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)

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

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

The natural history of sex-linked dystonia parkinsonism (XDP) has been well documented. However, its nonmotor features have not yet been fully described. We reviewed the available literature on the nonmotor features in XDP. We found five articles involving 79 XDP patients, three of which were on cognition and two on mood (anxiety and depression). There were two case reports showing executive dysfunction. The other paper showed impairments in abstract thinking and motor programming. Two articles were on mood (anxiety and depression). The prevalence of anxiety symptoms was 16.7% and 54.8-92.9% had depressive symptoms. The identification of these nonmotor features should lead to early and appropriate management.
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PMID:Nonmotor features in sex-linked dystonia parkinsonism. 2509 22

X-linked recessive dystonia-parkinsonism is a rare movement disorder that is highly prevalent in Panay Island in the Philippines. Earlier studies identified seven different genetic alterations within a 427-kb disease locus on the X chromosome; however, the exact disease-causing variant among these is still not unequivocally determined. To further investigate the genetic cause of this disease, we sequenced all previously reported genetic alterations in 166 patients and 473 Filipino controls. Singly occurring variants in our ethnically matched controls would have allowed us to define these as polymorphisms, but none were found. Instead, we identified five patients carrying none of the disease-associated variants, and one male control carrying all of them. In parallel, we searched for novel single-nucleotide variants using next-generation sequencing. We did not identify any shared variants in coding regions of the X chromosome. However, by validating intergenic variants discovered via genome sequencing, we were able to define the boundaries of the disease-specific haplotype and narrow the disease locus to a 294-kb region that includes four known genes. Using microarray-based analyses, we ruled out the presence of disease-linked copy number variants within the implicated region. Finally, we utilized in silico analysis and detected no strong evidence of regulatory regions surrounding the disease-associated variants. In conclusion, our finding of disease-specific variants occurring in complete linkage disequilibrium raises new insights and intriguing questions about the origin of the disease haplotype, the existence of phenocopies and of reduced penetrance, and the causative genetic alteration in XDP.
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PMID:New insights into the genetics of X-linked dystonia-parkinsonism (XDP, DYT3). 2560 58

X-linked dystonia-parkinsonism (XDP; OMIM314250), also referred to as DYT3 dystonia or "Lubag" disease, was first described as an endemic disease in the Philippine island of Panay. XDP is an adult-onset movement disorder characterized by progressive and severe dystonia followed by overt parkinsonism in the later years of life. Among the primary monogenic dystonias, XDP has been identified as a transcriptional dysregulation syndrome with impaired expression of the TAF1 (TATA box-binding protein associated factor 1) gene, which is a critical component of the cellular transcription machinery. The major neuropathology of XDP is progressive neuronal loss in the neostriatum (i.e., the caudate nucleus and putamen). XDP may be used as a human disease model to elucidate the pathomechanisms by which striatal neurodegeneration leads to dystonia symptoms. In this article, we introduce recent advances in the understanding of the interplay between pathophysiology and genetics in XDP.
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PMID:Clinicopathological Phenotype and Genetics of X-Linked Dystonia-Parkinsonism (XDP; DYT3; Lubag). 2867 41

The genetic combined dystonias are a clinically and genetically heterogeneous group of neurologic disorders defined by the overlap of dystonia and other movement disorders such as parkinsonism or myoclonus. The number of genes associated with combined dystonia syndromes has been increasing due to the wider recognition of clinical features and broader use of genetic testing. Nevertheless, these diseases are still rare and represent only a small subgroup among all dystonias. Dopa-responsive dystonia (DYT/PARK-GCH1), rapid-onset dystonia-parkinsonism (DYT/PARK-ATP1A3), X-linked dystonia-parkinsonism (XDP, DYT/PARK-TAF1), and young-onset dystonia-parkinsonism (DYT/PARK-PRKRA) are monogenic combined dystonias accompanied by parkinsonian features. Meanwhile, MYC/DYT-SGCE and MYC/DYT-KCTD17 are characterized by dystonia in combination with myoclonus. In the past, common molecular pathways between these syndromes were the center of interest. Although the encoded proteins rather affect diverse cellular functions, recent neurophysiological evidence suggests similarities in the underlying mechanism in a subset. This review summarizes recent developments in the combined dystonias, focusing on clinico-genetic features and neurophysiologic findings. Disease-modifying therapies remain unavailable to date; an overview of symptomatic therapies for these disorders is also presented.
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PMID:Combined dystonias: clinical and genetic updates. 3309 85


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