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Query: UMLS:C0008489 (chorea)
 2,102 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We describe a patient with Huntington's disease (HD) who showed asymmetrical upper limb amyotrophy as a main manifestation. Chorea and psychiatric symptoms were not prominent. Electromyography revealed generalized active and chronic denervation and fasciculations. A genetic test showed 46 CAG repeats in the huntingtin gene. Asymmetrical amyotrophy restricted to the upper limb has been reported in some patients with progressive chorea and amyotrophy without acanthocytosis, but genetically proven cases of HD have rarely been reported. It is not known why only a few HD patients show the motor neuronal loss; however, certain as-yet-unidentified genetic factors combined with some environment factors and the underlying cellular dysfunctions by polyglutamine aggregation could be responsible for the motor neuronal loss similar to that in amyotrophic lateral sclerosis.
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PMID:Genetically confirmed Huntington's disease masquerading as motor neuron disease. 1818 18

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder characterized by chorea, incoordination, and shortened life-span, and by huntingtin inclusions and neurodegeneration. We previously screened the 1040 FDA-approved compounds from the NINDS compound library and found that a compound, nipecotic acid, significantly reduced mutant huntingtin aggregations and blocked cell toxicity in an inducible cell model of HD. Because nipecotic acid does not cross the blood-brain barrier (BBB), we studied its analogue, tiagabine, which is able to cross the BBB, in both N171-82Q and R6/2 transgenic mouse models of HD. Tiagabine was administered intraperitoneally at 2 and 5 mg/kg daily in HD mice. We found that tiagabine extended survival, improved motor performance, and attenuated brain atrophy and neurodegeneration in N171-82Q HD mice. These beneficial effects were further confirmed in R6/2 HD mice. The levels of tiagabine at effective doses in mouse serum are comparable to the levels in human patients treated with tiagabine. These results suggest that tiagabine may have beneficial effects in the treatment of HD. Because tiagabine is an FDA-approved drug, it may be a promising candidate for future clinical trials for the treatment of HD.
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PMID:Tiagabine is neuroprotective in the N171-82Q and R6/2 mouse models of Huntington's disease. 1839 59

Non-human primates are valuable for modelling human disorders and for developing therapeutic strategies; however, little work has been reported in establishing transgenic non-human primate models of human diseases. Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder characterized by motor impairment, cognitive deterioration and psychiatric disturbances followed by death within 10-15 years of the onset of the symptoms. HD is caused by the expansion of cytosine-adenine-guanine (CAG, translated into glutamine) trinucleotide repeats in the first exon of the human huntingtin (HTT) gene. Mutant HTT with expanded polyglutamine (polyQ) is widely expressed in the brain and peripheral tissues, but causes selective neurodegeneration that is most prominent in the striatum and cortex of the brain. Although rodent models of HD have been developed, these models do not satisfactorily parallel the brain changes and behavioural features observed in HD patients. Because of the close physiological, neurological and genetic similarities between humans and higher primates, monkeys can serve as very useful models for understanding human physiology and diseases. Here we report our progress in developing a transgenic model of HD in a rhesus macaque that expresses polyglutamine-expanded HTT. Hallmark features of HD, including nuclear inclusions and neuropil aggregates, were observed in the brains of the HD transgenic monkeys. Additionally, the transgenic monkeys showed important clinical features of HD, including dystonia and chorea. A transgenic HD monkey model may open the way to understanding the underlying biology of HD better, and to the development of potential therapies. Moreover, our data suggest that it will be feasible to generate valuable non-human primate models of HD and possibly other human genetic diseases.
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PMID:Towards a transgenic model of Huntington's disease in a non-human primate. 1848 17

Huntington's disease (HD) is an autosomal, dominantly inherited neurodegenerative disorder, characterized by chorea, involuntary movements, and cognitive impairments. Tremendous progress has been made since the discovery of HD gene in 1993, in terms of developing animal models to study the disease process, unraveling the expression and function of wild-type and mutant huntingtin (Htt) proteins in the central and peripheral nervous systems, and understanding expanded CAG repeat containing mutant Htt protein interactions with CNS proteins in the disease process. HD progression has been found to involve several pathomechanisms, including expanded CAG repeat protein interaction with other CNS proteins, transcriptional dysregulation, calcium dyshomeostasis, abnormal vesicle trafficking, and defective mitochondrial bioenergetics. Recent studies have found that mutant Htt is associated with mitochondria and causes mitochondrial structural changes, decreases mitochondrial trafficking, and impairs mitochondrial dynamics in the neurons affected by HD. This article discusses recent developments in HD research, with a particular focus on intracellular and intramitochondrial calcium influx, mitochondrial DNA defects, and mitochondrial structural and functional abnormalities in HD development and progression. Further, this article outlines the current status of mitochondrial therapeutics with a special reference to Dimebon.
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PMID:Mitochondrial structural and functional dynamics in Huntington's disease. 1939 59

We present the clinical, electrophysiological and molecular genetic findings of a 58-year-old male with genetically confirmed Huntington's disease (HD) and concurrent clinically definite ALS by El Escorial criteria. The patient presented with asymmetric upper limb amyotrophy and weakness, and subsequently developed chorea and cognitive change. Genetic testing confirmed the presence of expanded trinucleotide repeats in huntingtin, consistent with a diagnosis of Huntington's disease. This case confirms the rare coexistence of Huntington's disease and motor neuron degeneration.
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PMID:Huntington's disease presenting as amyotrophic lateral sclerosis. 2000 77

Huntington's disease (HD) is characterized clinically by chorea, psychiatric disturbances, and dementia, while it is characterized pathologically by neuronal inclusions as well as striatal and cortical neurodegeneration. The neurodegeneration arises from the loss of long projection neurons in the cortex and striatum. In this study, we investigated the role of apoptosis signal-regulating kinase 1 (Ask1) in the pathogenesis of HD. We analyzed the expression of Ask1 and huntingtin (htt) within the striatum and cortex and also examined the interaction of Ask1 with htt fragments in HD (R6/2) mice. Additionally, we inhibited Ask1 and analyzed the resulting changes in brain-derived neurotrophic factor (BDNF) expression, motor function, and striatal atrophy. Ask1 activity was blocked using an Ask1 antibody raised against the C-terminus of the Ask1 protein. The anti-Ask1 antibody was infused into the striatum of the HD mice for four weeks using a micro-osmotic pump. The levels of Ask1 protein and endoplasmic reticulum (ER) stress were increased in HD mice. Binding of inactivated Ask1 to htt fragments was more prevalent in the cytosol than the nucleus of cortical neurons. Binding of inactivated Ask1 to htt fragments prevented translocation of the htt fragments into the nucleus, resulting in an improvement in motor dysfunction and atrophy. In the normal state, active Ask1 may help htt fragments enter the nucleus, while inactivated Ask1 hinders this translocation by binding to but not releasing fragmented htt into the nucleus. We propose that Ask1 may interact with htt fragments and subsequently induce ER stress. BDNF depletion may be prevented by targeting Ask1; this would decrease ER stress and possibly ameliorate behavioral or anatomical abnormalities that accompany HD. Therefore, regulating the amounts and activity of the Ask1 protein is a novel strategy for treatment of HD.
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PMID:Inhibition of apoptosis signal-regulating kinase 1 reduces endoplasmic reticulum stress and nuclear huntingtin fragments in a mouse model of Huntington disease. 1964 9

Huntington's disease (HD) is an inherited progressive neurodegenerative disorder associated with involuntary abnormal movements (chorea), cognitive deficits and psychiatric disturbances. The disease is caused by an abnormal expansion of a CAG repeat located in exon 1 of the gene encoding the huntingtin protein (Htt) that confers a toxic function to the protein. The most striking neuropathological change in HD is the preferential loss of medium spiny GABAergic neurons in the striatum. The mechanisms underlying striatal vulnerability in HD are unknown, but compelling evidence suggests that mitochondrial defects may play a central role. Here we review recent findings supporting this hypothesis. Studies investigating the toxic effects of mutant Htt in cell culture or animal models reveal mitochondrial changes including reduction of Ca2+ buffering capacity, loss of membrane potential, and decreased expression of oxidative phosphorylation (OXPHOS) enzymes. Striatal neurons may be particularly vulnerable to these defects. One hypothesis is that neurotransmission systems such as dopamine and glutamate exacerbate mitochondrial defects in the striatum. In particular, mitochondrial dysfunction facilitates impaired Ca2+ homeostasis linked to the glutamate receptor-mediated excitotoxicity. Also dopamine receptors modulate mutant Htt toxicity, at least in part through regulation of the expression of mitochondrial complex II. All these observations support the hypothesis that mitochondria, acting as "sensors" of the neurochemical environment, play a central role in striatal degeneration in HD.
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PMID:Mitochondria in Huntington's disease. 1968 70

Chorea is an involuntary movement that appears along with many diseases, it is commonly described as a frequent, brief, sudden, and twitch-like movement that is manifested in various parts of the body in a chaotic pattern. Huntington disease (HD) is a representative neurodegenerative disorder that presents with chorea. Although HD is caused by a CAG-repeat expansion in the IT-15 gene which encodes huntingtin, a small group of patients showing the symptoms and signs of HD do not have the causative CAG-repeat expansion, thereby showing that autosomal-dominant chorea is genetically heterogeneous. Recent studies have demonstrated that such disorders include dentatorubral pallidoluysian atrophy (DRPLA), spinocerebellar ataxia type 17 (SCA17), Huntington disease like 1 (HDL1), Huntington disease like 2 (HDL2), and benign hereditary chorea (BHC). We recently identified 2 Japanese families with adult-onset benign chorea that was inherited in an autosomal-dominant pattern that was linked to chromosome 8q22.2-q23.3, and we named this disease "benign hereditary chorea type 2 (BHC2)". Chorea can also be caused by a wide range of other hereditary diseases and sporadic disease such as metabolic, infectious, inflammatory, vascular, and drug-induced syndromes. In this article, we have reviewed the clinical features of the disorders associated with chorea.
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PMID:[Differential diagnosis of chorea]. 1969 86

Huntington's disease (HD) is an autosomal dominant neurodegenerative disease resulting from the expansion of a glutamine repeat in the huntingtin (Htt) protein. Current therapies are directed at managing symptoms such as chorea and psychiatric disturbances. In an effort to develop a therapy directed at disease prevention we investigated the utility of highly specific, anti-Htt intracellular antibodies (intrabodies). We previously showed that V(L)12.3, an intrabody recognizing the N terminus of Htt, and Happ1, an intrabody recognizing the proline-rich domain of Htt, both reduce mHtt-induced toxicity and aggregation in cell culture and brain slice models of HD. Due to the different mechanisms of action of these two intrabodies, we then tested both in the brains of five mouse models of HD using a chimeric adeno-associated virus 2/1 (AAV2/1) vector with a modified CMV enhancer/chicken beta-actin promoter. V(L)12.3 treatment, while beneficial in a lentiviral model of HD, has no effect on the YAC128 HD model and actually increases severity of phenotype and mortality in the R6/2 HD model. In contrast, Happ1 treatment confers significant beneficial effects in a variety of assays of motor and cognitive deficits. Happ1 also strongly ameliorates the neuropathology found in the lentiviral, R6/2, N171-82Q, YAC128, and BACHD models of HD. Moreover, Happ1 significantly prolongs the life span of N171-82Q mice. These results indicate that increasing the turnover of mHtt using AAV-Happ1 gene therapy represents a highly specific and effective treatment in diverse mouse models of HD.
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PMID:Intrabody gene therapy ameliorates motor, cognitive, and neuropathological symptoms in multiple mouse models of Huntington's disease. 1986 71

Huntington's disease (HD) is an inherited genetic disorder, characterized by cognitive dysfunction and abnormal body movements called chorea. George Huntington, an Ohio physician, described the disease precisely in 1872. HD is a dominantly inherited disorder, characterized by progressive neurodegeneration of the striatum but also involves other regions, primarily the cerebral cortex. The mutation responsible for this fatal disease is an abnormally expanded and unstable CAG repeat within the coding region of the gene encoding the huntingtin protein. Various hypotheses have been put forward to explain the pathogenic mechanisms of mutant huntingtin-induced neuronal dysfunction and cell death. None of these hypotheses, however, offers a clear explanation; thus, it remains a topic of research interest. HD is considered to be an important disease, embodying many of the major themes in modern neuroscience, including molecular genetics, selective neuronal vulnerability, excitotoxicity, mitochondrial dysfunction, apoptosis and transcriptional dysregulation. A number of recent reports have concluded that oxidative stress plays a key role in HD pathogenesis. Although there is no specific treatment available to block disease progression, treatments are available to help in controlling the chorea symptoms. As animal models are the best tools to evaluate any therapeutic agent, there are also different animal models available, mimicking a few or a larger number of symptoms. Each model has its own advantages and limitations. The present review deals with the pathophysiology and various cascades contributing to HD pathogenesis and progression as well as drug targets, such as dopaminergic, gamma-amino butyric acid (GABA)ergic, glutamate adenosine receptor, peptidergic pathways, cannabinoid receptor, and adjuvant therapeutic drug targets such as oxidative stress and mitochondrial dysfunction that can be targeted for future experimental study. The present review also focuses on the animal models (behavioral and genetic) used to unravel pathogenetic mechanisms and the identification of novel drug targets.
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PMID:Huntington's disease: pathogenesis to animal models. 2036 Jun 11


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