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)

Recent findings of antidystonic effects of NMDA and non-NMDA receptor antagonists in an inbred line of Syrian hamsters with primary generalized dystonia prompted us to investigate the effects of lamotrigine, an inhibitor of veratrine-induced glutamate release, on the severity of dystonia in mutant hamsters. In mutant dystonic hamsters the dystonic attacks which can be induced by mild environmental stimuli or handling are age-dependent with maximum severity between days 30 and 40 of life (maximum period). Thereafter the severity of dystonia slowly declines (post-maximum period) until the susceptibility to induction of dystonia disappears completely at an age of about 70 days. Lamotrigine (5.0, 10.0 or 30.0 mg/kg i.p.) dose dependently decreased the latency to onset of dystonic attacks. Furthermore, at a dose of 30 mg/kg the dystonic attacks were aggravated when lamotrigine was administered during the max and post-max period. Even in mutant hamsters older than 70 days, i.e. after spontaneous remission of dystonia, and in an inbred line of non-dystonic Syrian hamsters with genetic origin similar to the mutant hamsters, lamotrigine (10.0 or 30.0 mg/kg i.p. and 30.0 mg/kg p.o.) provoked dystonic disturbances. In a genetically different outbred line of Syrian hamsters, lamotrigine did not cause dystonic movements. The unexpected finding that lamotrigine exerts prodystonic effects in genetically susceptible hamsters may be due to the lack of selectivity of lamotrigine to block glutamate release. Tentatively, simultaneous inhibition of GABA (gamma-aminobutyric acid) release might be critically involved in the prodystonic activity of lamotrigine.
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PMID:The novel antiepileptic drug, lamotrigine, exerts prodystonic effects in a mutant hamster model of generalized dystonia. 769 75

Dystonia is a relatively common syndrome of sustained muscle contractions, frequently causing twisting and repetitive movements or abnormal postures. The most frequent type of dystonia is idiopathic generalized dystonia, whose pathophysiology is largely unknown. In this respect, mutant animal strains with inborn dystonia may be helpful to elucidate the pathophysiological defects involved in idiopathic dystonia. The genetically dystonic (dtsz) hamster is an animal model of paroxysmal dystonia that displays attacks of generalized dystonia either spontaneously or in response to mild environmental stimuli. In the present study, a quantitative autoradiographic analysis of ligand binding to different sites of the GABAA/benzodiazepine receptor-chloride ionophore complex was carried out in 123 brain areas from genetically dystonic mutant hamsters and age-matched control hamsters. Animals were killed 2 weeks after their last dystonic attack. Analysis of the GABA-binding site of the receptor complex, using the ligand [3H]muscimol, and the benzodiazepine site labelled with [3H]flunitrazepam revealed no significant alterations in the binding of either ligand in any of the brain regions examined. In contrast, widespread changes were observed in binding densities of [35S]t-butylbicyclophosphorothionate ([35S]t-butylbicyclophosphorothionate), which labels the picrotoxinin site of the GABAA receptor-chloride ionophore complex. Significantly increased [35S]t-butylbicyclophosphorothionate binding was found in several parts of the thalamus, cortex, and hippocampus as well as in the red nucleus, the subthalamic nucleus, and the granular layer of the cerebellum. Since high-affinity [35S]TBPS binding is thought to represent the closed conformation of the GABA-gated chloride ionophore, increased TBPS binding would indicate an impaired GABAergic function. The study is consistent with the concept that dystonia is caused by impaired connections between the basal ganglia, the thalamus, and frontal association areas. The data on increased [35S]TBPS binding are the first evidence implicating alterations in the GABA-gated chloride ion channel function in a movement disorder, i.e. idiopathic generalized dystonia.
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PMID:Alterations in the brain GABAA/benzodiazepine receptor-chloride ionophore complex in a genetic model of paroxysmal dystonia: a quantitative autoradiographic analysis. 770 8

The effects of three-week daily intrastriatal 45 mcg GABA, 5 and 15 mcg picrotoxin and 5 bicuculline microinjections in rats were investigated. The inhibition of avoidance conditioning in shuttle box was registered in first days of GABA microinjection; stereotyped behaviour and paradoxal freezing in further GABA effects were developed. After the short orofacial dyskinesia as the acute picrotoxin effects, the choreo-myoclonic limb jerks, with the distinct generalization stage were observed. Picrotoxin dose increasing in toxic convulsive status results. No any dystonia, but strong avoidance conditioning inhibition in all three weeks of bicuculline treatment were observed only. The novel functional and controlled model of choreo-myoclonic hyperkinesis is proposed. The role of the striatal GABA system in human neuro-motor dyskinesias were discussed.
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PMID:[Myoclonic hyperkinesis induced by repeated administration of picrotoxin into rat neostriatum]. 805 87

Attacks of sustained dystonia of the limbs and trunk can be initiated by handling or mild environmental stimuli (e.g. new cage) in mutant (gene symbol dtsz) Syrian golden hamsters. The severity of the dystonic syndrome in these mutant hamsters is age-dependent, with a peak at weaning (21 days of age) and a second peak at about 30-40 days of age. Spontaneous remission occurs at an age of about 70 days. The syndrome in hamsters is thus similar to transient paroxysmal dystonia in children. In the present experiments, it was examined whether dystonic hamsters exhibit age-dependent differences in susceptibility to drugs which affect GABA (gamma-aminobutyrate)ergic, glutamatergic or dopaminergic functions. After acute administration, the GABA-elevating drug aminooxyacetic acid was significantly less potent in attenuating the severity of dystonic attacks at 21 days than at 31 days of age. Similar but less marked age-dependent differences in antidystonic activity were found for phenobarbital and diazepam. In contrast to these GABAmimetic drugs, the NMDA receptor antagonist CGP 37849 (DL-[E]-2-amino-4-methyl-5-phosphono-3-pentenoic acid) or the dopamine receptor antagonist haloperidol had about the same antidystonic potency at both 21 and 31 days of age. Chronic treatment of dystonic hamsters with aminooxyacetic acid, starting at 21 days of age, did not alter the time course or the severity of dystonia.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Alterations in pharmacological sensitivity of GABAergic but not dopaminergic and glutamatergic systems during ontogenesis in dystonic mutant hamsters. 838 61

Serial trans-fontanellar sonographic examination in a patient with glutaric aciduria type I (GA I) demonstrated that the typical frontotemporal cerebral atrophy developed postnatally within three months paralleling the onset of dystonic symptoms. Pathogenesis of the accompanying macrocephaly remains unclear and can form a diagnostic pitfall. Diet low in lysine and tryptophan led to a dramatic fall in urinary glutaric acid (GA) excretion but as in other patients with GA I did not substantially influence clinical symptoms and course. We determined unchanged levels of GA in plasma and cerebrospinal fluid resulting from variable renal tubular secretion and reabsorption of GA. Monitoring urinary excretion of GA appears inappropriate to control dietary treatment in GA I. Substitutive correction of secondary carnitine depletion seems to protect from deleterious metabolic crises. Treatment with valproic acid resulted in a rise of GABA-concentration in cerebrospinal fluid but did not ameliorate clinical symptoms. This finding is in contrast with the hypothesis that inhibition of cerebral GABA-synthesis by GA is responsible for the development of dystonia in GA 1. Although we observed impressing fluctuation of dystonic symptoms, levodopa did not show therapeutic effects. The extreme variability in the severity of neurologic disease in metabolically identical individuals leads to a "two-hit"-hypothesis.
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PMID:[Development of brain atrophy, therapy and therapy monitoring in glutaric aciduria type I (glutaryl-CoA dehydrogenase deficiency)]. 844 49

Clinical, neurological, endoscopic, psychological findings, questionnaire data on vegetative sphere, diaphragm x-ray, articulation test and Viene test system evidence obtained on 25 patients with phonic spasm confirm organic neurological nature of spastic dysphonia as focal muscular dystonia. This condition can be accompanied with tremor, rotatory, winking and writers' spasms, oromandibular dystonia. As indicated by positive treatment outcomes, combined treatment of phonic spasm with GABA-ergic drugs of clonazepam (antelepsin) and baclofen, orthophonic voice correction, physiotherapy is pathogenetically justified.
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PMID:[Clinical features of spastic dysphonia]. 855 15

We studied the effects of intrathecal baclofen upon voluntary movements. Eleven patients with spasticity of different etiology and one patient with idiopathic dystonia were studied. Six patients participated in a double-blind trial. Kinematic/dynamic and electromyographic (EMG) patterns were recorded during attempts at single-joint elbow or ankle voluntary movements and isometric contractions. Reflex responses were also recorded. Baclofen suppressed spastic signs in 10 patients: it eliminated clonus and decreased the co-contraction of antagonist and distant muscle groups. Baclofen could induce weakness, particularly in patients with cerebral palsy (CP). Patients with hemi-syndromes did not notice any effects of baclofen in their 'unaffected' limbs. Intrathecal baclofen could improve voluntary movements in some patients with spasticity resulting in better walking and usage of arms. We hypothesize that spasticity induces an adaptive reaction at a segmental level that includes an increase in the number and/or affinity of GABA-sensitive receptors.
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PMID:Changes in voluntary motor control induced by intrathecal baclofen in patients with spasticity of different etiology. 923 40

The genetically dystonic rat exhibits a motor syndrome that closely resembles the human disease, generalized idiopathic dystonia. Although in humans dystonia is often the result of pathology in the basal ganglia, previous studies have revealed electrophysiological abnormalities and alterations in glutamate decarboxylase, the synthetic enzyme for GABA, in the cerebellum of dystonic rats. In this study, we further characterized the alterations in cerebellar GABAergic transmission in these mutants by examining the expression of the messenger RNA encoding glutamate decarboxylase (67000 mol. wt) with in situ hybridization histochemistry at the single cell level in Purkinje cells and neurons of the deep cerebellar nuclei. Glutamate decarboxylase (67000 mol. wt) messenger RNA levels were increased in the Purkinje cells and decreased in the deep cerebellar nuclei of dystonic rats compared to control littermates, suggesting opposite changes in GABAergic transmission in Purkinje cells and in their target neurons in the deep cerebellar nuclei. In contrast, levels of glutamate decarboxylase (67000 mol. wt) messenger RNA in the pallidum, and of enkephalin messenger RNA in the striatum, were unaffected in dystonic rats. The data indicate that both the Purkinje cells and GABAergic neurons of the deep cerebellar nuclei are the site of significant functional abnormality in the dystonic rat.
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PMID:Differential expression of glutamate decarboxylase messenger RNA in cerebellar Purkinje cells and deep cerebellar nuclei of the genetically dystonic rat. 946 32

Careful clinical delineation and advances in analytical methods have opened new possibilities for the detection of inherited neurometabolic disorders, some of which require specific CSF analyses for diagnosis. Although patients suffering from these disorders have recognizable phenotypes, there are strong indications that remain many undiagnosed, leading to a continuation of futile diagnostic searches and, for most disorders, withholding of available rational therapy. As there is still widespread uncertainty about when to perform specialist CSF investigations, it is the aim of this paper to define the place for CSF investigations in the diagnostic work-up of a child with an encephalopathy of unknown origin. Most neurometabolic disorders can be identified through serum, plasma and urine analyses in conjunction with neuroradiological investigations. Whenever CSF investigations are performed, the analysis should include quantitative determination of lactate, pyruvate and amino acids, the latter by methods especially suited for CSF, in addition to cells, glucose, protein, immunoglobulin classes, specific immunoglobulins, and an evaluation of the blood-brain barrier. If the disease course is non-progressive or if extracerebral symptoms are present in addition to an encephalopathy, e.g. endocrinological, hepatic, muscular or renal symptoms, investigations of metabolites in CSF over and above lactate, pyruvate and amino acids are generally noncontributary. Specific CSF investigations, which are discussed in detail, test metabolic pathways of brain metabolism, especially of neurotransmission. For a successful diagnosis of these defects, analyses must be planned individually, before CSF samples are taken, based on family history, clinical findings and disease course. Different determinations require different logistics from taking of the sample to shipment. One indication for specialized CSF analyses including biogenic monoamines and GABA is severe neonatal/infantile epileptic encephalopathy. In addition to a therapeutic trial of B6, folinic acid should be tried empirically for two to three days as the emerging syndrome of folinic acid responsive seizures appears to be the underlying cause in a sizable proportion of patients. In later infancy and childhood, defects in the metabolism of the biogenic monoamines may be suspected in patients with (fluctuating) extrapyramidal disorders, in particular Parkinsonism dystonia or more general "athetoid cerebral palsy", and vegetative disturbances. A severe epileptic encephalopathy and progressive mental retardation may be present. Neuroimaging findings do not show specific lesions. Determinations of folates and organic acids in CSF appear at present only warrantable individually in special constellations, e.g. classical clinical findings and disease course suggestive of glutaryl-CoA dehydrogenase deficiency with repeated negative quantitative analyses of organic acids in urine. The diagnosis of disorders, which require specific analyses of CSF, can only be achieved by conscious diagnostic decisions based on a concept of the respective disease and repeated scrupolous expert clinical evaluation aided by an array of investigations in blood and urine as well as neuroimaging findings. No single one investigation in CSF can serve as a "selective screening" test. A growing awareness of these disorders is needed and should lead to increased and earlier diagnosis of patients through fewer rather than more lumbar punctures.
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PMID:Cerebrospinal fluid investigations for neurometabolic disorders. 963 60

Niemann-Pick disease Type C (NPC) is a progressive neurovisceral metabolic disorder that is caused in most patients by a defect in a recently found gene, NPC-1. Neurological damage includes visual disorders such as vertical supranuclear gaze palsy, movement disorders such as dystonia and ataxia, dementia, and seizures. So far the biochemical deficit, most likely manifested by delayed intracellular cholesterol transport, has not been correlated with the progressive neurological damage. A mutant Balb/C mouse with a defect in the same gene is used as a model to study NPC. Pathological examination of brain tissue obtained by autopsy from NPC patients or brains of affected NPC mice of different ages, revealed signs of extensive damage throughout the brain, including neurofibrillary tangles and intracellular storage of various compounds. Loss of cerebellar Purkinje cells was the most significant specific damage. The present study examined whether the neurochemical changes present in the NPC mouse brain were related to the pathological changes. The results show major alterations in the levels of serotonin and its main metabolite, 5-hydroxyindoleacetic acid, in the cerebellum and cortex of NPC mice. The levels of the inhibitory amino acid glycine were threefold higher in the cerebellum of NPC mice and those of glutamate and GABA decreased in the cortex. Tyrosine hydroxylase immunoreactivity was present in Purkinje cells, and the levels of L-DOPA increased specifically in the vermis of the cerebellum. These results are the first to indicate changes in neurotransmitters in NPC and that these could be correlated with some of the neuropathology of this disease.
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PMID:Neurochemical alterations in the cerebellum of a murine model of Niemann-Pick type C disease. 967 2


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