Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0241981 (loss of balance)
 452 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A completely new mutational event associated with human diseases - the dynamic mutation - was discovered in the last decade. The molecular mechanism underlying dynamic mutation involves the expansion and intergenerational instability of a tandem-arrayed nucleotide sequence that acquire a pathological size, despite its polymorphic occurrence in normal individuals. To date, at least fourteen neurological disorders are associated with this phenomenon, including Huntington's disease (HD), dentatorubral and palidoluysian atrophy (DRPLA), spinobulbar and muscular atrophy (SBMA), myotonic dystrophy (DM), fragile X syndrome, FRAXE mental retardation and spinocerebellar ataxias (SCA) types 1-3, 6-8, 12 and 17. The spinocerebellar ataxias comprise a heterogeneous group of severe neurodegenerative-late onset disorders characterized by loss of balance and coordination. Most of the spinocerebellar ataxias exhibit an autosomal dominant pattern of inheritance and are promoted by the intergenerational expansion of a trinucleotide repeat (CAG)n inside the coding region of the respective gene. The expanded segment is translated into an abnormal polyglutamine tract in the protein, leading to the formation of nuclear aggregates that have been considered the basis of the pathogenesis in most of SCA types. One striking characteristic of these diseases is that the gene is expressed throughout the brain and also in other tissues but no pathological consequences are observed, despite the specific cellular degeneration. The characterization of the mutational event has led to the development of specific and sensitive molecular tests for direct DNA analysis, which allow confirmation of clinical diagnostic and an adequate therapeutic indication as well as genetic counseling.
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PMID:Dynamic mutation and human disorders: the spinocerebellar ataxias (review). 1471 38

Huntington's disease (HD) is caused by an expansion of glutamine repeats in the huntingtin protein (mHtt) that invokes early and prominent damage of the striatum, a region that controls motor behaviors. Despite its ubiquitous expression, why certain brain regions, such as the cerebellum, are relatively spared from neuronal loss by mHtt remains unclear. Previously, we implicated the striatal-enriched GTPase, Rhes (Ras homolog enriched in the striatum), which binds and SUMOylates mHtt and increases its solubility and cellular cytotoxicity, as the cause for striatal toxicity in HD. Here, we report that Rhes deletion in HD mice (N171-82Q), which express the N-terminal fragment of human Htt with 82 glutamines (Rhes(-/-)/N171-82Q), display markedly reduced HD-related behavioral deficits, and absence of lateral ventricle dilatation (secondary to striatal atrophy), compared to control HD mice (N171-82Q). To further validate the role of GTPase Rhes in HD, we tested whether ectopic Rhes expression would elicit a pathology in a brain region normally less affected in HD. Remarkably, ectopic expression of Rhes in the cerebellum of N171-82Q mice, during the asymptomatic period led to an exacerbation of motor deficits, including loss of balance and motor incoordination with ataxia-like features, not apparent in control-injected N171-82Q mice or Rhes injected wild-type mice. Pathological and biochemical analysis of Rhes-injected N171-82Q mice revealed a cerebellar lesion with marked loss of Purkinje neuron layer parvalbumin-immunoreactivity, induction of caspase 3 activation, and enhanced soluble forms of mHtt. Similarly reintroducing Rhes into the striatum of Rhes deleted Rhes(-/-)Hdh(150Q/150Q) knock-in mice, elicited a progressive HD-associated rotarod deficit. Overall, these studies establish that Rhes plays a pivotal role in vivo for the selective toxicity of mHtt in HD.
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PMID:Ectopic expression of the striatal-enriched GTPase Rhes elicits cerebellar degeneration and an ataxia phenotype in Huntington's disease. 2604 56

Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by an expanded CAG repeat. The clinical features are progressive motor dysfunction, cognitive deterioration, and psychiatric disturbances. Unpredictable choreic movements, among the most characteristic hallmarks, may contribute to gait disturbances and loss of balance in HD individuals. In this study, we aimed to investigate and characterize the gait abnormalities and choreic movements in a transgenic rat model of HD (tgHD). TgHD presents typical neuropathological, neurophysiological, and behavioral aspects mimicking some of the key features of human HD and is the only described experimental model for HD that exhibits choreiform movements. We used the Catwalk, with emphasis on static and dynamic gait parameters, to test the hypothesis that at symptomatic age (9 months) the dynamic measures of gait in HD are altered and coexist with choreiform movements. Our results showed that the dynamic parameters seem to be more affected than static parameters at this age in tgHD rats. The number of steps and step cycles and swing speed of the paws were increased in tgHD rat in comparison to wild-type controls. Our study demonstrates that gait abnormalities coexist with chorea rather than being caused by it. These symptoms may originate from distinct networks in the basal ganglia and downstream connections.
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PMID:Coexistence of Gait Disturbances and Chorea in Experimental Huntington's Disease. 2606 66

Spinocerebellar ataxias (SCAs) are a group of hereditary and progressive neurological disorders characterized by a loss of balance and motor coordination typically associated with cerebellar atrophy. The most prevalent SCA types are all polyQ disorders like Huntington's disease, sharing the most relevant events in pathogenesis with this basal ganglia disorder, but with most of the damage concentrated in cerebellar neurons, and in their afferent and efferent connections (e.g., brainstem nuclei). SCAs have no cure and effective symptom-alleviating and disease-modifying therapies are not currently available. However, based on results obtained in studies conducted in murine models and information derived from analyses in post-mortem tissue samples from patients, which show notably higher levels of CB1 receptors found in different cerebellar neuronal subpopulations, the blockade of these receptors has been proposed for acutely modulating motor incoordination in cerebellar ataxias, whereas their chronic activation has been proposed for preserving specific neuronal losses. Additional studies in post-mortem tissues from SCA patients have also demonstrated elevated levels of CB2 receptors in Purkinje neurons as well as in glial elements in the granular layer and in the cerebellar white matter, with a similar profile found for endocannabinoid hydrolyzing enzymes, then suggesting that activating CB2 receptors and/or inhibiting these enzymes may also serve to develop cannabinoid-based neuroprotective therapies. The present review will address both aspects. On one hand, the endocannabinoid system becomes dysregulated in the cerebellum and also in other CNS structures (e.g., brainstem, basal ganglia) in SCAs, which may contribute to the progression of pathogenic events in these diseases. On the other hand, these endocannabinoid alterations may be pharmacologically corrected or enhanced, and this may have therapeutic consequences, either alleviating specific symptoms or eliciting neuroprotective effects, an objective presently under investigation.
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PMID:Endocannabinoid System in Spinocerebellar Ataxia Type-3 and Other Autosomal-Dominant Cerebellar Ataxias: Potential Role in Pathogenesis and Expected Relevance as Neuroprotective Targets. 3106 88