Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004134 (ataxia)
 15,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A new autosomal recessive mouse mutation, Purkinje cell degeneration (pcd), is described. Mutants exhibit a moderate ataxia beginning at 3 to 4 weeks of age. The ataxia results from postnatal degeneration of virtually all cerebellar Purkinje cells beginning around 15 to 18 days of age and progressing rapidly over the next 2 weeks. In addition to the cerebellar disease there is slow progressive degeneration in the retina (photoreceptor cells) and olfactory bulb. Also, adult males have abnormal sperm.
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PMID:Purkinje cell degeneration, a new neurological mutation in the mouse. 106 Nov 18

The properties of [3H]clonazepam, [3H]diazepam and [3H]zolpidem (N,N,6[trimethyl-2-(4-methyl-phenyl)imidazo[1,2-a]pyridine-3-acetamide hemitratrate) binding to synaptic membranes of cerebellum, cortex, olfactory bulb, striatum and spinal cord of rat were compared to the binding properties of [3H]flunitrazepam, [3H]flumazenil and [3H]midazolam. In the cerebellar, cortical and olfactory bulb membranes, the density of high-affinity binding sites of all these tritiated benzodiazepine (BZ) ligands is almost identical. In contrast, in the striatum, the density of [3H]clonazepam and [3H]zolpidem binding sites is approximately 60 and 30%, respectively, of the density of [3H]diazepam, [3H]flunitrazepam or [3H]flumazenil sites. In spinal cord membranes, the number of high-affinity binding sites of [3H]clonazepam and [3H]zolpidem is less than 20% of the number of binding sites for [3H]diazepam, [3H]flunitrazepam, [3H]flumazenil and [3H]midazolam. Moreover, the displacement of [3H]flunitrazepam from spinal cord membranes by clonazepam and zolpidem was characterized by high IC50 values and Hill slopes significantly less than 1. Because [3H]BZ ligand binding in the spinal cord is enhanced by gamma-aminobutyric acid (GABA), these data suggest that different regions of the rat central nervous system may contain different GABA-BZ receptor subtypes. The different pharmacological properties of clonazepam, diazepam and zolpidem (i.e., regarding their ability to enhance bicuculline seizure threshold, to decrease locomotor activity, to induce ataxia or to elicit anticonflict action) further support the concept that in the rat central nervous system preferential occupancy of heterogeneous GABAA receptors by these drugs can be related to their effects on behavior.
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PMID:gamma-Aminobutyric acidA receptor heterogeneity in rat central nervous system: studies with clonazepam and other benzodiazepine ligands. 184 29

A mutant strain of Wistar rats which carries an autosomal gene defect is characterized by a progressively developing hyperexcitability, tremor, olfactory and gustatory movements, bradykinesia, ataxia and a pathologically increased muscle tone of hindlimbs which can be measured by recording tonic activity in the electromyogram (EMG) of the gastrocnemius-soleus muscle. The activity of the GABA synthesizing enzyme glutamic acid decarboxylase (GAD) and the receptor binding of GABA as estimated by [3H]GABA binding to synaptic membranes were examined in olfactory bulbs, frontal cerebral cortex, corpus striatum, hippocampus, thalamus, hypothalamus, tectum, substantia nigra, medulla oblongata, cerebellum, and pons of mutant rats. Mutant rats exhibit a lower activity of GAD in synaptosomal fractions of olfactory bulbs and substantia nigra whereas GAD activity within the pons was increased. The changes in the activity of GAD were accompanied by alterations in [3H]GABA binding to synaptic membranes: GABA binding was significantly elevated in the olfactory bulbs and the substantia nigra, but it was markedly reduced in the pons. The functional importance of impaired nigral GABAergic transmission in mutant rats was demonstrated by the fact that intranigral injection of the GABA agonist muscimol reduced the tonic extension of the hindlimbs as indicated by reduced tonic EMG activity of the gastrocnemius-soleus muscle, while intranigral injection of the GABA antagonist bicuculline increased the disturbance.
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PMID:Disturbed GABAergic transmission in mutant Han-Wistar rats: further evidence for basal ganglia dysfunction. 299 53

In an earlier report we presented evidence pointing to a differential effect of the mutant gene weaver on the dopamine-containing fiber systems innervating the striatum. In mice homozygous for the weaver mutation, there is a severe loss of dopamine in the caudoputamen, the main target of the nigrostriatal system. By contrast, dopamine is entirely conserved in the nucleus accumbens, a target of the mesolimbic system, and is moderately affected in the olfactory tubercle. The present study shows that these defects in dopamine are gene dose-dependent, that they are established by the end of the first month of life, and that the losses are permanent and not progressive. As in homozygous weavers, the greatest defects in striatal dopamine in heterozygous weavers occur in the dorsolateral caudoputamen and the lateral olfactory tubercle. The abnormalities in the striatal dopamine content of weaver mice are not accompanied by abnormalities in the turnover of dopamine, judging from measurements of the dopamine metabolite dihydroxyphenylacetic acid. Norepinephrine content is also normal in each striatal region. No deficits in striatal dopamine occur in mice homozygous for the mutant genes staggerer and Purkinje cell degeneration, which, like the weaver mutation, result in ataxia and cerebellar pathology. A survey of nonstriatal regions in the weaver mice showed that the effects of the weaver gene on the dopamine-containing innervation of the forebrain are not confined to striatal targets but also extend to the septum and the hypothalamus. By contrast, dopamine in the frontal cortex, the amygdala, the olfactory bulb, and the retina is entirely spared. The pattern and extent of loss of dopamine in the weaver forebrain is thus region- and system-specific. In confirmation of our initial findings, a ca. 30% depletion of dopamine occurs in the weaver midbrain, the region containing the cell bodies of origin of the mesostriatal dopamine systems. A comparison of histofluorescent sections through weaver and control midbrains revealed a reduction of catecholamine-containing neurons in the pars compacta of the weaver animals. These results point to a subpopulation of dopamine-containing neurons as primary targets of the weaver gene or as being closely associated with such primary targets. As a gene-dose effect has also been shown for the cerebellar granule cell loss in the weaver, the mutant gene must have at least 2 cellular targets. We suggest that the cerebellar and mesostriatal pathologies may be linked by a common molecular mechanism.
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PMID:Expression of the weaver gene in dopamine-containing neural systems is dose-dependent and affects both striatal and nonstriatal regions. 377 34

Blocks of tissue from the hypothalamus, olfactory bulb, or striatum of rats were incubated in vitro to study the basal and potassium-stimulated release of endogenous catecholamines. When ethanol (100-250 mM) was added to these preparations in vitro no changes in release were observed. When ethanol (3.0 g X kg-1) was injected intraperitoneally in vivo, however, and 3,4-dihydroxyphenylethylamine (DA, dopamine) release was measured in vitro at various times after drug administration, significant increases in the basal release and decreases in the potassium-stimulated release were observed in striatum and olfactory bulb. In striatum, these changes showed a more rapid onset and a longer duration than in olfactory bulb. In both brain regions, DA release did not differ from controls at 4-6 h after the ethanol injection, although blood ethanol concentrations remained elevated. This may imply the tissue's acquisition of acute functional tolerance to the drug. Similar increases and decreases in the basal and the potassium-induced release of DA from striatal tissues were also found at 1 h after injection of a lower dose of ethanol (1.0 g X kg-1). In terms of behavior, this lower dose of ethanol produced only mild intoxication and ataxia, in contrast to the loss of righting reflex following the higher dose.
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PMID:Effects of ethanol in vitro and in vivo on the release of endogenous catecholamines from specific regions of rat brain. 396 14

The mutant strain of Wistar rats carrying an autosomal recessive gene defect is characterized by a sequence of progressively developing behavioural alterations including hyperexcitability, tremor, olfactory and gustatory automatisms, bradykinesia, ataxia, rigidity, paresis and cachexia. The stereotypy and locomotor responses to increasing doses of apomorphine hydrochloride and D-amphetamine sulphate, and the catalepsy response to increasing doses of haloperidol were studied in mutant rats at the age of 6-7 weeks. In the mutants, both the stereotypy and locomotor responses to amphetamine were enhanced, while stereotypy and locomotor effects induced by apomorphine were unaltered. The cataleptic response to haloperidol was significantly diminished compared to controls. These findings indicate a derangement in the function of basal ganglia in the mutants.
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PMID:Stereotypy, locomotor and cataleptic effects produced by drugs influencing dopaminergic systems in a mutant strain of Wistar rats: a genuine model of basal ganglia dysfunction? 653 16

Systemic administration of N-methyl-D-aspartate (NMDA) receptor antagonists induces a well defined behaviour in rodents characterized by, for example increased locomotion and ataxia. It is not clear in what brain region(s) NMDA antagonists induce this behaviour. We have studied the possible involvement of olfactory pathways by making adult mice anosmic via intranasal injection of zinc sulphate, a procedure that is known to destroy the olfactory epithelium. The NMDA antagonist MK-801 was given intraperitoneally (0.1-1.0 mg/kg) and the animals were scored for locomotion and ataxia 60-90 min later. Before MK-801 administration, olfactory-lesioned mice did not differ from non-lesioned controls with regard to locomotion or ataxia. MK-801 caused locomotor activation (> or = 0.2 mg/kg) and ataxia (> or = 0.5 mg/kg) in both groups. In general, olfactory-lesioned animals showed more locomotion and less ataxia after MK-801 administration than non-lesioned animals. Lesioned animals displayed 2.0- (P < 0.05) and 3.7-fold (P < 0.05) more extensive locomotor activation than non-lesioned animals after 0.5 and 1.0 mg/kg of MK-801, respectively. No difference in the degree of ataxia was seen between the two groups at 0.5 mg/kg, whereas non-lesioned animals showed a 2.1-fold higher degree of ataxia after 1.0 mg/kg of MK-801, indicating that the enhanced MK-801-induced locomotor activation in olfactory-lesioned mice was not simply due to less ataxia. These results suggest that olfactory input is involved in NMDA antagonist-induced behaviour.
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PMID:The effect of anosmia on MK-801-induced behaviour in mice. 764 17

We report a 65-year-old woman with progressive multiple cranial neuropathy. She had been suffered from bronchial asthma since 1979 for which prednisolone had been prescribed. She noted an onset of pain around her nose in October, 1989, which extended into the periorbital regions bilaterally. In February, 1990, she was treated with stellate ganglion block and trigeminal nerve block; these treatments partially alleviated her pain. In May of 1991, she noted a difficulty in swallowing solid foods. In November of the same year, she developed right facial paresis; two weeks later, she noted numbness in her left face, and was hospitalized to our service on December 16, 1991. On admission, she was afebrile and general physical examination was unremarkable except for piping rales in her both lung fields. On neurologic examination, she was alert and oriented to all spheres; higher cerebral functions were intact. In the cranial nerves, her olfactory sense was lost bilaterally; her vision was markedly diminished bilaterally only to recognize hand movements; the optic fundi appeared normal; the pupils were isocoric and reacted to light promptly. The extraocular muscles were moderately weak to most of the directions more on the left; no nystagmus was present. Facial sensation was diminished bilaterally; the jaw deviated to right; right facial paresis of peripheral type was present; her hearing was diminished bilaterally more on the right. The movement of the soft palate was diminished on the right side; dysphagia was present; her voice was horse; the gag reflex was diminished. The sternocleidomastoid muscle was weak bilaterally; the tongue appeared normal. Examination of gait was differed because of headache, however, no apparent motor weakness was present. No ataxia or involuntary movement was noted. Deep reflexes were normally elicited and symmetric. Plantar response was flexor. Sensation in the extremities was intact. Kernig's sign was positive at 70 degree leg extension; eyeball tenderness was also present bilaterally, however, no nuchal stiffness was noted. Following abnormalities were present in the laboratory examination: WBC 11,400/microliters, ESR 50 mm/hr, CRP 6.1 mg/dl. The lumbar CSF was under a normal pressure containing 29 WBC/microliters (neutrophils 7, lymphocytes 20, others 2), 67 mg/dl of protein, and 53 mg/dl of sugar; cultures for acid-fast bacilli as well as for other bacteria were negative; no malignant cells were found. A cranial CT scan revealed an isodensity mass in the orbit and ill-defined low density areas in the white matters of the frontal lobes.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:[A 65-year-old woman with headache, facial pain, and progressive multiple cranial neuropathy]. 787 85

Inositol phospholipid-specific phospholipase C (PLC) generates two important second messengers, inositol triphosphate and diacylglycerol. The recently cloned rat PLC beta 4 cDNA is highly homologous to the norpA cDNA of Drosophila melanogaster. We have mapped the PLC beta 4 gene expression in rat brain tissue sections by in situ hybridization. The PLC beta 4 gene is expressed at high abundance in cerebellar Purkinje cells and neurones of the substantia nigra, the median geniculate bodies and the thalamic nuclei. PLC beta 4 transcripts are also detected in the mammillary nuclei, the neocortex, the habenula and the olfactory bulbs. The specific pattern of gene expression we have observed should help to clarify the relationships between the PLC beta 4 and various constituents of second-messenger systems involved in transduction mechanisms triggered by the stimulation of seven transmembrane domain receptors. The strong gene expression in Purkinje cells and retinal neurones suggests that PLC beta 4 may be involved in the pathogenesis of mouse and human neurological diseases characterized by ataxia and retinal degeneration.
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PMID:The rat phospholipase C beta 4 gene is expressed at high abundance in cerebellar Purkinje cells. 854 79

Angelman syndrome (AS) is a human genetic disorder characterized by mental retardation, seizures, inappropriate laughter, abnormal galt, tremor and ataxia. There is strong genetic evidence that the disorder is associated with a maternally expressed, imprinted gene mapping to chromosome 15q11-13. Affected patients demonstrate varied molecular abnormalities, including large maternal deletions, uniparental paternal disomy (UPD). Imprinting mutations and loss of function mutations of E6-associated-protein (E6-AP) ubiquitin-protein ligase (UBE3A). All of these abnormalities are associated with loss of maternal expression of UBE3A. Although mutations in UBE3A cause AS, indicating that maternal-specific expression of UBE3A is essential for a normal phenotype, evidence for maternal-specific expression of UBE3A has been lacking. Using mice with partial paternal UPD encompassing Ube3a to differentiate maternal and paternal expression, we found by in situ hybridization that expression of Ube3a in Purkinje cells, hippocampal neurons and mitral cells of the olfactory bulb in UPD mice was markedly reduced compared to non-UPD littermates. In contrast, expression of Ube3a in other regions of the brain was only moderately or not at all reduced in UPD mice. The major phenotypic features of AS correlate with the loss of maternal-specific expression of Ube3a in hippocampus and cerebellum as revealed in the mouse model.
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PMID:Imprinted expression of the murine Angelman syndrome gene, Ube3a, in hippocampal and Purkinje neurons. 928 1


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