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

X-linked dystonia-parkinsonism (XDP, DYT3), endemic in the Philippine island of Panay, is characterized by the clinical onset with dystonia followed by parkinsonism. We found a 35-year-old American male patient, originally from Panay with typical XDP, has a 2-year history of parkinsonism, dystonia, and tremor. Ancestral DYT3 haplotype and disease-specific SVA (short interspersed nuclear element, variable number of tandem repeats, and Alu composite) retrotransposon insertion were identified in the DYT3 proband and two female unaffected family members. No mutation(s) and expression changes in peripheral blood lymphocytes were observed in the TATA-binding protein-associated factor 1 gene (TAF1) or the chemokine CXC motif receptor 3 gene (CXCR3) of the proband or other DYT3 carriers. These findings indicate blood DNA test has a diagnostic utility and implications for genetic counseling in families with DYT3. In contrast, TAF1 and CXCR3 gene expression in peripheral blood lymphocytes is not a suitable surrogate disease marker for DYT3.
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PMID:Genetic study of an American family with DYT3 dystonia (lubag). 1895 44

Presently, 17 distinct monogenic primary dystonias referred to as dystonias 1- 4, 5a,b, 6-8, 10-13 and 15-18 (loci DYT 1-4, 5a,b, 6-8, 10-13, 15-18) have been recognized. Twelve forms are inherited as autosomal dominant, four as autosomal recessive and one as an X-linked recessive trait. Three additional autosomal dominant forms (DYT9, DYT19 and DYT20) might exist based on linkage mapping to regions apparently different from, yet in close proximity to or overlapping with the known loci DYT18, DYT10 and DYT8. Clinically, this group of movement disorders includes pure dystonias and dystonia plus syndromes. In addition, dyskinesias (paroxysmal dystonias), although phenotypically distinct from classical dystonias, are discussed within this group. In pure dystonias, dystonia is occasionally accompanied by tremor. In dystonia plus syndromes, dystonia as the prominent sign concurs with other movement abnormalities such as myoclonus and parkinsonism. In the dyskinesias, dystonia occurs as a paroxysmal sign in association with other movement anomalies and sometimes seizures. While gross neuropathological changes are absent in most primary dystonias, including the paroxysmal forms, striking morphological alterations are found in some, such as in the X-linked dystonia-parkinsonism syndrome (DYT3). Neuropathological findings at the microscopic level have also been reported in several cases of dystonia 1 and 5, both of which were previously thought to be morphologically normal. One locus, DYT14 had been erroneously assigned, by linkage mapping, in a family with dystonia 5. There are two forms of dystonia 5, one autosomal dominant and one autosomal recessive. These forms are designated here as dystonia 5a and dystonia 5b (DYT5a, DYT5b), respectively. The disease gene has been identified in 10 primary dystonias, seven autosomal dominant (TOR1A/DYT1, GCH1/DYT5a, THAP1/DYT6, PNKD1/MR-1/DYT8, SGCE/DYT11, ATP1A3/DYT12 and SLC2A1/DYT18), two autosomal recessive (TH/DYT5b and PRKRA/DYT16) and one X-chromosomal recessive (TAF1/DYT3). This article summarizes all known aspects on each of the monogenic primary dystonias, including phenotype, neuropathology, imaging, inheritance, mapping, molecular genetics, molecular pathology, animal models and treatment. Suggestions for the diagnostic procedure in primary dystonias are given. Although much is now known about the molecular basis of primary dystonias, treatment of patients is still mainly symptomatic. The only exceptions are dystonias 5a and 5b with their excellent long-term response to L-dopa substitution.
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PMID:The monogenic primary dystonias. 1957 24

THAP1 is a sequence-specific DNA binding factor that regulates cell proliferation through modulation of target genes such as the cell cycle-specific gene RRM1. Mutations in the THAP1 DNA binding domain, an atypical zinc finger (THAP-zf), have recently been found to cause DYT6 dystonia, a neurological disease characterized by twisting movements and abnormal postures. In this study, we report that THAP1 shares sequence characteristics, in vivo expression patterns and protein partners with THAP3, another THAP-zf protein. Proteomic analyses identified HCF-1, a potent transcriptional coactivator and cell cycle regulator, and O-GlcNAc transferase (OGT), the enzyme that catalyzes the addition of O-GlcNAc, as major cellular partners of THAP3. THAP3 interacts with HCF-1 through a consensus HCF-1-binding motif (HBM), a motif that is also present in THAP1. Accordingly, THAP1 was found to bind HCF-1 in vitro and to associate with HCF-1 and OGT in vivo. THAP1 and THAP3 belong to a large family of HCF-1 binding factors since seven other members of the human THAP-zf protein family were identified, which harbor evolutionary conserved HBMs and bind to HCF-1. Chromatin immunoprecipitation (ChIP) assays and RNA interference experiments showed that endogenous THAP1 mediates the recruitment of HCF-1 to the RRM1 promoter during endothelial cell proliferation and that HCF-1 is essential for transcriptional activation of RRM1. Together, our findings suggest HCF-1 is an important cofactor for THAP1. Interestingly, our results also provide an unexpected link between DYT6 and DYT3 (X-linked dystonia-parkinsonism) dystonias because the gene encoding the THAP1/DYT6 protein partner OGT maps within the DYT3 critical region on Xq13.1.
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PMID:The THAP-zinc finger protein THAP1 associates with coactivator HCF-1 and O-GlcNAc transferase: a link between DYT6 and DYT3 dystonias. 2020 Jan 53

The list of genetic causes of syndromes of dystonia parkinsonism grows constantly. As a consequence, the diagnosis becomes more and more challenging for the clinician. Here, we summarize the important causes of dystonia parkinsonism including autosomal-dominant, recessive, and x-linked forms. We cover dopa-responsive dystonia, Wilson's disease, Parkin-, PINK1-, and DJ-1-associated parkinsonism (PARK2, 6, and 7), x-linked dystonia-parkinsonism/Lubag (DYT3), rapid-onset dystonia-parkinsonism (DYT12) and DYT16 dystonia, the syndromes of Neurodegeneration with Brain Iron Accumulation (NBIA) including pantothenate kinase (PANK2)- and PLA2G6 (PARK14)-associated neurodegeneration, neuroferritinopathy, Kufor-Rakeb disease (PARK9) and the recently described SENDA syndrome; FBXO7-associated neurodegeneration (PARK15), autosomal-recessive spastic paraplegia with a thin corpus callosum (SPG11), and dystonia parkinsonism due to mutations in the SLC6A3 gene encoding the dopamine transporter. They have in common that in all these syndromes there may be a combination of dystonic and parkinsonian features, which may be complicated by pyramidal tract involvement. The aim of this review is to familiarize the clinician with the phenotypes of these disorders.
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PMID:Rare causes of dystonia parkinsonism. 2069 31

Sex-linked dystonia parkinsonism (XDP, DYT3, "Lubag") is an adult-onset, progressive, debilitating movement disorder first described in Filipino males from Panay Islands in 1975. XDP manifests predominantly as torsion dystonia, later combined with or sometimes replaced with parkinsonism. Within the Island of Panay, the prevalence rate is highest in the province of Capiz, where 1:4000 men suffer from the disorder. There is a high degree of penetrance and generalization. While women often serve as carriers, XDP is not limited to men. An updated XDP Philippine registry (as of January 2010) has identified 505 cases, with 500 males and 5 females. While some report that females may carry a milder form of the disorder, in our experience, both sexes generally follow a similar progressive clinical course.
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PMID:The unique phenomenology of sex-linked dystonia parkinsonism (XDP, DYT3, "Lubag"). 2104 75

The neuron-specific isoform of the TAF1 gene (N-TAF1) is thought to be involved in the pathogenesis of DYT3 dystonia, which leads to progressive neurodegeneration in the striatum. To determine the expression pattern of N-TAF1 transcripts, we developed a specific monoclonal antibody against the N-TAF1 protein. Here we show that in the rat brain, N-TAF1 protein appears as a nuclear protein within subsets of neurons in multiple brain regions. Of particular interest is that in the striatum, the nuclei possessing N-TAF1 protein are largely within medium spiny neurons, and they are distributed preferentially, though not exclusively, in the striosome compartment. The compartmental preference and cell type-selective distribution of N-TAF1 protein in the striatum are strikingly similar to the patterns of neuronal loss in the striatum of DYT3 patients. Our findings suggest that the distribution of N-TAF1 protein could represent a key molecular characteristic contributing to the pattern of striatal degeneration in DYT3 dystonia.
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PMID:Identification and localization of a neuron-specific isoform of TAF1 in rat brain: implications for neuropathology of DYT3 dystonia. 2161 29

By family-based screening, first Fuchs and then many other authors showed that mutations in THAP1 (THAP [thanatos-associated protein] domain-containing, apoptosis-associated protein 1) account for a substantial proportion of familial, early-onset, nonfocal, primary dystonia cases (DYT6 dystonia). THAP1 is the first transcriptional factor involved in primary dystonia and the hypothesis of a transcriptional deregulation, which was primarily proposed for the X-linked dystonia-parkinsonism (DYT3 dystonia), provided thus a new way to investigate the possible mechanism underlying the development of dystonic movements. Currently, 56 families present with a THAP1 mutation; however, no genotype/phenotype relationship has been found. Therefore, we carried out a systematic review of the literature on the THAP1 gene to colligate all reported patients with a specific THAP1 mutation and the associated clinical signs in order to describe the broad phenotypic continuum of this disorder. To facilitate the comparison of the identified mutations, we created a Locus-Specific Database (UMD-THAP1 LSDB) available at http://www.umd.be/THAP1/. Currently, the database lists 56 probands and 43 relatives with the associated clinical phenotype when available. The identification of a larger number of THAP1 mutations and collection of high-quality clinical information for each described mutation through international collaborative effort will help investigating the structure-function and genotype-phenotype correlations in DYT6 dystonia.
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PMID:DYT6 dystonia: review of the literature and creation of the UMD Locus-Specific Database (LSDB) for mutations in the THAP1 gene. 2179 5

Dystonia consists of involuntary repetitive twisting (torsion) or directional movements, sometimes leading to sustained postures. The movements are stereotyped and characterized by co-contraction of agonist and antagonist muscles. There is a broad clinical spectrum of dystonia which derives in part from the differential distribution of involvement. Dystonia may be localized, affecting a single body region, or generalized, affecting multiple extremities along with the trunk. Intermediate dystonic involvement can be described as segmental, designating two affected contiguous body regions, or multifocal, designating two or more noncontiguous affected body regions. Hemidystonia refers to dystonia affecting only one side of the body. Dystonia can also be categorized by age of onset and etiology. Early onset dystonia, occurring in childhood or adolescence (in some studies younger than 26 years old), is associated with more progressive disease [Greene et al. (1995). Mov. Disord. 10, 143]. In this age group, dystonia usually first appears in a limb and then spreads to involve other limbs and axial muscles; some early-onset patients may have involvement of laryngeal and other cranial muscles. Adult or late-onset dystonia typically begins in the neck, arm, or cranial muscles. Compared to early-onset dystonia, the area of involvement is more likely to remain focal or segmental. Dystonia can be considered either primary or nonprimary. Primary torsion dystonia (PTD), historically called dystonia musculorum deformans and Oppenheim's dystonia, describes dystonia in isolation, excepting tremor, without brain degeneration and without an identified acquired cause. Nonprimary or secondary dystonia encompasses a heterogeneous group of syndromes and etiologies including inherited (with or without brain degeneration), acquired, and complex neurological disorders. Monogenic forms of dystonia are labeled DYT and enumerated in the order in which they were discovered. The current 20 DYT loci comprise a heterogeneous group of disorders. (Table I) They can be divided into PTDs, dystonia-plus syndromes without brain degeneration, dystonia-parkinsonism with brain degeneration (i.e. DYT3), and paroxysmal dyskinesias. There are many neurodegenerative genetic disorders that share dystonia as a common feature of disease (Table II). This chapter will review the genetics of PTD, dystonia-plus syndromes without brain degeneration, and X-linked dystonia-parkinsonism. Other genetic dystonia-parkinsonism syndromes and the paroxysmal dyskinesias will not be discussed.
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PMID:Genetics and pharmacological treatment of dystonia. 2190 99

Dystonia is characterized by muscle contractions leading to abnormal postures with involuntary twisting and repetitive movements. Inherited dystonia designated by DYT locus symbols can be separated into three broad phenotypic categories: primary torsion dystonia (PTD), where dystonia is the only clinical sign (except for tremor) (DYT1, 2, 4, 6, 7, 13, 17, and 21); dystonia plus loci, where other phenotypes in addition to dystonia, including parkinsonism or myoclonus, are present (DYT3, 5/14, 11, 12, 15, and 16); and paroxysmal forms of dystonia/dyskinesia (DYT8, 9, 10, 18, 19, and 20). Currently, 19 loci including 10 genes have been identified for inherited dystonias. In this review, the phenotypes associated with these loci and the responsible genes will be discussed.
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PMID:Genetics of dystonia. 2226 82

X-chromosomal dystonia parkinsonism syndrome (XDP, 'lubag') is associated with sequence changes within the TAF1/DYT3 multiple transcript system. Although most sequence changes are intronic, one, disease-specific single-nucleotide change 3 (DSC3), is located within an exon (d4). Transcribed exon d4 occurs as part of multiple splice variants. These variants include exons d3 and d4 spliced to exons of TAF1, and an independent transcript composed of exons d2-d4. Location of DSC3 in exon d4 and utilization of this exon in multiple splice variants suggest an important role of DSC3 in the XDP pathogenesis. To test this hypothesis, we transfected neuroblastoma cells with four expression constructs, including exons d2-d4 [d2-d4/wild-type (wt) and d2-d4/DSC3] and d3-d4 (d3-d4/wt and d3-d4/DSC3). Expression profiling revealed a dramatic effect of DSC3 on overall gene expression. Three hundred and sixty-two genes differed between cells containing d2-d4/wt and d2-d4/DSC3. Annotation clustering revealed enrichment of genes related to vesicular transport, dopamine metabolism, synapse function, Ca(2+) metabolism and oxidative stress. Two hundred and eleven genes were differentially expressed in d3-d4/wt versus d3-d4/DSC3. Annotation clustering highlighted genes in signal transduction and cell-cell interaction. The data show an important role of physiologically occurring transcript d2-d4 in normal brain function. Interference with this role by DSC3 is a likely pathological mechanism in XDP. Disturbance of dopamine function and of Ca(2+) metabolism can explain abnormal movement; loss of protection against reactive oxygen species may account for the neurodegenerative changes in XDP. Although d3-d4 also affect genes potentially related to neurodegenerative processes, their physiologic role as splice variants of TAF1 awaits further exploration.
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PMID:X-linked dystonia parkinsonism syndrome (XDP, lubag): disease-specific sequence change DSC3 in TAF1/DYT3 affects genes in vesicular transport and dopamine metabolism. 2318 49


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