Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

hph-1 mice, which have defective tetrahydrobiopterin biosynthesis due to decreased GTP cyclohydrolase I activity, have been used to investigate the effects of tetrahydrobiopterin deficiency on aromatic L-amino acid monooxygenases and brain monoamine metabolism. Liver tetrahydrobiopterin levels were decreased, and tetrahydrobiopterin deficiency and reduced levels of dopamine, norepinephrine, serotonin, and their metabolites in the brain occurred both pre- and postnatally. Chronic subcutaneous tetrahydrobiopterin elevated brain levels to values higher than those seen in controls but had no effect on monoamine metabolism. In vivo activities of tyrosine hydroxylase and tryptophan hydroxylase were significantly decreased. There was a 30% decrease in the in vitro activity of striatal tyrosine hydroxylase and 50% decrease in liver phenylalanine hydroxylase. Western blotting demonstrated that the lower monooxygenase activities resulted from a reduced absolute amount of tyrosine hydroxylase and phenylalanine hydroxylase protein. The findings suggest involvement of tetrahydrobiopterin in the control of the steady-state concentration of the aromatic L-amino acid monooxygenases. In addition, demonstration of central monoamine changes in the hph-1 mouse make it a possible model system for the investigation of the neuropathological mechanisms in Dopa-responsive dystonia, which has recently been linked with mutations in the gene for GTP cyclohydrolase I.
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PMID:Tetrahydrobiopterin and biogenic amine metabolism in the hph-1 mouse. 876 4

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

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

Among heterogeneous diseases manifested by parkinsonism beginning early in life, there is a disease presenting with marked diurnal fluctuation of symptoms, called autosomal recessive early-onset parkinsonism with diurnal fluctuation (AR-EPDF). To identify the characteristics of this condition as a disease entity, we examined the clinical manifestations of AR-EPDF patients (Group I, n = 42) in comparison with those of early-onset parkinsonism patients without diurnal fluctuation (Group II, n = 34). Family history suggesting autosomal recessive inheritance was noted in 85.7% of Group I patients and 17.6% of Group II. The male-to-female ratio was 1: 1.8 in Group I, and 1:0.89 in Group II. Age at onset showed a standard distribution with an average of 25.6 years (SD: +/- 7.7) in Group I and an average of 32.7 with an increasing pattern toward 40 years in Group II. The initial symptom was dystonic gait disturbance in 42.9% of Group I and 5.9% of Group II, parkinsonian gait in 19.9% of Group I and 2.9% of Group II, and tremor in 28.6% of Group I and 41.2% of Group II. The main clinical feature was parkinsonism in both groups. Diurnal fluctuation of parkinsonism was remarkable in all but one (97.6%) of Group I, while it was not observed in Group II. Dystonic postures were noted in 79.4% of Group I and in 37.1% of Group II; hyperactive tendon reflexes in 74.3% of Group I patients and in 20% of Group II. Autonomic symptoms were mild in both groups. None of the Group I patients had dementia while two of Group II did. Levodopa was markedly effective in both groups. Dopa-induced dyskinesia was observed in 96.8% of Group I and in 61.8% of Group II. As for progression of the disease, the Hoehn-Yahr stage of patients on medication was evaluated as 2.2 +/- 0.7 (mean +/- SD) in Group I and 3.1 +/- 1.1 in Group II for a period of 10 to 20 years of onset, 2.5 +/- 0.8 in Group I and 3.3 +/- 0.5 in Group II for 20 to 30 years, and 3.2 +/- 0.9 in Group I and 4.3 +/- 0.6 in Group II after 30 years. There were significant differences between the two groups in the frequency of positive family history, in the mean and distribution of age at onset, in the incidence of dystonic gait as the initial symptom, and in the incidences and medians of the variables including dystonia, hyperreflexia and dopa-induced dyskinesia, as well as in the progression of the disease. Thus, we have successfully characterized the clinical features of AR-EPDF and demonstrated that diurnal fluctuation is a cardinal symptom of this disease. Reported pathologic studies on AR-EPDF showed the nigral lesion characterized by non-Lewy body type degeneration and the occurrence of melanin-poor neurons. These pathologic findings as well as the clinical manifestations differentiate AR-EPDF from Parkinson's disease and from autosomal-dominant familial parkinsonism. Low melanin-content of the nigral neurons is also a striking feature of hereditary progressive dystonia with diurnal fluctuation, in which unlike AR-EPDF there is no neuronal loss in the substantia nigra.
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PMID:[Autosomal recessive early-onset parkinsonism with diurnal fluctuation (AR-EPDF)--clinical characteristics]. 895 46

Clinicopathological identification of juvenile parkinsonism(JP) was described in reference to Dopa-responsive syndrome or to dopamine-dependent disorders. Recently, hereditary progressive dystonia(HPD), a dopamine-dependent disorder, was identified as a nosological entity from JP and Parkinson's disease(PD) by discovery of mutations of the gene. JP includes young onset Parkinson's disease(YOPD) and idiopathic JP with much younger-onset cases. YOPD belongs to PD-nosology based on clinical and pathological findings of our own autopsied cases. However, the idiopathic JP' might involve independent pathophysiological changes. Namely, cases of the JP are associated with atypical pathological findings with lack of Lewy body or hypoplasia of the substantia nigra and specific clinical manifestations of autosomal recessive trait and of dystonic feature and diurnal fluctuation of the symptoms.
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PMID:[Definition and nosological concept of juvenile parkinsonism]. 901 26

The clinical manifestations and the present status of our knowledge of the genetics of the idiopathic, myoclonic and Dopa-responsive dystonias are reviewed. The relevance of recent genetic findings to the classification of the idiopathic dystonias and to the molecular pathogenesis of Dopa-responsive dystonia are emphasized.
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PMID:Idiopathic, myoclonic and Dopa-responsive dystonia. 926 62

Dopa-responsive dystonia (DRD) is no longer a rare oddity. For the clinician, DRD poses a diagnostic challenge as its clinical presentation can be quite diverse. Marked and sustained response to L-dopa is the most crucial and absolute hallmark in confirming a diagnosis. Absence of degenerative nigral cell loss underlies the remarkable L-dopa response. The broadening spectrum of the clinical presentations, progress in molecular genetics with evidence of incomplete penetrance and phenotypic variability, biochemistry, utility of nuclear imaging in differential diagnosis, and treatment are discussed. I propose the concept of DRD as a syndrome, defined as selective nigrostriatal dopamine deficiency caused by genetic defects in dopamine synthesis without degenerative cell loss. I further propose the term DRD-plus, defined as inherited metabolic disorders which have symptomatic features of DRD, and those features not seen in DRD as well.
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PMID:Dopa-responsive dystonia: a syndrome of selective nigrostriatal dopaminergic deficiency. 928 24

Dopa-responsive dystonia, an autosomal-dominant disorder caused by mutations in the guanosine triphosphate (GTP)-cyclohydrolase I gene, is characterized by severe striatal dopamine depletion. Tardive dyskinesia, on the other hand, has often been associated with striatal dopamine overactivity. This article reports on a 44-year-old man with dopa-responsive dystonia who developed tardive dyskinesia on long-term haloperidol therapy. Nigrostriatal dopamine deficiency may be necessary for the development of tardive dyskinesia.
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PMID:Tardive dyskinesia in dopa-responsive dystonia: a reappraisal of the dopamine hypothesis of tardive dyskinesia. 956 61

Segawa disease (hereditary progressive dystonia with marked diurnal fluctuation) is an autosomal dominant, childhood onset, postural dystonia and the first hereditary basal ganglia disorder whose causative enzyme and gene defect were clarified. The initial symptom is unilateral pes equinovarus with marked diurnal fluctuation. Progression becomes slower after mid-teens and stationary after thirties. Postural tremor may occur after 10 years of age, especially after thirties. Parkinsonian resting tremor action and torsion dystonia. and disturbed locomotion do not occur. L-Dopa shows marked and sustained effect without side effects. F-Dopa PET and [11C] raclopride PET of over 20-year-old cases are normal. Deficiency of GTP cyclohydrolase I (GCH-I) was suggested from low CSF biopterin and neopterin. Mutation of GCH-I gene and decreased GCH-I were clarified as etiology. Twenty-five mutations discordant among families have been found. Autopsy of a gene proven case revealed decreased striatal tyrosine hydroxylase (TH) and dopamine (DA) in ventral striatum where direct pathway is predominant. Decreased GCH-I causes decreased tetrahydrobiopterin (BH4), TH and DA in nigrostriatal (NS) terminal. The lowest affinity of BH4 to TH causes selective involvement of DA. Postural dystonia is caused by decreased TH and DA affecting D1-direct pathway. Thalamic ventrolateral and pedunculo-pontine nuclei are spared. Diurnal fluctuation of symptoms is due to diurnal fluctuation of TH and DA at NS-DA terminal. Decreased DA to below 20% of normal, shown by polysomnographical studies, and its physiological age related decremental changes in NS-DA terminal underlies characteristic clinical course. High D2 receptor before early thirties masks D1 related hypertonus and manifest progression before 20 years of age. Other pteridine abnormalities also cause dopa responsive postural dystonia with diurnal fluctuation. A case of juvenile parkinsonism without dystonia showed decreased TH in dorsolateral putamen where indirect pathway is predominant. These suggest that decreased TH due to decreased BH4 involves D1-direct pathway causing dystonia, and decreased TH itself involves D2-indirect pathway causing parkinsonism.
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PMID:[Segawa disease]. 957 70

Dopa-responsive dystonia (DRD) due to mutant GTP cyclohydrolase I (GCH) shows the considerable heterogeneity of clinical phenotypic expression. To explain the clinical diversity, we studied a Japanese family with a novel mutant GCH (GCH-G90V), where an affected heterozygote had a higher mutant/normal mRNA ratio than an unaffected heterozygote. Coexpression experiments using the mutant with wild-type GCH showed that GCH-G90V inactivated the normal enzyme in a dose-dependent manner, suggesting that the dominant negative effect of a mutant GCH on the normal enzyme might be one of the molecular mechanisms for the clinical heterogeneity of DRD.
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PMID:A novel missense mutant inactivates GTP cyclohydrolase I in dopa-responsive dystonia. 1007 97


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