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)

Two patients with Menkes' kinky hair disease were examined. Both showed the characteristic clinical features of this disease in combination with a low plasma-copper level. However, for one of them, studies with 64Cu provided clues that the copper was handled in a way unusual for a Menkes patient, viz., incorporation of 64Cu into ceruloplasmin during an oral 64Cu-loading test and abnormal behavior of skin fibroblasts in in vitro experiments. A comparison with brindled mice and some clinical aspects, viz., the age at death, the quality of the hair and the macrocephaly, of both patients are discussed.
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PMID:Menkes' kinky hair disease. I. Comparison of classical and unusual clinical and biochemical features in two patients. 709 67

We studied 2 of 4 affected boys with a new disease associated with abnormalities of copper metabolism. The four cases occurred in two generations of a family. This syndrome was similar to Menkes disease in some respects: X-linked recessive inheritance, marked psychomotor retardation with seizures, low serum copper and ceruloplasmin levels, and a block in gut copper absorption. There were also striking differences from Menkes disease. Patients had normal birthweight at term, no hypothermia, and survived beyond the usual Menkes age group with static neurologic disease including hypotonia and choreoathetosis. In addition, general examination of both children was unremarkable apart from undescended testes and growth retardation. The hair, facies, and skin were normal and there was no radiologic evidence of bony changes. Detailed studies of copper absorption were performed.
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PMID:An X-linked disease of the nervous system with disordered copper metabolism and features differing from Menkes disease. 719 7

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

The CCC2 gene of the yeast Saccharomyces cerevisiae is homologous to the human genes defective in Wilson disease and Menkes disease. A biochemical hallmark of these diseases is a deficiency of copper in ceruloplasmin and other copper proteins found in extracytosolic compartments. Here we demonstrate that disruption of the yeast CCC2 gene results in defects in respiration and iron uptake. These defects could be reversed by supplementing cells with copper, suggesting that CCC2 mutant cells were copper deficient. However, cytosolic copper levels and copper uptake were normal. Instead, CCC2 mutant cells lacked a copper-dependent oxidase activity associated with the extracytosolic domain of the FET3-encoded protein, a ceruloplasmin homologue previously shown to be necessary for high-affinity iron uptake in yeast. Copper restored oxidase activity both in vitro and in vivo, paralleling the ability of copper to restore respiration and iron uptake. These results suggest that the CCC2-encoded protein is required for the export of copper from the cytosol into an extracytosolic compartment, supporting the proposal that intracellular copper transport is impaired in Wilson disease and Menkes disease.
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PMID:The Menkes/Wilson disease gene homologue in yeast provides copper to a ceruloplasmin-like oxidase required for iron uptake. 770 96

Occipital horn syndrome (OHS, Ehlers-Danlos syndrome type IX) belongs to the category of the copper metabolism disorders and is at present being investigated biochemically as is Menkes' disease. Unlike Menkes' disease, most patients with OHS have mild submentality. We report a case of OHS with severe central nervous system involvement and muscular atrophy in a 34-year-old male. He had psychomotor retardation and seizures since early childhood and now presented severe mental retardation and generalized muscular atrophy in addition to characteristic facial appearance, hyperelasticity of the skin and joint subluxation. Laboratory investigations revealed a low serum copper and ceruloplasmin level as well as intestinal non-absorption of copper. Radiographic imaging showed occipital exostoses, bladder diverticula, tortuosity of the peripheral vein and osteoporosis of the skeletal bones. The activity of lysyl oxidase, a copper-enzyme involved in cross-link formation in collagen, was found to be decreased in a skin-biopsy specimen. Electron-microscopic investigation of a muscle biopsy showed irregularity of the myofibrillar network and accumulation of concentric laminated bodies in the subsarcolemmal regions.
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PMID:Central nervous system involvement and generalized muscular atrophy in occipital horn syndrome: Ehlers-Danlos type IX. A first Japanese case. 809 5

Menkes disease (MD) is an X-linked recessively inherited neurodegenerative disorder of copper (Cu) metabolism leading to death in early childhood. Symptoms are attributed to deficient activity of Cu-dependent enzymes. Limited experience has been reported concerning clinical and biochemical consequences of parenteral treatment with copper-(histidine)2-complex (Cu-His) in MD. Cu-His was administered in a 13-week-old boy with MD by daily intramuscular injections. After 6 weeks of therapy, Cu and caeruloplasmin in serum and Cu in CSF were normalized. The excessive dopamine level in CSF was corrected after 3 months of treatment. After 6 weeks of Cu supplementation, complete reduction of epileptic discharges, improved muscular tone and increased motor activities were observed. Developmental regression stopped and was replaced by a slight progression. Death at the age of 19 months was caused by septicaemia due to a fulminant urinary tract infection; there was no evidence of chronic Cu toxicity. These findings suggest that Cu-His supplementation may be a promising palliative treatment in MD.
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PMID:Clinical and biochemical consequences of copper-histidine therapy in Menkes disease. 822 85

The macular mutant mouse is a model of Menkes' kinky hair disease, which is characterized by a deficiency of ceruloplasmin in the serum. In hemizygotic mice (ml/y), the antibody production against sheep red blood cells (SRBC) was decreased. Treatment with normal (+/y) mouse serum increased in a dose-dependent manner the antibody response of ml/y mouse spleen cells in vitro. However, +/y mouse serum had no effect on +/y mouse spleen cells, even at high doses up to 5%. In contrast, ml/y mouse serum decreased antibody production in +/y mouse spleen cells in a dose-dependent manner. Antibody production in +/y mouse spleen cells decreased with time, after pretreatment with ml/y mouse serum. However, serum from ml/y mice injected with ceruloplasmin did not decrease antibody production in +/y mouse spleen cells but rather increased it in ml/y mouse spleen cells. Ceruloplasmin had no effect on the production of antibodies against SRBC in ml/y and +/y mouse spleen cells in vitro. These findings suggest that one or more enhancers of antibody production exist in normal mouse serum and that one or more suppressors of normal antibody production exist in ml/y mouse serum. It is proposed that the activities of these factors in serum may be regulated by ceruloplasmin.
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PMID:Evidence for serum factors modulating antibody production in normal and macular mice. 836 4

The macular mutant mouse is a murine model of Menkes' kinky hair disease, characterized by a serum copper and ceruloplasmin deficiency. The hemizygote (ml/y) had a decreased antibody response to sheep red blood cells (SRBC). 1) In vivo; the administration of ceruloplasmin recovered antibody production in ml/y mice, but, had no effect on that of normal mice (+/y). The administration of heat treated ceruloplasmin did not increase antibody production in ml/y mice, whereas the administration of various concentrations of copper suppressed the anti-SRBC plaque-forming response in both ml/y and +/y mice. 2) in vitro; ceruloplasmin had no effect upon antibody production against SRBC in both ml/y and +/y mouse spleen cells. In contrast to ceruloplasmin, 1 microgram/ml of copper inhibited the antibody production in spleen cells from both +/y and ml/y mice as well as in vivo. These findings suggested that the decreased antibody production in ml/y mice was considered to be due the decreased ceruloplasmin.
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PMID:Recovery of decreased antibody production by ceruloplasmin in the macular mutant mouse. 848 41

To correlate genotype with response to early copper histidine therapy in Menkes disease, an X-linked disorder of copper transport, we performed mutational analysis in 2 related males who began treatment at the age of 10 days and prenatally at 32 weeks' gestation, respectively. A G to T transversion at the -1 exonic position of a splice donor site was identified, predicting a glutamine to histidine substitution at codon 724 of the Menkes copper-transporting ATPase gene. The Q724H mutation disrupts proper splicing and generates five mutant transcripts that skip from one to four exons. None of these transcripts is predicted to encode a functional copper transport protein. Copper histidine treatment normalized circulating copper and ceruloplasmin levels but did not improve the baseline deficiency of dopamine-beta-hydroxylase, a copper-dependent enzyme. At the age of 36 months, the first patient was living and had neurodevelopmental abilities ranging from 10 to 15 months. The second patient also showed delayed neurodevelopment and died of pulmonary complications at the age of 5 1/2 months. We conclude that early copper histidine therapy does not normalize neurological outcome in patients with the Q724H splicing mutation, and suggest that preservation of some residual Menkes ATPase activity may be a general prerequisite for significant clinical efficacy from such treatment.
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PMID:Early copper therapy in classic Menkes disease patients with a novel splicing mutation. 900 80

Animal and human studies have shown that copper is involved in the function of several enzymes. Studies have also shown that copper is required for infant growth, host defense mechanisms, bone strength, red and white cell maturation, iron transport, cholesterol and glucose metabolism, myocardial contractility, and brain development. Copper deficiency can result in the expression of an inherited defect such as Menkes syndrome or in an acquired condition. Acquired deficiency is mainly a pathology of infants; however, it has been diagnosed also in children and adults. Most cases of copper deficiency have been described in malnourished children. The most constant clinical manifestations of acquired copper deficiency are anemia, neutropenia, and bone abnormalities. Other, less frequent manifestations are hypopigmentation of the hair, hypotonia, impaired growth, increased incidence of infections, alterations of phagocytic capacity of the neutrophils, abnormalities of cholesterol and glucose metabolism, and cardiovascular alterations. Measurements of serum copper and ceruloplasmin concentrations are currently used to evaluate copper status. These indexes are diminished in severe to moderate copper deficiency; however, they are less sensitive to marginal copper deficiency. Erythrocyte superoxide dismutase and platelet cytochrome c activities may be more promising indexes for evaluating marginal copper deficiency.
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PMID:Copper as an essential nutrient. 861 66


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