiopterin (BH4). They have identified at least 7 GCH1 gene mutations that lead to tetrahydrobiopterin deficiency. When this disease is due to mutations in the gene GCH1, known as GTP cyclohydrolase 1 deficiency (GTPCH1). The GTPCH1 deficiency accounts for about 4% of all cases of tetrahydrobiopterin deficiency. Most mutations change GTP cyclohydrolase individual amino acids in 1. These mutations greatly reduce or eliminate the activity of this enzyme. Without enough GTP cyclohydrolase 1 little or no tetrahydrobiopterin is produced. Consequently, this cofactor is not available to participate in chemical reactions such as the conversion of phenylalanine to tyrosine. If phenylalanine to tyrosine is not converted, it can accumulate to toxic levels in the blood and other tissues. Moreover, a reduction in the activity of GTP cyclohydrolase 1 interrupts the output of neurotransmitters in the brain.
The PCBD1 gene, located on the long arm of chromosome 10 (10q22), encoding pterin-4 alpha-carbinolamine dehydratase. This enzyme helps carry out a step in the chemically recycling tetrahydrobiopterin (BH4). When tetrahydrobiopterin interacts with enzymes during chemical reactions, the cofactor is altered and must be recycled to a usable form. Pterin-4 alpha-carbinolamine dehydratase is one of two enzymes that help the recycling of tetrahydrobiopterin in the body. They have been described at least 9 mutations in the gene give rise PCBD1 to tetrahydrobiopterin deficiency. When the disease is due to genetic mutations PCBD1, it is known as Alpha-pterin carbinolamine dehydratase-4 (PCD). PCD deficiency accounts for approximately 5% of all cases of tetrahydrobiopterin deficiency. Some of these mutations change in individual amino pterin-4 alpha-carbinolamine dehydratase, while other mutations introduced early stop signal in encoding this enzyme. Changes in pterin-4 alpha-carbinolamine dehydratase reduce enzyme activity that affects the body's ability to recycle tetrahydrobiopterin. As a result, less cofactor is available to participate in chemical reactions such as the conversion of phenylalanine to tyrosine. If phenylalanine is not converted into tyrosine, excess can accumulate in the bloodstream and other tissues. Although people with PCD deficiency generally have high levels of phenylalanine in the blood, this form of tetrahydrobiopterin deficiency rarely causes significant medical problems. It is likely that other enzymes can compensate for the reduced activity pterin-4 alpha-carbinolamine dehydratase in people with genetic mutations PCBD1.
The PTS gene, located on the long arm of chromosome 11 (11q22.3), 6-pyruvoyltetrahydropterin synthase encoding. This enzyme is involved in the second of three steps in the production of tetrahydrobiopterin (BH4). We found more than 45 mutations in the PTS gene leading to tetrahydrobiopterin deficiency. When the disease is due to mutations in the PTS gene, known as 6-pyruvoyltetrahydropterin deficiency synthase (PTS). PTS deficiency accounts for more than half of all cases of tetrahydrobiopterin deficiency. Most of these mutations change single amino acid in 6-pyruvoyltetrahydropterin synthase, some mutations insert or remove small amounts of DNA in the PTS gene or interrupt coding the enzyme. Changes in 6-pyruvoyltetrahydropterin synthase reduce or eliminate the activity of the enzyme greatly. Without sufficient amount of this enzyme, little or no tetrahydrobiopterin occurs. As a result, less cofactor is available to participate in chemical reactions such as the conversion of phenylalanine to tyrosine. If phenylalanine to tyrosine is not converted, it can accumulate to toxic levels in the blood and other tissues. Moreover, a reduction in the activity of 6-pyruvoyltetrahydropterin synthase interrupts the output of neurotransmitters in the brain.
The QDPR gene, located on the short arm of chromosome 4 (4p15.31), dihydropteridine reductase encoding quinoid. This enzyme helps carry out a step in the chemically recycling tetrahydrobiopterin (BH4). They have identified more than 30 mutations in the gene QDPR lead to tetrahydrobiopterin deficiency. When the disease is due to genetic mutations QDPR, known as deficiency dihydropteridine reductase (DHPR). DHPR deficiency accounts for about a third of all cases of tetrahydrobiopterin deficiency. Most QDPR gene mutations change the individual amino acids in quinoid dihydropteridine reductase, although some mutations small amounts of DNA inserted in the gene or interrupt QDPR encoding the enzyme. These changes reduce or eliminate the activity of the enzyme greatly. Without enough of this enzyme, tetrahydrobiopterin not recycled properly.
This disease is inherited in an autosomal recessive pattern, that is, both copies of the gene in every cell must have mutations for alteration is expressed. The parents of an individual with an autosomal recessive disease have a copy of the mutated gene, but usually show no signs and symptoms of the disease.
Tests in IVAMI: in IVAMI perform detection of mutations associated with tetrahydrobiopterin deficiency, by complete PCR amplification of the exons of GCH1, PCBD1, PTS and QDPR, respectively, and subsequent sequencing genes.
Samples recommended: EDTA blood collected for separation of blood leukocytes, or impregnated sample card with dried blood (IVAMI may mail the card to deposit the blood sample).