Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0013421 (dystonia)
 8,418 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Complex I deficiency, either specific or associated with other respiratory chain defects, has been identified in myopathies, encephalomyopathies and in three 'neurodegenerative' disorders: Parkinson's disease, dystonia and Leber's hereditary optic neuropathy. The complex I defect is expressed in blood in all these three but, to date, only in LHON have specific mitochondrial DNA mutations been identified. Recent work with rho degrees cybrids indicates that, in a subgroup of patients at least, the complex I deficiency is determined by mtDNA, in contrast to dystonia where a nuclear gene defect or toxic influence appears a more likely cause. The actions of specific toxins, e.g., MPTP continue to play an important role in our understanding of pathogenesis of neurodegeneration, particularly in PD.
 ...
PMID:Human complex I defects in neurodegenerative diseases. 959 27

The cause and pathophysiology of dystonia remain unknown. The recent identification of mitochondrial complex I deficiency in platelets from patients with sporadic focal dystonia suggests that a defect of energy metabolism may be relevant in a proportion of patients. We have addressed the possible contribution of mitochondrial DNA (mtDNA) to the complex I deficiency in dystonia by the use of genome transfer technology. Platelets from patients deficient for complex I were fused with A549 p0 (mtDNA-less) cells to form cybrids comprising the A549 nucleus and dystonia mtDNA. Mixed cybrid cell lines were analyzed for 9 controls and 9 dystonia patients, and clonal cybrid lines were generated for 2 control and 2 dystonia patients. Subsequent biochemical analysis showed that the dystonia complex I defect was complemented in both the mixed and the clonal cybrid lines. These results contrast with similar studies in mitochondrial myopathy and Parkinson's disease patients, in which the mitochondrial defect was maintained in at least a proportion of A549 cybrids, and suggest that the complex I defect in dystonia is not caused by an mtDNA mutation.
 ...
PMID:Mitochondrial DNA in focal dystonia: a cybrid analysis. 970 50

Mitochondria play a critical role in cellular energy metabolism. The identification of a respiratory chain defect in Parkinson's disease (PD) provides not only a direct link with toxin models of parkinsonism but also insight into the mechanisms involved in etiology and pathogenesis. The presence of the complex I deficiency in PD substantia nigra and platelets suggests the involvement of a systemic cause. Genomic transplantation studies have been undertaken that involve the transfer to a novel nuclear background of mitochondrial DNA (mtDNA) from PD patients with a complex I defect, followed by both mixed and clonal expansion of the resulting cybrids. The mixed cybrids with the PD mtDNA expressed the complex I defect present in the original PD donor platelets. Clonal expansion of one such mixed cybrid culture produced a spectrum of clones with complex I and complex IV activities, ranging from severe deficiency to normal range, a pattern typical of a heteroplasmic mtDNA mutation. Histochemical, immunohistochemical, and functional assessments of delta psi(m) all showed a pattern in the PD clones typical of that produced by a mtDNA mutation. Patients with focal dystonia and a platelet complex I defect were used as disease controls for the cybrid studies. The mitochondrial abnormality was eradicated by transfer of dystonia mtDNA to a control nuclear background in both mixed and clonal cybrids, with no evidence of clonal heterogeneity. These results help to validate our findings in the PD patients and suggest that the complex I deficiency in dystonia is not due to an abnormality of mtDNA. We hypothesize that the mtDNA defect alone may be the cause of PD in a proportion of patients and may contribute to pathogenesis in others. Identification of the mtDNA genotype responsible for PD may allow the testing of neuroprotective strategies in appropriate patients.
 ...
PMID:Mitochondria in the etiology and pathogenesis of Parkinson's disease. 974 79

Leigh syndrome is a form of neurodegenerative disease which is associated with intracranial infarcts. The diagnosis is made by finding hyperlactacidaemia together with cerebral infarcts on neuroimaging. We report a 4-year-old Chinese girl with Leigh syndrome who had several atypical features. She presented with generalized dystonia and developmental regression. In addition, she suffered from an unusual feature of bladder dystonia. This patient appeared to be suffering from respiratory chain complex I deficiency from studies on cultured skin fibroblasts. Assays for respiratory chain enzymes as well as mitochondrial DNA point mutations and major deletions in muscle were normal. Dystonia persisted despite treatments with muscle relaxants and a ketogenic diet. Intramuscular botulinum toxin resulted in significant relief of dystonia.
 ...
PMID:A Chinese girl with Leigh syndrome: effect of botulinum toxin on dystonia. 976 17

We report the effect on complex I function of the 14484 Leber's hereditary optic neuropathy (LHON) mutation affecting the ND6 subunit gene. The same gene was also reported to carry another mutation, at position 14459, associated with the LHON/dystonia phenotype that induces a reduction of complex I-specific activity and increases the sensitivity to the product decylubiquinol. Given the proximity of both mutations in the ND6 gene, we tested the specific activity of complex I and its sensitivity to myxothiazol and nonylbenzoquinol, both inhibitors at the ubiquinol product site, in platelet submitochondrial particles from nine 14484 homoplasmic individuals, 8 Italians with Caucasian mtDNA haplogroup J (adjunctive 4216 and 13708 mutations), and 1 Tunisian with an African mtDNA haplogroup. The specific activity of complex I was not affected by the 14484 mutation, but the sensitivity to both inhibitors was significantly increased compared with control subjects regardless of the presence of haplogroup J polymorphisms. Analysis of 70 different amino acid sequences of the ND6 subunit indicated that the 14484 mutation affects an amino acid belonging to its most conserved region, which shows local similarities with cytochrome b regions interacting with ubiquinone or ubiquinol in complex III. Our results suggest that both 14484 and 14459 mutations may affect amino acids forming the interaction site of ubiquinol product, and the 14484 mutation produces a biochemical defect resembling in part that already reported for the common 11778/ND4 LHON mutation.
 ...
PMID:Biochemical features of mtDNA 14484 (ND6/M64V) point mutation associated with Leber's hereditary optic neuropathy. 1007 46

Leigh disease can be caused by defects of both nuclear and mitochondrially encoded genes. One mitochondrial DNA mutation, G14459A, has been associated with both respiratory chain complex I deficiency and Leber's hereditary optic neuropathy, with or without dystonia. Here, we report the occurrence of this mutation in 3 complex I-deficient patients from 2 separate pedigrees who presented with Leigh disease, with no evidence or family history of Leber's hereditary optic neuropathy or dystonia.
 ...
PMID:Leigh disease caused by the mitochondrial DNA G14459A mutation in unrelated families. 1089 22

Cardiomyopathy and neuromuscular abnormalities may simultaneously coexist and present with defects in mitochondrial DNA and bioenergetic function. We sought to evaluate the relationship between clinical and mitochondrial phenotypes in 28 young patients with both cardiomyopathy and neurologic disorders including seizures, dystonia, ophthalmoplegia, Kearns-Sayre syndrome, Leigh disease, and Friedreich's ataxia. All tissues examined displayed marked defects in respiratory complex activities. Five patients had abundant large-scale mitochondrial DNA deletions and one patient displayed a pathogenic point mutation previously reported with mitochondrial cytopathy. In this cohort, patients with hypertrophic cardiomyopathy displayed a higher incidence of complex I defects, fewer DNA deletions and mitochondrial structural abnormalities and were less often associated with developmental delay phenotype compared with patients with dilated cardiomyopathy. Although structural abnormalities are present in a subset of patients, evaluation of respiratory enzyme activity appears to be most informative whether tissues examined were derived from heart or skeletal muscle. Defects in mitochondrial DNA and bioenergetics are frequently present in children with cardiomyopathy presenting with a variety of neurologic abnormalities and are amenable to biochemical and molecular analysis.
 ...
PMID:Cardiomyopathy associated with neurologic disorders and mitochondrial phenotype. 1254 31

Mitochondrial DNA (mtDNA) mutations can cause rare forms of dystonia, but the role of mtDNA mutations in other types of dystonia is not well understood. We now report identification by sequencing, restriction endonuclease analyses, and clonal analyses of a heteroplasmic missense A to G base pair substitution at nucleotide position 3796 (A3796G) in the gene encoding the ND1 subunit of mitochondrial complex I in a patient with adult-onset dystonia, spasticity, and core-type myopathy. The mutation converts a highly conserved threonine to an alanine. The same mutation subsequently was identified in 2 of 74 additional unrelated adult-onset dystonia patients. A muscle biopsy was obtained from 1 of these 2 subjects and this revealed abnormalities of electron transport chain (ETC) activities. The mutation was absent in 64 subjects with early onset dystonia, 82 normal controls, and 65 subjects with Parkinson's disease or multiple system atrophy. The A3796G mutation previously has been reported in 3 of 226 subjects from mitochondrial haplogroup H. Each of the 3 subjects in our study harboring the A3796G mutation was also from haplogroup H. However, a subgroup analysis of haplogroup H subjects from our study indicates that the A3796G mutation is significantly overrepresented among haplogroup H adult-onset dystonia subjects compared with haplogroup H controls (P<0.01). This difference remains significant even after excluding the index patient (P=0.04). These data suggest that, among haplogroup H subjects, the presence of the A3796G mutation increases the risk of developing adult-onset dystonia.
 ...
PMID:A heteroplasmic mitochondrial complex I gene mutation in adult-onset dystonia. 1275 9

We report the molecular findings in two independent patients presenting with progressive generalized dystonia and bilateral striatal necrosis in whom we have identified a mutation (T14487C) in the mitochondrial ND6 gene. The mutation is heteroplasmic in all samples analyzed, and it fulfills all accepted criteria of pathogenicity. Transmitochondrial cell lines harboring 100% mutant mitochondrial DNA showed a marked decrease in the activity of complex I of the respiratory chain supporting the pathogenic role of T14487C.
 ...
PMID:Bilateral striatal necrosis associated with a novel mutation in the mitochondrial ND6 gene. 1452 Jun 68

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.
 ...
PMID:A novel recurrent mitochondrial DNA mutation in ND3 gene is associated with isolated complex I deficiency causing Leigh syndrome and dystonia. 1715 68


<< Previous 1 2 3 4 Next >>