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)

We report the case of a 60-year-old man with autopsy-proven dementia with motor neuron disease (D-MND) and Alzheimer's disease lesion. The patient presented with clumsiness of his right hand at the age of 55 years old and subsequently developed dysarthria, weakness and atrophy of his upper limbs. He was unaffectionate towards his family, repeated the same phrase, and showed severe disorientation of time and place. Neurological examination on admission showed not only diffuse lower motor neuron signs, such as weakness, atrophy, fasciculation and areflexia in both upper limbs, but also dementia (HDS-R 9/30). He died of respiratory insufficiency. Neuropathological examination showed mild atrophy of the frontal and temporal lobes and anterior spinal roots. Microscopic examination of cortical sections revealed degenerative changes with simple atrophy and gliosis, and these changes were predominant in layers 1 and 2 of the frontal and temporal cortices. Using immunohistochemical staining, ubiquitin-positive but tau-negative inclusions were frequently found in neurons of the hippocampal granular cell layers and temporal lobes. Many senile plaques and neurofibrillary tangles were present in all sections of the brain. Our final diagnosis was dementia with motor neuron disease accompanying Alzheimer's disease lesion, because of hypoperfusion in the parietal lobe as well as the frontal lobe demonstrated by SPECT, and the presence of many senile plaques and neurofibrillary tangles in the cerebral cortex. Overlapping of pathologically-proven D-MND and Alzheimer's disease lesion is extremely rare, and this case may improve our understanding of the process of neurodegeneration.
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PMID:[An autopsy case of dementia with motor neuron disease accompanying Alzheimer's disease lesion]. 1188 31

A 25-year-old woman presented with rapidly progressive motor weakness necessitating ventilation 10 months after the onset. Despite immunosuppressive therapy she died 27 months later, without developing significant extramotor features. Autopsy revealed evidence of both upper and lower motor neuron loss with wide-spread motor and extramotor intraneuronal basophilic inclusions, most of which did not show ubiquitin immunoreactivity. Motor neuron disease with basophilic inclusions appears to be a rare, but distinctive pathological subtype, with most reported cases occurring sporadically in young women and having a rapid clinical progression.
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PMID:December 2001: rapidly progressive motor weakness, starting in pregnancy. 1195 83

Acute myopathy is a common problem in intensive care units. Those at highest risk for developing critical illness myopathy are exposed to intravenous corticosteroids and paralytic agents during treatment of various illnesses. Diffuse weakness and failure to wean from mechanical ventilation are the most common clinical manifestations. Serum creatine kinase levels are variable. Electrodiagnostic studies reveal findings of a myopathic process, often with evidence of muscle membrane inexcitability. Based on animal model studies, the loss of muscle membrane excitability may be related to inactivation of sodium channels at the resting potential. In addition, human and animal pathologic studies reveal characteristic loss of myosin with relative preservation of other structural proteins. In some patients, there is also upregulation of proteolytic pathways, involving calpain and ubiquitin, in conjunction with increased apoptosis. Fortunately, the disorder is reversible, but there may be considerable morbidity.
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PMID:Critical illness myopathy. 1221 45

We report the autopsy findings of an 82-year-old woman who exhibited slowly progressive upper motor neuron signs (pseudobulbar palsy, muscle weakness and positive Babinski's sign) in the absence of lower motor neuron signs, which were followed by progressive dementia and frontotemporal atrophy, and who died 7 years and 4 months after onset of the disease. In this patient, the upper motor neuron system, including the precentral cortex and descending pyramidal tract, was severely degenerated, but the lower motor neurons and innervated skeletal muscles were well preserved. A few lower motor neurons were found to contain cytoplasmic inclusion bodies characteristic of amyotrophic lateral sclerosis (i.e., Bunina bodies and ubiquitin-positive skeins). However, fragmentation of the Golgi apparatus was not evident in the anterior horn cells examined. Therefore, it was considered that the lower motor neurons were also involved, but that the rate of degeneration of these neurons was very slow in the disease process. Marked frontotemporal lobar degeneration characterized by microvacuolation, and ubiquitin-positive neuronal inclusions and dystrophic neurites in cortical layer II were also observed, the precentral cortex being the most severely affected area. Similar ubiquitin-positive structures were also observed in the neostriatum. Finally, a survey of the literature based on this patient's clinical and pathological features led us to conclude that the rare clinical syndrome of primary lateral sclerosis is, in general, a rare upper-motor-predominant form of amyotrophic lateral sclerosis that is often accompanied by frontotemporal lobar degeneration with ubiquitinated neuronal inclusions.
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PMID:Primary lateral sclerosis: a rare upper-motor-predominant form of amyotrophic lateral sclerosis often accompanied by frontotemporal lobar degeneration with ubiquitinated neuronal inclusions? Report of an autopsy case and a review of the literature. 1273 67

We report the clinical and neuropathological features of a Japanese family with familial amyotrophic lateral sclerosis (FALS), whose members have an amino acid substitution of histidine by arginine in Cu/Zn superoxide dismutase. A 58-year-old woman developed muscle weakness in the legs, and died of respiratory insufficiency 7 months after the onset of her weakness. Her family history included 7 patients with FALS over 3 generations. Their pertinent neurological abnormalities consisted primarily of lower motor neuron signs, and their clinical progression was rapid. Autopsy of our patient showed the involvement of the lower and upper motor neuron systems with Lewy body-like hyaline inclusions, in addition to degeneration in the posterior columns, Clarke's nuclei and posterior spinocerebellar tracts. The inclusions reacted with both anti-SOD1 and anti-ubiquitin antibodies. This is the first report of the neuropathological findings of FALS with this mutation.
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PMID:[Clinical features and neuropathological findings of familial amyotrophic lateral sclerosis with an H43R mutation in Cu/Zn superoxide dismutase]. 1465 2

Acute quadriplegic myopathy (AQM; also called "critical illness myopathy") shows acute muscle wasting and weakness and is experienced by some patients with severe systemic illness, often associated with administration of corticosteroids and/or neuroblocking agents. Key aspects of AQM include muscle atrophy and myofilament loss. Although these features are shared with neurogenic atrophy, myogenic atrophy in AQM appears mechanistically distinct from neurogenic atrophy. Using muscle biopsies from AQM, neurogenic atrophy, and normal controls, we show that both myogenic and neurogenic atrophy share induction of myofiber-specific ubiquitin/proteosome pathways (eg, atrogin-1). However, AQM patient muscle showed a specific strong induction of transforming growth factor (TGF)-beta/MAPK pathways. Atrophic AQM myofibers showed coexpression of TGF-beta receptors, p38 MAPK, c-jun, and c-myc, including phosphorylated active forms, and these same fibers showed apoptotic features. Our data suggest a model of AQM pathogenesis in which stress stimuli (sepsis, corticosteroids, pH imbalance, osmotic imbalance) converge on the TGF-beta pathway in myofibers. The acute stimulation of the TGF-beta/MAPK pathway, coupled with the inactivity-induced atrogin-1/proteosome pathway, leads to the acute muscle loss seen in AQM patients.
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PMID:Constitutive activation of MAPK cascade in acute quadriplegic myopathy. 1475 18

Ten Spanish patients from six unrelated families diagnosed with desmin-related myopathy (DRM) were studied. The pattern of DRM inheritance was autosomal dominant in three families, autosomal recessive in one, and there was no family history in two cases. The disease onset was in early adulthood. Cardiac myopathy was the initial presentation in two patients, respiratory insufficiency in one, and lower limb weakness in all others. Cardiac involvement was observed in four patients. Lens opacities were found in four. CK level was normal or slightly elevated, and electrophysiological examination was consistent with myopathy. Muscle biopsies identified intracytoplasmic desmin-immunoreactive inclusions. In addition to desmin, synemin, actin, gelsolin, ubiquitin, alphaB-crystallin and amyloid betaA4 were also present in the deposits. Ultrastructural examination revealed areas of myofibrillary disruption, abnormal electron-dense structures and accumulations of granulofilamentous material. A missense R406W mutation and a novel single amino acid deletion in the desmin gene were identified in two patients; the other patients did not show mutations in desmin, synemin, syncoilin or alphaB-crystallin genes. Analysis of 10 Spanish DRM cases illustrates a wide clinical, myopathological and genetic spectrum of DRM, reinforcing the need for further exploration of genetic causes for this group of disorders.
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PMID:Desmin-related myopathy: clinical, electrophysiological, radiological, neuropathological and genetic studies. 1505 Apr 48

We describe a second large Italian kindred with autosomal dominant vacuolar myopathy characterized by variable severity, adult-onset weakness of distal limb muscles, and no cardiac involvement. At least 19 individuals over four generations are affected. Histopathological and immunochemical features of the vacuoles, present in many fibers, indicate protein degradation abnormalities with dysregulation of the lysosomal pathway and activation of the ubiquitin-proteasomal pathway. Linkage analysis localized the defect to the 19p13.3 locus in a region with no known genes. We speculate that the primary defect may be an abnormality in the lysosomal degradation pathway or related components.
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PMID:Abnormal lysosomal and ubiquitin-proteasome pathways in 19p13.3 distal myopathy. 1523 12

Cachexia is a syndrome and therefore does not have a specific definition. Patients are characterized by the presence of anorexia, early satiety, weight loss, weakness, anaemia and oedema. These features occur to a variable extent in different patients and may change in severity during the course of a patient's illness. The multifactorial origin of cachexia precludes a uniform pathophysiological definition. Taken together these factors have hindered clinical studies both at a fundamental level and in terms of the introduction of effective therapy. The advent of novel therapeutic targets (e.g., ubiquitin-proteasome pathway) and biological response modifiers has opened possibilities for new clinical trials in cachexia. Regulatory authorities feel it is important not only to demonstrate efficacy in terms of patients' nutritional status (e.g., lean body mass) but also functional status (e.g., performance status). This article reviews current methods to assess the latter. Methods focused on measuring physical activity level (e.g., doubly labelled water technique or physical activity meters) promise objective data which can be readily interpreted in terms of clinically meaningful benefit.
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PMID:Research methodology: cancer cachexia syndrome. 1533 19

Dose-dependent co-expression of enhanced green fluorescent protein (EGFP) and beta-galactosidase (beta-gal) in the cytoplasm of forebrain neurons of two independent mouse lines resulted in growth retardation, weakness, and premature lethality. In primary motor cortex and striatum, apoptosis, glial fibrillary acidic protein proliferation, and cell loss were found. In addition, we observed aggregations of EGFP and beta-gal that colocalized with ubiquitin. GFP is unlikely to be toxic per se, as a third mouse line that expressed twice as much GFP in the cytoplasm of forebrain neurons as the two affected lines was normal. Cytoplasmic aggregations of EGFP and beta-gal occurred in affected and phenotypically normal mice suggesting a storage function rather than being detrimental. We successfully prolonged survival of affected mice with granulocyte colony-stimulating factor (GCSF) and the antibiotic minocycline. These compounds could protect neurons from EGFP and beta-gal-induced dysfunction, as demise of mice started after treatment was discontinued.
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PMID:Neuronal co-expression of EGFP and beta-galactosidase in mice causes neuropathology and premature death. 1547 68


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