Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C1762617 (weakness)
 37,932 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Adult motor neuron disease (amyotrophic lateral sclerosis [ALS]) is a neurodegenerative disorder characterized by loss of motor neurons in the cortex, brain stem, and spinal cord, manifested by upper and lower motor neuron signs and symptoms affecting bulbar, limb, and respiratory musculature. Clinically, the disease course is characterized by progressive weakness, atrophy, spasticity, dysarthria, dysphagia, and respiratory compromise, ultimately resulting in death or mechanical ventilation in the vast majority of patients. Patterns of presentation and pathological features of the disease, along with clinical and electrophysiologic criteria for diagnosis, are discussed in this review. Since 8% to 22% of patients survive more than 10 years without ventilator use, meticulous medical and rehabilitation management is extremely important to ensure optimal health and quality of life in these patients. Major issues in the care of individuals with ALS include weakness and spasticity, impairments in activities of daily living and mobility, communication deficits and dysphagia in those with bulbar involvement, respiratory compromise, fatigue and sleep disorders, pain, and psychosocial distress. Research in ALS changes rapidly, but is currently focused on potential etiologic factors such as glutamate excitotoxicity, role of oxidative stress, autoimmunity to calcium channels, and cytoskeletal abnormalities, as well as related treatment initiatives including glutamate modulators, neurotrophic factors, antioxidants, antiapoptotic factors, and gene therapy. Recently, mutations in the gene encoding Cu/Zn superoxide dismutase were identified in a subset of familial ALS patients. Riluzole, a glutamate antagonist and Na-channel blocker, became the only drug currently approved for treatment of ALS after studies showed a small positive effect on survival. Until a definitive treatment or cure for ALS is found, the multifaceted rehabilitation team approach remains the best hope for improving health and survival in this devastating illness.
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PMID:Evaluation and rehabilitation of patients with adult motor neuron disease. 1045 74

Filamentous tau aggregates are hallmarks of tauopathies, e.g., frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) and amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC). Since FTDP-17 tau gene mutations alter levels/functions of tau, we overexpressed the smallest human tau isoform in the CNS of transgenic (Tg) mice to model tauopathies. These mice acquired age-dependent CNS pathology similarto FTDP-17 and ALS/PDC, including insoluble, hyperphosphorylated tau and argyrophilic intraneuronal inclusions formed by tau-immunoreactive filaments. Inclusions were present in cortical and brainstem neurons but were most abundant in spinal cord neurons, where they were associated with axon degeneration, diminished microtubules (MTs), and reduced axonal transport in ventral roots, as well as spinal cord gliosis and motor weakness. These Tg mice recapitulate key features of tauopathies and provide models for elucidating mechanisms underlying diverse tauopathies, including Alzheimer's disease (AD).
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PMID:Age-dependent emergence and progression of a tauopathy in transgenic mice overexpressing the shortest human tau isoform. 1059 24

Missense mutations in the gene encoding copper zinc superoxide dismutase (SOD1) have been found to cause one form of familial amyotrophic lateral sclerosis (FALS). Although the exact mechanism of disease is unknown, abnormalities in the ability of mutant SOD1 to bind zinc or copper ions may be crucial in the pathogenesis of disease. Because members of the metallothionein (MT) family of zinc and copper binding proteins function as important cellular regulators of metal ion bioavailability in the central nervous system, we used in situ hybridization and immunohistochemistry to study the expression pattern of these molecules in a transgenic mouse model of familial ALS. In adult wild-type mouse spinal cord, expression of MT-I and MT-II is restricted to ependymal cells and a subset of astrocytes located in white matter tracts, while MT-III synthesis is limited to neurons within gray matter. Compared to wild-type littermates, transgenic mice carrying the G93A SOD1 mutation demonstrate markedly increased expression of MT-I and MT-II within astrocytes in both white and gray matter as weakness develops. MT-III synthesis in neurons is also greatly upregulated as G93A SOD1 animals age, with glial cell expression of MT-III evident by later stages of the disease. Changes in MT expression occur before the onset of motor deficits or significant motor neuron pathology in G93A SOD1 mice and remarkably extend beyond ventral horn populations of neurons and glia. These results are consistent with the hypothesis that metallothioneins may serve an early and important protective function in FALS.
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PMID:Metallothionein expression is altered in a transgenic murine model of familial amyotrophic lateral sclerosis. 1071 86

Twelve cases of adult-onset progressive muscular atrophy variant of amyotrophic lateral sclerosis (PMA/ALS) were studied in a small rural population of 1500 in the Republic of Belarus (former Soviet Union). The patients were members of three apparently related kindreds, each showing autosomal dominant pattern of disease inheritance. The average age at clinical onset ranged from 26 to 57 years (mean, 40 years). Each patient suffered from skeletal muscle weakness and wasting, starting in the limbs and spreading to the trunk and neck, with very limited bulbar and no upper motor neuron involvement. Death from respiratory failure occurred from 13 to 48 months (mean, 28 months) after first symptoms. Dramatically decreased number of spinal motor neurons was the most characteristic neuropathologic feature in two autopsied cases. Most of the remaining degenerating neurons contained intracytoplasmic hyaline inclusion bodies. A D101N mutation in exon 4 of the SOD1 gene was identified in a PMA/ALS patient and in one of her three unaffected children. Our data support the view that some subtypes of familial ALS associated with SOD1 mutations may present as PMA. Diagnostic criteria of ALS should be accordingly modified to include the PMA variant of familial ALS.
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PMID:Progressive muscular atrophy variant of familial amyotrophic lateral sclerosis (PMA/ALS). 1098 Mar 8

Motor unit number estimation (MUNE) is a type of electrophysiological technique that measures the approximate number of lower motor neurons (LMNs) innervating a single muscle or a small group of muscles. Low MUNE counts provide evidence of LMN degeneration, but a single MUNE study does not determine if this loss is ongoing, recent or remote in time. Sequential change of MUNE count provides evidence for ongoing degeneration. Furthermore, sequential change in MUNE from a normal to abnormally low count provides evidence for progressive spread of signs within a region or to another region. MUNE has no established ability to identify other diseases that may provide a non-ALS explanation for the signs of LMN degeneration. If MUNE studies were to be incorporated into a future revision of the diagnostic criteria for ALS, prospective studies will be important to define more clearly the sensitivity and specificity of MUNE in patients with ALS and in patients with weakness that does not involve LMN degeneration. In addition to its potential contributions toward the diagnosis of ALS, MUNE may have greater potential in quantifying the rate of progression in studies of the natural history of ALS and the response to experimental treatment.
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PMID:Motor unit number estimation (MUNE): how may it contribute to the diagnosis of ALS? 1146 40

Malnutrition, present in 16-50% of ALS patients, is an independent prognostic factor for worsened survival. It is caused primarily by swallowing dysfunction, resulting from involvement of the lower sets of cranial nerves, but hypermetabolism is also implicated. Malnutrition itself can produce neuromuscular weakness and adversely affect patients' quality of life, thereby creating a vicious circle. The nutritional status of ALS patients can be assessed with dietary review and measurements of weight (W) and height (H). A body mass index (BMI = W/H2) below 18.5-20 kg/m2 indicates a state of malnutrition. Dietary counselling is important, but rapidly becomes insufficient, particularly in bulbar-onset ALS, where enteral nutritional support is then necessary. Percutaneous endoscopic gastrostomy tube placement is well tolerated, and provides more efficient enteral nutrition than nasogastric tube feeding. Enteral nutrition support can improve the respiratory status of ALS patients. The effect on survival remains to be confirmed.
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PMID:Nutritional assessment and survival in ALS patients. 1146 55

The detection of respiratory muscle weakness in ALS is necessary to plan initiation of noninvasive positive pressure ventilation and begin discussion of advanced directives. The authors measured the erect seated and supine forced vital capacity (FVC) in 38 patients with ALS and 15 controls. The supine FVC is significantly lower and the erect--supine FVC difference is significantly greater in patients with complaints of dyspnea, orthopnea, and daytime fatigue.
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PMID:Postural change of forced vital capacity predicts some respiratory symptoms in ALS. 1146 32

Transplantation of hNT Neurons derived from the human teratocarcinoma cell-line (NTera2/D1) has been shown to ameliorate motor dysfunction in a number of injury or disease models in which the deficits are fairly localized. However, these cells have not been used before in a model with more extensive neurodegeneration. The aim of this study is to determine the effects of hNT Neuron transplants on motor neuron function in a mouse model of familial amyotrophic lateral sclerosis (FALS) in which there is a substitution of Alanine for Glycine at position 93 of the human SOD1 gene (G93A). Amyotrophic lateral sclerosis is a fatal degenerative motor neuron disease affecting the spinal cord, brainstem, and cortex. This disease clinically manifests as progressive muscular weakness and atrophy, leading to paralysis and death within 3-5 years of diagnosis. The FALS represents 10-13% of all cases. A range of behavioral tests was used to examine spontaneous locomotor activity, coordination, and muscle strength of mice. Long-term (10-11 weeks) transplantation of hNT Neurons into the L(4)-L(5) segments of the ventral horn spinal cord of FALS(G93A) mice at 7 weeks of age (before onset of overt behavioral symptoms of disease) delayed the onset of motor dysfunction for at least 3 weeks. The average lifespan of the transplanted mice was 128 days compared to 106 days for media-injected group. The last mouse in the hNT Neuron transplanted group was euthanized at 135 days of age when it display partial paralysis of the hindlimbs. Immunohistochemical analysis of the implanted spinal cords demonstrated the survival of grafted hNT Neurons and showed many healthy-appearing motor neurons near the implant site. These results suggest that hNT Neuron transplantation may be a promising therapeutic strategy for ALS.
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PMID:Positive effect of transplantation of hNT neurons (NTera 2/D1 cell-line) in a model of familial amyotrophic lateral sclerosis. 1192 59

Hohara and Kozagawa in the Kii peninsula of Japan are reported to be high-incidence foci of amyotrophic lateral sclerosis (Kii ALS) and parkinsonism-dementia complex (Kii PDC). During the period between 1996 and 1999, three Kii ALS patients and 19 Kii PDC patients were confirmed neurologically in Hohara among which, one Kii ALS patient and two Kii PDC patients were examined neuropathologically. The ratio of positive family history where ALS or PDC occurred within the fourth degree of the relatives was 33.3% in the patients with Kii ALS, 78.9% in those with Kii PDC, and 72.7% in total. The ages of onset were between 57 years and 63 years (mean age: 60.0 years) in the patients with Kii ALS and between 53 years and 74 years (mean age: 66.5 years) in those with Kii PDC. All of the Kii ALS patients were female, and the male to female ratio of the Kii PDC patients was 1:1.7. The clinical features of Kii ALS were basically similar to those of classical ALS. The core clinical features of Kii PDC consisted of dementia and parkinsonism, frequently accompanied by motor neuron symptoms. The cardinal neuropathological features of Kii ALS/PDC included many neurofibrillary tangles (NFTs) associated with loss of nerve cells in the cerebral cortex and the brain stem, as well as morphological alterations diagnostic of ALS. Ultrastructurally, NFTs consisted of paired helical filaments. When we compared the clinical features of these Kii ALS patients with those that had been surveyed in 1969, the male to female ratio changed from male dominance to female dominance and the mean age of the onset of the disease was delayed by approximately 10 years. The most frequent initial symptom had been weakness of the lower limbs in the survey in 1969 and was bulbar palsy in this study. As to Kii PDC, this is the first report of the clinical features of many cases.
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PMID:[Neurological and neuropathological studies of amyotrophic lateral sclerosis/parkinsonism-dementia complex in the Kii Peninsula of Japan]. 1208 Jun 7

Intracytoplasmic filamentous tau inclusions are neuropathological hallmarks of amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) of Guam and the defining lesions of other neurodegenerative disorders known as tauopathies. Here we review current insights into the cell and molecular neuropathology of ALS/PDC, a common tauopathy in the Chamorro population on Guam. We also summarize recent advances in understanding this disorder through studies of transgenic (Tg) mouse models of this tauopathy. Briefly, overexpression of human tau isoforms in the central nervous system of Tg mice resulted in a neurodegenerative tauopathy with a phenotype similar to ALS/PDC. Specifically, argyrophilic, congophilic, and tau immunoreactive inclusions accumulated with age in cortical and brainstem neurons of these mice, but they were most abundant in spinal cord neurons, and the inclusions contained 10- to 20-nm tau-positive straight filaments. There also was extensive gliosis in spinal cord associated with axonal degeneration in the ventral roots, while remaining axons in spinal nerves showed a loss of microtubules and reduced fast axonal transport. With advancing age, these Tg mice showed increasing motor weakness, and this was accompanied by a progressive increase in the phosphorylation and insolubility of brain and spinal cord tau proteins. Thus, tau Tg mice recapitulate key phenotypic features of ALS/PDC neuropathology in an ethnic minority on Guam, and these animal models provide new opportunities to discover novel therapies for this and related tauopathies.
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PMID:Amyotrophic lateral sclerosis/parkinsonism dementia complex: transgenic mice provide insights into mechanisms underlying a common tauopathy in an ethnic minority on Guam. 1209 78


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