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)

Previous pharmacological studies have indicated that impairment of GABAergic transmission may be involved in the pathophysiology of dystonia in the mutant dtsz hamster, i.e., a genetic animal model for idiopathic dystonia. In the present experiments, the kinetic constants of [3H]flumazenil binding to the benzodiazepine site of the GABAA receptor were calculated from equilibrium binding measurements in various brain regions of genetically dystonic hamsters and age-matched controls. Because dystonia in mutant dtsz hamsters is transient and disappears after approximately 60-70 days of age, [3H]flumazenil binding was studied at the age of maximum severity of dystonia (30-40 days) and after disappearance of the disease, to examine which neurochemical changes were related to dystonia. In mutant hamsters with the maximum severity of dystonia, receptor affinity of [3H]flumazenil was increased in olfactory bulb, striatum, tectum, and cerebellum, as exemplified by significantly decreased dissociation constants (KD) in these regions. An increased number of binding sites (Bmax) were seen in striatum and frontal cortex but not in the other eight regions studied in this regard. All these changes in [3H]flumazenil binding disappeared in parallel with dystonia, implicating a causal relationship between altered benzodiazepine receptor binding and dystonia in mutant dtsz hamsters.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Regionally selective and age-dependent alterations in benzodiazepine receptor binding in the genetically dystonic hamster. 772

The genetically dystonic hamster is an animal model of idiopathic (torsion) dystonia that displays sustained abnormal movements and postures either spontaneously or in response to mild environmental stimuli. Since dystonic attacks occur in the absence of any lesion which can be defined by standard histopathological techniques in the central nervous system, the presumption is that dystonia in mutant hamsters is due to some biochemical disturbance activity in brain regions involved in motor functions. In the present study we determined the monoamine neurotransmitters dopamine, noradrenaline, adrenaline and serotonin (5-HT) as well as the dopamine metabolites homovanillic acid (HVA) and dihydroxyphenylacetic acid (DOPAC) and the 5-HT metabolite 5-hydroxyindoleacetic acid (5-HIAA) in 14 brain regions of male and female dystonic hamsters and age-matched non-dystonic controls. All determinations were done at age of maximum susceptibility for induction of dystonic attacks. Since both genders of dystonic hamsters exhibit the same characteristic age-dependent time-course of dystonia, it was assumed that only those biochemical alterations are critically involved in dystonia that occur in both female and male animals. The neurochemical data show that except for a significant decrease of dopamine and HVA in the olfactory bulb, no consistent changes in dopamine metabolism are present across brain regions, including the basal ganglia, of dystonic hamsters. In contrast, marked increases in noradrenaline and 5-HT or 5-HIAA were found in several brain areas of both genders, indicating an enhanced activity of central noradrenergic and serotonergic nuclei in the brainstem. The present results suggest the involvement of noradrenergic and serotonergic neural systems in the pathophysiology of dystonia. Based on these data and recent theoretical suggestions from clinical findings, drugs which reduce noradrenergic and serotonergic neurotransmission may be a useful therapeutic approach to dystonia.
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PMID:Marked regional disturbances in brain metabolism of monoaminergic neurotransmitters in the genetically dystonic hamster. 783 42

In patients with the trisomy 13 syndrome the most commonly encountered brain anomaly is holoprosencephaly, which occurs in approximately 80% of cases. In trisomy 13 patients without holoprosencephaly, previously reported anomalies include callosal dysgenesis, hippocampal hypoplasia, olfactory hypoplasia, and cerebellar dysplastic changes such as vermian hypoplasia and dysplastic cortices. Dysplasia of the cerebral cortex, however, has not been reported before. We describe a newborn with bilateral, dysplastic cortices at the perisylvian and rolandic regions. These dysplastic cortices probably accounted for the clinical findings of seizures, oromotor dysfunction, dystonia flexion contractures in the hands, which were consistent with a recently described syndrome labelled as the "congenital bilateral perisylvian syndrome".
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PMID:Bilateral, perisylvian and rolandic cortical dysplasia in trisomy 13 syndrome. 910 9

Dopamine (DA) uptake sites, or transporters, were examined with [125I]RTI-121 in mutant mice that exhibit motor control deficits, namely weaver, lurcher and dystonia musculorum. In lurcher mice, the distribution of [125I]RTI-121 binding was similar to controls, except for a decrease in the subthalamic nucleus. For dystonia musculorum mice, the labelling presented no differences between controls and mutants, except for decreases in the dorsal half of caudal neostriatum and in the ventral tegmental area. Moreover, in this mutant the left rostral neostriatum DA transporters were reduced, when compared to the right counterpart. In weaver heterozygote (wv/+) mice, the distribution and density gradients of [125I]RTI-121 labelling were similar as in their controls, except in caudal neostriatum, where binding was slightly higher. In contrast, the weaver homozygote (wv/wv) showed important decreases in labelling of the dorsal quadrant of rostral neostriatum as well as of the dorsal half of caudal neostriatum, where the reductions of binding densities were of 65% to 70%, respectively. There were also slight decreases in [125I]RTI-121 binding in olfactory tubercles as well as in subthalamic nucleus, but only in wv/wv mice. In substantia nigra pars compacta and ventral tegmental area of wv/wv mice the labelling was lower; however, while the 60% decrease in labelling in substantia nigra was highly significant, the 30% reduction in ventral tegmental area did not attain statistical significance. In summary, in the ataxic neurological mutant mice studied, important reductions of DA transporters were documented only for the weaver mice, the cerebellar mutant presenting, besides its cerebellar pathology, a known degeneration of mesencephalic dopaminergic neurons. The results rule out major alterations of the central DA systems in lurcher and dystonia musculorum, and are compatible with the hypothesis that the dopaminergic abnormalities of weaver mutants are not secondary to cerebellar atrophy, but may be a direct consequence of the abnormal weaver gene expressed by DA neurons leading to their apoptotic death.
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PMID:Distribution of dopamine transporters in basal ganglia of cerebellar ataxic mice by [125I]RTI-121 quantitative autoradiography. 946 Jul 3

Dystonia musculorum (dt(J)/dt(J)) mutant mice suffer from a degeneration of spinocerebellar tracts as well as a dystrophy of peripheral sensory tracts. This neurological mutant has been proposed as an animal model of human cerebellar ataxia, in particular of the Friedreich's type; thus, it was deemed of interest to examine the endogenous contents of dopamine (DA) and metabolites as well as the distribution of DA receptors of the D(1) and D(2) subtypes, in order to delimit the biochemical characteristics of this pathological disorder, and determine an eventual dopaminergic dysfunction in this mutant. Tissue DA and its major metabolites 3, 4-dihydroxyphenylacetic acid, homovanillic acid and 3-methoxytyramine were measured by HPLC coupled to electrochemical detection in six cortical regions, in four divisions of rostral neostriatum and two halves of caudal neostriatum, as well as in olfactory bulb, nucleus accumbens, septum, amygdala, hippocampus, thalamus, hypothalamus, brainstem, cerebellum, substantia nigra, and ventral tegmental area. The only significant difference between dt(J)/dt(J) mice and wild-type controls was an increase in hypothalamic DA contents (+47%). Quantitative autoradiography with [(3)H]SCH23390 and [(3)H]raclopride, to label D(1) and D(2) receptors, respectively, revealed only moderate changes in receptor densities in a few localized regions. In dt(J)/dt(J) mutants, D(1) receptor numbers were found to be higher in thalamus (+27%) as well as in the medio-dorsal (+16%) and in the latero-dorsal (+16%) quadrants of rostral neostriatum, while D(2) receptor densities were greater in the medio-ventral (+32%) and the latero-dorsal (+17%) quadrants. The present results indicate an overall conservation of dopaminergic functions, albeit the few localized sites of increased D(1) and D(2) receptor densities, and that are seemingly independent of the DA innervation pattern, as revealed by the tissue measurements of DA and metabolites. They also rule out a major pathology linked to deficits in DA neurotransmission, and validate this mutant as an animal model of human cerebellar ataxia, probably of the Friedreich type.
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PMID:Dopamine D(1) and D(2) receptors in the forebrain of dystonia musculorum mutant mice: an autoradiographic survey in relation to dopamine contents. 1084 46

Reflex epilepsy includes a group of epileptic syndromes in which seizures are induced by a stimulus, either simple (visual, somatosensory, olfactory, auditory) or more complex (e.g., eating, thinking, reading). We document a case of reflex epilepsy in which focal seizures are triggered exclusively by gait. The patient is a young boy whose walking was impaired by abnormal motor phenomena on the left side. These phenomena were elicited by gait and were accompanied by a distinctive ictal pattern with centro-temporal discharges. After comparing this patient with others reported in the literature, we determined that he has an unusual type of reflex epilepsy for which we coined the term "gait epilepsy." This disorder must be considered when physicians are making a differential diagnosis in patients who have symptoms that suggest paroxysmal kinesigenic dystonia (PKD) or selective epileptic gait disorder.
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PMID:Gait epilepsy. A case report of gait-induced seizures. 1155 99

We administered a culturally corrected University of Pennsylvania Smell Identification Test (ccUPSIT) consisting of 25 odor items to 20 patients with 'Lubag' or X-linked dystonia-parkinsonism and 20 control subjects matched by sex, age, educational background, smoking history, and geographical origin. The mean ccUPSIT score of Lubag patients (18 +/- 3.19) was statistically lower (P = 0.003) than controls (20.5 +/- 3.02). The smell scores did not correlate with phenotype, severity of dystonia, or duration of disease. Nine of 20 Lubag patients (45%) had ccUPSIT scores below the mean, with the lowest score being 11. This pilot study suggests that olfactory dysfunction may occur in Lubag patients.
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PMID:Smell testing is abnormal in 'lubag' or X-linked dystonia-parkinsonism: a pilot study. 1546 96

Myoclonus dystonia (M-D) is a hereditary movement disorder caused by a maternally imprinted gene that is often associated with psychiatric symptoms. Most cases of M-D are believed to result from mutations of the epsilon-sarcoglycan protein. The neuroanatomical distribution of epsilon-sarcoglycan-like immunoreactivity in mouse was investigated by using an antiserum against the epsilon-sarcoglycan protein. The expression of epsilon-sarcoglycan mRNA was studied by a sensitive fluorescence in situ hybridization (FISH) method. Immunohistochemistry and FISH revealed a wide distribution of epsilon-sarcoglycan protein and mRNA throughout the mouse brain. High expression levels of epsilon-sarcoglycan mRNA and immunoreactivity were found in the mitral cell layer of the olfactory bulb, the Purkinje cell layer in cerebellum, and the monoaminergic neurons in the mouse midbrain. Immunohistochemistry revealed a similar distribution of epsilon-sarcoglycan protein. Double-labeling FISH showed colocalization of tyrosine hydroxylase and epsilon-sarcoglycan mRNAs within all the midbrain dopaminergic (DAergic) cell groups. By combining FISH with fluorescence immunohistochemistry, coexpression of epsilon-sarcoglycan mRNA and tryptophan hydroxylase immunoreactivity was found in the serotonergic (5-HTergic) neurons within the dorsal raphe nucleus. The distribution of epsilon-sarcoglycan in the mouse brain suggests that the symptom complex of M-D may be related to the effects of decreased epsilon-sarcoglycan activity on the development or function of monoaminergic neurons.
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PMID:Epsilon-sarcoglycan immunoreactivity and mRNA expression in mouse brain. 1561 18

We have established that the frequency of LRRK2 mutations in a series of 118 cases of familial Parkinson's disease is 5.1%. In the largest family with autosomal dominant, late-onset Parkinson's disease where affected subjects share a Y1699C missense mutation we provide a detailed clinical, pathological and imaging report. The phenotype in this large British kindred included asymmetrical, levodopa-responsive parkinsonism where unilateral leg tremor at onset and foot dystonia were prominent features. There was no significant abnormality of cognition but there was prominent behavioural disorder. We observed a lower age of onset in successive generations. Histopathology in one patient showed substantia nigra cell loss and Lewy body formation, with small numbers of cortical Lewy bodies. 18F-dopa positron emission tomography (PET) in another patient showed a pattern of nigrostriatal dysfunction typical of idiopathic Parkinson's disease. 18F-dopa-PET scans in unaffected family members prior to identifying the disease locus did not detect subclinical nigrostriatal dysfunction. Olfaction was assessed in affected subjects and Lewy bodies were identified in the olfactory bulb as well as cortex and brainstem of one deceased patient. In order to assess the role of mutations in this gene in other familial cases we undertook a mutation screen of all 51 exons of LRRK2 in 117 other smaller British kindreds with familial Parkinson's disease. The commonest mutation was G2019S and we also identified two novel mutations, R1941H and T2356I, in the coding sequence. These data suggest that parkinsonism caused by mutations in LRRK2 is likely to represent the commonest locus for autosomal dominant Parkinson's disease with a phenotype, pathology and in vivo imaging similar to idiopathic, late-onset Parkinson's disease.
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PMID:Mutations in the gene LRRK2 encoding dardarin (PARK8) cause familial Parkinson's disease: clinical, pathological, olfactory and functional imaging and genetic data. 1631 Dec 69

Myoclonus-dystonia syndrome (MDS) is a genetically heterogeneous disorder characterized by myoclonic jerks often seen in combination with dystonia and psychiatric co-morbidities and epilepsy. Mutations in the gene encoding epsilon-sarcoglycan (SGCE) have been found in some patients with MDS. SGCE is a maternally imprinted gene with the disease being inherited in an autosomal dominant pattern with reduced penetrance upon maternal transmission. In the central nervous system, epsilon-sarcoglycan is widely expressed in neurons of the cerebral cortex, basal ganglia, hippocampus, cerebellum and the olfactory bulb. epsilon-Sarcoglycan is located at the plasma membrane in neurons, muscle and transfected cells. To determine the effect of MDS-associated mutations on the function of epsilon-sarcoglycan we examined the biosynthesis and trafficking of wild-type and mutant proteins in cultured cells. In contrast to the wild-type protein, disease-associated epsilon-sarcoglycan missense mutations (H36P, H36R and L172R) produce proteins that are undetectable at the cell surface and are retained intracellularly. These mutant proteins become polyubiquitinated and are rapidly degraded by the proteasome. Furthermore, torsinA, that is mutated in DYT1 dystonia, a rare type of primary dystonia, binds to and promotes the degradation of epsilon-sarcoglycan mutants when both proteins are co-expressed. These data demonstrate that some MDS-associated mutations in SGCE impair trafficking of the mutant protein to the plasma membrane and suggest a role for torsinA and the ubiquitin proteasome system in the recognition and processing of misfolded epsilon-sarcoglycan.
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PMID:SGCE missense mutations that cause myoclonus-dystonia syndrome impair epsilon-sarcoglycan trafficking to the plasma membrane: modulation by ubiquitination and torsinA. 1720 Jan 51


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