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)

A heteroplasmic G-to-A transition at nucleotide pair (np) 14459 within the mitochondrial DNA (mtDNA)-encoded NADH dehydrogenase subunit 6 (ND6) gene has been identified as the cause of Leber hereditary optic neuropathy (LHON) and/or pediatric-onset dystonia in three unrelated families. This ND6 np 14459 mutation changes a moderately conserved alanine to a valine at amino acid position 72 of the ND6 protein. Enzymologic analysis of mitochondrial NADH dehydrogenase (complex I) with submitochondrial particles isolated from Epstein-Barr virus-transformed lymphoblasts revealed a 60% reduction (P < 0.005) of complex I-specific activity in patient cell lines compared with controls, with no differences in enzymatic activity for complexes II plus III, III and IV. This biochemical defect was assigned to the ND6 np 14459 mutation by using transmitochondrial cybrids in which patient Epstein-Barr virus-transformed lymphoblast cell lines were enucleated and the cytoplasts were fused to a mtDNA-deficient (p 0) lymphoblastoid recipient cell line. Cybrids harboring the np 14459 mutation exhibited a 39% reduction (p < 0.02) in complex I-specific activity relative to wild-type cybrid lines but normal activity for the other complexes. Kinetic analysis of the np 14459 mutant complex I revealed that the Vmax of the enzyme was reduced while the Km remained the same as that of wild type. Furthermore, specific activity was inhibited by increasing concentrations of the reduced coenzyme Q analog decylubiquinol. These observations suggest that the np 14459 mutation may alter the coenzyme Q-binding site of complex I.
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PMID:Use of transmitochondrial cybrids to assign a complex I defect to the mitochondrial DNA-encoded NADH dehydrogenase subunit 6 gene mutation at nucleotide pair 14459 that causes Leber hereditary optic neuropathy and dystonia. 862 78

Molecular genetics is currently the most powerful tool for studying hereditary diseases of the central nervous system: Huntington's disease, dopa-nonresponsive dystonia, Friedreich's disease, etc. The review presents the most important results obtained in this field by the Department of Neurogenetics, Institute of Neurology, in collaboration with several Russian and foreign research institutes. The authors were the first to perform a molecular analysis of mutations and haplotypes in Huntington's disease, dopa-nonresponsive dystonia, Wilson's disease and studied the frequencies of various mutations and main genotype-phenotype correlations in the Russian population. The first direct diagnosis of Huntington's disease in Russia, as well as indirect diagnosis of Friedreich's disease, dopa-nonresponsive dystonia and Wilson's disease have been made. The authors began to investigate trinucleotide repeat expansion in dominant spinocerebellar ataxias and related disorders. The Department of Neurogenetics collected a valuable bank of DNA samples, which is sufficient to perform linkage analysis in essential tremor, novel forms of congenital cerebellar atrophy and progressive muscular atrophy.
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PMID:[Molecular genetic analysis--a new stage in the study of hereditary diseases of the central nervous system]. 875 71

A neurogenetic disorder is defined as a clinical disease caused by a defect in one or more genes which affect the differentiation and function of the neuroectoderm and its derivatives. Genetic findings in various neurogenetic disorders are discussed. Huntington disease, spinobulbar muscular atrophy, and the autosomal dominant cerebellar ataxias are examples of autosomal dominant disorders caused by the expansion of trinucleotides (CAG) within disease genes. The CAG expansions appear to result in a gain of gene function. Prenatal, presymptomatic, and differential diagnostic tests are based on the detection of the repeat expansions. Point mutations within disease genes result in many additional neurogenetic disorders. An autosomal dominant form of amyotrophic lateral sclerosis and various types of craniosynostotic syndromes are described. The mutations in the disease genes also appear to result in a gain of gene function. Molecular diagnosis in these disorders is based on the direct examination of the mutated gene by methods such as single-strand conformation polymorphism analysis, denaturing gradient gel electrophoresis, and direct DNA sequencing. In many neurogenetic disorders the disease gene has not yet been identified. Here molecular diagnosis relies on indirect approaches based on methods such as the analysis of linkage and of allelic association. Hereditary forms of dystonia are presented as examples. Common sporadic neurological disorders such as Alzheimer and Parkinson diseases frequently have multifactorial causes. Investigations into the molecular basis and the development of diagnostic tests in these two important diseases are discussed. At present no curative therapies exist in neurogenetic disorders. Gene therapeutic approaches, however, provide promise for a cure in at least some of these diseases. Basic principles of gene therapy are explained and attempts at gene therapy in Alzheimer and Parkinson diseases are described. Finally, some of the many obstacles are summarized that must be overcome before gene therapy becomes feasible in most monogenic neurological diseases.
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PMID:Neurogenetic diseases: molecular diagnosis and therapeutic approaches. 882 Apr 2

A new X-linked recessive deafness syndrome was recently reported and mapped to Xq22 (Mohr-Tranebjaerg syndrome). In addition to deafness, the patients had visual impairment, dystonia, fractures, and mental deterioration. The female carriers did not have any significant manifestations of the syndrome. We examined X chromosome inactivation in 8 obligate and 12 possible carriers by using a polymerase chain reaction analysis of the methylation-dependent amplification of the polymorphic triplet repeat at the androgen receptor locus. Seven of 8 obligate carriers and 1 of 5 carriers by linkage analysis had an extremely skewed pattern in blood DNA not found in 30 normal females. The X inactivation pattern in fibroblast DNA from 2 of the carriers with the extremely skewed pattern was also skewed but to a lesser degree than in blood DNA. One obligate carrier had a random X inactivation pattern in both blood and fibroblast DNA. A selection mechanism for the skewed pattern is therefore not likely. The extremely skewed X inactivation in 8 females of 3 generations in this family may be caused by a single gene that influences skewing of X chromosome inactivation.
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PMID:Inheritance of skewed X chromosome inactivation in a large family with an X-linked recessive deafness syndrome. 882 45

Trinucleotide repeat expansion in the Machado-Joseph disease (MJD) gene has been found in 26 patients from 20 unrelated Japanese families. Expanded alleles had 68 to 84 repeats, whereas normal alleles had 14 to 37 repeats. The age of onset was inversely correlated with the repeat length. To evaluate in detail the relationship between the repeat length and clinical features, we subdivided the 26 patients into three groups on the basis of the repeat length (group 1, 78 repeats or more; group 2, 74 to 77 repeats; group 3, 73 repeats or less). Group 1 and group 2 had common features of spasticity, hyperreflexia, Babinski sign, bulging eyes, facial myokymia and extrapyramidal signs as well as cerebellar ataxia and ophthalmoplegia. It should be noted that group 1 showed more prominent pyramidal and extrapyramidal signs than group 2. In contrast, group 3 showed hypotonia, hyporeflexia and sensory disturbance in addition to cerebellar ataxia and ophthalmoplegia. These findings suggest that the repeat length plays an important role in phenotypic variation. DNA analysis for the MJD mutation was clearly useful for making an accurate diagnosis in patients without bulging eyes, facial myokymia, dystonia or marked spasticity.
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PMID:The relationship between trinucleotide repeat length and phenotypic variation in Machado-Joseph disease. 883 72

Mitochondrial DNA mutations are important causes of movement disorders and are often associated with basal ganglia degeneration. Leigh's disease and a form of generalized dystonia are caused by mitochondrial DNA mutations. Recent biochemical and genetic evidence suggests that some cases of Parkinson's disease may be caused by oxidative phosphorylation defects.
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PMID:Mitochondrial defects in basal ganglia diseases. 884 35

Dopa-responsive dystonia (DRD) was originally described in a series of Japanese patients, but is now increasingly recognized in other countries. Recently the GTP cyclohydrolase I (GTPCH) gene was isolated as the first causative gene for dopa-responsive dystonia (DRD). Mutations were identified in three Japanese families with autosomal dominantly inherited DRD and in one sporadic Japanese patient. Characterisation of the exon-intron boundaries of this gene has now allowed the analysis of mutations at the level of genomic DNA. Amplifying all six exons, we analyzed the GTPCH gene in nine British families with 33 affected family members and in three sporadic cases and found six new mutations. Only point mutations were found, causing a stop codon in one family and an amino acid change in highly conserved regions of the gene in a further four families and in one sporadic case. None of these mutations were detected more than once and none of the mutations previously described were found in our patients. No mutations were identified in four families and in two sporadic cases.
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PMID:Dopa-responsive dystonia in British patients: new mutations of the GTP-cyclohydrolase I gene and evidence for genetic heterogeneity. 885 66

We describe the first Danish family with dentatorubral-pallidoluysian atrophy (DRPLA), containing 16 clinically affected individuals in five generations. Inheritance is autosomal dominant. The disorder was diagnosed as Huntington's disease (HD), but analysis of the IT15 gene for HD revealed normal alleles. The diagnosis of DRPLA was based on the finding of elongated CAG repeats in the B37 gene on chromosome 12 in affected individuals. The age at onset ranged from 13 to 60 years, with the most severe clinical picture being associated with onset in childhood. Clinical features included varying combinations of dementia, euphoria, visuomotor disturbances, speech problems, ataxia, tremor, epilepsy and involuntary movements presenting as chorea, athetosis, and dystonia. We discuss characteristics of DRPLA that may enable the differentiation from HD on a clinical basis. In conclusion, DRPLA should be considered and DNA analysis is recommended in patients manifesting varying combinations of extrapyramidal and cerebellar symptoms, especially when clinical features show pronounced intrafamilial variability, and dyscoordination, tremor, myoclonus, epilepsy, and euphoria are part of the syndrome.
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PMID:Dentatorubral-pallidoluysian atrophy. Clinical features of a five-generation Danish family. 886 94

GTP cyclohydrolase I (GTPCH) has recently been identified as the first causative gene for Dopa-responsive dystonia (DRD). DRD typically presents with dystonia in the lower limbs in childhood, but may produce an akinetic-rigid syndrome in middle and old age. We have sequenced the GTPCH gene in 29 Parkinsonian patients without a positive family history for DRD, but who shared at least one feature of the akinetic-rigid presentation of DRD: 23 patients had at least one living relative who also suffered from an akinetic-rigid syndrome; 2 patients had an abnormally mild course of their parkinsonism which was extremely dopa-responsive. DNA was also analysed from 4 brain samples of patients who were clinically diagnosed as suffering from Parkinson's disease, but then did not show any pathological findings at post mortem. No changes in the sequence of the GTPCH gene were detected. We conclude that so far there is no evidence that mutations of the GTPCH gene are responsible for the development of parkinsonism in patients without a positive family history of DRD.
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PMID:The GTP-cyclohydrolase I gene in atypical parkinsonian patients: a clinico-genetic study. 888 Jun 88

Fifty patients with Leber's hereditary optic neuropathy (LHON) with an associated pathogenic mutation of mitochondrial DNA (mtDNA) at base pair (bp) 11778 (35 cases), 14484 (eight cases) or 3460 (seven cases) were matched with 50 controls. The frequency of additional neurological features in LHON and the role of a number of past medical and environmental factors in the development of the disease were investigated using a case-control study. Additional neurological features were reported by 15 patients. Four patients had a multiple sclerosis-like illness; one had focal dystonia. Ten patients had tremor, which occurred at significantly higher frequency in patients than in controls. Alcohol and tobacco consumption were similar in patients with the 11778 mutation and matched controls, but were significantly increased in patients with the 3460 and 14484 mutations. No other associated past medical or environmental factors were identified.
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PMID:A case-control study of Leber's hereditary optic neuropathy. 893 73


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