Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030567 (Parkinson's disease)
 63,064 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

To elucidate the pathophysiological features of childhood onset dopa-responsive dystonia (DRD) we used a variety of quantitative analysis techniques to evaluate aspects of reflex- and voluntary motor control in two brothers with this disorder. The observed patterns were compared with those obtained in patients with adult onset Parkinson's disease (PD) and Huntington's disease (HD). In both brothers onset of the disease was in the first decade. Both responded either to treatment with L-Dopa or a combination of L-Dopa with trihexiphenidyl. Neurophysiological studies revealed slowing of different upper extremity voluntary motor activities and a low frequency postural tremor similar to results in other basal ganglia disorders including PD. In contrast to adult onset PD, fastest isometric voluntary index finger contractions did not show the typical kinetic tremor oscillations superimposed on the force trajectories. Also, different to adult PD, no impairment of stance regulating reflexes or saccadic and smooth pursuit eye movements was found in DRD. Magnetoelectrical stimulation of motor cortex showed normal efferent cortical spinal activity. Data indicate that like in other basal ganglia diseases slowing of voluntary motor activity is also a constant feature in DRD. DRD patients show, however, a clear difference to the pattern of motor abnormalities obtainable in PD. Both the pattern of motor control abnormalities is different, and the longlasting effect. In contrast to PD the pathophysiological mechanism in DRD possibly involves a lack of maturation of dopaminergic substantia nigra neurons rather than a degenerative process.
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PMID:Motor control in childhood onset dopa-responsive dystonia (Segawa syndrome). 251 99

We report the first neuropathological and neurochemical study of a patient with dopa-responsive dystonia. She had onset of foot dystonia at age 5 years and by age 8 years it was generalized with prominent right leg and arm involvement. On levodopa 750 mg daily she had complete symptomatic improvement that was sustained for 11 years until death. Pathological studies revealed normal numbers of hypopigmented substantia nigra neurons, normal tyrosine hydroxylase (TH) immunoreactivity and TH protein in the SN, no inclusion bodies or gliosis, and no evidence of a degenerative process in the striatum. Biochemical studies revealed reduced dopamine in the substantia nigra and striatum (8% in the putamen and 18% of control in the caudate) with a similar but not identical subregional distribution as in idiopathic Parkinson's disease. In the striatum, TH protein and TH activity was reduced, with the loss more pronounced in the putamen than the caudate. The GBR 12935 binding to DA transporter was normal in the caudate and at the lower end of the range of control values in the putamen. We conclude that disturbed dopamine synthetic capacity or a reduced arborization of striatal dopamine terminals may be the major disturbance in dopa-responsive dystonia.
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PMID:Dopa-responsive dystonia: pathological and biochemical observations in a case. 815 63

We studied six patients with adult-onset dystonia-parkinsonism (DYS-P) with 18F-6-fluoro-dopa (18F-dopa) positron emission tomography and compared their influx constants (Ki values) with those of six patients with classical childhood-onset dopa-responsive dystonia (DRD), 12 age-matched Parkinson's disease (PD) patients without dystonia, and 21 normal controls. The DYS-P group had significantly reduced mean caudate (67% of normal) and putamen (45% of normal) 18F-dopa uptake. These Ki values were similar to mean caudate and putamen Ki values obtained for the PD group. In contrast, the DRD group showed minor reductions in mean caudate (9%) and putamen (18%) 18F-dopa uptake when compared with normals. The mean caudate:putamen Ki ratio was 1.7 in the DYS-P group and 2.1 in the PD group. In the DRD and normal groups, the caudate:putamen ratios were close to unity. The findings of this study are that adult-onset DYS-P targets the nigrostriatal dopaminergic projections in a pattern similar to PD, with the putamen being more affected. This provides support for the hypothesis that DYS-P may be a phenotypic variant of Lewy body disease. DYS-P seems distinct from childhood-onset DRD, in which striatal 18F-dopa uptake is either normal or only mildly reduced.
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PMID:Comparison of striatal 18F-dopa uptake in adult-onset dystonia-parkinsonism, Parkinson's disease, and dopa-responsive dystonia. 835 Oct 12

Positron emission tomographic(PET) study using 18F-6-fluoro-L-dopa (18FDOPA) can provide efficient information on the pre-synaptic function of nigrostriatal dopaminergic neurons. In juvenile parkinsonism(JP), the accumulation of 18FDOPA is markedly decreased in the caudate nucleus and putamen on both hemispheres. This finding is different from those in dystonia syndromes such as dopa-responsive dystonia (DRD) and hereditary progressive dystonia with marked diurnal fluctuation(HPD), and it is rather similar to late onset of Parkinson's disease. Furthermore, we studied dopamine D2 receptor binding activity on the post-synaptic sites of the striatum using 11C-YM-09151-2(11C-YM), a highly selective dopamine D2 receptor antagonist. In JP, 11C-YM was highly accumulated in the striatum, and D2 receptor binding activity is not significantly different from that of age-matched young normal subjects, but much higher than that of aged subjects. This finding suggests that post-synaptic dopamine receptor function keeps still normal or hypersensitive in JP, and may be different from other degenerative disorders such as multiple system atrophy. Glucose metabolism using 18F-fluoro-2-deoxy-D-glucose(18FDG) was also within normal range in the cerebral cortex in JP, but was more increased in the striatum than in the cerebral cortex in some patients. These PET studies can provide efficient informations about the pathologic condition of JP.
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PMID:[PET study of dopamine metabolism and dopamine D2 receptor in juvenile parkinsonism]. 901 28

We examined age-dependent changes in voluntary eye movements in normal subjects (age : 5-76) using a visually guided saccade (V-saccade) task and a memory guided saccade (M-saccade) task. Changes were more evident in M-saccades. The latencies were long in children (< 12 y.o.) and elderly people (> 50 y.o.). Both young children and elderly people tended to break fixation by making a saccade to the cue stimulus that indicated the future target position. On the other hand, both young children and elderly people tended to be slow in making M-saccade promptly after the central fixation point went off. Thus, they had difficulties both in suppressing unnecessary saccades and in initiating saccades based on memory. Interestingly, similar difficulties were observed, in exaggerated forms, in patients in basal ganglia disorders, such as Parkinson's disease, juvenile parkinsonism, dopa-responsive dystonia, and hereditary progressive dystonia with marked diurnal fluctuation. These findings were consistent with the known functions of the basal ganglia which have been revealed by physiological studies using trained monkeys. The substantia nigra pars reticulata exerts tonic inhibitory influences over the superior colliculus, thereby preventing excitatory inputs from triggering unnecessary saccades. The tonic inhibition, however, is removed by a phasic inhibition largely originating in the caudate nucleus. Thus, inhibition and disinhibition are key mechanisms of the basal ganglia. In fact, experimental manipulations of these serial inhibitory pathway in the basal ganglia led either to the difficulty in initiation of saccades, especially M-saccades, or to the difficulty in suppressing unnecessary saccades. These comparisons suggest that the functions of the basal ganglia are immature in young children while they become deteriorated in elderly people.
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PMID:[Changes and disorders in voluntary saccades during development and aging]. 914 26

Recent developments in molecular genetics have had a profound influence on the diagnosis and classification of inherited movement disorders. Huntington's disease is caused by the expansion of an unstable trinucleotide repeat sequence. Molecular diagnosis can now be performed by a simple PCR-based assay, and the study of the effects of the repeat expansion on the function of the encoded protein will allow to elucidate the molecular pathogenesis of the disease. Wilson's disease is caused by a large number of different mutations, which complicates molecular diagnosis. Genes for a number of inherited dystonic syndromes have been mapped, one of them, the gene for dopa-responsive dystonia, has already been identified. The genetic basis of several other prevalent movement disorders, such as essential tremor and the restless-legs syndrome however, is still obscure. Current research is also directed at the identification of inherited risk-factors in genetically complex movement disorders, such as Parkinson's disease.
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PMID:Advances in the genetics of movement disorders: implications for molecular diagnosis. 924 18

Levodopa (LD) is the most effective drug for symptomatic control of Parkinson's disease, but has been suspected to be toxic to substantia nigra (SN) dopaminergic neurons. Tissue culture and animal studies of LD toxicity have produced contradictory evidence, and one study reported that a human subject exposed to a large cumulative dose (cd) of LD over 4 years had no evidence of SN damage. We report the cases of five patients, each of whom received a large cd of LD over a long period. Fluorodopa positron-emission tomography performed in one case indicated parkinsonism. Autopsies in two cases indicated a normal SN in one and a hypopigmented SN with normal cell complement in the other. Three patients had essential tremor, one had nonprogressive parkinsonism, and one had dopa-responsive dystonia. LD (without decarboxylase inhibitor) was administered over 21 years (cd = 21.99 kg), 9 years (cd = 6.6 kg), 26 years (cd = 18.7 kg), 11 years (cd = 3 kg), and 26 years (cd = 23.93 kg), respectively. None of the patients with essential tremor developed clinical features of parkinsonism that indicated significant SN damage, and one had a normal SN at autopsy. The parkinsonian patient displayed no detectable acceleration of disease process, and the patient with dopa-responsive dystonia had a normal complement of SN neurons at autopsy. We conclude that LD, administered at a dose commonly used for treating Parkinson's disease, was not toxic to SN neurons in these cases.
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PMID:Is levodopa toxic to human substantia nigra? 953 60

The pathophysiology of akinesia and chorea involve disruption of the motor basal ganglia circuit. This circuit begins with cortical output to the striatum, followed by projections from striatum to pallidum, pallidum to thalamus, and finally thalamus to cortex. Abnormal thalamic output to the frontal cortex, particularly the supplementary motor cortex, is responsible for chorea and akinesia. The substantia nigra and subthalamic nucleus are also important parts of this circuit. Chemical or pathological changes in these nuclei that lead to reduced thalamic outflow to the cortex are associated with parkinsonism. Most disorders affect the nigrostriatal dopaminergic projection. The overall consequence of loss of nigrostriatal dopamine is a loss of inhibitory input to the striatum. This feeds through the circuit resulting in reduced thalamic outflow. Local factors that may affect symptoms are the degree of dopamine loss, the involvement of ventral or dorsal parts of substantia nigra, effect on direct and indirect pallidal pathways, topographical representation of the body in the striatum, and the presence of parallel basal ganglia circuits serving cognition and mood. Ageing, dopa-responsive dystonia, juvenile dystonia-Parkinson syndrome and Parkinson's disease have different effects on the nigrostriatal tract. In Parkinson's disease the speed and regional variation in nigrostriatal dopamine loss are associated with a significant pre-symptomatic period, steady rate of progression and a particular topography of L-dopa dyskinesias.
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PMID:Functional neuropathology in Parkinson's disease. 938 99

The clinical distinction between dopa-responsive dystonia (DRD) and juvenile Parkinson's disease JPD) can pose a diagnostic challenge. Both conditions are dopa responsive. However, long-term L-dopa benefit is very different between the two. The difference in the prognosis is due to presence or absence of nigral cell loss. In JPD, there is degenerative nigral cell loss, whereas there are enzymatic defects in dopamine synthesis without cell loss in DRD. Mutations have been found in the GTP cyclohydrolase I (GCH-I) and tyrosine hydroxylase genes in DRD. As the discovered mutations are multiple and more are expected to be found, it is difficult to confirm or exclude DRD by mutation studies. Measurement of cerebrospinal fluid (CSF) neopterin will detect DRD from mutations in the GCH-I gene but not from mutations in tyrosine hydroxylase. The dopamine transporter (DAT) is a protein in the dopaminergic nerve terminals. (1R)-2beta-Carbomethoxy-3beta-(4-[123I]iodophenyl)tropane ([123I]beta-CIT) is a ligand for the DAT, and it was shown to be a useful nuclear imaging marker for neurons that degenerate in Parkinson's disease (PD). As DRD was shown to have a normal DAT without nigral cell loss in a postmortem study, we predicted that the DAT measured in vivo by nuclear imaging will be normal in DRD and will differentiate DRD from JPD. Therefore, we performed [123I]beta-CIT single-photon emission computed tomography ([123I]beta-CIT SPECT) in clinically diagnosed DRD, PD, and JPD, and examined whether DAT imaging can differentiate DRD from PD and JPD. We then examined whether DAT imaging can provide a screening tool for molecular genetic studies, by studying mutations in the candidate gene GCH-I and measuring CSF neopterin. Five females (4 from two families, and 1 sporadic) were diagnosed as DRD based on early-onset foot dystonia and progressive parkinsonism beginning at ages 7 to 12. All patients were functioning normally on L-dopa 100 to 250 mg/day for up to 8 years. SPECT imaging was obtained after intravenous injection of [123I]beta-CIT; 15 healthy volunteers served as normal control, and 6 PD and 1 JPD as disease controls. [123I]beta-CIT striatal binding was normal in DRD, whereas it was markedly decreased in PD and JPD. Gene analysis showed a novel nonsense mutation in the GCH-I gene in one family. No mutation was found in the other family or in the sporadic case. CSF neopterin was markedly decreased in the 4 tested patients. [123I]beta-CIT SPECT is a sensitive method for probing the integrity of nigrostriatal dopaminergic nerve terminals. A normal striatal DAT in a parkinsonian patient is evidence for a nondegenerative cause of parkinsonism and differentiates DRD from JPD. Finding a new mutation in one family and failure to demonstrate mutations in the putative gene in other cases supports the usefulness of DAT imaging in diagnosing DRD.
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PMID:Dopamine transporter density measured by [123I]beta-CIT single-photon emission computed tomography is normal in dopa-responsive dystonia. 962 49


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