Tetrahydrobiopterin Deficiency
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Tetrahydrobiopterin deficiency (THBD, BH4D) is a rare
metabolic disorder A metabolic disorder is a disorder that negatively alters the body's processing and distribution of macronutrients, such as proteins, fats, and carbohydrates. Metabolic disorders can happen when abnormal chemical reactions in the body alter the ...
that increases the blood levels of
phenylalanine Phenylalanine (symbol Phe or F) is an essential α-amino acid with the chemical formula, formula . It can be viewed as a benzyl group substituent, substituted for the methyl group of alanine, or a phenyl group in place of a terminal hydrogen of ...
. Phenylalanine is an
amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...
obtained normally through the diet, but can be harmful if excess levels build up, causing
intellectual disability Intellectual disability (ID), also known as general learning disability (in the United Kingdom), and formerly mental retardation (in the United States), Rosa's Law, Pub. L. 111-256124 Stat. 2643(2010).Archive is a generalized neurodevelopmental ...
and other serious health problems. In healthy individuals, it is metabolised (
hydroxylated In chemistry, hydroxylation refers to the installation of a hydroxyl group () into an organic compound. Hydroxylations generate alcohols and phenols, which are very common functional groups. Hydroxylation confers some degree of water-solubility ...
) into
tyrosine -Tyrosine or tyrosine (symbol Tyr or Y) or 4-hydroxyphenylalanine is one of the 20 standard amino acids that are used by cells to synthesize proteins. It is a conditionally essential amino acid with a polar side group. The word "tyrosine" is ...
, another amino acid, by
phenylalanine hydroxylase Phenylalanine hydroxylase (PAH) () is an enzyme that catalyzes the hydroxylation of the aromatic side-chain of phenylalanine to generate tyrosine. PAH is one of three members of the biopterin-dependent aromatic amino acid hydroxylases, a clas ...
. However, this
enzyme An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...
requires
tetrahydrobiopterin Tetrahydrobiopterin (BH4, THB), also known as sapropterin ( INN), is a cofactor of the three aromatic amino acid hydroxylase enzymes, used in the metabolism of amino acid phenylalanine and in the biosynthesis of the neurotransmitters serotoni ...
as a cofactor and thus its deficiency slows phenylalanine metabolism. 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 intellectual disability, movement disorders, difficulty swallowing, seizures, behavioral problems, progressive problems with development, and an inability to control
body temperature Thermoregulation is the ability of an organism to keep its body temperature within certain boundaries, even when the surrounding temperature is very different. A thermoconforming organism, by contrast, simply adopts the surrounding temperature ...
. It was first characterized in 1975.


Signs and symptoms


Genetics

This condition is inherited in an
autosomal recessive In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the Phenotype, effect of a different variant of the same gene on Homologous chromosome, the other copy of the chromosome. The firs ...
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.


Related genes

Mutations in the GCH1, 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 Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...
s, including phenylalanine, to other essential molecules in the body. It is also involved in the production of
serotonin Serotonin (), also known as 5-hydroxytryptamine (5-HT), is a monoamine neurotransmitter with a wide range of functions in both the central nervous system (CNS) and also peripheral tissues. It is involved in mood, cognition, reward, learning, ...
,
dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. It is an amine synthesized ...
,
epinephrine Adrenaline, also known as epinephrine, is a hormone and medication which is involved in regulating visceral functions (e.g., respiration). It appears as a white microcrystalline granule. Adrenaline is normally produced by the adrenal glands a ...
, and
norepinephrine Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic compound, organic chemical in the catecholamine family that functions in the brain and human body, body as a hormone, neurotransmitter and neuromodulator. The ...
neurotransmitter A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a Chemical synapse, synapse. The cell receiving the signal, or target cell, may be another neuron, but could also be a gland or muscle cell. Neurotra ...
s that transmit signals between nerve cells in the brain. THB deficiency can be caused by
mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, ...
s in one of several genes, including GCH1, PCBD1, PTS, and QDPR. These genes control the production of
hydroxylase In chemistry, hydroxylation refers to the installation of a hydroxyl group () into an organic compound. Hydroxylations generate Alcohol (chemistry), alcohols and phenols, which are very common functional groups. Hydroxylation confers some degre ...
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 The brain is an organ (biology), organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It consists of nervous tissue and is typically located in the head (cephalization), usually near organs for ...
. Tetrahydrobiopterin deficiency also disrupts the levels of certain neurotransmitters in the brain, which affects the function of the
central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain, spinal cord and retina. The CNS is so named because the brain integrates the received information and coordinates and influences the activity o ...
(CNS), and dysregulation of the
nitric oxide Nitric oxide (nitrogen oxide, nitrogen monooxide, or nitrogen monoxide) is a colorless gas with the formula . It is one of the principal oxides of nitrogen. Nitric oxide is a free radical: it has an unpaired electron, which is sometimes den ...
cycle leads to a buildup of peroxynitrite, an inflammatory oxidant that further degrades BH4 and perpetuates a state of inflammation.


Pathophysiology

Tetrahydrobiopterin deficiency can be caused by a deficiency of the enzyme dihydrobiopterin reductase (DHPR), whose activity is needed to replenish quinonoid-dihydrobiopterin back into its tetrahydrobiopterin form. Those with this deficiency may produce sufficient levels of the enzyme phenylalanine hydroxylase (PAH) but, since tetrahydrobiopterin is a cofactor for PAH activity, deficient dihydrobiopterin reductase renders any PAH produced unable to use phenylalanine to produce tyrosine. Tetrahydrobiopterin is a cofactor in the production of L-DOPA from tyrosine and 5-hydroxy-L-tryptophan from tryptophan, which must be supplemented as treatment in addition to the supplements for classical PKU. Other underlying causes of tetrahydrobiopterin deficiency are: * 6-Pyruvoyltetrahydropterin synthase (PTPS) deficiency * Autosomal recessive guanosine triphosphate cyclohydrolase I (GTPCH) deficiency * Autosomal dominant guanosine triphosphate cyclohydrolase I (GTPCH) deficiency * Pterin-4 alpha-carbinolamine dehydratase deficiency


Diagnosis

Directed by screening newborn for elevated plasma levels of phenylalanine. The normal level of phenyl alanine in plasma is 1–2 mg/dl and in PKU, it normally ranges between 20–65 mg/dl. The main test for confirmation of PKU is the
Guthrie test The neonatal heel prick is a blood collection, blood collection procedure done on newborns. It consists of making a pinprick puncture in one heel of the newborn to collect their blood. This Medical procedure, technique is used frequently as the m ...
, which is a
Bacillus subtilis ''Bacillus subtilis'' (), known also as the hay bacillus or grass bacillus, is a gram-positive, catalase-positive bacterium, found in soil and the gastrointestinal tract of ruminants, humans and marine sponges. As a member of the genus ''Bacill ...
Bioassay. Phenyl pyruvate in urine can also be detected using Ferric Chloride test.


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 -DOPA, also known as -3,4-dihydroxyphenylalanine and used medically as levodopa, is made and used as part of the normal biology of some plants and animals, including humans. Humans, as well as a portion of the other animals that utilize -DO ...
and
5-HTP 5-Hydroxytryptophan (5-HTP), used medically as oxitriptan, is a naturally occurring amino acid and chemical precursor as well as a metabolic intermediate in the biosynthesis of the neurotransmitter serotonin. 5-HTP can be manufactured and us ...
) and supplements of
folinic acid Folinic acid, also known as leucovorin, is a medication used to decrease the toxic effects of methotrexate and pyrimethamine. It is also used in combination with 5-fluorouracil to treat colorectal cancer and pancreatic cancer, may be used to ...
in DHPR deficiency. Tetrahydrobiopterin is available as a tablet for
oral administration Oral administration is a route of administration whereby a substance is taken through the Human mouth, mouth, swallowed, and then processed via the digestive system. This is a common route of administration for many medications. Oral administ ...
in the form of ''tetrahydrobiopterin dihydrochloride'' (BH4*2HCL). BH4*2HCL is FDA approved under the trade name Kuvan. The typical cost of treating a patient with Kuvan is $100,000 per year. BioMarin holds the patent for Kuvan until at least 2024, but Par Pharmaceutical has a right to produce a generic version by 2020. BH4*2HCL is indicated at least in tetrahydrobiopterin deficiency caused by GTPCH deficiency or PTPS deficiency.


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
Taiwan Taiwan, officially the Republic of China (ROC), is a country in East Asia. The main geography of Taiwan, island of Taiwan, also known as ''Formosa'', lies between the East China Sea, East and South China Seas in the northwestern Pacific Ocea ...
, about 30% of newborns with elevated levels of phenylalanine have a deficiency of THB. Subclinical deficiency can be found in individuals with poor diet (including low intake of
folate Folate, also known as vitamin B9 and folacin, is one of the B vitamins. Manufactured folic acid, which is converted into folate by the body, is used as a dietary supplement and in food fortification as it is more stable during processing and ...
or
vitamin C Vitamin C (also known as ascorbic acid and ascorbate) is a water-soluble vitamin found in citrus and other fruits, berries and vegetables. It is also a generic prescription medication and in some countries is sold as a non-prescription di ...
) or genetic mutations in the MTHFR genes, which are involved in BH4 synthesis and recycling.


See also

*
Phenylketonuria Phenylketonuria (PKU) is an inborn error of metabolism that results in decreased metabolism of the amino acid phenylalanine. Untreated PKU can lead to intellectual disability, seizures, behavioral problems, and mental disorders. It may also r ...
(PKU) *
Tetrahydrobiopterin Tetrahydrobiopterin (BH4, THB), also known as sapropterin ( INN), is a cofactor of the three aromatic amino acid hydroxylase enzymes, used in the metabolism of amino acid phenylalanine and in the biosynthesis of the neurotransmitters serotoni ...
(THB, BH4) * Mild non-BH4-deficient hyperphenylalaninemia - disorder arising due to mutations of the DNAJC12 gene.


References


External links

{{Metabolic disorders of vitamins, coenzymes, and cofactors Amino acid metabolism disorders Autosomal recessive disorders Vitamin, coenzyme, and cofactor metabolism disorders Disorders causing seizures Intellectual disability Rare diseases