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)

A 55 year-old male experienced a dystonia of the right upper limb followed by a ptosis with complete ophthalmoplegia and cataract. He developed a sensory neuropathy and personality changes. Ragged-red fibers were found on muscle biopsy. There was a major defect in complex III and IV activity.
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PMID:[Segmental dystonia and mitochondrial encephalomyopathy]. 131 69

A 45-year-old woman with an acquired multifocal neurologic syndrome, including chorea, dystonia, cerebellar dysfunction, multiple cranial neuropathies, and pure sensory neuropathy, was found at autopsy to have oat cell carcinoma. Neuropathologic examination revealed several features typically associated with remote effects of malignancy on the nervous system. We believe that this is the first described case of chorea as a remote effect of malignancy.
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PMID:Chorea and dystonia: a remote effect of carcinoma. 285 39

C57BL/KsJ db/db inbred mice have an hereditary autosomal recessive disease resembling in some respects maturity onset human diabetes mellitus. At 8--11 months of age, they displayed intermittent symptoms suggestive of a mild sensory neuropathy. These symptoms consisted of adduction of their hind limbs and flexing hind paws when raised by the tail, and inability to maintain their position on the roto wheel. Peripheral nerves and sensory ganglia of the diabetic mice were compared with those of the unafflicted littermates and studied with respect to Schwann cell counts and myelinated nerve fiber diameter measurements. In addition, teased fibers of peripheral nerves were compared for obvious changes in internodal distance and demyelination. Chromatolytic neurons were moe abundant in lumbosacral spinal ganglia of diabetic mice than in corresponding ganglia of controls or in more anterior spinal ganglia and trigeminal ganglia of diabetics. Histologic studies showed an increase in Schwann cell counts in longitudinal sections of peripheral nerves. A similar but larger increase was observed in peripheral nerves of mice affected with an hereditary sensory neuropathy, dystonia musculorum. A small but general decrease in myelinated fiber diameter was observed in sensory and motor nerves.
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PMID:Peripheral neuropathy in mouse hereditary diabetes mellitus. I. Comparison of neurologic, histologic, and morphometric parameters with dystonic mice. 696 18

In normal subjects the execution of single rapid one-joint movements is characterized by an electromyographic (EMG) pattern composed of three discrete bursts of activity; two bursts (first and second agonist bursts, or AG1 and AG2) are present in the agonist muscle separated by an almost complete period of electrical silence. During this pause, another burst (antagonist burst, or ANT) occurs in the antagonist muscle. If a rapid movement is executed during tonic activation of the agonist muscle, tonic activity is inhibited just prior to AG1 onset (agonist inhibition). Similarly, if the movement is performed during tonic activation of the antagonist muscle, such activity is also inhibited prior to AG1 onset (antagonist inhibition). Antagonist inhibition also starts prior to AG1 onset and lasts until ANT onset. A general descriptor of the kinematic features related to the EMG pattern described above is a symmetrical and unimodal velocity profile that is bell-shaped and shows an acceleration time roughly equal to the deceleration time. This holds true for movements performed under low accuracy constraints; as accuracy demands become stricter and stricter, the peak velocity decreases but, as long as the movement is made with one continuous trajectory, the velocity profile remains roughly symmetrical. In general terms, the function of AG1 is to provide the impulsive force to start the movement; the function of ANT is to halt the movement at the desired end-point; and the function of AG2 is to dampen out the oscillations which might occur at the end of the movement. The timing and size of the bursts vary according to the speed and amplitude of the movement. The origin of the EMG pattern is a central programme, but afferent inputs can modulate the voluntary activity. In this paper, we also review the EMG and kinematic abnormalities that are present during the execution of single-joint, rapid arm movements in patients with Parkinson's disease, Huntington's disease, Sydenham's chorea, dystonia, athetosis, cerebellar deficits, upper motor neuron syndrome, essential tremor and large-fibre sensory neuropathy. The data from these studies lead us to the following conclusions: (i) the basal ganglia have a role in scaling the size of AG1, reinforcing the voluntary command and inhibiting inappropriate EMG activity; (ii) the cerebellum has a role in timing the voluntary bursts and probably in implementing muscle force phasically; (iii) the corticospinal tract has a role in determining spatial and temporal recruitment of motor units; (iv) proprioceptive feedback is not necessary to produce the triphasic pattern but it contributes to the accuracy of both the trajectory and the end-point of rapid movements.
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PMID:Single-joint rapid arm movements in normal subjects and in patients with motor disorders. 880 Sep 55

Dystonia musculorum (dt) is an autosomal recessive sensory neuropathy in mice resulting from a mutation in the gene encoding the cytoskeletal linker protein Bpag1. In addition to neurodegeneration, dt mice display myelination abnormalities in the peripheral nervous system. In this report we investigated whether myelination abnormalities are also present in the central nervous system of dt(Tg4) mice. Transcripts for both neural isoforms of Bpag1 (a1 and a2) were detected in optic nerves and spinal cords of wild-type mice. Light microscopy of resin-embedded thin sections revealed a reduction in myelinated axons in both optic nerves and spinal cords in dt(Tg4) mice. As well, hypermyelinated axons were detected in these tissues. Ultrastructural analysis of optic nerves and spinal cords from dt(Tg4) mice revealed an increase in the number of amyelinated axons, the presence of hypo- and hypermyelinated axons, and redundant myelin that course away from axons. Changes in the level of myelin proteins accompanied the morphological alterations. Myelin-associated glycoprotein levels were reduced in optic nerves of dt(Tg4) mice, and myelin basic protein levels were altered in optic nerves, sciatic nerves, and spinal cords of affected mice. Short-term cultures of oligodendrocytes derived from dt(Tg4) mice did not show morphological alterations.
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PMID:Alterations in myelination in the central nervous system of dystonia musculorum mice. 1211 5

Dystonia musculorum (dt) mice suffer from a severe sensory neuropathy caused by mutations in the gene encoding the cytoskeletal cross-linker protein dystonin/bullous pemphigoid antigen 1 (Bpag1). Loss of function of dystonin/Bpag1 within neurons leads to a loss in the maintenance of cytoskeletal organization and to the development of focal axonal swellings prior to death of the neuron. In the present study, we demonstrate that neurons within the sciatic nerves of dt27J mice undergo axonal degeneration as has been previously reported for the dorsal roots. Furthermore, ultrastructural studies reveal a perturbed organization of the neurofilament and microtubule networks within the axons of sciatic nerves in dt27J mice. The disrupted cytoskeletal organization suggested that axonal transport is affected in dt mice. To address this, we assessed fast axonal transport by measuring the rate of accumulation of acetylcholinesterase (AChE) proximal and distal to a surgically introduced ligature on the sciatic nerves of normal and dt27J mice. Our findings demonstrate that axonal transport of AChE in both orthograde and retrograde directions is markedly affected, and allow us to conclude that axonal transport defects do exist in the sciatic nerves of dt27J mice.
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PMID:Impaired fast axonal transport in neurons of the sciatic nerves from dystonia musculorum mice. 1285 70

Dystonia musculorum (dt) is a mouse inherited sensory neuropathy caused by mutations in the dystonin gene. While the primary pathology lies in the sensory neurons of dt mice, the overt movement disorder suggests motor neurons may also be affected. Here, we report on the contribution of motor neurons to the pathology in dt(27J) mice. Phenotypic dt(27J) mice display reduced alpha motor neuron cell number and eccentric alpha motor nuclei in the ventral horn of the lumbar L1 spinal cord region. A dramatic reduction in the total number of motor axons in the ventral root of postnatal day 15 dt(27J) mice was also evident. Moreover, analysis of the trigeminal nerve of the brainstem showed a 2.4 fold increase in number of degenerating neurons coupled with a decrease in motor neuron number relative to wild type. Aberrant phosphorylation of neurofilaments in the perikaryon region and axonal swellings within the pre-synaptic terminal region of motor neurons were observed. Furthermore, neuromuscular junction staining of dt(27J) mouse extensor digitorum longus and tibialis anterior muscle fibers showed immature endplates and a significant decrease in axon branching compared to wild type littermates. Muscle atrophy was also observed in dt(27J) muscle. Ultrastructure analysis revealed amyelinated motor axons in the ventral root of the spinal nerve, suggesting a possible defect in Schwann cells. Finally, behavioral analysis identified defective motor function in dt(27J) mice. This study reveals neuromuscular defects that likely contribute to the dt(27J) pathology and identifies a critical role for dystonin outside of sensory neurons.
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PMID:Motor unit abnormalities in Dystonia musculorum mice. 2169 55

Mutations in the mitochondrial DNA polymerase gamma (POLG) cause a highly pleomorphic disease spectrum, and reports about their frequencies in ataxia populations yield equivocal results. This leads to uncertainties about the role of POLG genetics in the workup of patients with unexplained ataxia. A comprehensive characterization of POLG-associated ataxia (POLG-A) will help guide genetic diagnostics and advance our understanding of the disease processes underlying POLG-A. Thirteen patients with POLG-A were assessed by standardized clinical investigation, nerve conduction studies, motor-evoked potentials, magnetic resonance imaging (MRI) and transcranial sonography (TCS). The findings were compared with 13 matched patients with Friedreich's ataxia (FA). In addition to the well-known POLG-associated features of chronic external ophthalmoplegia (100 %), areflexia to the lower extremity (100 %), impaired vibration sense (100 %), bilateral ptosis (69 %) and epilepsy (38 %), also hyperkinetic movement disorders were frequent in POLG-A patients, including chorea (31 %), dystonia (31 %) and myoclonus (23 %). Similar to FA, polyneuropathy was of sensory axonal type (100 %). In contrast to FA, none of the POLG-A patients showed impaired central motor conduction. TCS demonstrated less enlargement of the fourth ventricle and more diffuse cerebellar hyperechogenicity in POLG-A. Corresponding to TCS, MRI revealed no or only mild cerebellar atrophy in most POLG-A patients (85 %). POLG ataxia presents with the clinical characteristics of both afferent and cerebellar ataxia. Cerebellar alterations diffusely involve various parts of the cerebellum, yet cerebellar atrophy is generally mild. POLG-A presents with a high load of distinct non-ataxia features, namely, sensory neuropathy, external ophthalmoplegia, ptosis, epilepsy and/or hyperkinetic movement disorders. Involvement of the corticospinal tract, however, is rare.
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PMID:Characterizing POLG ataxia: clinics, electrophysiology and imaging. 2252 63

A newly identified lethal form of hereditary sensory and autonomic neuropathy (HSAN), designated HSAN-VI, is caused by a homozygous mutation in the bullous pemphigoid antigen 1 (BPAG1)/dystonin gene (DST). The HSAN-VI mutation impacts all major neuronal BPAG1/dystonin protein isoforms: dystonin-a1, -a2 and -a3. Homozygous mutations in the murine Dst gene cause a severe sensory neuropathy termed dystonia musculorum (dt). Phenotypically, dt mice are similar to HSAN-VI patients, manifesting progressive limb contractures, dystonia, dysautonomia and early postnatal death. To obtain a better molecular understanding of disease pathogenesis in HSAN-VI patients and the dt disorder, we generated transgenic mice expressing a myc-tagged dystonin-a2 protein under the regulation of the neuronal prion protein promoter on the dt(Tg4/Tg4) background, which is devoid of endogenous dystonin-a1 and -a2, but does express dystonin-a3. Restoring dystonin-a2 expression in the nervous system, particularly within sensory neurons, prevented the disorganization of organelle membranes and microtubule networks, attenuated the degeneration of sensory neuron subtypes and ameliorated the phenotype and increased life span in these mice. Despite these improvements, complete rescue was not observed likely because of inadequate expression of the transgene. Taken together, this study provides needed insight into the molecular basis of the dt disorder and other peripheral neuropathies including HSAN-VI.
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PMID:Transgenic expression of neuronal dystonin isoform 2 partially rescues the disease phenotype of the dystonia musculorum mouse model of hereditary sensory autonomic neuropathy VI. 2438 11

Oligodendrocyte differentiation and central nervous system myelination require massive reorganization of the oligodendrocyte cytoskeleton. Loss of specific actin- and tubulin-organizing factors can lead to impaired morphological and/or molecular differentiation of oligodendrocytes, resulting in a subsequent loss of myelination. Dystonin is a cytoskeletal linker protein with both actin- and tubulin-binding domains. Loss of function of this protein results in a sensory neuropathy called Hereditary Sensory Autonomic Neuropathy VI in humans and dystonia musculorum in mice. This disease presents with severe ataxia, dystonic muscle and is ultimately fatal early in life. While loss of the neuronal isoforms of dystonin primarily leads to sensory neuron degeneration, it has also been shown that peripheral myelination is compromised due to intrinsic Schwann cell differentiation abnormalities. The role of this cytoskeletal linker in oligodendrocytes, however, remains unclear. We sought to determine the effects of the loss of neuronal dystonin on oligodendrocyte differentiation and central myelination. To address this, primary oligodendrocytes were isolated from a severe model of dystonia musculorum, Dstdt-27J, and assessed for morphological and molecular differentiation capacity. No defects could be discerned in the differentiation of Dstdt-27J oligodendrocytes relative to oligodendrocytes from wild-type littermates. Survival was also compared between Dstdt-27J and wild-type oligodendrocytes, revealing no significant difference. Using a recently developed migration assay, we further analysed the ability of primary oligodendrocyte progenitor cell motility, and found that Dstdt-27J oligodendrocyte progenitor cells were able to migrate normally. Finally, in vivo analysis of oligodendrocyte myelination was done in phenotype-stage optic nerve, cerebral cortex and spinal cord. The density of myelinated axons and g-ratios of Dstdt-27J optic nerves was normal, as was myelin basic protein expression in both cerebral cortex and spinal cord. Together these data suggest that, unlike Schwann cells, oligodendrocytes do not have an intrinsic requirement for neuronal dystonin for differentiation and myelination.
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PMID:Cytoskeletal Linker Protein Dystonin Is Not Critical to Terminal Oligodendrocyte Differentiation or CNS Myelination. 2688 50


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