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)

Dyskinesias occur in the majority of patients with Parkinson's disease chronically treated with L-DOPA and also occur in several nonhuman primate species after 1-methyl-4phenyl-1,2,3,6-tetrahydropyridine (MPTP) and L-DOPA treatment. The common marmoset (Callithrix jacchus) shows parkinsonian motor deficits after MPTP administration, and we now report dyskinesias occurring in this species during chronic L-DOPA exposure. Marmosets rendered chronically parkinsonian after MPTP administration were treated orally with L-DOPA plus carbidopa for 3 weeks. After several days the animals began to display chorea, choreoathetosis, and dystonia. The severity of dyskinesias varied between the animals, with the most severely parkinsonian animals displaying the most dyskinetic movements. Each animal showed an idiosyncratic pattern of dyskinesias, which was highly reproducible. These L-DOPA-primed animals also received other D2 D1, and mixed D1/D2 agonist drugs. Quinpirole, bromocriptine, pergolide, apomorphine, and A-77636 all produce dyskinesias that were identical in character to those seen after L-DOPA administration, but the D1 agonist A-77636 gradually abolished dyskinesias while preserving its antiparkinsonian activity. The MPTP-treated marmoset provides a useful model in which to study dyskinesias in Parkinson's disease and to examine new therapeutic strategies aimed at alleviating this common side effect of chronic dopamine replacement therapy.
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PMID:Chronic L-DOPA administration induces dyskinesias in the 1-methyl-4- phenyl-1,2,3,6-tetrahydropyridine-treated common marmoset (Callithrix Jacchus). 874 92

Levodopa-induced dyskinesias result in considerable functional impairment for patients and formidable therapeutic challenges for physicians. A practical method of treating such dyskinesias is first to classify the levodopa dyskinesias according to their temporal profile after drug administration, namely, into predictable (interdose, biphasic and 'off-period') and unpredictable ('on-off') dyskinesias. Treatment of each type of dyskinesia requires a different and relatively specific therapeutic strategy. With progression of Parkinson's disease, the threshold for interdose dyskinesia lowers, while the threshold for antiparkinsonian efficacy is unchanged; therefore, the strategy is to maintain levodopa concentrations between these 2 thresholds and avoid high concentrations. Frequent small doses of liquid levodopa preparations may be indicated. Clozapine appears to increase the threshold for dyskinesia. However, its usefulness is limited primarily by dose-related sedation and by dose-unrelated agranulocytosis. Buspirone and fluoxetine may have specific antidyskinetic benefit. Surgical treatment may aid selected patients, although criteria for selection are not fully established. The biphasic dyskinesias occur just before and just after an oral dose of levodopa. They result when levodopa concentrations fall below or rise above the threshold for therapeutic efficacy; therefore, the strategy is to maintain concentrations as nearly constant as possible above that threshold. Dopamine agonists such as subcutaneous apomorphine combined with domperidone may be particularly helpful. Thalamic stimulation can also benefit selected patients. 'Off-period' dyskinesias occur at times of predicted low concentrations of levodopa. The treatment strategy is to provide sufficient levodopa or dopaminergic stimulation during those intervals. Dopamine agonists (e.g. bromocriptine at night) may help the characteristic early foot dystonia. Anticholinergic agents may also help. The unpredictable ('on-off') dyskinesias are first analysed to establish a pattern of response. Then, on the basis of that pattern, they are treated by maintaining levodopa concentrations or dopaminergic tone during the periods that would ordinarily be 'off.' Administration of liquid levodopa preparations, addition of dopaminergic agents, restriction of treatment during the morning hours as well as restriction of the majority of dietary protein in the evening meal may provide a period of predictable good function early in the day. Clozapine, even early in treatment, appears to reduce the incidence of these dyskinesias. Rescue with apomorphine during a malignant prolonged 'off' phase is particularly valuable.
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PMID:Methods of managing levodopa-induced dyskinesias. 882 14

We report six patients with dystonia-parkinsonism syndrome having a common characteristic clinical course of dystonia with subsequent development of levodopa-responsive parkinsonism. Various types of dystonic symptoms were observed such as hemidystonia, torticollis, axial dystonia, focal dystonia, or cranial dystonia (Meige's syndrome). Intervals between the onset of dystonia and that of parkinsonism varied from one year to about 20 years or the more. Levodopa and a dopamine against had inconstant effects on their dystonic symptoms except for the torticollis of the patients; on the other hand, parkinsonism were well relieved by levodopa in all of them. Dystonic symptoms showed heterogeneous drug effects. Carbamazepine had a beneficial effect on hemidystonia in a patient with hemidystonia-parkinsonism. In a patient with an unilateral hand cramp-ipsilateral parkinsonism, the focal dystonic symptom was evoked by cigarette smoking. Meige's syndrome became worse by the administration of levodopa. In contrast, in a patient with younger onset toriticollis-parkinsonism, both symptoms were fully relieved by levodopa. From the clinical and pharmacological points of views, this type of dystonia-parkinsonism, characterized by dystonia with later development of dopa-responsive parkinsonism, is a syndrome showing heterogeneous dopa-response, and it remains uncertain, at the present, that whether or not patients reported here share the same clinicopathological background such as striatal dopamine deficiency.
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PMID:[Dystonia preceding dopa-responsive parkinsonism--heterogeneous clinical features]. 886 94

In 1954, at the age of 5 years, our patient had an encephalitic syndrome associated with a prolonged lethargic state. After this episode, he developed a severe parkinsonian syndrome that, after a few years, was associated with axial dystonia and stereotyped abnormal movements of the upper limbs. This complex and progressive extrapyramidal syndrome had many similarities to the encephalitis lethargica as described by von Economo. Results of cerebral computed tomography and magnetic resonance imaging were normal. Fluorodopa positron emission tomography showed a significant bilateral reduction of tracer accumulation in both putamen, similar to that observed in patients with idiopathic Parkinson's disease. However, in this patient, treatment with L-Dopa suppressed all akinetic, dystonic and dyskinetic symptoms. The effectiveness of L-Dopa was abolished by administration of a D2 antagonist and was fully reproduced by a D2 agonist. In conclusion, this patient presented a complex postencephalitic, extrapyramidal syndrome, with akinetic symptoms and involuntary movements. These symptoms appeared to be related to a limited lesion of the dopaminergic neurons of the zona compacta of the substantia nigra.
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PMID:Postencephalitic stereotyped involuntary movements responsive to L-Dopa. 886 99

A 27-year-old Japanese woman was admitted to Kyoto University Hospital because of gait disturbance since age 25. Her elder sister had been suffering from childhood-onset dystonia-parkinsonism with diurnal fluctuation which initially responded well to levodopa therapy, but later larger dose of levodopa was needed because of severe treatment-related fluctuation of the clinical symptoms. Physical examination revealed left foot dystonia, mild parkinsonism with kinesie paradoxale and dyskinesia of lower limbs. Symptoms were relieved by sleep and worsened by walking. Laboratory data including serum ceruloplasmin, serum and urinary amino acid analysis, and hexosaminidase and beta-glucosidase activity in leukocytes were all normal. Homovanillic acid (HVA) in cerebrospinal fluid was normal (68 ng/ml) at 8 pm but markedly decreased (7 ng/ml) at 4 pm. Cranial MRI was normal. 18F-6-fluorodopa PET demonstrated decreased dopa uptake in the bilateral striatum, especially in the putamen. 18F-fluoro-2-deoxyglucose PET showed decreased regional glucose metabolism in the bilateral putamen. Levodopa therapy rendered equivocal effects while trihexyphenydil was effective. This case indicated that some cases of dopa-unresponsive dystonia with parkinsonism might be a clinical variant of juvenile parkinsonism. 18F-6-fluorodopa PET is useful in evaluating juvenile dystonia-parkinsonism, though it may not predict levodopa effectiveness. 18F-fluoro-2-deoxyglucose PET study will be helpful in predicting the effect of levodopa therapy, because decreased regional glucose metabolism in the putamen probably indicates poor response to levodopa. Further study including dopaminergic receptor imaging study is needed to clarify the physiological mechanism of co-existing dystonia and parkinsonism in patients with juvenile parkinsonism and related disorders.
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PMID:[A case of familial juvenile dystonia-parkinsonism: 18F-6-fluorodopa and 18F-fluoro-2-deoxyglucose PET study]. 890 84

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

Hereditary progressive dystonia with marked diurnal fluctuation (HPD, Segawa's disease), also known as DOPA-responsive dystonia (DRD), was found to be caused by mutation of GTP cyclohydrolase I (GCH) gene. GCH activity in mononuclear blood cells was decreased to less than 20% of the normal values. The decrease in GCH activity causes the decrease in tetrahydrobiopterin (BH4) levels, resulting in decreased tyrosine hydroxylase (TH) activity and finally in decreased dopamine levels in the nigrostriatal dopamine neurons. In contrast, GCH activity in mononuclear blood cells in juvenile parkinsonism was normal. Recessive dystonia was shown to have a point mutation in TH gene. Thus, HPD (Segawa's disease) is distinct from recessive dystonia and juvenile parkinsonism. Patients with Parkinson's disease had decreased GCH activity in parallel with the decreases in TH activity and dopamine in the striatum, probably as the results of cell death.
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PMID:[Molecular genetics of hereditary progressive dystonia (HPD/Segawa's disease)]. 896 84

From its characteristic clinical features, decrease of tyrosine hydroxylase (TH) in the terminal of the nigrostriatal (NS) dopamine (DA) neuron is considered the main lesion of HPD and the decrease of neopterin as well as biopterin in the cerebrospinal fluid suggested GTP cyclohydrolase I (GCH-I) as the responsible enzyme. By detecting the gene locus of GCH-I, Ichinose and his colleagues showed the abnormalities of GCH-I gene located on 14q 22.1 q22.2 as the cause of HPD. Since the first report of Ichinose et al, 11 mutations and frame shifts of the gene have been detected, in which the locus of abnormality differed among families but is identical in a family, but more than several families have been left with undetected abnormalities including those having linkage to 14q. However, the DNA of these families as well as those with detected gene abnormalities failed to synthesize GCH-I if inoculated with E. coli and the levels of GCH-I in mononuclear blood cells were below 20% of normal values in HPD patients while they were 37 and 38% in two asymptomatic carriers. Ratio of mutant mRNA of GCH-I gene was 28% in a patient and 8.3% in an asymptomatic case. These lines of evidence on GCH-I show HPD is a dominant inherited disorder with abnormalities of GCH-I gene. GCH-I is the limiting enzyme for synthesizing tetrahydrobiopterin (BH4), coenzyme transmitters for the synthesizing hydroxylases of aminergic neurotransmitters, but the affinity is the least for TH. This might cause a rather selective involvement of TH preserving serotonin synthesis un- or less affected. Fluoro-DOPA and [11C] racropride PET studies were normal in HPD. Studies of an autopsied case with dopa responsive dystonia, which was confirmed to have GCH-I gene abnormalities, neuropathologically revealed no abnormalities except for a decrease in melanin pigmentation in the substantia nigra and histochemically a decrease in TH enzyme activities and its protein only in the striatum. There was mild decrease of DA content, the interregional caudate/putamen and subregional rostrocaudal patterns which were similar to Parkinson disease, but subdivisionally different with predominant reduction in the ventral subdivision of the caudate nucleus. In the ventral part of the basal ganglia the striatal direct projection exists predominantly. Cases with recessive abnormalities of pteridin metabolism other than HPD, 6-pyruvoyl-tetra-hydropterin synthase (PSPS) deficiency and dihydropteridine reductase deficiency also show dystonia with diurnal fluctuation responding to levodopa, though not as marked as HPD. MPTP monkey studies revealed no involvement of striatal indirect pathway for peak dose dystonia. So it is suggested that in HPD, decrease of TH at the terminal of the NS-DA neuron due to partial reduction of GCH-I develops postural dystonia through the striatal direct projection in childhood with diurnal fluctuation depending on age and circadian variation of TH activities at the terminals.
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PMID:[Segawa disease (hereditary progressive dystonia with marked diurnal fluctuation-HPD) and abnormalities in pteridin metabolism]. 912 93

We studied the clinical features and molecular genetics of a family, afflicted with a form of atypical parkinsonism, originating from the Madeira Islands of Portugal. We examined four affected individuals and reviewed clinical information on one other affected family member. Mean age at onset was 31 years. Parkinsonism (akinesia, rigidity, gait disturbance) was the most prominent feature in advanced disease. Levodopa responsiveness with peak-dose dyskinesia was present in one individual. Initial symptoms and other clinical features were variable and included other extrapyramidal signs (dystonia, action tremor of the limbs and bulbar muscles, synkinesis), ophthalmologic abnormalities (ptosis, slow saccades, progressive external ophthalmoplegia, hypometric saccades, saccadic pursuit movements), speech abnormalities (dysarthria, hypernasality), cortical impairment (dementia, frontal lobe dysfunction, palilalia, perseveration), minor cerebellar signs (dysmetria, gait ataxia), pyramidal abnormalities (spasticity, hyperreflexia), and peripheral nervous system abnormalities (propioceptive loss, areflexia, distal weakness, atrophy). The length of trinucleotide repeats in the MJD1 gene was in the normal range for all affected individuals.
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PMID:Atypical parkinsonism in a family of Portuguese ancestry: absence of CAG repeat expansion in the MJD1 gene. 915 59

The radiotracer [123I]beta-CIT is a sensitive marker of dopamine uptake sites that can be used to visualize dopaminergic nerve endings in vivo in the human brain. We report on [123I]beta-CIT single-photon emission computed tomography (SPECT) findings in a patient with DOPA-responsive dystonia (DRD). [123I]beta-CIT SPECT showed a striatal radiotracer uptake in the upper range of normal, indicating intact dopamine transporters and structural integrity of nigrostriatal neurons. This differentiates DRD from clinically similar cases with juvenile-onset parkinsonism with dystonia that have a considerable poorer prognosis. [123I]-beta-CIT SPECT may provide a method equally as useful as fluorodopa positron emission tomography in DRD.
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PMID:[123I]beta-CIT single-photon emission tomography in DOPA-responsive dystonia. 915 46


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