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)

Fibroblasts provide a source of living cells that can be obtained easily from humans and used to evaluate inherited differences in the activities of enzymes important in neurotransmitter and drug metabolism. Here, we describe biochemical characteristics of catechol-O-methyltransferase (COMT, EC 2.1.1.6) activity in homogenates of cultured human skin fibroblasts. Many properties of the enzyme, including apparent affinity for dihydroxybenzoic acid and S-adenosyl methionine, optimal pH and (Mg++), and inhibition by Ca++, are similar to those reported in lysates of human erythrocytes. Culture and assay conditions have been established for optimal and reproducible measurement of COMT activity in individual fibroblast lines. In 16 control lines, COMT activity ranged from 115 to 263 pmol/min/mg protein with a mean of 181 pmol/min/mg protein. Enzyme activity did not vary with the age or sex of the donor. The COMT activities in fibroblasts from eight patients with dystonia musculorum deformans, an inherited movement disorder of unknown etiology, were not significantly different from controls. Monoamine oxidase (MAO, EC 1.4.3.4) type A activity was measured in 12 lines from patients with dystonia, and values did not differ significantly from age- and sex-matched controls. We conclude that inherited variation in activity of these two catabolic enzymes is not sufficient to explain alterations in monoamine metabolism described in this disorder.
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PMID:Catechol-O-methyltransferase activity in cultured human skin fibroblasts from controls and patients with dystonia musculorum deformans. 729 45

Parkinson's disease (PD) is one of the major neurological diseases affecting elderly subjects. Presumed prevalence of PD is 80-100 per 100 thousands and it is estimated that there are approximately 100 thousands patients in Japan. From a statistic on age distribution of patients visiting doctors, it is estimated that patients with ages at 75-79(639/100,000) and 80-84(632/100,000) are highest in number. Juvenile parkinsonism is a syndrome with parkinsonian motor symptoms and dystonia developing before and after ten years of age. Reports on this syndrome have been accumulated in Japan and gene abnormality in a enzyme relating to dopamine metabolism was discovered in the hereditary progressive dystonia with marked diurnal fluctuation (Segawa). Among symptomatic parkinsonism, cerebrovascular parkinsonism is mainly due to multiple infarction in the basal ganglia or Binswanger's disease in Japan, and both conditions develops parkinsonism, pseudobulbar palsy and dementia progressively. Diffuse Lewy body disease and a unique type of progressive supranuclear palsy presenting a disorder designated "pure akinesia" were studied mainly in Japan. In drug therapies of PD, it has been argued why the maintenance dose of levodopa or dopamine agonists was generally low in Japan. In addition to constitution and drug metabolism, attitude of Japanese people to worry side effects more than merit with beneficial effects by a drug may have inevitably lead to low maintenance dose. Development of new drugs have been undertaken in parallel with US and Europe. Talipexole hydrochloride has been on market in Japan recently, but MAO-B inhibitors and COMT inhibitors are in final stages to wait evaluations by the governmental committee.
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PMID:[Clinical characteristics and trends in research of Parkinson's disease and parkinsonism in Japan]. 901 16

Our experience with atypical antipsychotics in patients with PD is that their motor effects are not predictable. The multiple reports concerning clozapine's beneficial effects on tremor, dystonia, nocturnal akathisia, and dyskinesias all underscore this observation. However, the appearance of even minor degrees of parkinsonism in normal volunteers or schizophrenics should suggest that an antipsychotic will not be well-tolerated in patients with PD. The treatment of PD is probably the most stringent test of a drug's freedom from parkinsonian side effects. The data from trials in schizophrenia concerning parkinsonian effects cannot always be confidently interpreted. Virtually all subjects in these trials have been treated with typical neuroleptics until shortly before study entry. Because the parkinsonian side effects of these drugs may persist for several months, patients may still show declining levels of parkinsonism even when placed on a drug that induces it if this effect is milder than that induced by the pre-study neuroleptic. Depending on the pre-study drug used and the duration of the study, distinguishing placebo from a low-potency neuroleptic may be impossible. Furthermore, the standard measure of parkinsonism in psychiatric studies is the Simpson-Angus scale which is heavily weighted toward rigidity and may underscore bradykinesia, gait, and posture abnormalities. The prolactin response to an antipsychotic drug may turn out to be a good predictor of its freedom from parkinsonian side effects. That would fit with the data presented above of clozapine and quetiapine having less parkinsonian effects, olanzapine having more but variable effects and risperidone being poorly tolerated. With the data presented above, comprising a current review of all reports of the use of atypical antipsychotics in PD that we could locate, we can say little with certainty. The only drug with confirmed benefit without worsening parkinsonism is clozapine. Open-label trials involving over 400 patients and two multicenter, placebo-controlled, double-blind trials have demonstrated that it is effective in treating the psychosis. It improves tremor, does not worsen other motor functions to any significant extent, and is safe at low doses. Limited data provide conflicting information on both risperidone and olanzapine. Quetiapine seems to be well-tolerated with some, but definitely less, worsening of PD motor features than risperidone and olanzapine. Based on the current literature, our personal experience, and anecdotal experience of other PD specialists which we solicited, we will venture our own interpretation and recommendations. We think risperidone is poorly tolerated and should be used only as a last resort; that olanzapine is better than risperidone but will, in a majority of patients with PD, worsen motor function. We are optimistic, but not yet convinced, that quetiapine may prove to be as effective and better tolerated than clozapine. It will not require cumbersome monitoring because it does not induce a blood dyscrasia. We therefore recommend that DP be treated in the following manner. First, the anti-PD medications should be simplified and reduced as much as tolerated. We think, in general, side effects multiply more with increasing numbers of drugs than with drug dose, so that patients are more likely to tolerate a higher dose of levodopa than a lower dose of levodopa combined with other adjunctive anti-PD medications. In reducing anti-PD medications, we recommend tapering and stopping, if necessary, the drugs with the highest risk-to-benefit ratio first. Anticholinergics are stopped first, then selegiline, dopamine agonists, amantadine, and finally COMT inhibitors, which have no psychotomimetic action of their own. Finally, levodopa is reduced. Generally, a point is reached at which the anti-PD medications cannot be reduced without jeopardizing motor function. If psychosis persists at this point, then an antipsychotic is added. (ABS
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PMID:Atypical antipsychotics in the treatment of drug-induced psychosis in Parkinson's disease. 1075 67

Camptocormia is characterized by pronounced forward flexion of the thoracolumbar spine, which increases while walking and disappears in recumbent position. The clinical spectrum of the described disorders with concomitant camptocormia is heterogenous. It was described for the first time in idiopathic Parkinson's disease in 1999. The pathophysiology of this phenomenon remains unclear but seems to be not related to antiparkinsonian treatment. The authors present the case of a 54 years old woman, with idiopathic Parkinson disease diagnosed 5 years ago. The rapid progression of the disease was associated with good response to Levodopa therapy, although the dose had to be increased up to 1400 mg/d (with peripheral decarboxylase and COMT inhibitor). After 5 years she developed painful spasms of paraspinal muscles which resulted in trunk flexion. The clinical picture resembled the described cases of camptocormia. There was no correlation between the appearance of camptocormia and the regime of levodopa administration (time or dosage). Therefore, one can conclude, that presumably camptocormia is not a form of dystonia of the trunk but, the result of till now unclear other factors (dysfunction in other non-dopaminergic nigrostriatal projections?).
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PMID:[Camptocormia, a rare form of motor system disorders in Parkinson's disease]. 1198 8

Cervical dystonia, a late onset focal dystonia, has a complex genetic background. Multiple lines of evidence point to a role for aberrant dopamine levels in dystonia. We assessed whether common variation within genes that regulate brain dopamine levels and in key genes of the dopamine metabolic pathway, modulate the risk for cervical dystonia. DNA was collected from 363 Dutch CD patients and a cohort of Dutch control individuals. Haplotype-tagging single nucleotide polymorphisms (SNPs) complemented with selected variants of functional importance in COMT, DAT, TH, MAO-A and -B, DDC and DBH were investigated. We tested the 143 markers in single-SNP, haplotype and epistasis analyses. We did not find an association with any of the selected 143 SNPs in these key dopamine genes. Our data shows that common variations in key genes of the dopamine pathway do not contribute to dystonia risk in the Dutch population. Possibly, risk alleles in this pathway may be rarer than detectable in this study, or might be located in downstream dopamine signaling pathway. Alternatively, found dopamine level changes are secondary to the dystonia disease processes.
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PMID:Cervical dystonia and genetic common variation in the dopamine pathway. 2298 Nov 86