Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0015672 (fatigue)
 51,768 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A thirty-two year old female had chronic progressive external ophthalmoplegia (CPEO), exertional fatigue, dysarthria, dysphagia, and bilateral hearing impairment. Histochemical stains, obtained from the right vastus lateralis, showed ragged-red fibers and wide-spread abnormalities in the number, size, and the structure of mitochondria under electronomicroscopic examination. A biochemical analysis showed a low activity of NADH-cytochrome C reductase, NADH dehydrogenase and a normal activity of succinate cytochrome C reductase and cytochrome C oxidase. This data suggests a specific defect in the NADH dehydrogenase of complex I (NADH CoQ reductase). We believe that this is the first biochemically defined mitochondrial myopathy reported in Taiwan and provides additional evidence for the existence of biochemical heterogeneity in mitochondrial disorders of CPEO.
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PMID:Chronic progressive external ophthalmoplegia with NADH-CoQ reductase deficiency: report of a case. 132 93

Fatigue and myalgia are common in patients with acquired immunodeficiency syndrome (AIDS). To determine whether altered muscle metabolism or impaired activation of muscle might account for these symptoms, we utilized three different exercise protocols to produce fatigue in nine AIDS patients who complained of both fatigue and exercise-exacerbated myalgia. Five were taking azidothymidine (AZT), which may cause a mitochondrial myopathy. Simultaneous measures of force, EMG, and muscle metabolites (phosphocreatine, inorganic phosphate, adenosine triphosphate, and intracellular pH) using phosphorus nuclear magnetic resonance spectroscopy were performed during fatigue and recovery. There were no significant differences between patients and controls in terms of fatigability, muscle metabolism, or muscle activation. These results provide no support for the hypothesis that fatigue or myalgia in AIDS patients derives from altered muscle metabolism or that AZT produces mitochondrial myopathy.
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PMID:Fatigue and myalgia in AIDS patients. 192 2

Chronic administration of the NADH-CoQ reductase inhibitor, diphenyleneiodonium to rats at two dose levels, 1.0 and 1.5 mg/kg per day, caused a 40% and 60% reduction, respectively, in the in vitro rate of NAD-linked respiration by skeletal muscle mitochondria. At the highest dose, muscle fatigue, lactic acidosis and an over-utilization of phosphocreatine was observed in the gastrocnemius muscle during mild stimulation of 1 Hz frequency. The resynthesis of phosphocreatine following muscle stimulation was about 2 fold slower in the treated animal group. At the low dose, no significant biochemical changes were observed during muscle stimulation at 4 Hz. The results are discussed in terms of skeletal muscle "oxidative reserve", twitch tension maintenance and the relevance to the human diseased state of mitochondrial myopathy.
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PMID:An animal model of mitochondrial myopathy: a biochemical and physiological investigation of rats treated in vivo with the NADH-CoQ reductase inhibitor, diphenyleneiodonium. 312 47

An animal model for the human condition of mitochondrial myopathy has been established and characterized physiologically and biochemically. The NADH: coenzyme Q reductase inhibitor diphenyleneiodonium [Bloxham (1979) Biochem. Soc. Trans. 7, 103-106] was either infused acutely in vivo into rat hind limb or injected chronically into rats. Both modes of delivery resulted in a reduced muscle oxidative capacity and increased fatigue. Analysis of muscle metabolites by h.p.l.c. and 31P-n.m.r. indicated that ATP concentrations were similar to control values during periods of stimulation and these were maintained by the phosphocreatine pool. During the recovery period after muscle stimulation in the experimental animals the muscle pH remained depressed and the rate of phosphocreatine synthesis was markedly delayed as compared with controls. Factors thought to be involved in the fatigue response are discussed in relation to this model.
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PMID:Experimentally induced defects of mitochondrial metabolism in rat skeletal muscle. Biological effects of the NADH: coenzyme Q reductase inhibitor diphenyleneiodonium. 392 66

A 44-year-old man with a documented 12-year history of progressive sensorineural hearing loss developed a generalized tonic-clonic seizure followed by a visual field deficit and apraxia. Six months later he developed a peripheral neuropathy and muscle fatigue followed by a slowly progressive aphasia and cortical blindness as well as increased seizure activity. A computed tomography scan showed bilateral basal ganglion calcification. The serum lactate level was elevated at 3.4 mEq/dL. A muscle biopsy enabled the diagnosis of mitochondrial myopathy. This disorder is presented as an unusual cause of progressive sensorineural hearing loss in adults.
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PMID:Mitochondrial encephalomyopathy: a rare genetic cause of sensorineural hearing loss. 757 56

We have investigated a 15 year old girl with progressive external ophthalmoplegia, including bilateral ptosis and retinal rod and cone cell dysfunction with atypical retinal pigmentation, complicated by cerebellar ataxia, partial cardiac conduction block, and diabetes mellitus. In infancy she had a severe crisis of bone marrow depression, and as a child she suffered from hypersensitivity to light, increasing fatigue, and vertigo, signs that were initially though to be psychosomatic. Histological examination showed mitochondrial myopathy, and subsequent mitochondrial DNA (mtDNA) analysis showed a deletion of approximately 5500 base pairs in 35 to 40% of her muscle mtDNA. We therefore conclude that this patient has developed the Kearns-Sayre syndrome after a Pearson syndrome-like crisis in her first year of life.
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PMID:Juvenile Kearns-Sayre syndrome initially misdiagnosed as a psychosomatic disorder. 815 37

We studied muscle fatigue and serum lactate and pyruvate levels in 20 patients with mitochondrial myopathy with progressive external ophthalmoplegia (PEO). Fatigue was assessed in the adductor pollicis muscle (AP) using a low-intensity exercise protocol (20 min). Forces (TFs) and relaxation times of ulnar nerve evoked twitches, compound muscle action potentials (CMAPs), and maximal voluntary contractions (MVCs) were monitored. Serum lactate and pyruvate levels were independently measured at rest and after exercise on a bicycle (15 min, 30 W). Most patients showed abnormal fatigue of the AP with a reduction of TFs and MVCs and normal CMAPs. The reduced TFs were significantly correlated with lactate levels at rest (r= - 0.60, P<0.05) and less so with those after exercise (r=- 0.47,P<0.05). Pyruvate levels revealed a similar correlation although they were widely scattered. We conclude that abnormal fatigue in PEO is metabolic, is localized beyond the muscle fiber membrane, and involves the electrome-chanical coupling and the contractile apparatus. Serum lactate levels at rest are good predictors of fatigue in PEO.
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PMID:Muscle fatigue, lactate, and pyruvate in mitochondrial myopathy with progressive external ophthalmoplegia. 862 24

A 14-year-old girl presented with a 3-month history of easy fatigue and exercise intolerance, especially when climbing stairs. She had a mild ptosis and mild limitation of upward gaze. Her puberty was delayed, and she manifested hypogonadotrophic hypogonadism. Serum lactic and pyruvic acids were elevated. Cranial magnetic resonance imaging was normal. Muscle biopsy documented typical ragged-red fibers. A point mutation at nucleotide 3243 in the tRNALeu(UUR) (typical mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) mutation) was detected in mitochondrial DNA from both blood and muscle tissues, indicating that our patient was suffering from a mitochondrial myopathy. Hypogonadism may be a manifestation of the MELAS nucleotide 3243 mutation.
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PMID:mtDNA nt3243 mutation, external ophthalmoplegia, and hypogonadism in an adolescent girl. 965 Jun 85

Zidovudine is known to be responsible for a mitochondrial myopathy with ragged-red fibres and mitochondrial DNA depletion in muscle. Lactic acidosis alone or associated with hepatic abnormalities has also been reported. A single report mentioned the concomitant occurrence of muscular and hepatic disturbances and lactic acidosis in a patient receiving zidovudine, but muscle and liver tissues were not studied. A 57-year-old man with AIDS, who had been treated with zidovudine for 3 years, developed fatigue and weight loss. Serum creatine kinase and hepatic enzyme levels were high. Lactic acidosis was present. Liver biopsy showed diffuse macrovacuolar and microvacuolar steatosis. After withdrawal of zidovudine, creatine kinase, aspartate aminotransferase, and alanine aminotransferase levels normalised within 5 days, and lactacidaemia decreased. Acidosis persisted. The patient became confused and febrile and died 8 days after detection of high blood lactic acid. A muscle sample obtained at autopsy showed mitochondrial abnormalities with ragged-red fibres and lipid droplet accumulation. Southern blot analysis showed depletion of mitochondrial DNA, affecting skeletal muscle and liver tissue. No depletion was found in myocardium and kidney. This case emphasises that zidovudine treatment can induce mitochondrial multisystem disease, as revealed in our case by myopathy, liver steatosis and lactic acidosis.
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PMID:Zidovudine-induced mitochondrial disorder with massive liver steatosis, myopathy, lactic acidosis, and mitochondrial DNA depletion. 1070 83

Patients treated with nucleoside analogue reverse transcriptase inhibitors (NRTIs) develop a varying degree of myopathy or neuropathy after long-term therapy. Zidovudine (AZT) causes myopathy; zalcitabine (ddC), didanosine (ddl) and lamuvidine (3TC) cause neuropathy; stavudine (d4T) and fialuridine (FIAU) cause neuropathy or myopathy and lactic acidosis. The tissue distribution of phosphorylases responsible for phosphorylation of NRTIs relates to their selective tissue toxicity. The myopathy is characterized by muscle wasting, myalgia, fatigue, weakness and elevation of CK. The neuropathy is painful, sensory and axonal. In vitro, NRTIs inhibit the gamma-DNA polymerase, responsible for replication of mtDNA, and cause mtDNA dysfunction. In vivo, patients treated with AZT, the best studied NRTI, develop a mitochondrial myopathy with mtDNA depletion, deficiency of COX (complex IV), intracellular fat accumulation, high lactate production and marked phosphocreatine depletion, as determined with in vivo MRS spectroscopy, due to impaired oxidative phosphorylation. Animals or cultured cells treated with NRTIs develop neuropathy, myopathy, or cell destruction with similar changes in the mitochondria. There is evidence that the NRTI-related neuropathy is also due to mitochondrial toxicity. The NRTIs (AZT, ddC, ddl, d4T, 3TC) contain azido groups that compete with natural thymidine triphosphate as substrates of DNA pol-gamma and terminate mtDNA synthesis. In contrast, FIAU that contains 3'-OH groups serves as an alternate substrate for thymidine triphosphate with DNA pol-gamma and is incorporated into the DNA causing permanent mtDNA dysfunction. The NRTI-induced mitochondrial dysfunction has an influence on the clinical application of these agents, especially at high doses and when combined. They have produced in humans a new category of acquired mitochondrial toxins that cause clinical manifestations resembling the genetic mitochondrial disorders.
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PMID:Peripheral neuropathy and antiretroviral drugs. 1129 2


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