Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0013421 (dystonia)
 8,418 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A deficiency of dihydrobiopterin synthesis was found in a 27-year-old man with mild mental retardation, rigid spasticity, hyperreflexia, dystonia, myoclonus, and delay in the initiation of action, since age 10. Symptoms improved after sleep. Urine contained large amounts of neopterin and a trace of biopterin. Dihydropteridine reductase activity in red blood cells was normal. CSF levels of HVA and 5-HIAA were low. Tetrahydrobiopterin administration lowered serum phenylalanine and improved the symptoms.
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PMID:Dihydrobiopterin synthesis defect: an adult with diurnal fluctuation of symptoms. 243 82

Tetrahydrobiopterin deficiencies are highly heterogeneous disorders, with more than 30 molecular lesions identified in the past 2 years in the GTP cyclohydrolase I and 6-pyruvoyl-tetrahydropterin synthase genes. The spectrum of mutations causing a reduction of these two biosynthetic enzymes is reviewed. Only three mutations, two present homozygously, are reported in the GTP cyclohydrolase I gene to cause the rare autosomal recessively inherited form of hyperphenylalaninemia. Most of the other mutations, which are scattered over the entire coding region for the six exon-containing GTP cyclohydrolase I gene, are observed in a heterozygous state with the wild-type allele and are associated with the dominant DOPA-responsive dystonia. Compound heterozygous or homozygous mutations spread over all six exons encoding the 6-pyruvoyl-tetrahydropterin synthase cause an autosomal recessively inherited variant of hyperphenylalaninemia, mostly accompanied by a deficiency of dopamine and serotonin.
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PMID:Mutations in the GTP cyclohydrolase I and 6-pyruvoyl-tetrahydropterin synthase genes. 922 55

Tetrahydrobiopterin (BH4) is synthesized from guanosine triphosphate (GTP) by GTP cyclohydrolase I (GCH), 6-pyruvoyltetrahydropterin synthase (PTS), and sepiapterin reductase (SPD). GCH is the rate-limiting enzyme. BH4 is a cofactor for three pteridine-requiring monooxygenases that hydroxylate aromatic L-amino acids, i.e., tyrosine hydroxylase (TH), tryptophan hydroxylase (TPH), and phenylalanine hydroxylase (PAH), as well as for nitric oxide synthase (NOS). The intracellular concentrations of BH4, which are mainly determined by GCH activity, may regulate the activity of TH (an enzyme-synthesizing catecholamines from tyrosine), TPH (an enzyme-synthesizing serotonin and melatonin from tryptophan), PAH (an enzyme required for complete degradation of phenylalanine to tyrosine, finally to CO2 + H2O), and also the activity of NOS (an enzyme forming NO from arginine), Dominantly inherited hereditary progressive dystonia (HPD), also termed DOPA-responsive dystonia (DRD) or Segawa's disease, is a dopamine deficiency in the nigrostriatal dopamine neurons, and is caused by mutations of one allele of the GCH gene. GCH activity and BH4 concentrations in HPD/DRD are estimated to be 2-20% of the normal value. By contrast, recessively inherited GCH deficiency is caused by mutations of both alleles of the GCH gene, and the GCH activity and BH4 concentrations are undetectable. The phenotypes of recessive GCH deficiency are severe and complex, such as hyperphenylalaninemia, muscle hypotonia, epilepsy, and fever episode, and may be caused by deficiencies of various neurotransmitters, including dopamine, norepinephrine, serotonin, and NO. The biosynthesis of dopamine, norepinephrine, epinephrine, serotonin, melatonin, and probably NO by individual pteridine-requiring enzymes may be differentially regulated by the intracellular concentration of BH4, which is mainly determined by GCH activity. Dopamine biosynthesis in different groups of dopamine neurons may be differentially regulated by TH activity, depending on intracellular BH4 concentrations and GCH activity. The nigrostriatal dopamine neurons may be most susceptible to a partial decrease in BH4, causing dopamine deficiency in the striatum and the HPD/DRD phenotype.
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PMID:Regulation of pteridine-requiring enzymes by the cofactor tetrahydrobiopterin. 1032 73

Tetrahydrobiopterin (BH4) is an essential cofactor for tyrosine hydroxylase. BH4 can be synthesized from GTP through three enzymatic reactions. The rate-limiting step of the BH4 synthesis is catalyzed by GTP cyclohydrolase I (GCH). Recently, we found that GCH is a causative gene for hereditary progressive dystonia/dopa-responsive dystonia (HPD/DRD). However, several problems still remain to be solved. The first concern is the presence of asymptomatic carriers in the disease. The difference between symptomatic and asymptomatic carriers is unknown. Second, we cannot find any mutation in the coding region of the GCH gene in about 40% of the patients. What kind of mutation would be present in these patients. The last concern is the molecular mechanism how the enzymatic activity is decreased to less than 20% of normal values. Further studies are required to solve the questions.
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PMID:[The relation between metabolism of biopterin and dystonia-parkinsonism]. 1046 80

Tetrahydrobiopterin (BH(4)) cofactor is essential for various processes, and is present in probably every cell or tissue of higher organisms. BH(4) is required for various enzyme activities, and for less defined functions at the cellular level. The pathway for the de novo biosynthesis of BH(4) from GTP involves GTP cyclohydrolase I, 6-pyruvoyl-tetrahydropterin synthase and sepiapterin reductase. Cofactor regeneration requires pterin-4a-carbinolamine dehydratase and dihydropteridine reductase. Based on gene cloning, recombinant expression, mutagenesis studies, structural analysis of crystals and NMR studies, reaction mechanisms for the biosynthetic and recycling enzymes were proposed. With regard to the regulation of cofactor biosynthesis, the major controlling point is GTP cyclohydrolase I, the expression of which may be under the control of cytokine induction. In the liver at least, activity is inhibited by BH(4), but stimulated by phenylalanine through the GTP cyclohydrolase I feedback regulatory protein. The enzymes that depend on BH(4) are the phenylalanine, tyrosine and tryptophan hydroxylases, the latter two being the rate-limiting enzymes for catecholamine and 5-hydroxytryptamine (serotonin) biosynthesis, all NO synthase isoforms and the glyceryl-ether mono-oxygenase. On a cellular level, BH(4) has been found to be a growth or proliferation factor for Crithidia fasciculata, haemopoietic cells and various mammalian cell lines. In the nervous system, BH(4) is a self-protecting factor for NO, or a general neuroprotecting factor via the NO synthase pathway, and has neurotransmitter-releasing function. With regard to human disease, BH(4) deficiency due to autosomal recessive mutations in all enzymes (except sepiapterin reductase) have been described as a cause of hyperphenylalaninaemia. Furthermore, several neurological diseases, including Dopa-responsive dystonia, but also Alzheimer's disease, Parkinson's disease, autism and depression, have been suggested to be a consequence of restricted cofactor availability.
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PMID:Tetrahydrobiopterin biosynthesis, regeneration and functions. 1072 95

Tetrahydrobiopterin ((6R)-L-erythro-tetrahydrobiopterin, BH4) is de novo synthesized from GTP. Enzymes involved in its synthesis are the rate limiting enzyme GTP cyclohydrolase I, 6-pyruvoyl tetrahydropterin synthase (PTPS) and sepiapterin reductase. Abnormalities in the metabolism of BH4 have been demonstrated in some diseases affecting the central nervous systems such as atypical phenylketonuria, hereditary progressive dystonia (Segawa's disease). Furthermore, BH4 has been shown to be involved in vascular protection. It is suggested that the dysfunction of endothelial BH4 leads to atherosclerosis. Recently we established BH4-deficient mice by disrupting the PTPS gene to investigate the effects of BH4 depletion on the animals and the involvement of BH4 in regulating biological functions including neural systems. Investigation utilizing this model animal can contribute to the development of new therapeutic strategies toward various diseases involving neurological and vascular systems. Pterin derivatives other than biopterin may also be involved in the regulation of a variety of biological functions. We found that ciliated protozoan Tetrahymena pyriformis synthesizes tetrahydromonapterin, isomer of BH4, and its levels alter according to the progress of the cell cycle. How pterin derivatives are related to the human physiology and diseases is an interesting subject of investigation.
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PMID:[Perspectives on tetrahydrobiopterin research]. 1177 54

Dopa-responsive dystonia (DRD) is an extrapyramidal disorder caused by deficit of 5,6,7,8-tetrahydrobiopterin (BH4), cofactor for tyrosine hydroxylase (TH). In these patients the nigrostriatal dopaminergic neurons normally express TH and the cellular machinery for the dopamine uptake. LA-N-1 is a human neuroblastoma cell line expressing tyrosine hydroxylase. Here we show that LA-N-1 cells are able to take up exogenous dopamine (DA) by an high-affinity mechanism; significant amounts of serotonin and its metabolite 5HIAA, but neither DA nor its metabolites, DOPAC and HVA, could be measured in the cell culture homogenate. 5,6,7,8-Tetrahydrobiopterin, cofactor for both tyrosine and tryptophan hydroxylases, is able to activate dopamine synthesis and also decreases the content of 5HIAA by 50%, indicating that LA-N-1 might be a useful model for studying dopamine-serotonin interaction in cultured cells and the neuronal mechanism of DRD.
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PMID:6R-Tetrahydrobiopterin induces dopamine synthesis in a human neuroblastoma cell line, LA-N-1. A cellular model of DOPA-responsive dystonia. 1210 Oct 48

Little information is available on the long-term course and adult outcome of patients with 6-pyruvoyl-tetrahydropterin synthase (PTPS) deficiency. We describe the course of a 32-year-old woman with hypotonia, dystonia, choreoathetosis, mental retardation, behavioral disturbances, and incomplete puberty due to PTPS deficiency. From the age of 6 months she developed progressive hypotonia and choreoathtetoid movements despite good control of hyperphenylalaninemia. Tetrahydrobiopterin deficiency was diagnosed at age 3 years. She had a dramatic response to L-dopa, which persisted at a stable dose for 29 years. Reducing the L-dopa dose led to severe axial hypotonia and limb dystonia, and increasing it led to florid abnormal movements and behavioral disorders. This report illustrates the role of dopamine modulation in motor, psychiatric, and endocrine functions.
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PMID:Long-term follow-up and adult outcome of 6-pyruvoyl-tetrahydropterin synthase deficiency. 1616 Nov 43

Tetrahydrobiopterin (BH(4)) deficiencies are a highly heterogeneous group of disorders with several hundred patients, and so far a total of 193 different mutant alleles or molecular lesions identified in the GTP cyclohydrolase I (GTPCH), 6-pyruvoyl-tetrahydropterin synthase (PTPS), sepiapterin reductase (SR), carbinolamine-4a-dehydratase (PCD), or dihydropteridine reductase (DHPR) genes. The spectrum of mutations causing a reduction in one of the three biosynthetic (GTPCH, PTPS, and SR) or the two regenerating enzymes (PCD and DHPR) is tabulated and reviewed. Furthermore, current genomic variations or SNPs are also compiled. Mutations in GCH1 are scattered over the entire gene, and only 5 out of 104 mutant alleles, present in a homozygous state, are reported to cause the autosomal recessive form of inheritable hyperphenylalaninemia (HPA) associated with monoamine neurotransmitter deficiency. Almost all other 99 different mutant alleles in GCH1 are observed together with a wild-type allele and cause Dopa-responsive dystonia (DRD, Segawa disease) in a dominant fashion with reduced penetrance. Compound heterozygous or homozygous mutations are spread over the entire genes for PTS with 44 mutant alleles, for PCBD with nine mutant alleles, and for QDPR with 29 mutant alleles. These mutations cause an autosomal recessive inherited form of HPA, mostly accompanied by a deficiency of the neurotransmitters dopamine and serotonin. Lack of sepiapterin reductase activity, an autosomal recessive variant of BH(4) deficiency presenting without HPA, was diagnosed in patients with seven different mutant alleles in the SPR gene in exons 2 or 3 or in intron 2. Details on all mutations presented here are constantly updated in the BIOMDB database (www.bh4.org).
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PMID:Mutations in the BH4-metabolizing genes GTP cyclohydrolase I, 6-pyruvoyl-tetrahydropterin synthase, sepiapterin reductase, carbinolamine-4a-dehydratase, and dihydropteridine reductase. 1691 93

Tetrahydrobiopterin (BH4) deficiencies are disorders affecting phenylalanine metabolism in the liver and neurotransmitter biosynthesis in the brain. BH4 is the essential cofactor in the enzymatic hydroxylation of 3 aromatic amino acids (phenylalanine, tyrosine, and tryptophan). BH4 is synthesized from guanosine triphosphate (GTP), catalyzed by GTP cyclohydrolase I (GTPCH), 6-pyruvoyl-tetrahydropterin synthase, and sepiapterin reductase (SR), and in aromatic amino acids, the hydoxylating system is regenerated by pterin-4a-carbinolamine dehydrolase and dihydropteridine reductase (DHPR). BH4 deficiency has been diagnosed in patients with hyperphenylalaninemia (HPA) by neonatal mass-screening based on BH4 oral-loading tests, analysis of urinary or serum pteridines, and measurement of DHPR activity in blood using a Guthrie card. BH4 deficiency without treatment causes combined symptoms of HPA and neurotransmitter (dopamine, norepinephrine, epinephrine, and serotonin) deficiency, such as red hair, psychomotor retardation, and progressive neurological deterioration. However, autosomal dominant GTPCH deficiency and autosomal recessive SR deficiency leads to BH4 and neurotransmitter deficiency without HPA and may not be detected by neonatal screening for phenylketonuria. The former is Segawa's disease, which is characterized by dopa-responsive dystonia with marked diurnal fluctuation and is caused by a defect of GTPCH, and the latter is SR deficiency, which is characterized by progressive psychomotor retardation, dystonia, and severe dopamine and serotonin deficiencies. Biochemical diagnosis is performed by the measurement of neopterin and biopterin levels, since both are low in Segawa disease, and the biopterin level is high in SR deficiency in cerebrospinal fluid. We must consider metabolic disorders of biopterin in child neurologic diseases with dystonia.
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PMID:[Biopterin and child neurologic disease]. 1917 9


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