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)

The renaissance of functional neurosurgery in the treatment of Parkinson's disease has sparked also the interest in other movement disorders which are refractory to medical treatment. Deep brain stimulation (DBS) has been used only since a few years in dystonia patients. This review summarizes the available data on pallidal and thalamic DBS for various dystonic syndromes. The major advantage of DBS as compared to radiofrequency lesioning is that it allows performing contemporaneous bilateral surgery with relatively low morbidity in these patients. The posteroventral lateral globus pallidus internus (GPi) has been the preferred target in most instances, thus far. While phasic dystonic movements may improve early after surgery, the response of tonic dystonic movements to chronic stimulation may be delayed. The most beneficial results have been achieved in patients with primary genetic generalized and segmental dystonia, myoclonic dystonia, and complex cervical dystonia. Outcome has been varied in patients with other dystonic disorders, in particular those with secondary dystonia. Most studies have reported on relatively short follow-up periods, on single cases, or were retrospective. Pallidal DBS has been shown to be effective in complex cervical dystonia yielding both symptomatic and functional benefit for up to 2.5 years of follow-up. Dramatic improvement has been obtained in children and in adults with DYT1 positive dystonia. Also, patients with non DYT1 genetic dystonia achieved sustained benefit for up to 2 years of follow-up. Preliminary experience indicates that choreoathetosis in patients with cerebral palsy responds less well to pallidal DBS, and that it may not be effective at all in some patients. In single instances unilateral pallidal DBS has been shown to yield valuable benefit in patients with hemidystonia. The experience with DBS for treatment of Meige syndrome and other focal dystonias has been explored only recently. There is much less experience with thalamic DBS for dystonia. Thalamic DBS has been shown to be effective in single cases with posttraumatic dystonia, postanoxic dystonia and paroxysmal nonkinesigenic dystonia. Future perspectives of DBS for treatment of dystonia include the development of new technology, the evaluation of the possible role of other targets, and carefully planned studies to further establish the role of surgery.
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PMID:Deep brain stimulation for dystonia in adults. Overview and developments. 1265 41

Stimulation electrodes are implanted under general anesthesia, without intra-operative electrophysiology or clinical testing, based only on stereotactic MRI and direct anatomical localization of the postero-ventro-basal GPi. We retrospectively analyzed the surgical procedure that has been designed and implemented in our center, using the Leksell G frame, for initiating deep brain stimulation in 65 dystonic patients. We report the surgical technique and the hardware and software complications. We recommend immediate postoperative stereotactic MRI under general anesthesia as a prerequisite to check the reliability of MR acquisition (magnet stability) and the exact localization of each electrode. This technique allowed us to reduce the duration of the operation to 4 h, including general anesthesia, frame fixation, MRI acquisition, implantation of two electrodes under radioscopic control, immediate postoperative stereotactic MRI and frame removal. Surgery-related morbidity was very low with a 0% hemorrhage rate and three delayed unilateral infections re-operated 6 months later. Hardware and software complications were rare. The advances in 3D-MR imaging permit the electrode implantation for deep brain stimulation without resorting to intraoperative localization techniques, which is especially helpful in children and for treating dystonia. The maximum follow-up period is 58 months (first case: November 1996). GPi stimulation has proven to be an effective treatment for most dystonic syndromes with particular efficacy in the disease due to the DYT1 mutation.
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PMID:Deep brain stimulation for dystonia. Surgical technique. 1265 42

Early-onset primary dystonia is an inherited disorder characterized by involuntary twisting, repetitive movements and abnormal postures. It has recently been demonstrated that the DYT1 gene is the most relevant gene associated with primary generalized dystonia. The DYT1 gene product is a 332-aminoacid long protein, termed TorsinA, whose function is still not clear. Based on the results obtained in other species, we proposed that TorsinA, similarly to OOC-5 in nematodes, directs and/or stabilizes the subcellular localization of specific kinases, which may in turn phosphorylate microtubule associated proteins, such as tau. In this way, TorsinA may contribute to maintaining the appropriate site-directed polarization and control neurite outgrowth.
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PMID:TorsinA, microtubules and cell polarity. 1276 Apr 8

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

Deletion of a single glutamate in torsinA correlates with early-onset dystonia, the most severe form of a neurological disorder characterized by uncontrollable muscle contractions. TorsinA is targeted to the ER (endoplasmic reticulum) in eukaryotic cells. We investigated the processing and membrane association of torsinA and the dystonia-associated Glu-deletion mutant (torsinAdeltaE). We found that the signal sequence of torsinA (residues 1-20 from the 40 amino-acid long N-terminal hydrophobic region) is cleaved in Drosophila S2 cells, as shown by the N-terminal sequencing after partial protein purification. TorsinA is not secreted from S2 cells. Consistently, sodium carbonate extraction and Triton X-114 treatment showed that torsinA is associated with the ER membrane in CHO (Chinese-hamster ovary) cells. In contrast, a variant of torsinA that contains the native signal sequence without the hydrophobic region Ile24-Pro40 does not associate with the membranes in CHO cells, and a truncated torsinA without the 40 N-terminal amino acids is secreted in the S2 culture. Thus the 20-amino-acid-long hydrophobic segment in torsinA, which remains at the N-terminus after signal-peptide cleavage, is responsible for the membrane anchoring of torsinA. TorsinAdeltaE showed similar cleavage of the 20 N-terminal amino acids and membrane association properties similar to wild-type torsinA but, unlike the wild-type, torsinAdeltaE was not secreted in the S2 culture even after deletion of the membrane-anchoring segment. This indicates that the dystonia-associated mutation produces a structurally distinct, possibly misfolded, form of torsinA, which cannot be properly processed in the secretory pathway of eukaryotic cells.
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PMID:Characterization of human torsinA and its dystonia-associated mutant form. 1278 Mar 49

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


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