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)

In this chapter, we have attempted to demonstrate that chronic manganese intoxication, in both animals and man, is a better model of dystonia than of Parkinson's disease. It is proposed that many of the monoamine and endocrine changes in dystonia may be the result of disturbances in manganese metabolism. A search for such modifications in human dystonia victims is presently underway. Preliminary studies indicate that head and pubic hair manganese concentrations are elevated in dystonia patients.
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PMID:Role of manganese in dystonia. 82 21

We have demonstrated that injection of manganese into one caudate nucleus in rats results in a predominant ipsilateral turning behavior, accompanied at higher doses by an intermittent, alternating and dose-related incidence of contralateral turning and stereotypies. Although the pharmacological evidence produced (effect of alpha-MT, L-DOPA, pargyline) indicates a definite participation of the dopaminergic system in the latter two phenomena, it is probable that ipsilateral turning is the result of involvement of other transmitter systems as well. Tegmental serotoninergic and intrastriatal cholinergic pathways appear to be involved in the production of the basic postural asymmetry resulting in turning. The amount of interference with the nigrostriatal and mesolimbic dopaminergic pathways may determine the speed of circling, and the concurrent inhibition of locomotion. This is more evident with bilateral injections. Manganese appears to act at presynaptic levels within the striatum by blocking release of the transmitter, thus creating a localized, relative deficit in caudate function. The end result is the release of the dominant "ipsilateral syndrome-inducing system' from its inhibitory control. Repeated or chronic administration of this metal in man or animals is known to result in a brain dopamine and/or serotonin deficit commensurate with the clinical manifestations of bradykinesia and dystonia. Our results are compatible with the anatomical findings of Poirier and collaborators and tend to support the dual ipsilateral and contralateral syndrome-inducing systems in the caudate postulated by Cools, and the complementary roles of dopamine, serotonin and acetylcholine within that nucleus. No one transmitter is involved alone in the experimental production of the manganese syndrome, or of its component symptoms.
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PMID:Behavioral effects in rats following intrastriatal microinjection of manganese. 117 15

Manganese produces signs and symptoms that suggest involvement of the basal ganglia, especially the globus pallidus and substantia nigra. Overt neurological signs have been reported in primates exposed to high levels of manganese (over 100 mg/kg) but little is known about the effects of lower doses. To examine these issues, three cebus monkeys were trained to operate a response device with their arms and legs by executing a rowing-like movement against a 3.9- to 4.1-kg spring through an arc length of 10 cm under a multiple fixed-ratio fixed-interval schedule of reinforcement. Over the course of 450 days, these monkeys were administered acute doses of 5 or 10 mg/kg iv of manganese chloride using a multiple baseline experimental design. Doses as low as 5 mg/kg provoked a large increase in the number of incomplete responses. The onset of manganese's effect appeared within days of exposure and developed over the course of several weeks. Its magnitude declined over the course of months, but after a cumulative dose of 10 to 40 mg/kg it did not return to baseline. Action tremor appeared at cumulative doses greater than 40 mg/kg and dystonia was never observed at the cumulative doses examined. Behavioral microanalysis revealed that manganese's effects initially appeared as increased variability of interresponse times and response duration. Later, the response pattern during the fixed ratio component shifted to one of progressively increasing durations through the course of the ratio. Magnetic resonance imaging revealed that the behavioral effects of manganese corresponded to an apparent increase in the manganese content of the globus pallidus and substantia nigra.
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PMID:Persistent effects of manganese on effortful responding and their relationship to manganese accumulation in the primate globus pallidus. 155 59

A patient developed a severe chorea whilst taking Chien Pu Wan pills. At examination only a high blood level of manganese (3 times the normal value) was found. Chemical analysis of these Chinese herbal pills showed that each pill contained 14 micrograms of manganese. By taking 3 to 5 pills a day, our patient was receiving 42 to 70 micrograms of manganese over and above the normal absorbed quantity of 60-90 micrograms daily. Because the chorea developed during the use of these pills and resolved when the blood levels of manganese went down, and because the high manganese blood levels were the only abnormality we found, we assumed these Chien Pu Wan pills and the subsequent manganese intoxication to be the cause of the chorea. Manganese poisoning may cause extrapyramidal signs such as parkinsonism, dystonia and chorea. This form of alternative therapy is not yet subject to legislation. In order to be able to control the nature and (side) effects of this kind of therapy, legislation is required.
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PMID:[Manganese poisoning due to use of Chien Pu Wan tablets]. 780 81

Using MRI and PET, we investigated the consequences of manganese intoxication in a primate model of parkinsonism and dystonia. Three rhesus monkeys were injected intravenously with doses of 10 to 14 mg/kg of MnCl2 on seven occasions, each a week apart. Two animals became hypoactive with abnormal extended posturing in the hind limbs. These motor disturbances did not improve with administration of levodopa. In all three monkeys, T1-weighted MRI demonstrated high signal intensities in the regions of the striatum, globus pallidus, and substantia nigra. No significant changes were found on [18F]6-fluoro-L-dopa, [11C]raclopride, or [18F]fluorodeoxyglucose PET. These results are consistent with the pathologic findings, which were primarily confined to the globus pallidus, and indicate that manganese intoxication is associated with preservation of the nigrostriatal dopaminergic pathway, despite clinical evidence of parkinsonian deficits. Chronic manganese intoxication may cause parkinsonism by damaging output pathways downstream to the nigrostriatal dopaminergic pathway. This is consistent with the demonstrated lack of therapeutic response to levodopa.
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PMID:MRI and PET studies of manganese-intoxicated monkeys. 778 89

We report a placebo-controlled study of levodopa in four patients with extrapyramidal deficits caused by chronic manganese intoxication. Their parkinsonism and dystonia had progressed slowly over a period of 5 years after they left the site of exposure. Initially the patients appeared to respond to levodopa in open observations, but this apparent benefit was not sustained. This short-term, double-blind study indicates that their parkinsonism and dystonia failed to respond to levodopa.
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PMID:Levodopa failure in chronic manganism. 793 78

Hyperintense symmetric pallidal lesions have been described in chronic hepatic failure. Similar lesions are reported in experimental models of manganese neurotoxicity. We describe an 8-year-old girl with chronic hepatic failure and dystonia in association with an elevated whole blood manganese level and symmetric hyperintense pallidal lesions on magnetic resonance imaging. After hepatic transplantation, her symptoms and signs resolved with normalization of magnetic resonance imaging and the whole blood manganese suggesting that in chronic hepatic failure, the pallidal lesions may be secondary to manganese deposition.
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PMID:Symptomatic manganese neurotoxicity in a patient with chronic liver disease: correlation of clinical symptoms with MRI findings. 802 63

Hyperintensity of the globus pallidus on T1-weighted magnetic resonance imaging (MRI) has been reported in patients with chronic liver disease. This abnormality has been associated with the severity of liver disease and tremor, but its cause is unknown. Similar MRI signal abnormalities have been reported in experimental models of manganese neurotoxicity. This case report describes a child with Alagille's syndrome and end-stage liver disease who developed dystonia and tremor associated with an elevated whole blood manganese level and symmetric hyperintense globus pallidi and subthalamic nuclei on T1-weighted but not T2-weighted MRI. Liver transplantation was performed; 2 months later, neurological function was improved, manganese levels were normal, and the MRI signal abnormality had completely resolved. This child had neurological findings described in manganese neurotoxicity with compatible laboratory and radiological findings. Manganese is excreted by the liver in bile, and toxicity may have resulted from the inadequacy of this mechanism, subsequently corrected by liver transplantation.
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PMID:Dystonia, hyperintense basal ganglia, and high whole blood manganese levels in Alagille's syndrome. 814 74

We gave three adult rhesus monkeys seven IV injections of manganese chloride at approximately 1-week intervals. We evaluated neurologic status by serial clinical examinations and performed a levodopa test if the animal developed features of basal ganglia dysfunction. After the animals were killed, we performed neuropathologic, neurochemical, and laser microprobe mass analysis (LAMMA) studies. Two of three animals developed a parkinsonian syndrome characterized by bradykinesia, rigidity, and facial grimacing suggestive of dystonia but not tremor. Neither animal responded to levodopa. Autopsy demonstrated gliosis primarily confined to the globus pallidus (GP) and the substantia nigra pars reticularis (SNr). We detected focal mineral deposits throughout the GP and SNr, particularly in a perivascular distribution. LAMMA studies noted that mineral deposits were primarily comprised of iron and aluminum. The severity of pathologic change correlated with the degree of clinical dysfunction. These studies demonstrate that, in contrast to Parkinson's disease (PD) and MPTP-induced parkinsonism, manganese primarily damages the GP and SNr and relatively spares the nigrostriatal dopaminergic system. Further, the results suggest that Mn-induced parkinsonism can be differentiated from PD and MPTP-induced parkinsonism by the clinical syndrome and response to levodopa. The accumulation of iron and aluminum suggests that iron/aluminum-induced oxidant stress may contribute to the damage associated with Mn toxicity.
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PMID:Manganese intoxication in the rhesus monkey: a clinical, imaging, pathologic, and biochemical study. 861 20

Chronic acquired hepatocerebral degeneration (CAHD) is a heterogeneous disorder that can occur with a primary neurologic, hepatic, or combined presentation. Little has been added to the understanding of this disorder since the detailed, early clinical and pathological descriptions. The spectrum of clinical presentations can be neuropsychiatric (apathy, lethargy, excessive somnolence), a movement disorder (ataxia, tremor, chorea, parkinsonism, myoclonus, dystonia), or both. Cortical laminar necrosis and polymicrocavitation in the cortex and basal ganglia are combined with cerebral and cerebellar atrophy. Microscopically, Alzheimer type II astrocytes and cytoplasmic glycogen granules are characteristic. Recent neuroradiological observations in patients with liver failure have shown a specific magnetic resonance (MR) imaging appearance with a hyperintense T1 signal in the pallidum, putamen, and, rarely, mesencephalon. Using clues from a similar MR appearance in patients receiving total parenteral nutrition as well as animals given parenteral manganese, and the knowledge that manganese is cleared by the hepatobiliary system, deposition of manganese in the brain is postulated in patients with CAHD. In this review we describe three cases of CAHD with detailed clinical and radiological documentation and discuss the aforementioned pathogenetic mechanisms.
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PMID:Chronic acquired hepatocerebral degeneration: case reports and new insights. 886 9


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