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)

The underlying mechanisms of various types of hereditary dystonia, a common movement disorder, are still unknown. Recent findings in a genetic model of a type of paroxysmal dystonia, the dt(sz) mutant hamster, pointed to striatal dysfunctions. In the present study, immunhistochemical experiments demonstrated a marked decrease in the number and density of parvalbumin-immunoreactive GABAergic interneurons in all striatal subregions of mutant hamsters. To examine the functional relevance of the reduction of these inhibitory interneurons, the effects of the GABA(A) receptor agonist muscimol on severity of dystonia were examined after microinjections into the striatum and after systemic administrations. Muscimol improved the dystonic syndrome after striatal injections to a similar extent as after systemic treatment, supporting the importance of the deficiency of striatal GABAergic interneurons for the occurrence of the motor disturbances. The disinhibition of striatal GABAergic projection neurons, as suggested by recent extracellular single-unit recordings in dt(sz) hamsters, should lead to an abnormal neuronal activity in the basal ganglia output nuclei. Indeed, a significantly decreased basal discharge rate of entopeduncular neurons was found in dt(sz) hamsters. We conclude that a deficit of striatal GABAergic interneurons leads by disinhibition of striatal GABAergic projection neurons to a reduced activity in the entopeduncular nucleus, i.e., to a decreased basal ganglia output. This finding is in line with the current hypothesis about the pathophysiology of hyperkinesias. The results indicate that striatal interneurons deserve attention in basic and clinical research of those movement disorders.
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PMID:Deficit of striatal parvalbumin-reactive GABAergic interneurons and decreased basal ganglia output in a genetic rodent model of idiopathic paroxysmal dystonia. 1099 51

Functional MRI (fMRI), visualizing changes in cerebral blood oxygenation, has to date not been performed either in patients with writer's cramp or in healthy subjects during writing. We compared the cerebral and cerebellar activation pattern of 12 patients with writer's cramp during writing with a group of 10 healthy subjects performing the same tasks over 30-s periods of rest or writing. Sixty echo planar imaging multislice datasets were analysed using SPM96 software. Data were analysed for each subject individually and groupwise for patients vs. controls. Healthy subjects showed a significant activation of the ipsilateral dentate nucleus, contralateral cerebellar hemisphere, contralateral primary sensorimotor cortex, and contralateral precentral gyrus during writing. Patients with writer's cramp showed significantly greater activation of the ipsilateral cerebellar hemisphere than controls. Also the activation in the primary sensorimotor cortex extended further caudally and anteriorly towards the premotor association area. Activation was observed in the thalamus during writing only among the patients. Our results indicate an increased basal ganglia output via the thalamus to the motor and premotor cortical areas in dystonia patients and support the notion of disinhibition of the motor cortex leading to cocontractions and dystonic postures.
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PMID:Cerebral activation patterns in patients with writer's cramp: a functional magnetic resonance imaging study. 1126 13

The pathogenesis of idiopathic adult onset dystonia (ID) is still unclear. Although neuropathologic studies did not reveal consistent abnormalities, electrophysiologic and neuroimaging findings point toward a disinhibition and overactivity of the frontal motor cortical areas caused by an altered basal ganglia outflow. The lentiform nuclei are assumed to play a major role in this scenario. Recent neurochemical analysis of brain tissue stimulated by transcranial ultrasound studies demonstrated an increased copper content of the lentiform nuclei in patients with ID. The shift of brain copper level may substantially influence neuronal activity causing a reduced inhibitory output from the lentiform nuclei to the motor cortex. The reason for the presumably altered copper metabolism is not clear, but preliminary findings suggest that reduced levels of the Menkes protein, a membrane ATPase exporting copper out of the cells, may be implicated. Disturbances of brain copper metabolism may explain various phenomena of ID; however, it needs to be determined whether these observations represent the basic pathogenetic mechanism of ID or reflect another as yet unidentified pathologic process.
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PMID:Evidence for disturbances of copper metabolism in dystonia: from the image towards a new concept. 1175 12

Spasticity is only one of several components of the upper motor neurone (UMN) syndrome, known collectively as the 'positive' phenomena, that are characterized by muscle overactivity. Other components include tendon hyper-reflexia, clonus, the clasp-knife phenomenon, flexor and extensor spasms, a Babinski sign, and spastic dystonia. Spasticity is a form of hypertonia due to hyperexcitable tonic stretch reflexes. It is distinguished from rigidity by its dependence upon the speed of the muscle stretch and by the presence of other positive UMN signs. Hyperactive spinal reflexes mediate most of these positive phenomena, while others are due to disordered control of voluntary movement or abnormal efferent drive. An UMN lesion disturbs the balance of supraspinal inhibitory and excitatory inputs, producing a state of net disinhibition of the spinal reflexes. These include proprioceptive (stretch) and nociceptive (flexor withdrawal and extensor) reflexes. The clinical syndrome resulting from an UMN lesion depends more upon its location and extent, and the time since it occurred, than on the pathology of the lesion. However, the change in spinal reflex excitability cannot simply be due to an imbalance in supraspinal control. The delayed onset after the lesion and the frequent reduction in reflex excitability over time, suggests plasticity in the central nervous system. Knowledge of the electrophysiology and neurochemistry of spinal reflexes, together with the action of antispasticity drugs, helps us to understand the pathophysiology of spasticity.
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PMID:The pathophysiology of spasticity. 1191 43

The underlying mechanisms of idiopathic dystonias are poorly understood. The dystonic phenotype in the dt(sz) mutant hamster, a model of paroxysmal dystonia, has been suggested to be based on a deficit of gamma-aminobutyric acid (GABA)ergic interneurons and changes of the GABA(A)-benzodiazepine receptor complex in the striatum. In order to confirm and extend previous observations, the effects of compounds which bind to different sites of the GABA(A) receptor on the severity of dystonia were determined after striatal microinjections in comparison to systemic treatments in dt(sz) mutants. The GABA(A) receptor agonist (muscimol) and the benzodiazepine (flurazepam) reduced the severity of dystonia after striatal and systemic injections. The antidystonic effects of the barbiturate phenobarbital were less marked both after striatal and intraperitoneal administration of drugs. Intrastriatal injections of GABA delayed the onset of dystonic attacks. Striatal and systemic treatments with the GABA(A) receptor antagonist, bicuculline, and with pentylenetetrazole, which reduces GABAergic function, accelerated the onset of dystonia at subconvulsant doses. The benzodiazepine receptor antagonists flumazenil aggravated dystonia after systemic and intrastriatal injections. In all, the present data substantiate the relevance of striatal GABAergic disinhibition in the pathogenesis of paroxysmal dystonia in dt(sz) mutants.
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PMID:Effects of striatal injections of GABA(A) receptor agonists and antagonists in a genetic animal model of paroxysmal dystonia. 1204 93

An initial report on the therapeutic application of delta 9-THC (THC) (Dronabinol, Marinol) in 8 children resp. adolescents suffering from the following conditions, is given: neurodegenerative disease, mitochondriopathy, posthypoxic state, epilepsy, posttraumatic reaction. THC effected reduced spasticity, improved dystonia, increased initiative (with low dose), increased interest in the surroundings, and anticonvulsive action. The doses ranged from 0.04 to 0.12 mg/kg body weight a day. The medication was given as an oily solution orally in 7 patients, via percutaneous gastroenterostomy tube in one patient. At higher doses disinhibition and increased restlessness were observed. In several cases treatment was discontinued and in none of them discontinuing resulted in any problems. The possibility that THC-induced effects on ion channels and transmitters may explain its therapeutic activity seen in epileptic patients is discussed.
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PMID:On the application of cannabis in paediatrics and epileptology. 1515 80

Adult-onset focal dystonia was the presenting sign of pantothenate kinase-associated neurodegeneration (PKAN) in a patient with a novel homozygous missense mutation (C856T). His brother shared the same mutation and showed similar, albeit minor, motor signs, but a different behavioral profile. Both brothers had an atypical form of PKAN. The neuropsychological assessment showed that, despite a normal Mini-Mental State Examination, both patients presented a deficit of executive functions and of attention. The profile of cognitive impairment in these cases was typically that of a subcortical dementia. Both patients fulfilled Diagnostic and Statistical Manual for Mental Disorders criteria for obsessive-compulsive disorder; however, paranoia was associated with depression and aggressive behavior in Patient 1, whereas Patient 2 had hyperactivity, disinhibition, and euphoria. Our findings suggest that these two brothers had a different pattern of involvement of motor and nonmotor basal ganglia-thalamocortical circuits.
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PMID:Clinical and neuropsychological correlates in two brothers with pantothenate kinase-associated neurodegeneration. 1539 30

Niemann-Pick disease, type C (NPC) is a neurometabolic genetic disorder that is distinguished from other types of Niemann-Pick disease by its later onset, more insidious progression, variable visceromegaly, and abnormalities of intracellular cholesterol metabolism. We report cases in 18-year-old and 20-year-old brothers who presented with disinhibition and involuntary movement of their hands. Both brothers presented various signs such as dementia, vertical supranuclear ophthalmoplegia (VSO), dysarthria, axial and limb dystonia, hyperreflexia, pathologic reflex, cerebellar ataxia, as reported. They also presented startle response. Brain MRI showed diffuse cerebral atrophy and abdominal CT reveals hepato-splenomegaly in both patients. These cases were suspected to be NPC based on dementia, VSO, cerebellar ataxia, hepato-splenomegaly and foam cells in the bone marrow. Generally, the diagnosis of NPC is based on deficient cholesterol esterification and excessive lysosomal filipin staining in cultured skin fibroblasts. However, culture of fibroblasts obtained from a biopsied skin samples is slow. We have rapidly made the diagnosis of NPC in our patients by filipin staining of foam cells from bone marrow. This diagnostic process using a bone marrow smear is more convenient and rapid than previous methods using cultured skin fibroblasts.
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PMID:[Diagnosis of adult type of Niemann-Pick disease (type C) in two brothers by filipin staining of bone marrow smears]. 1572 83

Various types of hereditary dystonia are regarded as a basal ganglia disorder, but the underlying mechanisms are still unknown. In the dt hamster, a genetic animal model of age-dependent paroxysmal dystonia, recent studies demonstrated a reduced density of striatal parvalbumin-immunoreactive (PV) GABAergic interneurons at an age of maximum severity of dystonia in comparison with age-matched nondystonic controls. So far, alterations of other types of striatal interneurons in dt hamsters cannot be excluded. Therefore, we determined the density of calretinin-immunoreactive (CR) interneurons in the dt mutant at an age of maximum severity and after spontaneous remission of dystonia in comparison with age-matched nondystonic controls using an image analysis system and a stereologic counting method in a blinded fashion. At an age of maximum severity of dystonia, CR interneuron density was significantly lower in dt hamsters in comparison with controls (-20%), whereas no significant differences between the animal groups could be detected after spontaneous remission of dystonia. The comparison of CR interneuron density between young hamsters with those at an age of > 90 days revealed a significant ontogenetic decrease of CR interneurons in both animal groups (dt hamsters: -38%, controls: -54%). These results demonstrate that alterations of striatal interneuron density in dt mutants are not restricted to PV ones. A deficit of CR interneurons that coexpress GABA may contribute to previous findings of disinhibition of striatal projection neurons in the dt mutant at an age of maximum expression of dystonia.
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PMID:Age-dependent alterations of striatal calretinin interneuron density in a genetic animal model of primary paroxysmal dystonia. 1614 87

Corticobasal syndrome is characterized by cortical dysfunction and L-dopa-unresponsive Parkinsonism, with asymmetrical onset of clinical presentation and evidence of atrophy and/or hypometabolism at neuroimaging. Recently, the heterogeneous pathologic substrate of corticobasal syndrome has been further expanded to include cases with pathologic diagnosis of frontotemporal lobar degeneration with ubiquitin/TDP-43 (TAR DNA binding protein 43)-positive inclusions associated with progranulin (PGRN) mutations. We report a family in which several individuals have been affected with a dementia/movement disorder phenotype. The proband presented at age 45 with spontaneous left arm levitation, ideational apraxia, asymmetric parkinsonism, and dystonia. Subsequently, he developed limb-kinetic apraxia, left-side hemineglect, memory loss, and executive dysfunction. Magnetic resonance imaging and [F]fluorodeoxyglucose-positron emission tomography studies revealed severe cerebral cortical atrophy and hypometabolism, which were significantly more pronounced in the parietal lobes (right > left). Neuropathologic examination displayed the highest degree of degeneration and ubiquitin/TDP-43 pathology in the proband's parietal areas. Genetic analysis revealed the presence of the c.26C>A PGRN mutation in 1 allele. This mutation has been reported in association with hereditary-dysphasic-disinhibition-dementia, Alzheimer-like dementia, progressive supranuclear palsy, and primary progressive aphasia. The peculiar findings observed in this patient indicate that the parietal lobe may represent the most vulnerable anatomical area in some of the PGRN-associated frontotemporal lobar degeneration with ubiquitin/TDP-43-positive inclusion cases.
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PMID:Corticobasal syndrome associated with the A9D Progranulin mutation. 1791 83


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