Wilson’s Disease

  • I. Herbert Scheinberg
  • Irmin Sternlieb


Wilson’s disease is an inherited abnormality of copper metabolism that has been observed only in man. The genetic defect leads to widely disseminated accumulations of copper that induce toxic effects most significantly in the liver and brain.


Copper Deficiency Copper Toxicity Copper Protein Copper Metabolism Central Pontine Myelinolysis 
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  1. 1.
    I.H. Scheinberg and I. Sternlieb, Metabolism of trace metals, in “Duncan’s Diseases of Metabolism,” 6th Ed. (P. K. Bondy, ed.) Vol. 2, pp. 1321–1334, Saunders, Philadelphia (1969).Google Scholar
  2. 2.
    B. Reiff and H. Schnieden, Plasma copper and iron levels and plasma paraphenylene diamine oxidase activity (plasma copper oxidase activity) in kwashiorkor, Blood 14:967–971 (1959).Google Scholar
  3. 3.
    A. Cordano and G. G. Graham, Copper deficiency complicating severe chronic intestinal malabsorption, Pediatrics 38:596–604 (1966).Google Scholar
  4. 4.
    I. Sternlieb and H. D. Janowitz, Absorption of copper in malabsorption syndromes, J. Clin. Invest. 43:1049–1055 (1964).CrossRefGoogle Scholar
  5. 5.
    A. Cordano, J. M. Baertl, and G. G. Graham, Copper deficiency in infancy, Pediatrics 34:324–336 (1964).Google Scholar
  6. 6.
    R. I. Henkin, H. R. Keiser, I. A. Jaffe, I. Sternlieb, and I. H. Scheinberg, Decreased taste sensitivity after d-penicillamine, reversed by copper administration. Lancet 2:1268–1271 (1967).CrossRefGoogle Scholar
  7. 7.
    D. M. Danks, B. J. Stevens, P. E. Campbell, J. M. Gillespie, J. Walker-Smith, J. Blomfield, and B. Turner, Menkes’ kinky-hair syndrome, Lancet 1:1100–1103 (1972).CrossRefGoogle Scholar
  8. 8.
    D. M. Danks, E. Cartwright, B. J. Stevens, and R. R. W. Townley, Menkes’ kinky hair disease: Further definition of the defect in copper transport, Science (Wash. D.C.) 179:1140–1142 (1973).CrossRefGoogle Scholar
  9. 9.
    J. H. French, E. S. Sherard, H. Lubell, M. Brotz, and C. L. Moore, Trichopoliodystrophy. I. Report of a case and biochemical studies, Arch. Neurol. 26:229–244 (1972).CrossRefGoogle Scholar
  10. 10.
    J. H. French, C. L. Moore, N. R. Ghatak, I. Sternlieb, S. Goldfischer, and A. Hirano, Trichopoliodystrophy (Menkes’ kinky hair syndrome): A copper dependent deficiency of mitochondrial energetics, Pediatr. Res. 7:386 (1973).Google Scholar
  11. 11.
    B. Magdoff-Fairchild, F. M. Lovell, and B. W. Low, An X-Ray crystallographic study of ceruloplasmin. Determination of molecular weight, J. Biol. Chem. 244:3497–3499 (1969).Google Scholar
  12. 12.
    C. B. Kasper and H. F. Deutsch, Physicochemical studies of human ceruloplasmin, J. Biol. Chem. 238:2325–2337 (1963).Google Scholar
  13. 13.
    S. Osaki, D. A. Johnson, and E. Freiden, The possible significance of the ferrous oxidase activity of ceruloplasmin in normal human serum, J. Biol. Chem. 241:2746–2751 (1966).Google Scholar
  14. 14.
    I. H. Scheinberg and D. Gitlin, Deficiency of ceruloplasmin in patients with hepatolenticular degeneration (Wilson’s disease), Science (Wash. D.C.) 116:484–485 (1952).CrossRefGoogle Scholar
  15. 15.
    H. Beinert, D. E. Griffiths, D. C. Wharton, and R. H. Sands, Properties of the copper associated with cytochrome oxidase as studied by paramagnetic resonance spectroscopy, J. Biol. Chem. 237:2337–2346 (1962).Google Scholar
  16. 16.
    P. R. Dallman, Cytochrome oxidase repair during treatment of copper deficiency: Relation to mitochondrial turnover, J. Clin. Invest. 46:1819–1827 (1967).CrossRefGoogle Scholar
  17. 17.
    B. F. Fell, C. F. Mills, and R. Boyne, Cytochrome oxidase deficiency in the motor neurones of copper-deficient lambs: A histochemical study, Res. Vet. Sci. 6:170–177 (1965).Google Scholar
  18. 18.
    F. C. Brown and D. N. Ward, Studies on mammalian tyrosinase. II. Chemical and physical properties of fractions purified by chromatography, Proc. Soc. Exp. Biol. 100:701–704 (1959).Google Scholar
  19. 19.
    T. B. Fitzpatrick, M. Seiji, and A. D. McGugan, Melanin pigmentation, N. Engl. J. Med. 265:328–332, 374-378, 430-434 (1961).CrossRefGoogle Scholar
  20. 20.
    J. M. McCord and I. Fridovich, Superoxide dismutase: An enzymatic function for erythrocuprein (hemocuprein), J. Biol. Chem. 244:6049–6055 (1969).Google Scholar
  21. 21.
    R. J. Carrico and H. F. Deutsch, Isolation of human hepatocuprein and cerebrocuprein: Their identity with erythrocuprein, J. Biol. Chem. 244:6087–6093 (1969).Google Scholar
  22. 22.
    G. Jung, M. Ottnad, W. Bremser, H.-J. Hartmann, and U. Weser, Elektronenbindungsenergien von Kupfer, Zink und Kobalt in modifizierten Cupreinen, Hoppe-Seyler’s Z. Physiol. Chem. 354:341–343 (1973).CrossRefGoogle Scholar
  23. 23.
    U. Weser, R. Prinz, A. Schallies, A. Fretzdorff, P. Krauss, W. Voelter, and W. Voetsch, Microbial and hepatic cuprein (Superoxide dismutase), Hoppe-Seyler’s Z. Physiol. Chem. 353:1821–1831 (1972).CrossRefGoogle Scholar
  24. 24.
    K.-E. Joester, G. Jung, U. Weber, and U. Weser, Superoxide dismutase activity of Cu2+-amino acid chelates, FEBS (Fed. Eur. Biochem. Soc.) Lett. 25:25–28 (1972).Google Scholar
  25. 25.
    D. W. Reed, P. G. Passon, and D. E. Hultquist, Purification and properties of a pink copper protein from human erythrocytes, J. Biol. Chem. 245:2954–2961 (1970).Google Scholar
  26. 26.
    H. Yamada and K. T. Yasunobu, Monoamine oxidase. II. Copper, one of the prosthetic groups of plasma monoamine oxidase, J. Biol. Chem. 237:3077–3082 (1962).Google Scholar
  27. 27.
    A. G. Morell, J. R. Shapiro, and I. H. Scheinberg, Copper binding protein of human liver, in “Wilson’s Disease, Some Current Concepts” (J. M. Walshe and J. N. Cumings, eds.) pp. 36–42, Blackwell, Oxford (1961).Google Scholar
  28. 28.
    G. W. Evans, Copper homeostasis in the mammalian system, Physiol. Rev. 53:535–570 (1973).Google Scholar
  29. 29.
    H. Porter, J. Johnston, and E. M. Porter, Neonatal hepatic mitochondrocuprein. I. Isolation of a protein fraction containing more than 4% copper from mitochondria of immature bovine liver. Biochim. Biophys. Acta 65:66–73 (1962).CrossRefGoogle Scholar
  30. 30.
    H. Porter, Copper proteins in brain and liver in normal subjects and in cases of Wilson’s disease, in “Wilson’s Disease — Birth Defects Original Article Series” (D. Bergsma, I. H. Scheinberg, and I. Sternlieb, eds.) Vol. 4, No. 2, pp. 23–28, The National Foundation — March of Dimes, New York (1968).Google Scholar
  31. 31.
    H. Fushimi, C. R. Hamison, and H. A. Ravin, Two new copper proteins from human brain, J. Biochem. 69:1041–1054 (1971).Google Scholar
  32. 32.
    S. Friedman and S. Kaufman, 3,4-Dihydroxyphenylethylamine β-hydroxylase: A copper protein, J. Biol. Chem. 240:552–554 (1965).Google Scholar
  33. 33.
    T. L. Sourkes, Influence of specific nutrients on catecholamine synthesis and metabolism, Pharmacol. Rev. 24:349–359 (1972).Google Scholar
  34. 34.
    H. K. Chuttani, P. S. Gupta, S. Gulati, and D. N. Gupta, Acute copper sulfate poisoning, Am. J. Med. 39:849–854 (1965).CrossRefGoogle Scholar
  35. 35.
    P. K. Wahal, V. P. Mittal, and O. P. Bansal, Renal complications in acute copper sulphate poisoning, Indian Pract. 18:807–812 (1965).Google Scholar
  36. 36.
    S. H. Hopper and H. S. Adams, Copper poisoning from vending machines, Public Health. Rep. 73:910–914 (1958).Google Scholar
  37. 37.
    W. McMullen, Copper contamination in soft drinks from bottle pourers, Health Bull. (Edinb.) 29:94–96 (1971).Google Scholar
  38. 38.
    N. A. Holtzman, D. A. Elliott, and R. H. Heller, Copper intoxication: Report of a case with observations on ceruloplasmin. N. Engl. J. Med. 275:347–352 (1966).CrossRefGoogle Scholar
  39. 39.
    J. Blomfield, J. McPherson, and C. R. P. George, Active uptake of copper and zinc during haemodialysis, Br. Med. J. 2:141–145 (1969).CrossRefGoogle Scholar
  40. 40.
    A. D. Manzler and A. W. Schreiner, Copper-induced acute hemolytic anemia, Ann. Int. Med. 73:409–412 (1970).Google Scholar
  41. 41.
    B. H. Barbour, M. Bischel, and D. E. Abrams, Copper accumulation in patients undergoing chronic hemodialysis: The role of Cuprophan, Nephron 8:455–462 (1971).CrossRefGoogle Scholar
  42. 42.
    I. H. Scheinberg and I. Sternlieb, Copper metabolism, Pharmacol. Rev. 12:355–381 (1960).Google Scholar
  43. 43.
    I. Sternlieb, Gastrointestinal copper absorption in man, Gastroenterology 52:1038–1041 (1967).Google Scholar
  44. 44.
    A. G. Beam and H. G. Kunkel, Metabolic studies in Wilson’s disease using Cu64, J. Lab. Clin. Med. 45:623–631 (1955).Google Scholar
  45. 45.
    P. Z. Neumann and A. Sass-Kortsak, The state of copper in human serum: Evidence for an amino acid-bound fraction, J. Clin. Invest. 46:646–658 (1967).CrossRefGoogle Scholar
  46. 46.
    B. Sarkar and T. P. A. Kruck, Copper-amino acid complexes in human serum, in “The Biochemistry of Copper” (J. Peisach, P. Aisen, and W. E. Blumberg, eds.) pp. 183–196, Academic Press, New York (1966).Google Scholar
  47. 47.
    I. Sternlieb, A. G. Morell, and I. H. Scheinberg, The uniqueness of ceruloplasmin in the study of plasma protein synthesis, Trans. Assoc. Am. Phys. 75:228–234 (1962).Google Scholar
  48. 48.
    T. Terao and C. A. Owen, Jr., Nature of copper compounds in liver supernate and bile of rats: Studies with 67 Cu, Am. J. Physiol. 224:682–686 (1973).Google Scholar
  49. 49.
    T. A. Waldman, A. G. Morell, R. D. Wochner, W. Strober, and I. Sternlieb, Measurement of gastrointestinal protein loss using 67 copper labelled ceruloplasmin, J. Clin. Invest. 46:10–20 (1967).CrossRefGoogle Scholar
  50. 50.
    I. H. Scheinberg and I. Sternlieb, Wilson’s disease, Ann. Rev. Med. 16:119–134 (1965).CrossRefGoogle Scholar
  51. 51.
    I. Sternlieb, C. J. A. van den Hamer, A. G. Morell, S. Alpert, G. Gregoriadis, and I. H. Scheinberg, Lysosomal defect of hepatic copper excretion in Wilson’s disease (hepatolenticular degeneration), Gastroenterologiy 64:99–105 (1973).Google Scholar
  52. 52.
    I. H. Scheinberg and I. Sternlieb, The liver in Wilson’s disease, Gastroenterology 37:550–564 (1959).Google Scholar
  53. 53.
    I. Sternlieb, Evolution of the hepatic lesion in Wilson’s disease (hepatolenticular degeneration), in “Progress in Liver Diseases” (H. Popper and F. Schaffner, eds.) Vol. 4, pp. 511–525, Grune & Stratton, New York (1972).Google Scholar
  54. 54.
    S. Goldfischer and I. Sternlieb, Changes in the distribution of hepatic copper in relation to the progression of Wilson’s disease (hepatolenticular degeneration), Am. J. Pathol. 53:883–901 (1968).Google Scholar
  55. 55.
    I. Sternlieb, Mitochondrial and fatty changes in hepatocytes of patients with Wilson’s disease, Gastroenterology 55:354–367 (1968).Google Scholar
  56. 56.
    S. A. K. Wilson, Progressive lenticular degeneration: A familial nervous disease associated with cirrhosis of the liver, Brain 34:295–509 (1912).CrossRefGoogle Scholar
  57. 57.
    N. V. Konovalov, “Gepatotzerebralnaia Distrofia,” Medgiz, Moscow (1960).Google Scholar
  58. 58.
    P. Castan, La myélinolyse centrale dans la dégénérescence hépato-lenticulaire: Essai sur sa signification, Rev. Neurol. (Paris) 117:391–409 (1967).Google Scholar
  59. 59.
    J. N. Cumings, “Heavy Metals and the Brain,” pp. 3–71, Charles C Thomas, Springfield, Ill. (1959).Google Scholar
  60. 60.
    S. Schulman, Wilson’s disease, in “Pathology of the Nervous System” (J. Minckler, ed.) Vol. 1, pp. 1139–1152, McGraw-Hill, New York (1968).Google Scholar
  61. 61.
    K. Ohta, Y. Okamoto, and O. Honda, Electron microscopic observations on the cerebrum of a case of Wilson’s disease, Psych. Neurol. Jap. 71:385–406 (1969).Google Scholar
  62. 62.
    A. Deiss, G. R. Lee, and G. E. Cartwright, Hemolytic anemia in Wilson’s disease, Ann. Int. Med. 73:413–418 (1970).Google Scholar
  63. 63.
    I. Sternlieb, The Kayser-Fleischer ring, Med. Radiogr. Photogr. 42:14–15 (1966).Google Scholar
  64. 64.
    E. S. Reynolds, R. L. Tannen, and H. R. Tyler, The renal lesion in Wilson’s disease, Am. J. Med. 40:518–527 (1966).CrossRefGoogle Scholar
  65. 65.
    A. G. Beam, Wilson’s disease, in “The Metabolic Basis of Inherited Disease” (J. B. Stanbury, J. G. Wyngaarden, and D. S. Frederickson, eds.) 3rd ed., pp. 1033–1050, McGraw-Hill, New York (1972).Google Scholar
  66. 66.
    M. L. Leu, G. T. Strickland, and R. A. Gutman, Renal function in Wilson’s disease: Response to penicillamine therapy, Am. J. Med. Sci. 260:381–398 (1970).CrossRefGoogle Scholar
  67. 67.
    I. Sternlieb and I. H. Scheinberg, The prevention of Wilson’s disease in asymptomatic patients, N. Engl. J. Med. 278:352–359 (1968).CrossRefGoogle Scholar
  68. 68.
    H. Wisniewski, M. Smialek, H. Szydlowska, and T. Zalewaska, Quantitative topography of copper in Wilson’s disease and in porto-systemic encephalography, Neuropathol. Pol. 5:92–103 (1967).Google Scholar
  69. 69.
    D. Denny-Brown, Hepatolenticular degeneration (Wilson’s disease), N. Engl. J. Med. 270:1149–1156 (1964).CrossRefGoogle Scholar
  70. 70.
    C. K. Smith and R. H. Mattson, Seizures in Wilson’s disease, Neurology 17:1121–1123 (1967).CrossRefGoogle Scholar
  71. 71.
    G. L. Heller and K. A. Kooi, The electroencephalogram in hepato-lenticular degeneration (Wilson’s disease), Electroencephalogr. Clin. Neurophysiol. 14:520–526(1962).CrossRefGoogle Scholar
  72. 72.
    I. H. Scheinberg, I. Sternlieb, and J. Richman, Psychiatrie manifestations in patients with Wilson’s disease, in “Wilson’s Disease: Birth Defects Original Article Series” (D. Bergsma, I. H. Scheinberg, and I. Sternlieb, eds.) Vol. 4, No. 2, pp. 85–87, The National Foundation — March of Dimes, New York (1968).Google Scholar
  73. 73.
    N. P. Goldstein, J. C. Ewert, R. V. Randall, and J. B. Gross, Psychiatrie aspects of Wilson’s disease (Hepatolenticular degeneration): Results of psychometric tests during long-term therapy, Am. J. Psychiatry 124:1555–1561 (1968).Google Scholar
  74. 74.
    I. H. Scheinberg, Psychosis associated with hereditary disorders, in “American Handbook of Psychiatry” (M. F. Reiser, ed.) Vol. 4 (in press).Google Scholar
  75. 75.
    J. N. Cumings, The effects of BAL in hepatolenticular degeneration, Brain 74:10–22 (1951).CrossRefGoogle Scholar
  76. 76.
    D. Denny-Brown and H. Porter, The effect of B.A.L. on hepatolenticular degeneration, N. Engl. J. Med. 245:917–925 (1951).CrossRefGoogle Scholar
  77. 77.
    J. M. Walshe, Penicillamine, a new oral therapy for Wilson’s disease, Am. J. Med. 21:487–495 (1956).CrossRefGoogle Scholar
  78. 78.
    I. Sternlieb and I. H. Scheinberg, Penicillamine therapy in hepatolenticular degeneration, J. Am. Med. Assoc. 189:748–754 (1964).CrossRefGoogle Scholar
  79. 79.
    J. M. Walshe, Wilson’s disease, A Review, in “The Biochemistry of Copper” (J. Peisach, P. Aisen, and W. E. Blumberg, eds.) pp. 475–498, Academic Press, New York (1966).Google Scholar
  80. 80.
    N. P. Goldstein, W. N. Tauxe, J. T. McCall, R. V. Randall, and J. B. Gross, Wilson’s disease (Hepatolenticular degeneration): Treatment with penicillamine and changes in hepatic trapping of radioactive copper, Arch. Neurol. 24:391–400 (1971).CrossRefGoogle Scholar
  81. 81.
    H. Jérôme and I. Sternlieb, La détection préclinique de la maladie de Wilson, Arch. Franç. Pédiatric 23:669–677 (1966).Google Scholar
  82. 82.
    M. Arima and K. Komiya, Prevention of Wilson’s disease: A long term follow-up, Paediatr. Univ. Tokyo 18:22–24 (1970).Google Scholar
  83. 83.
    H. P. Ting-Beall, D. A. Clark, C. H. Suelter, and W. W. Wells, Studies on the interaction of chick brain microsomal (Na+ + K+)-ATPase with copper, Biochim. Biophys. Acta 291:229–236 (1973).CrossRefGoogle Scholar
  84. 84.
    R. Peters, M. Shorthouse, and J. M. Walshe, Studies on the toxicity of copper. II. The behaviour of microsomal membrane ATPase of the pigeon’s brain tissue to copper and some other metallic substances, Proc. R. Soc. B. 166:285–294 (1966).CrossRefGoogle Scholar
  85. 85.
    K. Bowler and C. J. Duncan, The effect of copper on membrane enzymes, Biochim. Biophys. Acta 196:116–119 (1970).CrossRefGoogle Scholar
  86. 86.
    P. S. Epstein and H. Mcllwain, Actions of cupric salts on isolated cerebral tissues, Proc. R. Soc. B. 166:295–302 (1966).CrossRefGoogle Scholar
  87. 87.
    D. J. Chiarandini, E. Stefani, and H. M. Gerschenfeld, Inhibition of membrane permeability to chloride by copper in molluscan neurones, Nature (Lond.) 213:97–99 (1967).CrossRefGoogle Scholar
  88. 88.
    H. M. Smith, Effects of sulfhydryl blockade on axonal function. J. Cell. Comp. Physiol. 51:161–171 (1958).CrossRefGoogle Scholar
  89. 89.
    F. S. Vogel and L. Kemper, Biochemical reactions of copper within neural mitochondria, with consideration of the role of the metal in the pathogenesis of Wilson’s disease, Lab. Invest. 12:171–179 (1963).Google Scholar
  90. 90.
    R. Peters and J. M. Walshe, Studies on the toxicity of copper. I. The toxic action of copper in vivo and in vitro, Proc. R. Soc. B. 166:273–284 (1966).CrossRefGoogle Scholar
  91. 91.
    H. Bal, Effects of copper sulphate poisoning in white rats, Naturwissenschaften 51:139 (1964).CrossRefGoogle Scholar
  92. 92.
    F. S. Vogel and J. W. Evans, Morphologic alterations produced by copper in neural tissues with consideration of the role of the metal in the pathogenesis of Wilson’s disease, J. Exp. Med. 113:997–1004 (1961).CrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1975

Authors and Affiliations

  • I. Herbert Scheinberg
    • 1
  • Irmin Sternlieb
    • 1
  1. 1.Division of Genetic Medicine, Department of Medicine, Albert Einstein College of MedicineYeshiva UniversityBronxUSA

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