conspectus of researchon copper metabolism and requirements

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2006 KARL E. MASON the disease, as originally recorded by Menkes et al. (513), are: short, broken, spirally twisted scalp hair (pili torti) with loss of pigment; frequent convulsive sei zures, failure to thrive or poor weight gain, mental retardation and, at necropsy, wide spread degenerative changes in the cere brum and cerebellum. To these manifesta tions have since been added: hypothermia (56, 72, 145, 148, 168, 225, 530); marked tortuosity, associated with defects of the internal elastic lamina and hyperplasia of the overlying intima, of large muscular arteries, particularly those supplying the brain and its appendages (4, 12, 114, 145, 146, 422, 582, 713, 717, 808, 817); excessive Wormian bone formation (283, 645, 732, 835) and pronounced changes in certain long bones similar to those of scurvy and/ or the battered child syndrome (56, 145, 168, 669, 713, 717, 732). Biochemically, there is increased copper content of the intestinal mucosa ( 145, 148, 470 ) ; greatly reduced levels of serum copper and ceruloplasmin (55, 72, 148, 168, 310, 530, 713, 817) despite normal copper levels in erythrocytes, and much reduced levels of copper in the liver ( 145, 148, 329, 817) and brain (145, 817). Other reports have made reference to deficient visual functions and ocular ab normalities (49, 310, 453, 697, 717, 863) and to neurogenic bladders with diverticulum formation (306, 838), presumably due to defective innervation or vascular abnor malities. In the only known case of Menkes' disease in a black infant, Volpintesta (809 ) observed a remarkable light skin in con trast to the dark-skinned parents, an un usual mottled skin pigmentation in a 7-year old female sibling, and a small degree of pili torti in the mother and two female siblings. Manifestations typical of Menkes' syndrome, except for the absence of steely hair, have been reported in a Japanese in fant by Osaka et al. (582) who question whether some cases of the disease may go unrecognized because of too great a re liance on the hair abnormality as a diag nostic feature. Several new observations have special relevance to early diagnosis of Menkes' disease. A recently described method for measuring ceruloplasmin using a dried blood clot (21) may have value in screen ing for early diagnosis, but only when ap plied at 3 months of age or later (495). An intense metachromasia sue cultures of fibroblasts in primary tis has interesting possibilities as a genetic marker in early diagnosis and in identification of homozy gotes and hÃ©tÃ©rozygotes in affected fam ilies (145, 147). This defective cellular metabolism dicated by of copper in fibroblasts is in other observations that cul tured skin fibroblasts from subjects Menkes' disease have an abnormally with high copper content (259) and also can incor porate much greater amounts of 84Cu from the medium than do fibroblasts of un affected subjects (358). The copper con tent of the culture medium may be critical in such evaluations. Regrettably, there exist rather limited prospects that im provements in early diagnosis will be paral lelled by more effective therapeutic mea sures. Widespread degeneration of cerebral grey matter, secondary to degeneration of cerebral white matter and diffuse atrophy of the cerebral cortex, associated with bizarre changes in shape and arrangement of Purkinje cells, as first described by Menkes et al. (513), has been confirmed by later neuropathologic studies ( 11, 251, 336, 624, 802, 810). Nerve tracts of the spinal cord may sometimes be involved (11, 251). Peripheral nerves are not affected. It is proposed that these lesions reflect two types of change; viz., cerebral necrosis due to abnormalities of the extracranial arteries, and typical dystrophic lesions in the cerebellar cortex (810). Confirming and extending the original descriptions of the cerebellar lesions by Menkes et al. (513) and Aguilar et al. (Il), ultrastructural studies of the bizarre elaboration of perisomatic dendrites of Purkinje cells sug gest retarded development of the somal membrane of these cells (336, 624). Such evidence is cited in support of the concept that the disease process is operative in utero (340). A careful light and electron microscopic study of the eye has revealed degeneration of retinal ganglion cells, loss of nerve fibers, optic atrophy, abnormal pigment epithe lium and abnormal elastin in Bruch's mem brane (863). A similar study of aorta and Downloaded from jn.nutrition.org by guest on February 27, 2013
COPPER METABOLISM AND REQUIREMENTS OF MAN 2007 skin in Menkes' disease has demonstrated abnormalities of elastic fibers similar to those observed in animal studies on copper deficiency (566). Reported ultrastructural changes in skeletal muscle (251) have not been confirmed (717). Neurochemical studies on two infants whose neuropathology was described by Aguilar et al. (Il) record abnormally low levels of polyunsaturated glycerophosphates, especially in the frontal gray matter, and accumulation of oxidized lipid products in the neurones, suggesting an interference with the molec ular machinery of the cells (567). These observations have been both challenged (469) and confirmed (645). French et al. (224, 225) who proposed the term "trichopoliodystrophy" report much reduced levels of cytochrome a and a3 in mitochon dria of brain, muscle and liver, and con clude that deficient terminal respiration and failure of tissue energetics, secondary to diminished body copper content, may explain some of the neuropathology of Menkes' disease. Significantly reduced levels of erythrocyte Superoxide dismutase and of dopamine ÃŸ-hydroxylasemay have bearing upon manifestations of the disease (645). Metabolic abnormalities Danks et al. (145, 147) propose that the primary defect in Menkes' disease is dimin ished ability to transfer copper across ab sorptive cells of the intestinal mucosa to the serosal side and the portal circulation. While considering this an important factor, Bucknall et al. (72), based upon studies on a 3-month old infant, speculate that neurological damage may occur in utero, perhaps as a result of defective placental transport of copper. This is supported by reports of the occurrence of one or more manifestations of Menkes' disease at term or within the week thereafter (283, 513, 530). However, defective placental trans port may not provide the total answer. Heydorn et al. (329) and Horn et al. (359) consider that defective binding of copper in the fetal liver or atypical distri bution in fetal tissues may be involved. The conclusions of Heydorn et al. (329) are based upon tissue analyses of a fetus suspected of Menkes' disease, obtained by therapeutic abortion at 18 weeks gesta tion. Compared to four normal fetuses of 15 to 21 weeks gestation, copper concen trations in brain, lung, spleen, kidney, pan creas, muscle, skin and placenta were several times greater than, but liver cop per was only about one-third, that of con trols. Yet, the estimated total copper con tent of all fetuses was essentially the same. These findings, until substantiated, do not eliminate possibilities of defective placental transfer. However, they do raise questions regarding copper storage in fetal liver and atypical distribution of copper in other fetal tissues and organs in Menkes' disease (329, 635). Menkes' disease and nutritional copper deficiency have certain features in com mon; 1) usual occurrence in infancy; 2) subnormal plasma levels of copper and ceruloplasmin; 3) tortuosity and defects in elastin of the aorta due to lack of lysyl oxidase; 4) scorbutic-like changes in costochondral junctions and epiphyses of long bones; and 5) decreased pigmentation of skin or hair. Menkes' disease differs from the state of dietary copper deficiency in the following respects: 1) alterations of hair structure and decreased pigmentation of hair, the latter attributable to lack of tyrosinase; 2) highly variable and often extensive lesions involving both white and gray matter of the cerebrum and cerebel lum, usually ascribed to lack of cytochrome oxidase and Superoxide dismutase which, in turn, may also be factors involved in 3) hypothermia, a frequently observed phenomenon; and 4) the almost routine occurrence of convulsive seizures and mental retardation. To these may be added 5) absence of anemia and neutropenia and 6) unresponsiveness to orally administered copper other than significant increases in plasma levels of copper and ceruloplasmin. Separate oral and intravenous adminis tration of '"Cu, permitting calculation of the percentage of dose absorbed, indicates that children with Menkes' disease absorb only 11 to I3c/c of oral copper as com pared to 46^ by unaffected controls, sug gesting a reduced absorption of copper as an important factor in the disorder ( 159). Also, most of the copper absorbed is re tained by the liver for extended periods of Downloaded from jn.nutrition.org by guest on February 27, 2013
Page 1 and 2: A CONSPECTUS OF RESEARCH ON COPPER
Page 3 and 4: INTRODUCTION The discovery of coppe
Page 5 and 6: COPPER METABOLISM AND REQUIREMENTS
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Page 55 and 56: Ã®1co 1stW Â»aÂ«a3 COPPER MET
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COPPER METABOLISM AND REQUIREMENTS
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