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

From its characteristic clinical features, decrease of tyrosine hydroxylase (TH) in the terminal of the nigrostriatal (NS) dopamine (DA) neuron is considered the main lesion of HPD and the decrease of neopterin as well as biopterin in the cerebrospinal fluid suggested GTP cyclohydrolase I (GCH-I) as the responsible enzyme. By detecting the gene locus of GCH-I, Ichinose and his colleagues showed the abnormalities of GCH-I gene located on 14q 22.1 q22.2 as the cause of HPD. Since the first report of Ichinose et al, 11 mutations and frame shifts of the gene have been detected, in which the locus of abnormality differed among families but is identical in a family, but more than several families have been left with undetected abnormalities including those having linkage to 14q. However, the DNA of these families as well as those with detected gene abnormalities failed to synthesize GCH-I if inoculated with E. coli and the levels of GCH-I in mononuclear blood cells were below 20% of normal values in HPD patients while they were 37 and 38% in two asymptomatic carriers. Ratio of mutant mRNA of GCH-I gene was 28% in a patient and 8.3% in an asymptomatic case. These lines of evidence on GCH-I show HPD is a dominant inherited disorder with abnormalities of GCH-I gene. GCH-I is the limiting enzyme for synthesizing tetrahydrobiopterin (BH4), coenzyme transmitters for the synthesizing hydroxylases of aminergic neurotransmitters, but the affinity is the least for TH. This might cause a rather selective involvement of TH preserving serotonin synthesis un- or less affected. Fluoro-DOPA and [11C] racropride PET studies were normal in HPD. Studies of an autopsied case with dopa responsive dystonia, which was confirmed to have GCH-I gene abnormalities, neuropathologically revealed no abnormalities except for a decrease in melanin pigmentation in the substantia nigra and histochemically a decrease in TH enzyme activities and its protein only in the striatum. There was mild decrease of DA content, the interregional caudate/putamen and subregional rostrocaudal patterns which were similar to Parkinson disease, but subdivisionally different with predominant reduction in the ventral subdivision of the caudate nucleus. In the ventral part of the basal ganglia the striatal direct projection exists predominantly. Cases with recessive abnormalities of pteridin metabolism other than HPD, 6-pyruvoyl-tetra-hydropterin synthase (PSPS) deficiency and dihydropteridine reductase deficiency also show dystonia with diurnal fluctuation responding to levodopa, though not as marked as HPD. MPTP monkey studies revealed no involvement of striatal indirect pathway for peak dose dystonia. So it is suggested that in HPD, decrease of TH at the terminal of the NS-DA neuron due to partial reduction of GCH-I develops postural dystonia through the striatal direct projection in childhood with diurnal fluctuation depending on age and circadian variation of TH activities at the terminals.
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PMID:[Segawa disease (hereditary progressive dystonia with marked diurnal fluctuation-HPD) and abnormalities in pteridin metabolism]. 912 93

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 (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