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)

Renewed interest in stereotaxy for dystonia followed the introduction of deep brain stimulation (DBS) in Parkinson's disease and essential tremor in the 1990s. DBS evolved from ablative surgery, which was applied with varying results in the 1950s in patients with movement disorders such as Parkinson's disease, essential tremor and dystonia. The present review summarizes the current knowledge on clinical aspects of DBS in dystonia (Dec. 2002). Excellent results have been achieved in dystonic patients carrying a mutation in the DYT1 gene with improvements up to 90 %. Similar results may also be obtained in patients with idiopathic generalized dystonia, myoclonus-dystonia syndrome, and tardive dystonia. Substantial improvement has been observed in patients with focal dystonia (for instance cervical dystonia). Patients with secondary dystonia often display a lesser and more variable degree of improvement. Long-term studies are warranted to assess both motor and neuropsychological sequelae of DBS in dystonia. Furthermore, the optimal target for different dystonic disorders remains to be determined, although the globus pallidus internus has currently emerged as the most promising target for dystonia.
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PMID:Deep brain stimulation in dystonia. 1276 37

Highly variable phenotype expression has long been recognized in DYT1 carrier patients. We report here an Ashkenazi-Jewish woman who carried a DYT1 mutation and developed a predominant unilateral myoclonic-dystonia (MD) displaying a fluctuating course. The present case is the second supporting the variability of DYT1 phenotype and further illustrates its ability to mimic the MD syndrome.
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PMID:Unusual phenotypic expression of the DYT1 mutation. 1278 94

A three-nucleotide (GAG) deletion in the TOR1A gene is the most common cause of inherited dystonia, DYT1. Because the mutant protein, TorsinA (TA), is thought to act in a dominant manner to cause disease, inhibiting expression from the mutant gene represents a potentially powerful therapeutic strategy. In an effort to develop therapy for this disease, we tested whether small interfering RNA (siRNA) could selectively silence expression of mutant TA. Exploiting the three-base pair difference between wild-type and mutant alleles, we designed siRNAs to silence expression of mutant, wild-type, or both forms of TA. In transfected cells, siRNA successfully suppressed wild-type or mutant TA in an allele-specific manner: for example, mutant-specific siRNA reduced the levels of mutant TA to less than 1% of controls with minimal effect on wild-type TA expression. In cells expressing both alleles, thus simulating the heterozygous state, siRNA-mediated suppression remained robust and allele specific. Our siRNA studies demonstrate allele-specific targeting of a dominant neurogenetic disease gene and suggest the broad therapeutic potential of siRNA for DYT1 dystonia and other dominantly inherited neurological diseases.
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PMID:Toward therapy for DYT1 dystonia: allele-specific silencing of mutant TorsinA. 1278 25

Since the advent of widespread testing for the presence of the DYT1 gene mutation, the range of phenotypes that have been associated with this genetic abnormality has expanded. We report on 5 DYT1 gene-positive patients with unusual phenotypes. Two of them had late presentation, one of these after peripheral injury. Three additional patients had late progression of symptoms, onset after exposure to haloperidol, and severe bulbar involvement, respectively. The clinical heterogeneity of this condition raises problems for clinicians in selecting appropriate patients for diagnostic testing. Also, because of the low phenotypic penetrance of DYT1 dystonia, the discovery of the DYT1 mutation in a patient with an atypical clinical syndrome may not necessarily suggest a causal relationship. We have, therefore, analysed all published clinical studies of DYT1 dystonia to guide clinical decision making concerning DYT1 gene testing based on current information.
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PMID:Unusual phenotypes in DYT1 dystonia: a report of five cases and a review of the literature. 1278 78

Sensory processing is impaired in focal hand dystonia (FHD), with most previous studies having evaluated only the symptomatic limb. The purpose of this study was to establish whether the sensory system is affected in other types of dystonias and whether the contralateral hand is also involved in FHD. We used a spatial acuity measure (Johnson-Van Boven-Phillips domes) to evaluate sensory spatial discrimination in both hands of patients with different forms of dystonias including primary generalized DYT1 dystonia (associated with a unique deletion in the DYT1 gene) (n = 13), FHD (n = 15), benign essential blepharospasm (n = 9), cervical dystonia (n = 10) and in age-matched controls. Clinical evaluation included the Fahn dystonia scale for the focal dystonia groups and the Marsden-Burke-Fahn scale for the generalized dystonia group. Spatial discrimination was normal in patients with DYT1 dystonia, despite all of these patients having hand dystonia. However, spatial discrimination thresholds were significantly increased in both hands in the focal dystonia groups (thresholds were similar for each group) and did not correlate significantly with either severity or duration of dystonic symptoms. Thresholds were significantly increased in the dominant hand compared with the non-dominant hand only within the FHD group. Our observations demonstrate involvement of both the dominant and non-dominant somatosensory cortices, and suggest that abnormal sensory processing is a fundamental disturbance in patients with focal dystonia. These findings of altered sensory processing in idiopathic focal but not generalized DYT1 dystonia suggest both a primary pathophysiological role for the phenomenon in focal dystonia and divergent pathophysiological processes in the two conditions.
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PMID:Abnormalities of spatial discrimination in focal and generalized dystonia. 1282 12

A mutation in the DYT1 gene on chromosome 9q34 causes early-onset primary torsion dystonia with autosomal dominant inheritance but low phenotypic penetrance. The aim of the present study was to assess the functional consequences of the DYT1 gene, by comparing the electrophysiology of cortical and spinal circuits in clinically affected and unaffected carriers of the DYT1 gene mutation. We assessed intracortical inhibition (ICI), intracortical facilitation (ICF), the cortical silent period (SP) and spinal reciprocal inhibition (RI) in 10 manifesting DYT1 gene carriers (MDYT1), seven non-manifesting DYT1 gene carriers (NMDYT1) and 13 healthy controls. The MDYT1 subjects had abnormalities similar to those seen in previous studies of non-genetically characterized individuals with primary dystonia. They had reduced ICI, shorter SP and absent presynaptic phase of RI compared with the healthy controls. NMDYT1 subjects also had a significant reduction in cortical inhibition (ICI and SP), but their spinal RI was not different from controls. We conclude that clinical expression of dystonia depends on widespread electrophysiological deficits, and the presence of the DYT1 gene mutation itself leads only to a subset of these changes. This is consistent with the hypothesis that additional environmental/genetic insults may be needed to reveal clinical symptoms in DYT1 gene carriers.
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PMID:Different patterns of electrophysiological deficits in manifesting and non-manifesting carriers of the DYT1 gene mutation. 1282 14

The question of whether a fetus carrying the GAG deletion on the DYT1 gene responsible for Oppenheim's dystonia should be aborted is frequently raised. The objective of this study was to characterize the clinical spectrum and natural course of Oppenheim's dystonia in Israel. Thirty-three patients (19 male) with genetically confirmed Oppenheim's dystonia were evaluated. The Dystonia Rating Scale (maximum score 120) and the Disability Scale (maximum score 30) were used to score severity at the last visit. After a mean of 15.5 +/- 13.8 years of symptoms, the mean Dystonia Rating Scale and Disability Scale scores were 22.7 +/- 14.7 and 7.7 +/- 4.3, respectively. Twenty-one patients (63.6%) have progressed into generalized dystonia. Five patients (15%) are wheelchair bound and three (9%) are using walking aids. All patients have normal cognitive function. Baclofen, trihexyphenidyl, and botulinum toxin were the drugs used. Nine patients (one patient had both) underwent neurosurgical intervention: thalamotomy for six (two bilateral) and pallidotomy for four (three bilateral). The bilateral pallidotomy provided only short-term benefit. The modern treatments combining drugs, botulinum toxin, and functional neurosurgery allow most patients with Oppenheim's dystonia to have independence and a relatively good quality of life.
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PMID:Natural history of Oppenheim's dystonia (DYT1) in Israel. 1282 16

Previous positron emission tomography (PET) studies have shown that nonmanifesting carriers of the DYT1 dystonia mutation express an abnormal pattern of resting glucose metabolism. To determine whether motor behavior is impaired in these subjects, we compared movement and sequence learning in 12 clinically unaffected DYT1 carriers with 12 age-matched controls. Regional differences in brain function during task performance were assessed with simultaneous H(2) (15)O/PET. We found that motor performance was similar in the DYT1 and control groups, with no significant differences in movement time and spatial accuracy measured during each of the tasks. In contrast, sequence learning was reduced in gene carriers relative to controls (p < 0.01). PET imaging during motor execution showed increased activation in gene carriers (p < 0.001, uncorrected) in the left premotor cortex and right supplementary motor area, with concomitant reduction in the posterior medial cerebellum. During sequence learning, activation responses in DYT1 carriers were increased in the left ventral prefrontal cortex, and lateral cerebellum. These findings suggest that abnormalities in motor behavior and brain function exist in clinically nonmanifesting DYT1 carriers. Although localized increases in neural activity may enable normal movement execution in these subjects, this mechanism may not compensate for their defect in sequence learning.
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PMID:Impaired sequence learning in carriers of the DYT1 dystonia mutation. 1283 25

Dystonia is a syndrome characterised by sustained muscle contractions, producing twisting, repetitive, and patterned movements, or abnormal postures. The dystonic syndromes include a large group of diseases that have been classified into various aetiological categories, such as primary, dystonia-plus, heredodegenerative, and secondary. The diverse clinical features of these disorders are reflected in the traditional clinical classification based on age at onset, distribution of symptoms, and site of onset. However, with an increased awareness of the molecular and environmental causes, the classification schemes have changed to reflect different genetic forms of dystonia. To date, at least 13 dystonic syndromes have been distinguished on a genetic basis and their loci are referred to as DYT1 to DYT13. This review focuses on the molecular and phenotypic features of the hereditary dystonias, with emphasis on recent advances.
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PMID:Classification and genetics of dystonia. 1284 29

Multiple movement disorders presenting in the same family are rare. We present an unusual family where generalized dystonia, Huntington's disease, progressive supranuclear palsy and secondary paroxysmal dyskinesia co-exist. The index case presented with young-onset dystonia and tested negative for the DYT1 gene deletion. Her father was similarly affected. The father's brother (paternal uncle of the index) also had abnormal movements-a mixture of chorea and dystonia-and tested positive for the HD expansion. His son had secondary paroxysmal dyskinesia, and tested negative for the HD expansion. The index case and her father were also negative for the HD expansion. A paternal aunt of two of the cases had a clinical diagnosis of progressive supranuclear palsy. Dystonia is known to be a genetically heterogeneous condition. The co-existence of inherited generalized dystonia with other movement disorders may provide clues to its genetic localization.
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PMID:An unusual family with multiple movement disorders. 1288 19


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