Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
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Target Concepts:
Gene/Protein
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Enzyme
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Query: UMLS:C0013421 (
dystonia
)
8,418
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Myoclonus
dystonia
(DYT11) is a movement disorder caused by loss-of-function mutations in
SGCE
and characterized by involuntary jerking and
dystonia
that frequently improve after drinking alcohol. Existing transgenic mouse models of DYT11 exhibit only mild motor symptoms, possibly due to rodent-specific developmental compensation mechanisms, which have limited the study of neural mechanisms underlying DYT11. To circumvent potential compensation, we used short hairpin RNA (shRNA) to acutely knock down S
gce
in the adult mouse and found that this approach produced
dystonia
and repetitive, myoclonic-like, jerking movements in mice that improved after administration of
ethanol
. Acute knockdown of
Sgce
in the cerebellum, but not the basal ganglia, produced motor symptoms, likely due to aberrant cerebellar activity. The acute knockdown model described here reproduces the salient features of DYT11 and provides a platform to study the mechanisms underlying symptoms of the disorder, and to explore potential therapeutic options.
...
PMID:Acute cerebellar knockdown of
Sgce
reproduces salient features of myoclonus-dystonia (DYT11) in mice. 3186 64
Ethanol
-responsive movement disorders are a group of movement disorders of which clinical manifestation could receive significant improvement after
ethanol
intake, including essential tremor, myoclonus-
dystonia
, and some other hyperkinesia. Emerging evidence supports that the sensitivity of these conditions to
ethanol
might be attributed to similar anatomical targets and pathophysiologic mechanisms. Cerebellum and cerebellum-related networks play a critical role in these diseases. Suppression of inhibitory neurotransmission and hyper-excitability of these regions are the key points for pathogenesis. GABA pathways, the main inhibitory system involved in these regions, were firstly linked to the pathogenesis of these diseases, and GABA
A
receptors and GABA
B
receptors play critical roles in
ethanol
responsiveness. Moreover, impairment of low-voltage-activated calcium channels, which were considered as a contributor to oscillation activity of the nervous system, also participates in the sensitivity of
ethanol
in relevant disease. Glutamate transporters and receptors that are closely associated with GABA pathways are the action sites for
ethanol
as well. Accordingly, alternative medicines aiming at these shared mechanisms appeared subsequently to mimic
ethanol
-like effects with less liability, and some of them have achieved positive effects on different diseases with well-tolerance. However, more clinical trials with a large sample and long-term follow-ups are needed for pragmatic use of these medicines, and further investigations on mechanisms will continue to deepen the understanding of these diseases and also accelerate the discovery of ideal treatment.
...
PMID:Mechanisms and Pharmacotherapy for Ethanol-Responsive Movement Disorders. 3298 23
Patients with essential tremor, vocal tremor, torticollis, myoclonus-
dystonia
and posthypoxic myoclonus often benefit in a surprisingly rapid and robust manner from ingestion of a modest amount of alcohol (
ethanol
). Despite considerable investigation, the mechanism of
ethanol
's ability to produce this effect remains a mystery. In this paper, we review the pharmacology of
ethanol
and its analogue GHB (or sodium oxybate), summarize the published literature of alcohol-responsive hyperkinetic movement disorders, and demonstrate videos of patients we have treated over the last fifteen years with either an
ethanol
challenge or with chronic sodium oxybate therapy. We then propose a novel explanation for this phenomenon-namely, that ingestion of
modest
doses of
ethanol
(or sodium oxybate) normalizes the aberrant motor networks underling these disorders. We propose that alcohol and its analogues improve clinical symptoms and their physiologic correlate by restoring the normal firing pattern of the major outflow pathways of the cerebellum (the Purkinje cells and deep cerebellar nuclei), We present evidence to support this hypothesis in animal models and in affected patients, and suggest future investigations to test this model.
...
PMID:Alcohol-Responsive Hyperkinetic Movement Disorders-a Mechanistic Hypothesis. 3317 85
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