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)

The syndrome of dopa-responsive dystonia comprises a minority of patients with dystonia, yet it is of considerable diagnostic importance because patients respond dramatically to L-dopa therapy. Benefits from this treatment are lasting, and the problems associated with long-term L-dopa therapy in patients with Parkinson's disease are generally absent. It has been suggested that this condition is due to a defect in the dopamine synthetic pathway, which is bypassed when patients are treated with L-dopa. We have studied [18F]dopa uptake in 6 patients with classic dopa-responsive dystonia (5 familial patients and 1 sporadic patient), aged 18 to 66 years. Data have been analyzed according to a graphic approach, calculating an influx constant for each region studied. We have also studied a seventh, clinically atypical, patient with juvenile dystonia-parkinsonism. Similar data have been calculated for a group of 10 healthy control subjects and 10 patients with Parkinson's disease. The 6 patients with typical dopa-responsive dystonia had a modest but significant reduction in the uptake of tracer into both caudate and putamen, which indicates a defect in the decarboxylation, vesicular uptake, and storage of [18F]dopa. This argues against the proposition that dopa-responsive dystonia is due to an inherited defect of tyrosine hydroxylase alone. In the atypical patient, however, we found a greater reduction of [18F]dopa uptake into both caudate and putamen, comparable with that in patients with Parkinson's disease.
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PMID:Dopa-responsive dystonia: [18F]dopa positron emission tomography. 168 82

The authors describe the dopamine deficiency syndrome in children with the disease beginning during their first year and unusual dystonia symptoms resulting in total immobilization and speech loss. All symptoms of the disease can be eliminated by low doses of nakom but reappear on withdrawal of the drug. Tyrosine hydroxylase studies made on these patients at various stages of the disease showed a different pattern of enzyme activity from that observed in children with similar pathology failing to improve dramatically under nakom treatment.
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PMID:Dopamine deficiency syndrome in children with a special reaction to treatment with levodopa preparations. 198 6

Unilateral caudate-putamen (CP) lesions induced by the glutamate receptor agonist ibotenic acid in baboons produced a neuropathological and behavioral model of Huntington's disease (HD) in the nonhuman primate. Neuropathological evaluation of the lesioned caudate-putamen revealed a neurodegenerative pattern resembling HD. The ibotenic acid-infused CP areas showed a neuronal loss in Nissl-stained sections and a marked astrocytic gliosis by immunohistochemical staining for glial-fibrillary-acidic protein. Acetylcholinesterase fiber staining was severely reduced in the lesioned CP, while afferent dopaminergic fibers, as shown by tyrosine hydroxylase staining, were relatively spared. There was a moderate reduction of met-enkephalin staining in the globus pallidus-pars lateralis ipsilateral to the ibotenic acid lesion, indicating a partial denervation of this structure following the lesion. In the behavioral studies a dyskinetic syndrome with features in common with HD was provoked in the lesioned animals following dopamine receptor agonist administration (1-2 mg/kg apomorphine). The symptoms included hyperkinesia, chorea, dystonia, postural asymmetries, head, and orofacial dyskinesia. The apomorphine test was highly reproducible and individual animals responded with a similar set and incidence of dyskinesia in successive tests. Since the behavioral observations following excitotoxic caudate-putamen damage parallel symptoms in HD patients given dopamine stimulatory drugs, a hypothesis is presented for the observed abnormal movements suggesting that the CP lesions reduce movement thresholds while the activation of dopaminoceptive regions induces dyskinesias.
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PMID:A primate model of Huntington's disease: behavioral and anatomical studies of unilateral excitotoxic lesions of the caudate-putamen in the baboon. 213 53

It has been suggested that a form of inherited dystonia responsive to levodopa might be due to an abnormality of tyrosine hydroxylase gene. This hypothesis has been tested using a cDNA tyrosine hydroxylase gene probe in three families with this disorder. No evidence for genetic linkage between the disease and tyrosine hydroxylase loci was found; it is possible that the disorder results from a post-transcriptional defect confined to the brain.
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PMID:Tyrosine hydroxylase and levodopa responsive dystonia. 256 77

The neurological mouse mutant dystonia musculorum exhibits bizarre appendicular and truncal dystonia without known cerebellar histopathology. We evaluated striatal dopamine and cerebellar norepinephrine metabolism in this mutant and compared the results with those obtained in wild-type BALB/c and B6C3 controls. Tyrosine hydroxylase activity and dopamine metabolite levels (homovanillic acid and 3,4-dihydroxyphenylacetic acid) in the striatum of the mutant were similar to controls. Tyrosine hydroxylase activity and the steady-state level of 3-methoxy-4-hydroxyphenethyleneglycol, a metabolite of norepinephrine, in the cerebellum were 38% and 42-66%, respectively, greater in the mutant. However, the level of norepinephrine was similar (approximately 350 ng/g). Further, a Purkinje cell-specific marker, cGMP-dependent protein kinase, was unchanged in the mutant and no Purkinje cell pathology was observed with light microscopy. The lack of Purkinje cell derangement and similar levels of cerebellar norepinephrine and cGMP-dependent protein kinase activity suggest that increased norepinephrine metabolism in the cerebellum of this mutant is not a morphological response to gross target cell loss during morphogenesis. The observed changes may be a reaction to abnormal impulse traffic or altered input/output pathways to the mutant cerebellum during its development.
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PMID:Increased noradrenergic metabolism in the cerebellum of the mouse mutant dystonia musculorum. 611 89

Clinical and experimental evidence suggests that alpha methylparatyrosine (AMPT), an inhibitor of tyrosine hydroxylase, can potentiate the effects of other dopamine antagonists. We therefore treated patients having various forms of dystonia and chorea with tetrabenazine (TBZ), and then added AMPT to determine if further improvement could be obtained. Side effects of both drugs were common, and they often necessitated withdrawal of the drug. Patients with Huntington's chorea and tardive dyskinesia were improved by TBZ. They obtained additional benefit from the combination of AMPT and TBZ. The results in the dystonia patients were disappointing with both drugs. Although a small number of patients did improve, and short- and long-term remissions occurred in a few, most patients with dystonia were not benefited by either drug.
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PMID:Alpha methylparatyrosine and tetrabenazine in movement disorders. 613 Aug 39

The past 18 months have seen significant advances in our understanding of dopa(dihydroxyphenylalanine)-responsive dystonia. Clinical investigations have broadened the spectrum of disease with particular attention manifestations in infancy. Pathophysiological investigations have revealed features that distinguish dopa-responsive dystonia from childhood-onset parkinsonism. A pathological study has confirmed the 'developmental' nature of the disease. Finally, mutations causing the autosomal dominant form of dopa-responsive dystonia have been identified in the gene coding for GTP cyclohydrolase I. Mutations in tyrosine hydroxylase have been identified in two brothers and put forward as evidence of an autosomal recessive form of the disease.
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PMID:Dopa-responsive dystonia. 758 48

GTP cyclohydrolase I activity in mononuclear blood cells from patients with juvenile parkinsonism (JP) was found to be normal compared to healthy controls. The normal activity in JP contrasts strongly with the decreased activity of 2-20% normal levels in hereditary progressive dystonia with marked diurnal fluctuation (HPD) or dopa responsive dystonia (DRD). The result indicates that the decreased dopamine level in the basal ganglia in JP is not due to decreased activity of GTP cyclohydrolase I, the enzyme for the biosynthesis of the tetrahydrobiopterin cofactor of tyrosine hydroxylase (TH), and the enzyme activity in mononuclear blood cells could be a reliable method for differential diagnosis between JP and HPD/DRD.
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PMID:GTP cyclohydrolase I activity in mononuclear blood cells in juvenile parkinsonism. 764 24

Hereditary progressive dystonia with marked diurnal fluctuation (HPD or dopa-responsive dystonia) is a clinical entity characterized by childhood-onset dystonia followed by parkinsonism, which shows dramatic response to levodopa. However, the same combination of the symptoms is also characteristic of some patients with juvenile parkinsonism (JP: manifesting below the age of 40), and sometimes the correct differentiation between these HPD and JP patients, in the early course of the disorder, may be difficult. In this study, therefore, we analyzed cerebrospinal fluid (CSF) biopterin (BP) and neopterin (NP) concentrations in 2 patients with HPD, 58 with idiopathic parkinsonism (IP: this group includes 25 cases with JP), 9 with dopa-nonresponsive dystonia (DNRD) and 18 controls, to search for biochemical differences among these disorders. Biopterin is the natural cofactor for tyrosine hydroxylase and NP consists of degradation products of dihydroneopterin triphosphate, which is the first intermediate in the BP biosynthesis from guanosine triphosphate (GTP). As a result, the mean BP level in the IP patients (8.5 +/- 0.3 pmol/ml; mean +/- SE) was significantly lower than those in both the controls (13.2 +/- 0.5, p < 0.001) and the DNRD patients (14.2 +/- 1.2, p < 0.001). The BP levels in the HPD patients (7.1, 5.9) were lower than the mean BP level in the IP patients. With regard to NP content, there were no significant differences in the mean NP levels among the controls (25.2 +/- 2.0 pmol/ml; mean +/- SE) and the patients with IP and DNRD (22.6 +/- 1.0, 25.2 +/- 2.2).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Significance of CSF biopterin and neopterin in hereditary progressive dystonia with marked diurnal fluctuation (HPD)--a clue to pathogenesis]. 766 28

We report two patients with diurnally fluctuating hereditary progressive dystonia, that presented with dystonic movements and parkinsonian symptoms with marked diurnal fluctuations. There was a significant and maintained improvement of symptoms with small doses of L-Dopa. The pathogenesis of this disease could be a functional alteration of basal ganglia in the dopaminergic striatonigral region. The diurnal fluctuation of symptoms would be related to the circadian variation of tyrosine hydroxylase function.
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PMID:[Progressive hereditary dystonia with diurnal fluctuations: report of 2 cases]. 790 16


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