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 dystonin/Bpag1 gene encodes several tissue-specific alternatively spliced transcripts that encode cytoskeletal binding proteins. These various isoforms are necessary for maintaining the structural integrity of epithelial, neural, and muscle tissues. Mutations in the dystonin/Bpag1 gene cause dystonia musculorum (dt), a hereditary neuropathy of the mouse characterized by the progressive degeneration of sensory neurons. Several dt mutant alleles exist, most of which have arisen through spontaneous mutations. In this article we demonstrate that the dt locus encodes 107 exons spanning 400 kb. The high frequency of occurrence of spontaneous dt mutants may therefore be a result of the large size of the gene. Analysis of genomic DNA from several dt spontaneous mutant alleles, dt(24J), dt(27J), dt(Alb), and dt(Frk), shows a deletion of the central portion of the gene in dt(Alb) but no large rearrangements or deletions in the other alleles. These other alleles likely have small deletions or rearrangements, or point mutations. To determine the impact of the known and unknown mutations on transcript levels, RT-PCR was performed to detect various coding regions of the dystonin/Bpag1 transcripts in brain and muscle from multiple dt alleles: dt(Tg4), dt(Alb), dt(24J), dt(27J), and dt(Frk). With the exception of dt(Frk), reduced transcript levels were observed for all alleles tested. Such alterations likely result in reduced or absent dystonin/Bpag1 protein levels. Thus, distinct genetic defects lead to a common outcome of reduced transcript expression causing the same phenotype in multiple dt alleles.
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PMID:Genetic alterations at the Bpag1 locus in dt mice and their impact on transcript expression. 1634 70

We investigated a Japanese family with generalized dystonia attributed to striatal degeneration, which occurred in childhood, and late-onset optic neuropathy. We determined the entire nucleotide sequence of mitochondrial DNA (mtDNA) from the proband and compared our findings with the 2001 Revised Cambridge Reference Sequence. The mtDNA of the proband showed a total of 42 nucleotide changes. We identified two A3203G and G14459A mutations, which were completely absent in a population of 200 healthy Japanese, by estimating the frequency of each nucleotide change. The nucleotide G14459A mutation occurs in NADH dehydrogenase subunit 6, and has been suggested previously as the disease-causing mutation in Hispanic, African-American and Caucasian families of Leber's hereditary optic neuropathy (LHON) and/or dystonia. The significance of the A3203G mutation remains unknown. To our knowledge, this is the first case of LHON with dystonia that revealed a mtDNA mutation in a Japanese family.
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PMID:Leber's hereditary optic neuropathy with dystonia in a Japanese family. 1638 Jan 32

Dystonia represents a genetically and clinically heterogeneous disorder, characterized by abnormal and sustained muscle contractions and rigid postures. At least 15 different loci (DYT1-DYT15) have been identified in dystonia. Adult-onset idiopathic focal dystonia affecting specific parts of the body, such as the eye (blepharospasm), neck (cervical dystonia), and hand (writer's cramp), is mostly associated with the DYT7 locus, which was originally mapped to chromosome 18p by genomewide linkage analysis in a large family showing autosomal dominant inheritance. We have identified a family in which the mother is affected with dystonia and the son shows signs of dystonia. Using fluorescent BAC probes spanning 18p, we were able to identify a deletion in these two individuals, spanning the entire short arm of 18p. This deletion is accompanied by a centric fusion involving chromosome 14. The 18p deleted region spans 15 megabases of DNA, with a number of interesting DYT7 candidate genes, including genes involved in G-protein-coupled signaling (GNAL), cell death (CIDEA), muscle development (MYOM1 and MRLM), mitochondrial activity (NDUFV2), and neuronal function (ADYCAP1, TGIF, DAP-1, and AFG3L2).
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PMID:Unbalanced whole arm translocation resulting in loss of 18p in dystonia. 1654 53

Dopa-responsive dystonia (DRD) is a clinical syndrome characterized by childhood-onset dystonia and a dramatic and sustained response to low doses of levodopa. There are at least three causative genes for DRD: (1) the GCH1 gene on chromosome 14q22.1-q22.2, which encodes GTP cyclohydrolase I (GTPCH), the first enzyme in the biosynthetic pathway for tetrahydrobiopterin (BH4; the essential cofactor for tyrosine hydroxylase [THI]), (2) the TH gene on 11 p15.5, coding for the enzyme TH that catalyzes the rate-limiting step in the catecholamine biosynthesis, and (3) an as yet undefined gene on 14q13 (DYT14). In reports on DRD, in which conventional genomic DNA sequencing of GCH1 was conducted in a relatively large number of pedigrees, mutations in the coding region (including the splice sites) of this gene were found in approximately 60% (range: 49-79%) of DRD families. In our series, after conducting additional GCH1 testing (Southern blotting, cDNA sequencing, etc.) and TH analysis, 86% of families with DRD or dystonia with motor delay (an intermediate phenotype between GTPCH-deficient DRD [mild] and GTPCH-deficient hyperphenylalaninemia [severe]) had identifiable GCH1 or (rarely) TH mutations. Up to the present, only one pedigree with autosomal dominant DRD linked to the DYT14 locus has been reported. Neuropathological findings (no Lewy bodies and a normal population of cells with reduced melanin in the substantia nigra) in DRD patients with GTPCH dysfunction were similar to those in a patient with DYT14 dystonia. There have been no reports of autopsied patients with TH-deficient DRD. Neurochemical data suggest that striatal dopamine reduction in GTPCH-deficient DRD is caused not only by decreased TH activity resulting from a low cofactor (BH4) level but also by actual loss of TH protein without nerve terminal loss. This TH protein reduction in the striatum, especially in the putamen, may be due to a diminished regulatory effect of BH4 on stability (rather than expression) of TH molecules or to a dysfunction of TH protein transport from the substantia nigra to the striatum. The extent of striatal TH protein loss may be critical in determining DRD symptomatology and could contribute to gender-related incomplete penetrance of GCH1 mutations in GTPCH-deficient DRD families. Notwithstanding the discovery of the three causative loci for DRD, a therapeutic trial with low doses of levodopa is still the most practical approach to the diagnosis of this treatable disorder. The trial should be considered in all children with dystonic and/or parkinsonian symptoms or with unexplained gait disorders. Analyses of total biopterin and neopterin as well as neurotransmitter metabolites in CSF appear to be useful for the diagnosis of GTPCH-deficient DRD (the major form of DRD) and of TH-deficient DRD (the mild form of TH deficiency). Findings of the precise mechanism of striatal TH protein loss in GTPCH-deficient DRD, the actual status of dopaminergic systems in TH-deficient DRD, and the novel causative gene on the DYT14 locus will better define the pathogenesis of DRD.
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PMID:[Dopa-responsive dystonia: clinical, genetic, and biochemical studies]. 1654 91

Defects in NADH:ubiquinone oxidoreductase (complex I), the largest complex of the mitochondrial respiratory chain, account for most cases of respiratory chain deficiency in human. Complex I contains at least 45 subunits, 7 of which are encoded by mitochondrial DNA (mtDNA). Here we report a novel 10197G>A mutation of the ND3 gene in three unrelated families with Leigh syndrome (LS) or dystonia. Variable degrees of heteroplasmy were found in all tissues tested and a high percentage of mutant mtDNA was observed in muscle. The 10197G>A mutation modifies a hydrophobic alanine residue into a hydrophilic threonine (A47T) in a highly conserved domain of ND3 subunit. Furthermore, this defect could be transferred along with the mutant mtDNAs to rho degrees lymphoblastoid cells in cybrid experiments. However, nuclear modifier genes may also play a role in the phenotypic expression and severity of the 10197G>A mutation. The association of the 10197G>A ND3 mutation with an isolated biochemical defect involving complex I and the discovery of the 10197G>A mutation with a similar phenotype in three unrelated families establish its pathogenicity and demonstrate that the amino acid position A47 is important for the function of complex I. These results show that the 10197G>A mutation in the mitochondrial ND3 gene should be considered as a common mtDNA mutation responsible for LS and dystonia.
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PMID:A novel recurrent mitochondrial DNA mutation in ND3 gene is associated with isolated complex I deficiency causing Leigh syndrome and dystonia. 1715 68

X-linked dystonia-parkinsonism (XDP) is a movement disorder endemic to the Philippines. The disease locus, DYT3, has been mapped to Xq13.1. In a search for the causative gene, we performed genomic sequencing analysis, followed by expression analysis of XDP brain tissues. We found a disease-specific SVA (short interspersed nuclear element, variable number of tandem repeats, and Alu composite) retrotransposon insertion in an intron of the TATA-binding protein-associated factor 1 gene (TAF1), which encodes the largest component of the TFIID complex, and significantly decreased expression levels of TAF1 and the dopamine receptor D2 gene (DRD2) in the caudate nucleus. We also identified an abnormal pattern of DNA methylation in the retrotransposon in the genome from the patient's caudate, which could account for decreased expression of TAF1. Our findings suggest that the reduced neuron-specific expression of the TAF1 gene is associated with XDP.
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PMID:Reduced neuron-specific expression of the TAF1 gene is associated with X-linked dystonia-parkinsonism. 1766 93

One pedigree with four patients has been recently described with mitochondrial DNA depletion and mutation in SUCLA2 gene leading to succinyl-CoA synthase deficiency. Patients had a Leigh-like encephalomyopathy and deafness but besides the presence of lactic acidosis, the profile of urine organic acid was not reported. We have studied 14 patients with mild 'unlabelled' methylmalonic aciduria (MMA) from 11 families. Eight of the families are from the Faroe Islands, having a common ancestor, and three are from southern Italy. Since the reaction catalysed by succinyl-CoA synthase in the tricarboxylic acid (TCA) cycle represents a distal step of the methylmalonic acid pathway, we investigated the SUCLA2 gene as a candidate gene in our patients. Genetic analysis of the gene in the 14 patients confirmed the defect in all patients and led to the identification of three novel mutations (p.Gly118Arg; p.Arg284Cys; c.534 + 1G --> A). The defect could be convincingly shown at the protein level and our data also confirm the previously described mitochondrial DNA depletion. Defects in SUCLA2 can be found at the metabolite level and are defined by mildly elevated methylmalonic acid and C4-dicarboxylic carnitine concentrations in body fluids in association with variable lactic acidosis. Clinically the diagnosis should be considered in patients with early/neonatal onset encephalomyopathy, dystonia, deafness and Leigh-like MRI abnormalities mainly affecting the putamen and the caudate nuclei. The frequency of the mutated allele in the Faroese population amounted to 2%, corresponding with an estimated homozygote frequency of 1 : 2500. Our data extend knowledge on the genetic defects causing MMA. Our patients present with an early infantile Leigh-like encephalomyopathy with deafness, and later on a progressive dystonia. Mild MMA, lactic acidosis and specific abnormalities in the carnitine ester profile are the biochemical hallmarks of the disease. In view of the frequency of the mutated allele on the Faroe Islands, measures become feasible to prevent the occurrence of the disease on the islands. We confirm and extend the findings on this inborn error of metabolism in the TCA cycle that must be carefully investigated by accurate metabolite analyses.
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PMID:SUCLA2 mutations are associated with mild methylmalonic aciduria, Leigh-like encephalomyopathy, dystonia and deafness. 1730 Oct 81

Mitochondrial disorders have notoriously variable clinical presentations, particularly in children. A growing number of reports describe mutations in the mitochondrial DNA (mtDNA)-encoded subunits of complex I (EC 1.6.5.3) causing early-onset encephalopathy. Here, we describe two Korean siblings with childhood-onset progressive generalized dystonia and one Korean child with strokelike episodes in infancy; all three had bilateral lesions of the basal ganglia and partial deficiencies of complex I. Analysis of their mtDNA revealed a novel heteroplasmic m.10197G>A mutation (A47T) in the ND3 (NADH dehydrogenase subunit 3) gene. This study underscores the importance of screening mtDNA-encoded respiratory chain structural genes, including ND3, in pediatric patients with unexplained encephalopathies.
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PMID:A novel ND3 mitochondrial DNA mutation in three Korean children with basal ganglia lesions and complex I deficiency. 1741 73

Haloperidol is a widely used neuroleptic drug for the treatment of acute and chronic psychosis. The use of haloperidol is limited by extrapyramidal movement disorders such as Parkinsonism, akathesia, dystonia, and tardive dyskinesia (TD). Treatment with haloperidol increases oxyradicals which are implicated in TD. Spirulina is widely used as nutritional supplement rich in proteins and antioxidants. The present study is proposed to study the effect of spirulina on haloperidol induced TD and oxidative stress by studying TD, various enzymatic and nonenzymatic antioxidants and lipid peroxidation. Haloperidol 1 mg/kg/i.p was used to induce vacuous chewing movements in rats. Spirulina maxima suspended in 1% between 80 at a dose of 45, 90 and 180 mg/kg were administered by gavage along with haloperidol from 21st day to 49th day of treatment. Spirulina supplementation at a dose of 180 mg/kg significantly improved enzymatic and nonenzymatic antioxidants and decreased the tardive dyskinesia induced by haloperidol. In conclusion, the results of present investigation suggest that spirulina decreases haloperidol induced oxidative stress and TD by many mechanisms as it is cocktail of antioxidants. On chronic use it may inhibit haloperidol induced reduced expression of DNA thereby increases the expression of enzymatic and nonenzymatic antioxidants and protects against oxidative stress induced neurodegeneration and TD.
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PMID:Effect of spirulina maxima on the haloperidol induced tardive dyskinesia and oxidative stress in rats. 1753 Jan 60

Because of the occurrence of different types of mutations, comprehensive genetic testing for Parkinson's disease (PD), dopa-responsive dystonia (DRD), and myoclonus-dystonia (M-D) should include screening for small sequence changes and for large exonic rearrangements in disease-associated genes. In diagnostic and research settings, the latter is frequently omitted or performed by laborious and expensive quantitative real-time PCR (qPCR). Our study aimed to evaluate the utility of a novel method, multiplex ligation-dependent probe amplification (MLPA), in molecular diagnostics of movement disorders. We have analyzed, by MLPA, genomic DNA from 21 patients affected with PD, DRD, or M-D, in which the presence of exon rearrangement(s) (n = 20) or of a specific point mutation (detectable by MLPA, n = 1) had been established previously by qPCR or sequencing. In parallel, we have studied, in a blinded fashion, DNA from 49 patients with an unknown mutational status. Exon rearrangements were evident in 20 samples with previously established mutations; in the 21st sample the known specific point mutation was detected. We conclude that MLPA represents a reliable method for large-scale and cost-effective gene dosage screening of various movement disorders genes. This finding reaches far beyond a simple technical advancement and has two major implications: (1) By improving the availability of comprehensive genetic testing, it supports clinicians in the establishment of a genetically defined diagnosis; (2) By enabling gene dosage testing of several genes simultaneously, it significantly facilitates the mutational analysis of large patient and control populations and thereby constitutes the prerequisite for meaningful phenotype-genotype correlations.
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PMID:Rapid and reliable detection of exon rearrangements in various movement disorders genes by multiplex ligation-dependent probe amplification. 1767 14


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