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)

Catecholamine biosynthesis is regulated by tyrosine hydroxylase (TH) requiring tetrahydrobiopterin (BH4) as the cofactor. We found four (human TH type 1-4) and two isoforms (TH type 1 and 2) in humans and monkeys, while non-primate animals have a single TH corresponding to human TH type 1. BH4 is synthesized from GTP, and GTP cyclohydrolase I (GCH) is the first and regulatory enzyme. Mutations in GCH gene were found to cause both GCH deficiency with autosomal recessive trait and hereditary progressive dystonia with marked diurnal fluctuation (HPD) (Segawa's disease)/or DOPA-responsive dystonia (DRD) with autosomal dominant trait. When GCH activity is decreased to less than 20% of the normal value, the activity of TH in the nigrostriatal dopaminergic neurons may be first decreased resulting in decreases in TH activity and dopamine level, and in the symptoms of HPD/DRD. In contrast to HPD/DRD, juvenile parkinsonism (JP) have normal GCH activity. In Parkinson's disease (PD), GCH, TH, and dopamine in the striatum may decrease in parallel, as the secondary effects caused by cell death.
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PMID:GTP cyclohydrolase I gene, tetrahydrobiopterin, and tyrosine hydroxylase gene: their relations to dystonia and parkinsonism. 918 49

Tetrahydrobiopterin deficiencies are highly heterogeneous disorders, with more than 30 molecular lesions identified in the past 2 years in the GTP cyclohydrolase I and 6-pyruvoyl-tetrahydropterin synthase genes. The spectrum of mutations causing a reduction of these two biosynthetic enzymes is reviewed. Only three mutations, two present homozygously, are reported in the GTP cyclohydrolase I gene to cause the rare autosomal recessively inherited form of hyperphenylalaninemia. Most of the other mutations, which are scattered over the entire coding region for the six exon-containing GTP cyclohydrolase I gene, are observed in a heterozygous state with the wild-type allele and are associated with the dominant DOPA-responsive dystonia. Compound heterozygous or homozygous mutations spread over all six exons encoding the 6-pyruvoyl-tetrahydropterin synthase cause an autosomal recessively inherited variant of hyperphenylalaninemia, mostly accompanied by a deficiency of dopamine and serotonin.
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PMID:Mutations in the GTP cyclohydrolase I and 6-pyruvoyl-tetrahydropterin synthase genes. 922 55

Stereotactic surgery for movement disorders is currently undergoing a re-evaluation. A new understanding of the pathophysiology makes the surgical lesion a logical step for the aleviation of both hyperkinetic symptoms such as tremor and hypokinetic symptoms like bradykinesia. Advances in imaging and electrophysiological control render these procedures more accurate and safer. Indications are medically refractory, Parkinsonean tremor, essential tremor, cerebellar tremor, bradykinesia and L-Dopa induced dyskinesis. The standard procedure is ablative surgery, i.e. thalamotomy for tremors and pallidotomy for bradykinesia, dystonia and L-Dopa induced dyskinesias. Deep brain stimulation is a novel alternative for selected patients which is currently evaluated. Neural transplantation of autologus, fetal or genetically manipulated cell suspensions into the striatum for the time being is experimental.
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PMID:[Stereotactic treatment of movement disorders]. 931 81

The primary objective of this study was to assess the effect of tolcapone on levodopa dosage in parkinsonian patients whose "wearing-off" phenomenon has been controlled with more frequent levodopa dosage. After a 1-week placebo run-in, 97 patients were assigned randomly to receive placebo or tolcapone 200 or 400 mg three times daily (t.i.d.). Levodopa dosage was reduced by -35% on day 1 of study and subsequently retitrated as required. After 6 weeks, the tolcapone groups crossed over to receive the other dose for a further 3 weeks for exploratory purposes. Both tolcapone groups had greater reductions in levodopa dosage than the placebo group at week 6 (not statistically different). The 200-mg t.i.d. group showed greatest improvement in estimated mean scores for all efficacy parameters (p < 0.05 versus placebo for change in Unified Parkinson's Disease Rating Scale Subscale II). Fewer dopaminergic and nondopaminergic adverse events were associated with tolcapone 200 mg t.i.d. than with tolcapone 400 mg t.i.d. The most frequently reported dopaminergic adverse events were nausea, cramps, dyskinesia, and dystonia. The most frequently reported unanticipated adverse event was diarrhea. Tolcapone 200 mg t.i.d. may provide additional benefit to patients with moderately advanced Parkinson's disease with treated "wearing-off" phenomenon.
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PMID:Tolcapone added to levodopa in stable parkinsonian patients: a double-blind placebo-controlled study. Tolcapone in Parkinson's Disease Study Group II (TIPS II). 939 17

Corticobasal degeneration (CBD) was first reported by Rebeiz et al as corticodentatonigral degeneration with neuronal achromasia in 1967. After Gibb et al described 7 cases including 4 cases from the literature under the term of corticobasal degeneration, CBD has become widely recognized. The disease starts mainly in one's fifties and sixties with the duration of 6 to 7 years. The clinical features include asymmetric parkinsonism, cerebral cortical signs, and others. Typically, patients present with unilateral clumsiness with akinetic-rigid syndrome and limb-kinetic apraxia. Postural instability, gait disturbance and involuntary movements such as dystonia are not uncommon. The parkinsonism is DOPA-resistant. BEsides apraxia, alien limb syndrome, cortical sensory disturbances, frontal lobe-release signs, and dementia are representative cortical signs. Other clinical features include dysarthria, pyramidal tract signs and supranuclear gaze palsy. MRI, SPECT or PET reveals asymmetric atrophy, decrease in blood flow or reduction in metabolism of the frontal parietal region around the central sulcus. Electrophysiological and magnetic stimulation studies demonstrated increase in excitability of the cerebral cortex. Myoclonus in CBD is cortical in origin but without any preceding potential or giant somatosensory evoked potential. Neuropathologically CBD is characterized by involvement of the particular cortices and substantia nigra. Other structures such as the putamen, pallidum, thalamus, subthalamus, cerebellar dentate nucleus and brainstem are affected to various extents. Histological features include achromatic, ballooned neurons as well as tau and Gallyas positive neuronal and glial intracytoplasmic inclusions. Astrocytic plaque is considered to be a form of glial inclusions specific to CBD. Diagnosis of typical cases of CBD appears easy but atypical cases were reported with showed dementia or aphasia as a main feature, or were devoid of the asymmetry of signs and symptoms. CBD, progressive supranuclear palsy and Pick's disease share both clinical and neuropathological features to some extent while they are clearly distinct among typical cases. The etiology and pathomechanism of CBD remain to be elucidated.
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PMID:[Corticobasal degeneration]. 957 68

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

A consistent neurochemical abnormality in Parkinson's disease (PD) is degeneration of dopaminergic neurons in substantia nigra, leading to a reduction of striatal dopamine (DA) levels. As tyrosine hydroxylase (TH) catalyses the formation of L-DOPA, the rate-limiting step in the biosynthesis of DA, the disease can be considered as a TH-deficiency syndrome of the striatum. Similarly, some patients with hereditary L-DOPA-responsive dystonia, a neurological disorder with clinical similarities to PD, have mutations in the TH gene and decreased TH activity and/or stability. Thus, a logical and efficient treatment strategy for PD is based on correcting or bypassing the enzyme deficiency by treatment with L-DOPA, DA agonists, inhibitors of DA metabolism, or brain grafts with cells expressing TH. A direct pathogenetic role of TH has also been suggested, as the enzyme is a source of reactive oxygen species (ROS) in vitro and a target for radical-mediated oxidative injury. Recently, it has been demonstrated that L-DOPA is effectively oxidized by mammalian TH in vitro, possibly contributing to the cytotoxic effects of DOPA. This enzyme may therefore be involved in the pathogenesis of PD at several different levels, in addition to being a promising candidate for developing new treatments of this disease.
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PMID:Tyrosine hydroxylase and Parkinson's disease. 962 67

Niemann-Pick disease Type C (NPC) is a progressive neurovisceral metabolic disorder that is caused in most patients by a defect in a recently found gene, NPC-1. Neurological damage includes visual disorders such as vertical supranuclear gaze palsy, movement disorders such as dystonia and ataxia, dementia, and seizures. So far the biochemical deficit, most likely manifested by delayed intracellular cholesterol transport, has not been correlated with the progressive neurological damage. A mutant Balb/C mouse with a defect in the same gene is used as a model to study NPC. Pathological examination of brain tissue obtained by autopsy from NPC patients or brains of affected NPC mice of different ages, revealed signs of extensive damage throughout the brain, including neurofibrillary tangles and intracellular storage of various compounds. Loss of cerebellar Purkinje cells was the most significant specific damage. The present study examined whether the neurochemical changes present in the NPC mouse brain were related to the pathological changes. The results show major alterations in the levels of serotonin and its main metabolite, 5-hydroxyindoleacetic acid, in the cerebellum and cortex of NPC mice. The levels of the inhibitory amino acid glycine were threefold higher in the cerebellum of NPC mice and those of glutamate and GABA decreased in the cortex. Tyrosine hydroxylase immunoreactivity was present in Purkinje cells, and the levels of L-DOPA increased specifically in the vermis of the cerebellum. These results are the first to indicate changes in neurotransmitters in NPC and that these could be correlated with some of the neuropathology of this disease.
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PMID:Neurochemical alterations in the cerebellum of a murine model of Niemann-Pick type C disease. 967 2

This report concerns one new mutation in the tyrosine hydroxylase (TH) gene in three patients originating from three unrelated Dutch families with autosomal recessive L-DOPA-responsive dystonia (DRD). In this study, all exons of the TH gene were amplified by the polymerase chain reaction and subjected to analyses by single-strand conformation polymorphism. An aberrant migration pattern was observed for exon 6 of the TH gene in all patients. Direct sequencing of the coding region of exon 6 revealed the presence of one novel missense mutation. An a698g transition resulted in the substitution of the evolutionary conserved arginine 233 by a histidine (R233H). All patients were homozygous for the mutation. This new mutation in the TH gene was confirmed by restriction enzyme analysis with the restriction enzyme HhaI. Thus, a high proportion of defective TH alleles may be R233H in The Netherlands.
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PMID:A common point mutation in the tyrosine hydroxylase gene in autosomal recessive L-DOPA-responsive dystonia in the Dutch population. 970 25

The development of autosomal dominant DOPA-responsive dystonia (AD-DRD) is stipulated by mutation in GTP-cyclohydrolase I gene. GTP-cyclohydrolase I is the first and key enzyme of tetrahydrobiopterin biosynthesis. Its deficiency in nigrostriatal dopaminergic neurons cause a decrease in tyrosine hydroxylase activity and therefore dopamine deficiency. However, administration of low doses of dopamine can control the development of AD-DRD. Determination of GTP-cyclohydrolase I activity in mononuclear blood cells is convenient diagnostic method.
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PMID:[Autosomal-dominant DOPA-responsive dystonia, caused by mutations in the GTP-cyclohydrolase I gene]. 970 21


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