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)

Some of the most common diseases in humans occur intermittently in people who are otherwise healthy and active. Such disorders include migraine headache, epilepsy, and cardiac arrhythmias. Because electrical signals are critical to the function of neurons, muscle cells, and heart cells, proteins that regulate electrical signaling in these cells are logical sites where abnormalities might lead to disease. All of these diseases have prominent genetic components. Difficulty in understanding these diseases arises from the complexity of the clinical phenotypes as well as from the genetic heterogeneity that is almost certain to exist. Therefore, early work in may laboratory was aimed at understanding the pathogenesis of rare disorders that are similar in their episodic nature. These disorders of muscle (the periodic paralyses), lead to attacks of weakness that occur intermittently in otherwise normal people. We, and others, have shown that hyperkalemic periodic paralysis (hyperKPP) and paramyotonia congenita (PC) result from mutations in a gene encoding a skeletal muscle sodium channel. We have also shown that hypokalemic periodic paralysis (hypoKPP) is caused by mutations in a gene encoding a voltage-gated calcium channel. The characterization of these diseases as channelopathies has served as a paradigm for other episodic disorders. One example is periodic ataxia, which results from mutations in voltage-gated potassium calcium channels. Long QT syndrome, an episodic cardiac dysrhythmia syndrome, is known to result from mutations in either voltage-gated sodium or potassium channels. We have recently mapped genes that cause a familial paroxysmal dyskinesia (non-kinesiogenic paroxysmal dystonia/choreoathetosis) in humans and a reflex epilepsy in mice. The similarities among all these disorders, including their episodic nature, precipitating factors, and therapeutic responses, are striking. Understanding gained from work in these rare monogenic episodic disorders is not only allowing characterization of the molecular and physiologic basis of these diseases, but may ultimately shed light on our understanding of the pathophysiology of more common and genetically complex disorders of the central nervous system.
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PMID:Channelopathies: ion channel disorders of muscle as a paradigm for paroxysmal disorders of the nervous system. 919 7

A 62 year old woman developed dystonic movements following induction of anesthesia with thalamonal and alfentanil. The patient remained awake during the episode. A small dose of thiopental sodium followed by succinylcholine aborted the unpleasant state. The case is being presented to emphasize the point that even small doses of opioid narcotic can cause tonic movements and frank seizures in some patients.
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PMID:Dystonic movements following thalamonal and alfentanil induction--a case report. 955 16

Analysis of the molecular defects in mouse mutants can identify candidate genes for human neurological disorders. During the past 2 years, mutations in sodium channels, calcium channels and potassium channels have been identified by positional cloning of the spontaneous mouse mutants motor endplate disease, tottering, lethargic and weaver. The phenotypes of four allelic mutations identified in the sodium channel gene Scn8a range from ataxia and muscle weakness through severe dystonia and progressive paralysis, indicating that human mutations in this gene could be associated with a variety of clinical syndromes. Mutations of the calcium channel subunits beta 4 in the lethargic mouse and alpha 1A in the tottering mouse have specific effects on cerebellar function. Targeted mutation of ligand-gated ion channels has also been used to generate new models of neurological disease. We will review these recent achievements and their implications for human neurological disease. The mouse studies indicate that mutations in ion channel genes are likely to be responsible for a broad spectrum of clinical phenotypes in human neurological disorders.
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PMID:Ion channel mutations in mouse models of inherited neurological disease. 956 26

The mouse Scn8a sodium channel and its ortholog Na6 in the rat are abundantly expressed in the CNS. Mutations in mouse Scn8a result in neurological disorders, including paralysis, ataxia, and dystonia. In addition, Scn8a has been observed to mediate unique persistent and resurgent currents in cerebellar Purkinje cells (Raman et al., 1997). To examine the functional characteristics of this channel, we constructed a full-length cDNA clone encoding the mouse Scn8a sodium channel and expressed it in Xenopus oocytes. The electrophysiological properties of the Scn8a channels were compared with those of the Rat1 and Rat2 sodium channels. Scn8a channels were sensitive to tetrodotoxin at a level comparable to that of Rat1 or Rat2. Scn8a channels inactivated more rapidly and showed differences in their voltage-dependent properties compared with Rat1 and Rat2 when only the alpha subunits were expressed. Coexpression of the beta1 and beta2 subunits modulated the properties of Scn8a channels, but to a lesser extent than for the Rat1 or Rat2 channels. Therefore, all three channels showed similar voltage dependence and inactivation kinetics in the presence of the beta subunits. Scn8a channels coexpressed with the beta subunits exhibited a persistent current that became larger with increasing depolarization, which was not observed for either Rat1 or Rat2 channels. The unique persistent current observed for Scn8a channels is consistent with the hypothesis that this channel is responsible for distinct sodium conductances underlying repetitive firing of action potentials in Purkinje neurons.
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PMID:Functional analysis of the mouse Scn8a sodium channel. 969 4

Prolonged neuroleptic exposure is often associated with several forms of tardive movement disorders, conditions adversely affecting the patient's quality of life. Risk factors for individual tardive movement disorders is noted. Once they develop, one should modify neuroleptic regimen with preferential replacement of conventional neuroleptics with lower potency ones. The subsequent algorithm is difficult to formulate, and its success is sometimes hampered by coexisting psychiatric disease. Several suggestions to be tried are as follows: high doses of anticholinergics and/or dantrolene sodium against tardive dystonia, and reduction of anticholinergic dose and/or clonidine, a alpha2 agonist, against tardive dyskinesia and tardive akathisia.
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PMID:Algorithms for neuroleptic-associated tardive movement disorders. 1056 Aug 94

Encephalopathy with electrical status epilepticus during sleep or ESES is an age-dependent and self-limited syndrome whose distinctive features include a characteristic age of onset (with a peak around 4-5 years), heterogeneous seizures types (mostly partial motor or unilateral seizures during sleep and absences or falls while awake), a typical EEG pattern (with continuous and diffuse paroxysms occupying at least 85% of slow wave sleep) and a variable neuropsychological regression consisting of IQ decrease, reduction of language (as in acquired aphasia or Landau-Kleffner syndrome), disturbance of behaviour (psychotic states) and motor impairment (in the form of ataxia, dyspraxia, dystonia or unilateral deficit). Despite the long-term favourable outcome of epilepsy and status epilepticus during sleep (SES), the prognosis is guarded because of the persistence of severe neuropsychological and/or motor deficits in approximately half of the patients. No specific treatment has been advocated for this syndrome, but valproate sodium, benzodiazepines and ACTH have been shown to control the seizures and the SES pattern in many cases, although often only temporarily. Subpial transection is proposed in some instances as in non-regressive acquired aphasia. Recent data support the concept that ESES syndrome may include a large subset of developmental or acquired regressive conditions of infancy.
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PMID:Encephalopathy with electrical status epilepticus during slow sleep or ESES syndrome including the acquired aphasia. 1099 61

The human genome contains 10 voltage-gated sodium channel genes, 7 of which are expressed in neurons of the CNS and PNS. The availability of human genome sequences and high-throughput mutation screening methods make it likely that many human disease mutations will be identified in these genes in the near future. Mutations of Scn8a in the mouse demonstrate the broad spectrum of neurological disease that can result from different alleles of the same sodium channel gene. Null mutations of Scn8a produce motor neuron failure, loss of neuromuscular transmission, and lethal paralysis. Less severe mutations result in ataxia, tremor, muscle weakness, and dystonia. The effects of Scn8a mutations on channel properties have been studied in the Xenopus oocyte expression system and in neurons isolated from the mutant mice. The Scn8a mutations provide insight into the mode of inheritance, effect on neuronal sodium currents, and role of modifier genes in sodium channel disease, highlighting the ways in which mouse models of human mutations can be used in the future to understand the pathophysiology of human disease.
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PMID:Sodium channels and neurological disease: insights from Scn8a mutations in the mouse. 1149 24

Spontaneous and induced mutations of neuronal Na+ channels in human patients and mutant mice result in a broad range of neurological-disease. Epilepsy, a disorder of neuronal hyperexcitability, has been associated with delayed inactivation of SCN2A in mice, and with altered kinetics of SCN1A in human patients. Movement disorders including tremor, ataxia, dystonia and paralysis have been observed in mice with mutations of SCN8A. Electrophysiological recordings from neurons isolated from mice with mutations in individual channels reveal the contributions of each channel to in vivo firing patterns. In addition to monogenic disease, Na+ channel mutations are likely to contribute to polygenic disease susceptibility and to normal variation in neuronal function. Advances in molecular methods coupled with genomic sequences from the Human Genome Project will permit identification of many new patient mutations and generation of animal models to dissect their physiological and cellular consequences.
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PMID:Mutations of voltage-gated sodium channels in movement disorders and epilepsy. 1177 52

Dystonic mutant dt(sz) hamsters are a model for paroxysmal dystonia. Handling/stress provoke the dystonic attacks. This phenomenon subsedes with maturation, but can be reinvoked when these animals receive sodium channel blockers such as lamotrigine, suggesting a dysfunction of striatal sodium channels. Voltage-gated fast sodium currents (I(Na(+))) were studied in acutely isolated striatal neurons from healthy and dt(sz) hamsters in whole-cell voltage clamp recordings. The action of lamotrigine was tested on (a) current/voltage relationship, (b) kinetics, and (c) steady-state inactivation and activation. Under control conditions, properties of I(Na(+)) were not different between healthy and dt(sz) neurons. With lamotrigine, however, (a) peak currents were significantly less depressed by the drug in neurons from dt(sz) hamsters as compared to healthy cells, and (b) the steady-state inactivation curve shift of I(Na(+)) was less pronounced in dt(sz) neurons. The results suggest that in dt(sz) hamsters, fast sodium currents in striatal neurons are more resistant to blockade. This sodium channel alteration might be causal for a functional imbalance between input and output structures of the basal ganglia under conditions of compromised I(+)(Na).
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PMID:Sodium currents in striatal neurons from dystonic dt(sz) hamsters: altered response to lamotrigine. 1189 77

Extrapontine (EPM) and central pontine myelinolysis (CPM) are rare and frequently related to rapid correction of hyponatremia. We describe a 60-year-old woman who developed an unusual evolving spectrum of movement disorders secondary to EPM and CPM following intravenous sodium replacement therapy for severe hyponatremia. She presented initially with confusion, generalized coarse postural limb tremor, myoclonic jerks and quadriparesis. Subsequently her mental state improved and her tremor and weakness resolved. Over the following months, she developed progressive painful dystonia of her facial musculature and lower limbs. This gradually became generalized and associated with choreoathethosis in her limbs. In addition, she had increasing bradykinesia and rigidity, which responded poorly to levodopa treatment. Our case illustrates that while the myelin destruction occurs during the initial insult of the osmotic demyelinating process, its delayed clinical effects resulting from ineffective reorganization of neuronal structures may be progressive, evolve with time, and difficult to treat.
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PMID:Evolving spectrum of movement disorders in extrapontine and central pontine myelinolysis. 1464 2


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