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)

In the dt(sz) mutant hamster with idiopathic generalized dystonia, functional abnormalities of several neurotransmitters have been suggested to play a role in the development of symptoms. In the present study, we have used histochemistry with (35)S-ATP labeled oligonucleotides to determine whether these abnormalities are associated with modulation in the expression of neurotransmitter genes in motor regions. We examined the expression of genes encoding cholecystokinin (CCK), somatostatin (SRIF), thyrotropin-releasing hormone (TRH), glutamic acid decarboxylase (GAD), tyrosine hydroxylase (TH) and growth-associated protein 43 (GAP43) in the cortex and basal ganglia of dystonic hamsters and of non-dystonic control hamsters of a related inbred line and of a non-related outbred line. The distribution of these mRNAs in normal hamster brain was similar to that in normal rat brain. In all cortical regions studied (frontal, parietal and piriformis), the expression of CCK was similar in dystonic and inbred controls but was significantly greater than in outbred controls. In the anterior thalamus, CCK expression was lower in dystonic hamsters than in both control groups. SRIF expression was significantly decreased in the cortex and striatum of dystonic animals than in inbred and outbred control hamsters. GAD expression was lower in the striatum and substantia nigra, pars reticulata of dystonic than in outbred hamsters, but similar values were found in all groups in the other regions studied. TH was lower in the substantia nigra of dystonic than in inbred controls. No changes were found in GAP43 expression. This study demonstrates that changes in modulation of the expression of some peptides and neurotransmitter enzymes can be found in the dystonic hamster, which is in contrast to other animal models such as the dystonic rat, where no such changes have been found. The present data are consistent with previous findings in dt(sz) hamsters that suggest a dysfunction within the basal ganglia-thalamocortical circuits.
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PMID:Expression of cholecystokinin, somatostatin, thyrotropin-releasing hormone, glutamic acid decarboxylase and tyrosine hydroxylase genes in the central nervous motor systems of the genetically dystonic hamster. 1055 May 8

The causative genes of two types of hereditary dopa-responsive dystonia (DRD) due to dopamine (DA) deficiency in the nigrostriatum DA neurons have been elucidated. Autosomal dominant DRD (AD-DRD) was originally described by Segawa as hereditary progressive dystonia with marked diurnal fluctuation (HPD). We cloned the human GTP cyclohydrolase I (GCH1) gene, and mapped the gene to chromosome 14q22.1-q22.2 within the HPD/DRD locus, which had been identified by linkage analysis. GCH1 isthe rate-limiting enzyme for the biosynthesis of tetrahydrobiopterin (BH4), the cofactor for tyrosine hydroxylase (TH), which is the first and rate-limiting enzyme of DA synthesis. We proved that the GCH1 gene is the causative gene for HPD/DRD based on the identification of mutations of the gene in the patients and decreases in the enzyme activity expressed in mononuclear blood cells to 2-20% of the normal value. About 60 different mutations (missense, nonsense, and frameshift mutations) in the coding region or in the exon-intron junctions of the GCH1 gene have been reported in patients with AD-DRD all over the world. Recent findings indicate that the decreased GCH1 activity in AD-DRD may be caused by the negative interaction of the mutated subunit with the wild-type one, i.e., a dominant negative effect, and/or by decreases in the levels of GCH1 mRNA and protein caused by inactivation of one allele of the GCH1 gene. Autosomal recessive DRD (AR-DRD) with Segawa's syndrome was discovered in Germany. The AR-DRD locus was mapped to chromosome 11p15.5 in the chromosomal site of the TH gene. In the AR-DRD with Segawa's syndrome, a point mutation in TH (Gln381Lys) resulted in a pronounced decrease in TH activity to about 15% of that of the wild type. Several missense mutations in the TH gene have been found in AR-DRD in Europe. The phenotype of AR-DRD with the Leu205Pro mutation in the TH gene, which produces a severe decrease in TH activity to 1.5% of that of the wild type, was severe, not dystonia/Segawa's syndrome, but early-onset parkinsonism. However, a marked improvement of all clinical symptoms with a low dose of L-dopa was reported in AR-DRD/parkinsonism patients. These findings on DRD indicate that the nigrostriatal DA neurons may be most susceptible to the decreases in GCH1 activity, BH4 level, TH activity, and DA level, and that DRD is the DA deficiency without neuronal death in contrast to juvenile parkinsonism or Parkinson's disease with DA cell death.
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PMID:Molecular genetics of dopa-responsive dystonia. 1066 62

Hemiatrophy has been reported in association with a variety of neurologic conditions, including parkinsonism. Patients with the hemiparkinson-hemiatrophy syndrome (HP-HA) have asymmetric parkinsonism with limb atrophy on the more affected side. Several authors have suggested that asymmetric brain damage early in life results in both atrophy and parkinsonism. Dopa-responsive dystonia (DRD) is a disease in which a deficiency of tetrahydrobiopterin, or, less commonly, of tyrosine hydroxylase, results in levodopa-responsive dystonia with parkinson features in children. We have recently identified four patients with DRD who had asymmetric dystonia and limb atrophy on the more affected side. Based on these patients, we suggest that a deficiency of the nigrostriatal dopamine system may, by itself, be sufficient to cause body atrophy and may underlie the limb atrophy in both DRD and HP-HA.
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PMID:Parkinsonism, dystonia, and hemiatrophy. 1083 Apr 21

To date, at least 12 types of primary dystonia can be distinguished on a genetic basis. A 3-bp deletion in the DYT1 gene causes early onset, generalized torsion dystonia (TD), and mutations in the GTP cyclohydrolase I and the tyrosine hydroxylase genes result in dopa-responsive dystonia (DYT5). A missense change in the D2 dopamine receptor in one large family (DYT11) has recently been implicated in myoclonus-dystonia. Furthermore, seven other loci for dystonia genes have been mapped to chromosomal regions, including a locus for a mixed dystonia phenotype (DYT6), one form of focal dystonia (DYT7), three types of paroxysmal dystonia (DYT8-10), X-linked dystonia-parkinsonism (DYT3), and rapid-onset dystonia-parkinsonism (DYT12). No positive linkage results have yet been obtained for autosomal recessive TD (DYT2) and several other families of different types of dominantly inherited TD (DYT4). In addition, hereditary secondary dystonia may occur as part of familial diseases of the basal ganglia, metabolic and storage disorders, and various X-linked and other familial neurodegenerative syndromes affecting the basal ganglia. It may be anticipated that the traditional clinical and etiological classifications of dystonia will increasingly be replaced by a genetic one and that the identification of more dystonia genes may lead to a better understanding of these largely nondegenerative disorders.
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PMID:[Genetics of dystonia]. 1091 37

Hereditary progressive dystonia with marked diurnal fluctuation or the strictly defined dopa-responsive dystonia (HPD/DRD) is an autosomally dominantly inherited dystonia caused by abnormalities of the gene of the GTP cyclohydrolase I (GCH 1) located on the 14q22. 1-q22.2. The heterozygotic gene abnormality induces partial decrement of tetrahydrobiopterin (BH4) and affects synthesis of tyrosine hydroxylase (TH) rather selectively. The reduction of TH exists at the terminals of the nigrostriatal (NS) dopamine (DA) neuron, predominantly in the ventral area of the striatum and disfacilitates the D1 receptor-striatal direct pathway. This consequently disinhibit the inhibitory efferent pathways and develops postural dystonia via the particular descending pathways to the reticulospinal tract and postural tremor via the ascending pathways to the ventralis lateralis (VL) nucleus of the thalamus. This also inhibits the efferents to the superior colliculus, and affects voluntary saccade but spares that to the pedunculo-pontine nucleus (PPN) preserving locomotive movement clinically. The DA-D2 receptors, the striatal indirect pathways or the efferent connecting to these pathways are not involved in the pathophysiology of HPD/DRD. So parkinsonian plastic rigidity, parkinsonian resting tremor, cogwheel rigidity or levodopa induced dyskinesia are not observed. In some patients, particularly in compound hetereozygotes, there are symptoms suggesting the involvement of serotonergic neurons or those thought to be caused by exaggeration of DA-D2 receptors. Neuropathologically there is no degenerative changes. Clinical laboratory examinations suggest that levels of TH and DA activities are around 20% of the normal values throughout the course of illness. Therefore, the age-dependent clinical course, marked progression in the first one and one half decades, its subsiding in the third decade and almost stationary course from the fourth decade are just the reflection of age-related decremental variation of the TH activities at the terminal of the normal NS-DA neuron. The diurnal fluctuation is also the reflection of circadian oscillation of the TH activities at the terminal. Functional maturation of the striatal indirect pathways in the first one and one half decades and developmental decremental variation of the DA-D2 receptor in the first three decades also reflect in the age-dependent variation of symptoms by modulating the background tone of muscle. The later functional development of the ascending efferents of the basal ganglia to the thalamus, may cause the postural tremor which appears in the second decade and becomes predominant in the fourth decade. Early decrease of TH due to deficiency of BH4 in HPD/DRD also affects the DA-D4 receptor of the tuberoinfundibular DA neuron and cause stagnation of increase of body length in childhood. With normal preservation of the fundamental function of the NS-DA neuron, levodopa, by replacing the DA content at the terminal, alleviates the motor symptoms completely and the effects sustain without any side effects. Levodopa also improves the short body length, if it is administrated before puberty. Up to now 60 mutations have been detected in the GCH 1 gene. The locus of mutation differs among families except for two pare of families with different ethnic background which showed identical mutations. Experimentally, one abnormal heterozygotic gene decreased the production of the enzyme to less than 50%, e.g. some below 20% and others around 30-40%, which clinically as symptomatic patients and asymptomatic carriers, respectively. Other experiments show dominant negative effects which differ among families or the loci of mutation. These might be the background for developing the intra-familial variation, that is, in some there is anticipation, and in the other the symptoms and clinical course are identical or vary in a family without any relation to the generation. (ABSTRACT TRUNCATED)
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PMID:Hereditary progressive dystonia with marked diurnal fluctuation. 1098 64

Mutations of the guanosine triphosphate (GTP)-cyclohydrolase I (GCH-I) gene, which catalyzes the first step in the tetrahydrobiopterin (the natural cofactor for tyrosine hydroxylase) biosynthesis, are demonstrated to cause HPD, i.e. strictly defined dopa-responsive dystonia. We analyzed the GCH-I gene of patients who fulfilled clinical criteria for typical hereditary progressive dystonia (HPD) to finalize the diagnosis. Two novel point mutations in two independent families and one novel de novo point mutation in one sporadic patient were identified. In a Japanese family, a T-to-C transition was found at exon 2, which resulted in a substitution of Cys 141 to Arg. In another Japanese family, a C-to-T mutation in exon 4 caused a nonsense codon Gln180Stop. In a clinically sporadic Japanese patient, T-to-G transition in exon 1 brought Met 102 Arg missense mutation, which was not observed in its biological parents. These three mutations were not observed in previously reported 57 pedigrees/patients and no polymorphisms in the coding region of the GCH-I gene were identified. None of the mutations of GCH-I gene in HPD reported to date or in this study have been detected more than once in any ethnicity suggesting a relatively high spontaneous mutation rate in this gene.
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PMID:Gene mutation in hereditary progressive dystonia with marked diurnal fluctuation (HPD), strictly defined dopa-responsive dystonia. 1098 68

Tyrosine hydroxylase deficiency was confirmed biochemically and genetically in four unrelated Dutch patients. The patients have a hypokinetic-rigid parkinsonian syndrome with symptoms in early infancy (3 to 6 months of age). Only sporadic dystonic movements were seen. There was no diurnal fluctuation. All patients showed a rapid favorable response to low-dose L-dopa/carbidopa treatment. Motor performance improved but did not fully normalize. The patients have mild mental retardation.
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PMID:L-dopa-responsive infantile hypokinetic rigid parkinsonism due to tyrosine hydroxylase deficiency. 1113 1

Neurotransmission is regulated by neurotransmitters at the synapses in the neuronal circuits. Main neurotransmitters are classified into the groups of amino acids, amines, purines, peptides, and nitric oxide. In principle, neurotransmitters except peptides are synthesized in the presynaptic neuroterminals from the precursors by the synthesizing enzymes, stored in the synaptic vesicles, released by exocytosis into the synaptic cleft, combined with the postsynaptic membrane receptors, and induce a series of signal transduction to produce acute, short-term, or long-term physiological effects. Termination of the neurotransmission is carried out either by re-uptake into presynaptic nerve terminals through plasma membrane transporters and storage into synaptic vesicles through vesicular transporters or by degradation through metabolizing enzymes (acetylcholine and peptides). Almost all genes related to neurotransmitters have been cloned and the structures of the genes and the protein products have been characterized. Molecular mechanisms of neurotransmission have been elucidated by mouse molecular genetics such as transgenic or knockout mice. Over-expression of human tyrosine hydroxylase (TH). the rate-limiting enzyme of catecholamine synthesis, in transgenic mice (Kaneda et al, Neuron 6, 583-584, 1991) or conversion of norepinephrine neurons to epinephrine neurons (Kobayashi et al, Proc Natl Acad Sci USA 89, 1631-1635, 1992) does not significantly change the phenotype due to compensatory mechanisms such as receptor down-regulation. In contrast, TH (-/-) mutant mice die at perinatal period due to heart failure caused by norepinephrine deficiency in the sympathetic neurons (Kobayashi et al, J Biol Chem 270, 27235-27243, 1995). TH (+/-) mice show a partial decrease in norepinephrine and a modest memory impairment (Kobayashi et al, J Neurosci 20, 2418-2426, 2000). One problem with adult phenotype in transgenic or knockout mice is that mutations cause the confounding effect of the developmental compensation. Thus conditional knockout of a specific type of neurons at a definite time after birth is required. Immunotoxin mediated conditional cell targeting (IMCT) (Kobayashi et al, Proc Natl Acad Sci 92, 1132-1136, 1995) is a novel transgenic technique for elucidating the function of a neuron in a neuronal circuit. Human molecular genetics of genetic neurological diseases are also useful for elucidating molecular mechanisms of neurotransmission. Autosomal dominant dopa-responsive dystonia (DRD) (Segawa's disease) with mutations of GTP cyclohydrolase I (Ichinose et al, Nature Genet 8, 236-242, 1994) causes a partial decrease in dopamine in the nigrostriatal dopamine neurons and produces a dystonia phenotype (Segawa's syndrome). In contrast, autosomal recessive GTP cyclohydrolase I deficiency with complete loss of the enzyme activity produces deficiencies of dopamine, norepinephrine, and serotonin and complex phenotypes with severe neurological symptoms (Ichinose et al, J Biol Chem 270, 10062-10071, 1995).
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PMID:[Molecular mechanisms of neurotransmission]. 1146 53

The dystonias are a common clinically and genetically heterogeneous group of movement disorders. More than ten loci for inherited forms of dystonia have been mapped, but only three mutated genes have been identified so far. These are DYT1, encoding torsin A and mutant in the early-onset generalized form, GCH1 (formerly known as DYT5), encoding GTP-cyclohydrolase I and mutant in dominant dopa-responsive dystonia, and TH, encoding tyrosine hydroxylase and mutant in the recessive form of the disease. Myoclonus-dystonia syndrome (MDS; DYT11) is an autosomal dominant disorder characterized by bilateral, alcohol-sensitive myoclonic jerks involving mainly the arms and axial muscles. Dystonia, usually torticollis and/or writer's cramp, occurs in most but not all affected patients and may occasionally be the only symptom of the disease. In addition, patients often show prominent psychiatric abnormalities, including panic attacks and obsessive-compulsive behavior. In most MDS families, the disease is linked to a locus on chromosome 7q21 (refs. 11-13). Using a positional cloning approach, we have identified five different heterozygous loss-of-function mutations in the gene for epsilon-sarcoglycan (SGCE), which we mapped to a refined critical region of about 3.2 Mb. SGCE is expressed in all brain regions examined. Pedigree analysis shows a marked difference in penetrance depending on the parental origin of the disease allele. This is indicative of a maternal imprinting mechanism, which has been demonstrated in the mouse epsilon-sarcoglycan gene.
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PMID:Mutations in the gene encoding epsilon-sarcoglycan cause myoclonus-dystonia syndrome. 1152 94

Inborn errors of catecholamine biosynthesis are rare but of great interest as they are genetic disorders, and in some, treatment may completely reverse severe neurological abnormalities. They also provide insights into the action of the biogenic amines in the developing brain. We describe the clinical course of an infant with tyrosine hydroxylase (TOH) deficiency over a 30-month period. The parents are consanguineous, and genetic analysis revealed the infant to be homozygous for the common G698A mutation in the TOH gene. TOH deficiency can be seen as a model of pure catecholamine deficiency. Experimental evidence, reports of other disorders of biogenic amines, and our experience with this infant suggest that the symptoms of catecholamine deficiency in infancy can be broadly subdivided. Signs of dopamine deficiency include tremor, hypersensitivity to levadopa (L-dopa) therapy, oculogyric crises, akinesia, rigidity, and dystonia. Manifestations of norepinephrine deficiency include ptosis, miosis, profuse oropharyngeal secretions, and postural hypotension. Hypersensitivity to L-dopa was a particular management problem in this infant.
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PMID:Tyrosine hydroxylase deficiency: clinical manifestations of catecholamine insufficiency in infancy. 1192 Nov 23


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