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Query: UMLS:C0013421 (dystonia)
 8,418 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Primary dystonia is a clinically and genetically heterogeneous movement disorder characterized by sustained involuntary muscle contractions causing repetitive movements and/or abnormal postures. Recently, the gene locus (DYT1) and mutation responsible for a substantial number of cases suffering from early-onset primary dystonia was described. Here we report 2 German families and 1 sporadic patient with early-onset dystonia due to the DYT1 mutation in order to illustrate the variability of clinical manifestation within this molecularly defined entity. We demonstrate that writer's cramp or focal cervical dystonia is a clinical presentation of DYT1 as well as generalized dystonia.
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PMID:Phenotypic variability of the DYT1 mutation in German dystonia patients. 1022 57

We examined 57 patients with idiopathic torsion dystonia (ITD) for the 3-bp GAG deletion in the DYT1 gene on human chromosome 9q34. Three of five patients with early limb-onset ITD, one of them with a positive family history, tested positive for the mutation, as did one young patient with multifocal dystonia and a short course of the disease. Two patients with early-onset generalized dystonia beginning in the cervical muscles, as well as five other patients with multifocal, 14 patients with segmental, and 30 patients with focal cervical dystonia did not carry the mutation. This suggests that the GAG deletion is responsible for a major portion of cases of typical early limb-onset dystonia, but not for other types of dystonia, in our population.
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PMID:GAG deletion in the DYT1 gene in early limb-onset idiopathic torsion dystonia in Germany. 1043 8

Dystonia musculorum deformans is an inherited severe disease, with a wide clinical polymorphism. The most severe clinical forms with early onset carry a high risk of life-threatening complications. In the absence of any efficient medical treatment, bilateral pallidotomy has previously been reported to be of value in the management of this disease. We report the first clinical case of a severe early-onset generalized dystonia dramatically improved by a bilateral stimulation of the internal globus pallidus. In November 1996, we proposed this neurosurgical procedure for a 8-year-old girl, who had suffered since the age of 3 from severe generalized dystonia, and who progressively became totally dependent and bedridden. She had been under sedation and permanent controlled respiratory assistance for the last two months. The etiology of the disease remained unknown (the DYT1 mutation was absent). Under general anesthesia, we bilaterally implanted a four-contacts electrode in the internal globus pallidus, using the Leksell's stereotactic frame and a 1.5 tesla MRI control. A dramatic improvement was noted 6 weeks later and led us to connect the two electrodes to neurostimulators inserted under the abdominal skin.
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PMID:[Treatment of early-onset generalized dystonia by chronic bilateral stimulation of the internal globus pallidus. Apropos of a case]. 1044 55

A GAG deletion in the DYT1 gene accounts for most early, limb onset primary torsion dystonia (PTD). The genetic bases for the more common adult onset and focal PTD are less well delineated. Genetic loci for an "intermediate dystonia" phenotype and for torticollis, named DYT6 and DYT7 respectively, have recently been mapped in single families. To evaluate the contribution of these genetic loci to other families with familial "non-DYT1" dystonia five large families with dystonia were studied using genetic markers spanning the DYT6 and DYT7 regions. There was no evidence of linkage to either locus in any family. These findings illustrate the genetic heterogeneity of the dystonias and indicate the existence of one or more as yet unmapped genes for dystonia. Large collaborative efforts will be required to identify these, and additional genes, causing PTD.
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PMID:Primary torsion dystonia: the search for genes is not over. 1044 67

Hereditary torsion dystonia represent a clinically and genetically heterogeneous group of movement disorders. The most severe and frequent form of hereditary torsion dystonia is early-onset generalized dystonia, DYT1. The DYT1 gene (Ozelius et al., 1997) encodes an ATP-binding protein torsin A. A unique 3-bp deletion (GAG) was found in the heterozygous state in almost all patients with early-onset dystonia from different populations. We observed 39 patients with early-onset generalized torsion dystonia belonging to 22 families from Russia. Seven families were of Ashkenazi Jewish (AJ) ethnic background, and other patients originated from the Slavonic population of Russia. The GAG deletion was identified in 24 affected persons from 15 families (68.2% of the families studied). In all the 7 families of AJ origin the disease was found to be caused by the deletion. In Slavs, the deletion was identified in 8 of 15 families (53%). In two deletion-positive families we observed the co-occurrence of typical early-onset generalized dystonia and atypical phenotypes-either isolated postural hand tremor or stutter.
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PMID:A common 3-bp deletion in the DYT1 gene in Russian families with early-onset torsion dystonia. 1047 37

A white Italian family affected by primary torsion dystonia (PTD) is described. The family phenotype most commonly presented with adult onset, cranial cervical involvement, and focal or segmental distribution without progression to generalization. Thirty-nine family members and nine spouses were studied. Five subjects received a diagnosis of definite PTD, three of probable PTD. Age at onset was in adulthood for all. In four definitely affected subjects, dystonia started in the cranial or cervical districts; in one it presented as writer's cramp. Familial writer's cramp also occurred in the family of the unrelated parent of the latter patient. The mean age at time of examination was 61.8 years in the individuals with a definite diagnosis; 60 in those with a probable diagnosis. At the time of examination, in most of the affected subjects, dystonia was focal; in three cases (two definitely and one probably affected), it was segmental. DNA linkage analysis, although limited by the size of the family, suggested exclusion of linkage between the disease and known PTD loci (DYT6 and DYT7). The GAG deletion in the DYT1 gene was excluded in the proband and in the family member affected by writer's cramp.
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PMID:Italian family with cranial cervical dystonia: clinical and genetic study. 1049 44

To gain insight into the neural pathways involved in the pathogenesis of DYT1 dystonia, we have mapped the cellular expression of the mRNA encoding torsinA and the closely related family member, torsinB, in normal adult human brain. Here, we report an intense expression of torsinA mRNA in the substantia nigra pars compacta dopamine neurons, the locus ceruleus, the cerebellar dentate nucleus, Purkinje cells, the basis pontis, numerous thalamic nuclei, the pedunculopontine nucleus, the oculomotor nucleus, the hippocampal formation, and the frontal cortex. Within the caudateputamen, the cellular expression of torsinA mRNA was heterogeneous; a moderate signal was found overlying large cholinergic neurons, and most striatal neurons exhibited only a very weak signal. A moderate signal was detected in numerous midbrain and hindbrain nuclei. A weak cellular signal was detected in neurons of the globus pallidus and subthalamic nucleus. In marked contrast to torsinA, no specific mRNA signal was detected for torsinB. That torsinA mRNA is enriched in several basal ganglia nuclei, including the dopamine neurons in the substantia nigra, is intriguing since it suggests that DYT1 dystonia may be associated with a dysfunction in dopamine transmission.
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PMID:Distribution of the mRNAs encoding torsinA and torsinB in the normal adult human brain. 1055 94

Early-onset, generalized primary torsion dystonia (PTD) is an autosomal dominantly inherited disorder, characterized by involuntary movements and abnormal postures. The majority of cases are caused by a 3-bp deletion in the DYT1 gene on chromosome 9q34 that allows for specific genetic testing. We developed a simple, reliable, and cost-effective, PCR-based screening method for this mutation. Testing results from a cohort of 550 cases, including patients with different forms of dystonia and unclassified movement disorders, revealed that 72.2% of the patients with typical early-onset generalized PTD carried the GAG deletion in the DYT1 gene. Among 300 cases with late-onset focal/segmental dystonia, only 3 patients tested positive for the GAG deletion whereas 12.8% of the patients with an unclassified movement disorder were GAG positive. Our results confirm a genotype/phenotype correlation in early-onset PTD and show that application of strict clinical criteria leads to accurate prediction of carrier status in more than two-thirds of patients with this type of dystonia. Currently, we suggest that testing be recommended in individuals with age of onset of dystonia below 30 years and/or a positive family history of early-onset PTD. Testing is not recommended in patients with onset of symptoms after 30 years or in asymptomatic individuals under the age of 18.
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PMID:Genetic testing for early-onset torsion dystonia (DYT1): introduction of a simple screening method, experiences from testing of a large patient cohort, and ethical aspects. 1062 38

Dystonia is a disease of basal ganglia function, the pathophysiology of which is poorly understood. Primary torsion dystonia is one of the most severe types of inherited dystonia and can be transmitted in an autosomal dominant manner. Recently, one mutation causing this disorder was localized to a gene on chromosome 9q34, designated DYT1, which encodes for a novel protein termed torsinA. The role of this protein in cellular function, in either normal or dystonic individuals is not known. We have developed a polyclonal antibody to torsinA and report its localization and distribution in normal human and rat brain. We demonstrate that torsinA is widely expressed in brain and peripheral tissues. Immunohistochemical studies of normal human and rat brain reveal the presence of torsinA in the dopaminergic neurons of the substantia nigra pars compacta (SNc), in addition to many other regions, including neocortex, hippocampus, and cerebellum. Labeling is restricted to neurons, as shown by double-immunofluorescence microscopy, and is present in both nuclei and cytoplasm. An ATP-binding property for torsinA has been suggested by its homology to ATP-binding proteins; this was confirmed by enrichment of torsinA in ATP-agarose affinity-purified fractions from tissue homogenates. An understanding of the role of torsinA in cellular function and the impact of the mutation (deletion of a glutamic acid at residue 303) is likely to provide insights into the etiopathogenesis of primary dystonia.
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PMID:Immunohistochemical localization and distribution of torsinA in normal human and rat brain. 1064 Jun 17

Most cases of early onset torsion dystonia are caused by a 3-bp deletion (GAG) in the coding region of the TOR1A gene (alias DYT1, DQ2), resulting in loss of a glutamic acid in the carboxy terminal of the encoded protein, torsin A. TOR1A and its homologue TOR1B (alias DQ1) are located adjacent to each other on human chromosome 9q34. Both genes comprise five similar exons; each gene spans a 10-kb region. Mutational analysis of most of the coding region and splice junctions of TOR1A and TOR1B did not reveal additional mutations in typical early onset cases lacking the GAG deletion (N = 17), in dystonic individuals with apparent homozygosity in the 9q34 chromosomal region (N = 5), or in a representative Ashkenazic Jewish individual with late onset dystonia, who shared a common haplotype in the 9q34 region with other late onset individuals in this ethnic group. A database search revealed a family of nine related genes (50-70% similarity) and their orthologues in species including human, mouse, rat, pig, zebrafish, fruitfly, and nematode. At least four of these genes occur in the human genome. Proteins encoded by this gene family share functional domains with the AAA/HSP/Clp-ATPase superfamily of chaperone-like proteins, but appear to represent a distinct evolutionary branch.
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PMID:The TOR1A (DYT1) gene family and its role in early onset torsion dystonia. 1064 35


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