Tetrahydrobiopterin deficiency
Encyclopedia
Tetrahydrobiopterin deficiency (THBD, BH4D), also called THB or BH4 deficiency, is a rare metabolic 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
(THB, BH4) 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.
It was first characterized in 1975.
, about 30 % of newborns with elevated levels of phenylalanine have a deficiency of THB.
, PCBD1
, PTS
and QDPR
genes directly cause BH4 deficiency. Additionally, mutations of the MTHFR gene (A1298C variant) and DHFR can interfere with the recycling of BH4 and lead to less severe, but still clinifically significant, deficiencies of BH4.
BH4 is a compound that helps convert several amino acid
s, including phenylalanine, to other essential molecules in the body. It is also involved in the production of serotonin
, dopamine
, epinephrine
, and norepinephrine
– neurotransmitter
s that transmit signals between nerve cells in the brain. THB deficiency can be caused by mutation
s in one of several genes, including GCH1, PCBD1, PTS, and QDPR. These genes control the production of hydroxylase enzymes that are critical for producing and recycling THB. If just one of the enzymes fails to function correctly because of a gene mutation, little or no BH4 is produced. As a result, phenylalanine from the diet builds up in the bloodstream and other tissues, potentially damaging 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
(CNS), and dysregulation of the nitric oxide
cycle leads to a buildup of peroxynitrite
, an inflammatory oxidant that further degrades BH4 and perpetuates a state of inflammation.
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.
in DHPR deficiency.
Phenylalanine
Phenylalanine is an α-amino acid with the formula C6H5CH2CHCOOH. This essential amino acid is classified as nonpolar because of the hydrophobic nature of the benzyl side chain. L-Phenylalanine is an electrically neutral amino acid, one of the twenty common amino acids used to biochemically form...
. Phenylalanine is an amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
obtained through the diet. It is found in all proteins and in some artificial sweeteners
Sugar substitute
A sugar substitute is a food additive that duplicates the effect of sugar in taste, usually with less food energy. Some sugar substitutes are natural and some are synthetic. Those that are not natural are, in general, called artificial sweeteners....
. If tetrahydrobiopterin
Tetrahydrobiopterin
Tetrahydrobiopterin or sapropterin is a naturally occurring essential cofactor of the three aromatic amino acid hydroxylase enzymes, used in the degradation of amino acid phenylalanine and in the biosynthesis of the neurotransmitters serotonin , melatonin, dopamine, norepinephrine ,...
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
Tetrahydrobiopterin
Tetrahydrobiopterin or sapropterin is a naturally occurring essential cofactor of the three aromatic amino acid hydroxylase enzymes, used in the degradation of amino acid phenylalanine and in the biosynthesis of the neurotransmitters serotonin , melatonin, dopamine, norepinephrine ,...
(THB, BH4) deficiency. The resulting signs and symptoms range from mild to severe. Mild complications may include temporary low muscle tone. Severe complications include mental retardation
Mental retardation
Mental retardation is a generalized disorder appearing before adulthood, characterized by significantly impaired cognitive functioning and deficits in two or more adaptive behaviors...
, movement disorders, difficulty swallowing, seizures, behavioral problems, progressive problems with development, and an inability to control body temperature.
It was first characterized in 1975.
Epidemiology
This condition is very rare; approximately 600 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 TaiwanTaiwan
Taiwan , also known, especially in the past, as Formosa , is the largest island of the same-named island group of East Asia in the western Pacific Ocean and located off the southeastern coast of mainland China. The island forms over 99% of the current territory of the Republic of China following...
, about 30 % of newborns with elevated levels of phenylalanine have a deficiency of THB.
Related genes
Mutations in the GCH1GTP cyclohydrolase I
GTP cyclohydrolase I is a member of the GTP cyclohydrolase family of enzymes. GTPCH is part of the folate and biopterin biosynthesis pathways. It is responsible for the hydrolysis of guanosine triphosphate to form 7,8-dihydroneopterin 3'-triphosphate .GTPCH is encoded by the gene GCH1...
, PCBD1
PCBD1
Pterin-4-alpha-carbinolamine dehydratase is an enzyme that in humans is encoded by the PCBD1 gene.-Interactions:PCBD1 has been shown to interact with DYRK1B and HNF1A.-Further reading:...
, PTS
PTS (gene)
6-pyruvoyltetrahydropterin synthase, also known as PTS, is a human gene which facilitates folate biosynthesis.-See also:* 6-pyruvoyltetrahydropterin synthase* 6-Pyruvoyltetrahydropterin synthase deficiency-Further reading:...
and QDPR
QDPR
QDPR is a human gene that produces the enzyme quinoid dihydropteridine reductase. This enzyme is part of the pathway that recycles a substance called tetrahydrobiopterin, also known as BH4. Tetrahydrobiopterin works with an enzyme called phenylalanine hydroxylase to process a substance called...
genes directly cause BH4 deficiency. Additionally, mutations of the MTHFR gene (A1298C variant) and DHFR can interfere with the recycling of BH4 and lead to less severe, but still clinifically significant, deficiencies of BH4.
BH4 is a compound that helps convert several amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
s, including phenylalanine, to other essential molecules in the body. It is also involved in the production of serotonin
Serotonin
Serotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract, platelets, and in the central nervous system of animals including humans...
, dopamine
Dopamine
Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...
, epinephrine
Epinephrine
Epinephrine is a hormone and a neurotransmitter. It increases heart rate, constricts blood vessels, dilates air passages and participates in the fight-or-flight response of the sympathetic nervous system. In chemical terms, adrenaline is one of a group of monoamines called the catecholamines...
, and norepinephrine
Norepinephrine
Norepinephrine is the US name for noradrenaline , a catecholamine with multiple roles including as a hormone and a neurotransmitter...
– neurotransmitter
Neurotransmitter
Neurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...
s that transmit signals between nerve cells in the brain. THB deficiency can be caused by mutation
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
s in one of several genes, including GCH1, PCBD1, PTS, and QDPR. These genes control the production of hydroxylase enzymes that are critical for producing and recycling THB. If just one of the enzymes fails to function correctly because of a gene mutation, little or no BH4 is produced. As a result, phenylalanine from the diet builds up in the bloodstream and other tissues, potentially damaging nerve cells in the brain
Brain
The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...
. Tetrahydrobiopterin deficiency also disrupts the levels of certain neurotransmitters in the brain, which affects the function of the central nervous system
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
(CNS), and dysregulation of the nitric oxide
Nitric oxide
Nitric oxide, also known as nitrogen monoxide, is a diatomic molecule with chemical formula NO. It is a free radical and is an important intermediate in the chemical industry...
cycle leads to a buildup of peroxynitrite
Peroxynitrite
Peroxynitrite is the anion with the formula ONOO−. It is an unstable structural isomer of nitrate, NO3−, which has the same formula but a different structure. Although peroxynitrous acid is highly reactive, its conjugate base peroxynitrite is stable in basic solution...
, an inflammatory oxidant that further degrades BH4 and perpetuates a state of inflammation.
Genetics
Treatment
Treatment of THB deficiencies consists of THB supplementation (2–20 mg/kg per day) or diet to control blood phenylalanine concentration and replacement therapy with neurotransmitters precursors (L-DOPA and 5-HTP) and supplements of folinic acidFolinic acid
Folinic acid or leucovorin , generally administered as calcium or sodium folinate , is an adjuvant used in cancer chemotherapy involving the drug methotrexate. It is also used in synergistic combination with the chemotherapy agent 5-fluorouracil.Levofolinic acid and its salts are the enantiopure...
in DHPR deficiency.