Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022716 (Menkes)
 1,057 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Veterinary nutritional science has embraced the study of copper for decades, but copper has languished as an orphan among human nutritionists because of the obscurity of clinical copper-deficiency states in man. As medical investigators, we may have gone down a long road, missing the forest for the trees. Indeed, overt copper-deficiency syndromes in humans have been recognized since the 1960s, and the list of contributing factors is expanding. Unwise self-medication with megadoses of zinc, for instance, might produce a mini-epidemic of copper deficiency. Moreover, induced copper deficiency may someday prove to be a legitimate therapeutic intervention in some disease states. But, the influence of subtle differences in dietary intakes of copper on human health may be much more important than frank copper depletion. Moreover, the recognition of disordered copper metabolism simulating a deficiency state--as occurs in Menkes' KHS and in variant Elhers-Danlos syndrome--has important implications. The full description of the relationship that thionein and other intracellular proteins might have in the etiology of these alterations has yet to be written. The elegance of the interplay of biochemical defects, physiological dysfunction, and clinical manifestations in copper metabolism is virtually unmatched in nutritional biology; yet, our present abilities to determine human copper status are limited. Now that it is clear that intracellular redistribution as well as total-body depletion can effect the disruption of copper-dependent functions, a concerted effort to improve status assessment through the use of functional indices should become a high priority. Finally, the pursuit of the bases of copper's involvement in host defenses, antiotoxidant protection and carbohydrate metabolism--functions in which clear links to established mammalian cuproenzyme are at present elusive--should provide exciting substrate for investigators for years to come.
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PMID:Biochemical, metabolic, and clinical role of copper in human nutrition. 392 87

Copper deficiency of nutritional origin has been recognized as an important part of complex nutritional problems in Peru, as an occasional even in premature babies in Western countries, and as a real hazard of over-zealous zinc therapy or of prolonged parenteral alimentation in children or adults. Anaemia, osteoporosis and scurvy-like bone changes are recognized in the deficiency, and they respond to copper. Copper intake is falling in western countries as a result of prepackaging of foods, and low-grade chronic deficiency may become a problem. The features seen in Menkes' syndrome suggest that human beings may be rather susceptible to the vascular and neurological effects of copper deficiency; these effects may be encountered as a consequence of prolonged mild copper deficiency. Measurement of the serum concentrations of caeruloplasmin before and after moderate copper repletion is suggested as a method of detecting mild copper deficiency.
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PMID:Copper deficiency in humans. 611 May 26

Cultured lymphoblasts derived from infants with Menkes' disease exhibit the same increased avidity for copper as do fibroblasts and most extrahepatic tissues from these patients. The Menkes' cells preferentially take up not only copper but also, on exposure to elevated metal concentrations, the other metallothionein-binding metals, zinc and cadmium. Menkes' lymphoblasts contain larger amounts of metallothionein than normal cells following exposure to each of these metals; the amount bound to this protein quantitatively accounted for the total cellular increment in metal in Menkes' cells. Induction of metallothionein synthesis caused both normal and Menkes' cells to subsequently take up increased amounts of 67Cu. These observations suggest that an enhanced capacity of Menkes' cells to accumulate metallothionein may be responsible for their increased uptake and retention of copper.
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PMID:Metallothionein accumulation may account for intracellular copper retention in Menkes' disease. 627 42

Metallothionein is a cysteine-rich, low molecular weight protein that binds zinc, copper and cadmium. It is inducible in liver, kidney and intestine by glucocorticoids, changes in the dietary zinc supply, acute administration of various metals, food restriction, infection, stress and endotoxin treatment. Regulation of synthesis involves altered gene expression. The protein is fairly rapidly degraded when zinc is the primary metal species bound, but the degradation rate is diminished when cadmium or copper are bound as well. The net result of metallothionein production seems to be accumulation of bound metal and/or intracellular metal redistribution. The accumulation of copper in various tissues of individuals with Menkes' and Wilson's diseases may be related to altered metallothionein turnover. The physiological function is not clear, but the response of metallothionein to hormonal stimuli is suggestive of an important role in cellular metabolism.
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PMID:Metallothionein--aspects related to copper and zinc metabolism. 641 69

Menkes' kinky hair syndrome is a lethal X-linked disorder marked by tissue-specific increases in copper content. An animal model of kinky hair syndrome is provided by mice mutant at the X-linked mottled locus. The basic defect is unknown. In order to discriminate among potential etiologies, we asked whether the expression of the mottled mutation causes abnormalities in the metabolism of trace metals other than copper in hemizygous mottled (blotchy) cultured skin fibroblasts, and whether we can differentiate mutant and normal cells according to their response to metal inducers of metallothionein. Blotchy fibroblasts accumulated up to 12 times more 64Cu than control (littermate) cells, over time and over a range of 64Cu concentrations. A saturable high affinity component to 64Cu accumulation over a fixed time interval was revealed in these studies. While 64Cu uptake kinetics were indistinguishable in mutant and control cells, the patterns of 64Cu exit differed. In both cell types, the rate of release of a rapidly exchangeable fraction of newly acquired 64Cu was similar. However, in mutant cells, a larger fraction of recently accumulated 64Cu is retained. In contrast to the results for 64Cu, accumulation and exit of 65Zn and 109Cd were not distinguishable in mutants and controls. With exposure to either a strong (cadmium) or weaker (zinc) inducer of metallothionein, 64Cu accumulation was increased in normal cells, while there was no change from the already elevated level of 64Cu accumulation in blotchy cells.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Trace metal metabolism in cultured skin fibroblasts of the mottled mouse: response to metallothionein inducers. 654 92

This paper reports the results of a multielement analysis of postmortem samples of Menkes patients, of which one was untreated and two had been treated for various lengths of time with intramuscular injections of copper-EDTA. The findings have been compared with data from a Menkes fetus and from controls. The results confirm that copper accumulates in various tissues and demonstrate a further increase in copper levels as a result of the treatment with copper-EDTA. Although no clinical improvement was observed, the levels of some copper-containing enzymes normalized during the copper-therapy. Furthermore, in agreement with the identification of the copper-binding protein in the kidney as metallothionein, it was found that not only copper, but also zinc, cadmium, and mercury are trapped in this tissue. A low copper concentration in the brain was also found in a Menkes fetus, indicating that brain damage might already have occurred before birth. Speculation Until recently, Menkes' disease was considered to be due to copper deficiency. However, the symptoms are more typical of a storage disease in which copper is irreversibly trapped in some tissues, in particular in the kidneys, by metallothionein. This abnormal storage pattern gives rise to copper deficiency elsewhere in the organism, particularly in the brain where it may cause irreversible damage in the foetus. Parenteral administration of copper does not lead to clinical improvement. The only "therapy" that seems feasible at present is tracing the carriers of the disease and advising abortion when prenatal diagnosis indicates a male fetus carrying the disease.
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PMID:Trace element studies in three patients and a fetus with Menkes' disease. Effect of copper therapy. 678 98

Copper-binding proteins in the tissues from the patients with Menkes' kinky hair disease were examined by gel filtration on a Sephadex G-75 column. In the kidney, major part of copper was found to bind to low molecular weight protein, which corresponded chromatographically to metallothionein. This copper-binding protein contained a large amount of copper and a small amount of zinc. Cu: Zn ratio of this protein was different from that of metallothionein found in the fetal liver. In the liver of the same patient, however, there was no increase of copper bound to this protein.
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PMID:Copper-binding proteins in the liver and kidney from the patients with Menkes' kinky hair disease. 683 61

Copper and zinc concentrations, and the nature of the copper- and zinc-binding proteins, were studied using tissues from a Menkes patient who had been given intravenous infusions of cupric acetate. The liver and brain copper contents were lower than in an untreated, non-Menkes control, and the spleen, intestine and kidney showed higher copper concentrations than control tissues. Zinc concentrations in all the organs (except the kidneys) from the Menkes patient were slightly lower than those the control child. Using Sephadex G-75 column chromatography of cytosols (105,000 x g supernatant), three copper- and zinc-containing peaks were eluted. In all the Menkes tissues studied, copper was prominent in peak 3. On the other hand, peak 3 was the smallest and peak 1 was the largest in the control tissues. Zinc predominated in peak 1 in both Menkes and control tissues, except for Menkes kidney. In this tissue peak 3 was again the largest. The copper- and zinc-binding material in peak 3 fractions from Menkes kidney was chromatographed on DEAE-cellulose columns. Three copper- and zinc-containing peaks were observed at the same positions as metallothionein from human adult kidneys.
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PMID:Nature of copper and zinc compounds in tissues from a patient with Menkes kinky hair syndrome. 727 94

Cultured cells of a variety of different types from human Menkes' syndrome patients and brindled mouse mutants exhibit similarly altered responses to changes in extracellular copper concentration. This suggests that the mutations in the mouse and human are very similar and that mutant gene expression is occurring in many different tissues. Intracellular copper levels are markedly elevated in mutant cells in normal medium and in medium containing a hundred-fold higher copper. Some cell lines from heterozygotes possess elevated copper levels. Elevated extracellular copper and zinc are significantly more toxic to mutant cells. Mutant cells exhibit normal rates of uptake of copper-64 over a 10-min period but abnormally high accumulation over 24 hr and low rates of efflux. Menkes' fibroblasts become saturated with copper-64 at lower extracellular concentrations than for normal fibroblasts. These data support the idea of enhanced intracellular binding in mutant cells.
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PMID:Altered copper metabolism in cultured cells from human Menkes' syndrome and mottled mouse mutants. 738 19

Wilson's disease is an autosomal recessive, inherited disorder of copper metabolism. In normal individuals, copper homeostasis is controlled by the balance between intestinal absorption of dietary copper and hepatic excretion of excess copper in bile. In Wilson's disease, hepatic copper is neither excreted in bile nor incorporated into ceruloplasmin and copper accumulates to toxic levels. The Wilson's disease gene (WND) encodes a putative copper-transporting protein that is expressed almost exclusively in the liver. The predicted structure of the protein product is that of a P-type ATPase with striking homology to bacterial copper transporters and the gene product of another inherited disorder of copper metabolism, Menkes' disease. A rat model of Wilson's disease has recently been identified. The Long-Evans Cinnamon (LEC) rat manifests elevated hepatic copper, defective incorporation of copper into ceruloplasmin, and reduced biliary excretion of copper. The rat homologue of the WND is abnormal in LEC rats. Clinical manifestations of Wilson's disease arise directly from copper-induced damage to hepatocytes (hepatic presentation) or indirectly after the release of copper from the liver with subsequent damage to the brain (neuropsychiatric presentation) and other organs. Genetic heterogeneity (different mutations in a single gene) may account for some of the variability in Wilsonian presentations. The diagnosis of Wilson's disease depends on the demonstration of disordered copper metabolism, manifested as elevated urinary and hepatic copper and low ceruloplasmin levels. However, none of the abnormal findings in Wilson's disease is pathognomonic. Genetic diagnosis, in the absence of family studies, is likely to be difficult since many different mutations result in the disease. Management of Wilson's disease involves decreasing excess levels of copper accumulated in the liver, brain, and other organs. Copper chelation therapy, to increase urinary excretion of copper, is the mainstay of treatment. In addition, oral zinc therapy may be useful at decreasing absorption of dietary copper and rendering tissue copper nontoxic, by increasing the formation of complexes with copper-binding proteins. Liver transplantation can be necessary for individuals with acute hepatic failure or complications of cirrhosis. Gene therapy may evolve in the future; however, medical management is effective in most patients.
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PMID:Wilson's disease: a new gene and an animal model for an old disease. 755 82


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