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

The life-span of Menkes syndrome patients is discussed in connection with a boy suffering from this disease who lived to the age of 13.5 years. The copper metabolism defect is described. Therapeutic trials, mainly copper substitution, and prospects are summed up.
 ...
PMID:Life-span and Menkes kinky hair syndrome: report of a 13-year course of this disease. 335 80

The accumulation of copper over 2 h by normal lymphoid cells and those from Menkes'-disease patients (Menkes' cells) was found to be biphasic, with an initial phase of rapid uptake, an approach to steady state at around 40-60 min, followed by a further accumulation phase. The accumulation of copper was not diminished by the addition of a variety of metabolic inhibitors, suggesting that copper uptake is not an active process. The presence of carbonyl cyanide m-chlorophenylhydrazone in the culture medium stimulated the uptake and accumulation of copper in both normal and Menkes' cells to the same absolute level. This effect appeared to be specific for copper, since the accumulation of Zn and Cd was unaffected. Menkes' cells did not differ from normal in their initial rate of copper uptake. Analysis of the uptake curve suggested that the membrane transport of copper involves both passive and facilitated diffusion. Initial rate of efflux from the cells was approximated by two methods. Menkes' cells did not appear to be affected in this function. It seems likely that the basic defect in Menkes' disease involves a step in intracellular copper transport rather than the membrane transport of copper.
 ...
PMID:Uptake and efflux of copper-64 in Menkes'-disease and normal continuous lymphoid cell lines. 342 41

A boy who died at 6 months of age was noted to have sparse, stubby and light hair, pili torti were observed microscopically, and his skin was dry and redundant. As a suspicion of Menkes disease was first raised after his death, serum copper and ceruloplasmin in serum were not measured. Unfortunately, no fibroblasts were available - only fixed and paraffin-embedded samples of brain, spleen and liver. The copper contents of the brain and the liver were lower than in an age-matched control. Fibroblast cultures from the mother, the maternal grandmother, and a maternal aunt of the index patient were analysed for 64Cu-uptake. All these females showed the uptake values expected for Menkes carriers, thus supporting the clinical suspicion of Menkes disease in the index patient. From the above-mentioned results it was highly likely that the index patient had suffered from Menkes disease. Adequate genetic counseling could thus be offered to the family, and in the next pregnancy a first trimester prenatal diagnosis was performed.
 ...
PMID:Postmortem Menkes diagnosis from carrier testing of female relatives. 343 89

The difficulties of early diagnosis of Menkes' kinky hair syndrome are described guided by the clinical courses of three related patients. One of these children could be observed continuously from birth. Different from other descriptions the diagnostic value of the clinical features observed in our patients is estimated as follows: 1. severe cerebral degeneration with seizures in the first year of life; 2. subdural hygroma; 3. decreased levels of serum copper and serum coeruloplasmin; 4. hair abnormalities; 5. skin abnormalities. The diagnosis is likely, if serum copper and serum coeruloplasmin are decreased. The diagnosis is proved by increased copper uptake into cultured fibroblasts. The prenatal diagnosis is possible by chorionic villus biopsy or amniocentesis. The importance of carrier detection by cultured fibroblasts and subsequent genetic counselling is underlined.
 ...
PMID:[Clinical aspects of Menkes syndrome]. 343 7

A study was carried out on the uptake of copper, zinc, or cadmium ions and their induction of metallothionein synthesis in Menkes' and normal lymphoblastoid cells. The main difference between Menkes' and normal cells in the uptake of these metal ions was an increased uptake of copper ions in Menkes' cells at a low concentration of CuCl2 (2.1 microM). The CuCl2 concentration necessary to induce metallothionein synthesis in Menkes' cells was 50 microM, whereas that in normal cells was about 200 microM. The levels of zinc or cadmium ions needed to induce metallothionein in Menkes' cells were similar to those in normal cells. At least four isomers of metallothionein were induced by copper, zinc, and cadmium ions in both types of cells. Metallothionein synthesis in Menkes' and normal cells was induced when the amounts of intracellular copper reached a threshold level of approximately 0.2 nmol/10(6) cells, and the rate of metallothionein synthesis in these cells was increased as a function of the amounts of intracellular copper (0.2-1.7 nmol/10(6) cells). These results indicate that the induction of metallothionein synthesis in lymphoblastoid cells is controlled by the level of intracellular copper, suggesting that the major defect in Menkes' cells is not due to the abnormal regulation of metallothionein synthesis but to an alteration of the copper metabolism in cells by which the levels of intracellular copper become larger than those in normal cells and just lower than the threshold level for induction of metallothionein synthesis.
 ...
PMID:Induction of metallothionein synthesis in Menkes' and normal lymphoblastoid cells is controlled by the level of intracellular copper. 349 30

There are several known examples of mutations which influence copper homeostasis in humans and animals. Pleiotropic effects are observed when the mutant gene disturbs copper flux. In some cases, the mutation alters the level of a specific copper ligand (enzyme) and the clinical consequences are unique. The two most widely studied genetic maladies in humans are Menkes' and Wilson's diseases. Menkes' disease is an X-linked fatal disorder in which copper accumulates in some organs (intestine and kidney) and is low in others (liver and brain). Wilson's disease is an autosomal recessive disorder in which copper accumulates, if untreated, in liver and subsequently in brain and kidney. Pathophysiological consequences of copper deficiency and toxicity characterize these two disorders. Specific mutations of human cuproenzymes include overproduction of copper-zinc superoxide dismutase in Down's syndrome, absence of tyrosinase in albinism, hereditary mitochondrial myopathy due to reduction in cytochrome c oxidase, and altered lysyl oxidase in X-linked forms of cutis laxa and Ehlers-Danlos syndrome. Mutations altering copper metabolism are also known in animals. Several murine mutants have been studied. The most extensively investigated mutants are the mottled mice, in particular brindled mice, which have a mutation analogous to that of Menkes' disease. Another recently described murine mutation is toxic milk (tx) an autosomal recessive disorder that is characterized by copper accumulation in liver. Two other mutants, crinkled and quaking, were once thought to exhibit abnormal copper metabolism. Recent data has not confirmed this. A mutation in Bedlington terriers has been described which is very similar to Wilson's disease.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Genetic diseases of copper metabolism. 351 56

Several mutations affecting the transport of copper and zinc in humans and in mice have been discovered over the last 15 years, joining the long known disturbance of copper transport in Wilson's disease. Menkes' disease (classical and mild variant forms) and X linked Ehlers-Danlos syndrome (type IX, X linked cutis laxa) have features in common with one another and with the brindled (Mobr) and blotchy (Moblo) mouse mutants, respectively. There may be one allelic series of mutants in each species or two loci may be involved in each. The toxic milk mutant (tx) in the mouse may be homologous to Wilson's disease in man. The defect of intestinal absorption of zinc in acrodermatitis enteropathica has no homologue yet in the mouse. However, the lethal milk (lm) mutant in the mouse may be homologous to a condition of zinc deficiency described in a few breastfed, low birth weight infants. Many more genetic defects of transport of copper and of zinc may await discovery. Conversely, these mutants are valuable in elucidating the normal processes of copper and zinc transport.
 ...
PMID:Of mice and men, metals and mutations. 351 72

Metallothioneins are a family of ubiquitous, cysteine rich proteins, whose amino acidic and genomic sequences have been highly conserved during evolution. MT synthesis is induced by heavy metals, glucocorticoids and a bacterial lipopolysaccharide in vivo and in vitro. MT forms stable complexes with heavy metals. One MTIIA gene, four MTI class genes and five pseudogenes have been isolated in humans. The cluster of MT genes is located on chromosome 16. The cloned, transfected genes retain metal inducibility. The first 150 bp of the 5' flanking region of mouse and human MT genes are essential for transcription and metal regulation. Two control regions have been identified. The distal region, between -151 and -78 is essential for efficient transcription and binding of cellular factor(s) which regulates MT gene expression. In Menkes' disease, a lethal X-linked recessive disorder, copper accumulates intracellularly bound to MT. Low doses of copper induce MT synthesis in Menkes' fibroblasts, but not in normal controls. Transfection experiments using the mouse MTI promoter fused to CAT show that the effect of copper in MT transcription is in trans. Menkes' cells are more sensitive to copper than normal controls and respond to copper poisoning by synthesizing two heat-shock like proteins. A mutation affecting copper transport or metabolism is discussed.
 ...
PMID:Metallothionein gene regulation in Menkes' disease. 353 Sep 53

The effects of plasma components on the kinetics of copper transport by rat hepatocytes were examined in an attempt to determine how copper is mobilized from plasma for uptake by the liver. Specific protein-facilitated transport was indicated by saturation kinetics, competition by related substrates, and similar kinetic parameters for uptake and efflux. For copper uptake, Km = 11 +/- 0.6 microM and Vmax = 2.7 +/- 0.6 nmol Cu/(min X mg protein). Zinc is a competitive inhibitor of copper uptake, and copper competes for zinc uptake. Copper efflux from preloaded cells is biphasic. The kinetic parameters for the initial rapid phase are similar to the parameters for uptake. Copper transport by hepatocytes is strictly passive. A variety of metabolic inhibitors have no effect on uptake and initial rates are solely dependent on extracellular-intracellular concentration gradients. Albumin markedly inhibits copper uptake by a substrate removal mechanism, and histidine facilitates albumin-inhibited copper uptake. The active species that delivers copper to hepatocytes under conditions of excess albumin and excess histidine is the His2Cu complex. Experiments with [3H]His2 64Cu showed that the transported species is free ionic copper. The kinetic parameters of copper transport by hepatocytes isolated from the brindled mouse model of Menkes' disease are normal. However, these cells show a decreased capacity to accumulate copper on prolonged incubation. An intracellular metabolic defect seems to be involved.
 ...
PMID:Mechanism of copper transport from plasma to hepatocytes. 353 45

Menkes kinky hair syndrome is an X-linked neurodegenerative disorder, causing tissue-specific increases in copper and metallothionein content. A mouse model is provided by hemizygotes for mutant alleles at the X-linked mottled locus. Herein we test the possibility that the primary defect in both species is in metallothionein gene regulation. We show that metallothionein-I messenger RNA (mRNA) (mouse) and metallothionein-II mRNA (human) are elevated in mutant fibroblasts. However, comparable dose-response curves in mutant and control cells are generated when mouse metallothionein-I mRNA concentrations are measured in cells exposed to varying concentrations of cadmium or copper (metallothionein inducers). Furthermore, when mutant and control cells are grown to achieve overlapping intracellular copper concentrations in the two cell types, metallothionein-I (mouse) and metallothionein-II (human) mRNA levels are proportional to the intracellular copper concentrations. Finally, in paired determinations in blotchy hemizygote and littermate kidneys containing comparable copper levels, metallothionein-I mRNA contents are very similar. The observations suggest that elevated intracellular copper in these mutants induces metallothionein synthesis by normal regulatory mechanisms.
 ...
PMID:Metallothionein messenger RNA regulation in the mottled mouse and Menkes kinky hair syndrome. 357 89


<< Previous 1 2 3 4 5 6 7 8 9 10