Biometals

, Volume 16, Issue 1, pp 205–213 | Cite as

Aceruloplasminemia, an inherited disorder of iron metabolism

  • Hiroaki Miyajima
  • Yoshitomo Takahashi
  • Satoshi Kono
Article

Abstract

Ceruloplasmin, a multi-copper ferroxidase that affects the distribution of tissue iron, has antioxidant effects through the oxidation of ferrous iron to ferric iron. Aceruloplasminemia is an inherited disorder of iron metabolism due to the complete lack of ceruloplasmin ferroxidase activity caused by mutations in the ceruloplasmin gene. It is characterized by iron accumulation in the brain as well as visceral organs. Clinically, the disease consists of the triad of retinal degeneration, diabetes mellitus, and neurological disease, which include ataxia, involuntary movements, and dementia. These symptoms reflect the sites of iron deposition. The unique involvement of the central nervous system distinguishes aceruloplasminemia from other inherited and acquired iron storage disorders. Twenty-one mutations in the ceruloplasmin gene have been reported in 24 families worldwide. In Japan, the incidence was estimated to be approximately one per 2,000,000 in the case of non-consanguineous marriages. Excess iron functions as a potent catalyst of biologic oxidation. Previously we showed that an increased iron concentration is associated with increased levels of lipid peroxidation in the serum, cerebrospinal fluid, and erythrocyte membranes. The levels of malondialdehyde and 4-hydroxynonenals, indicators of lipid peroxidation, were also elevated in the basal ganglia and cerebral cortex. Positron emission tomography showed diminished brain metabolism of glucose and oxygen. Enzyme activities in the mitochondrial respiratory chain of the basal ganglia were reduced to approximate 45% and 42%, respectively, for complexes I and IV. These findings suggest that iron-mediated free radicals causes neuronal cell damage through lipid peroxidation and mitochondrial dysfunction in aceruloplasminemia brains.

ceruloplasmin free radicals iron lipid peroxidation mitochondrial respiratory chain 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Bowling AC, Beal MF. 1995 Bioenergetic and oxidative stress in neurodegenerative diseases. Life Sci 56, 1151-1171.Google Scholar
  2. Bowling AC, Mutisya EM, Walker LC et al. 1993 Age-dependent impairment of mitochondrial function in primate brain. J Neurochem 60, 1964-1967.Google Scholar
  3. Bull PC, Thomas GR, Rommens JM et al. 1993 TheWilson disease gene is a putative copper transporting P-type ATPase similar to the Menkes gene. Nat Genet 5, 327-337.Google Scholar
  4. Chelly J, Tumer Z, Tonnesen T et al. 1993 Isolation of a candidate gene for Menkes disease that encodes a potential heavy metal binding protein. Nat Genet 3, 14-19.Google Scholar
  5. Daimon M, Kato T, Kawanami T et al. 1995 A nonsense mutation of the ceruloplasmin gene in hereditary ceruloplasmin deficiency with diabetes mellitus. Biochem Biophys Res Commun 217, 89-95.Google Scholar
  6. Daimon M, Suga S, Ohizumi T et al. 2000 A novel mutation of the ceruloplasmin gene in a patient with heteroallelic ceruloplasmin gene mutation (HypoCPGM). Tohoku J Exp Med 191, 119-125.Google Scholar
  7. Feder JN, Gnirke A, Thomas W et al.. 1996 A novel HMC class I-like gene is mutated in patients with hereditary haemochromatosis. Nat Genet 13, 399-408.Google Scholar
  8. Frieden E. 1986 Perspectives on copper biochemistry. Clin Physiol Biochem 4, 11-19Google Scholar
  9. Fry M, Green DE. 1981 Cardiolipin requirement for electron transfer in complex I and III of the mitochondrial respiratory chain. J Biol Chem 256, 1874-1880.Google Scholar
  10. Gutteridge JMC. 1983 Antioxidant properties of caeruloplasmin towards iron-and copper-dependent oxygen radical formation. FEBS Lett 157, 37-40.Google Scholar
  11. Harris ZL, Takahashi Y, Miyajima H et al. 1995 Aceruloplasminemia: molecular characterization of this disorder of iron metabolism. Proc Natl Acad Sci USA 92, 2539-2543.Google Scholar
  12. Harris ZL, Migas MC, Hughes AE et al. 1996 Familial dementia due to a frameshift mutation in the caeruloplasmin gene. QJM 89, 355-359.Google Scholar
  13. Hellman NE, Schaefer M, Gehrke S et al. 2000 Hepatic iron overload in aceruloplasminemia. Gut 47, 858-860.Google Scholar
  14. Klomp LWJ, Gitlin JD. 1996 Expression of the ceruloplasmin gene in the human retina and brain: implications for a pathogenetic model in aceruloplasminemia. Hum Mol Genet 5, 1989-1996.Google Scholar
  15. Kohno S, Miyajima H, Takahashi Y, Inoue Y. 1999 Aceruloplasminemia with a novel mutation associated with parkinsonism. Neurogenet 2, 237-238.Google Scholar
  16. Logan JI, Harveyson KB, Wisdom GB, Hughes AE, Archbold GPR. 1994 Hereditary caeruloplasmin deficiency, dementia and diabetes mellitus. QJM 87, 663-670.Google Scholar
  17. Mercer JF, Livingston J, Hall B et al. 1993 Isolation of a partial candidate gene for Menkes disease by positional cloning. Nat Genet 3, 20-25.Google Scholar
  18. Miyajima H, Nishimura Y, Mizoguchi K et al. 1987 Familial apoceruloplasmin deficiency associated with blepharospasm and retinal degeneration. Neurology 37, 761-767.Google Scholar
  19. Miyajima H, Takahashi Y, Shimizu H et al. 1996a Late onset diabetes mellitus in patients with hereditary aceruloplasminemia. Int Med 35, 641-645.Google Scholar
  20. Miyajima H, Takahashi Y, Serizawa M, Kaneko E, Gitlin JD. 1996b Increased plasma lipid peroxidation in patients with aceruloplasminemia. Free Radic Biol Med 20, 757-760.Google Scholar
  21. Miyajima H, Takahashi Y, Kamata T et al. 1997 Use of desferrioxamine in the treatment of aceruloplasminemia. Ann Neurol 41, 404-407.Google Scholar
  22. Miyajima H, Fujimoto M, Kohno S, Kaneko E, Gitlin JD. 1998a CSF abnormalities in patients with aceruloplasminemia. Neurology 51, 1188-1190.Google Scholar
  23. Miyajima H, Adachi J, Tatsuno Y et al. 1998b Increased verylong-chain fatty acids in erythrocyte membranes of patients with aceruloplasminemia. Neurology 50, 130-136.Google Scholar
  24. Miyajima H, Kohno S, Takahashi Y, Yonekawa O, Kanno T. 1999 Estimation of the gene frequency of aceruloplasminemia in Japan. Neurology 53, 617-619.Google Scholar
  25. Miyajima H, Adachi J, Kohno S et al. 2001 Increased oxysterols associated with iron accumulation in the brains and visceral organs of aceruloplasminemia patients. QJM 94, 417-422.Google Scholar
  26. Morita H, Ikeda S, Yamamoto K et al. 1995 Hereditary ceruloplasmin deficiency with hemosiderosis: A clinicopathological study of a Japanese family. Ann Neurol 137, 646-656.Google Scholar
  27. Narabayashi H, Takeshige K, Minakami S. 1982 Alteration of innermembrane components and damage to electron-transfer activities of bovine heart submitochondrial particles induced by NADPH-dependent lipid peroxidation. Biochem J 202, 97-105.Google Scholar
  28. Okamoto N, Wada S, Oga T et al. 1996 Hereditary ceruloplasmin deficiency with hemosiderosis. Hum Genet 97, 755-758.Google Scholar
  29. Osaki S, Johnson DA, Frieden E. 1966 The possible significance of the ferrous oxidase activity of ceruloplasmin in normal human serum. J Biol Chem 241, 2746-2751.Google Scholar
  30. Petrukhin K, Fischer SG, Pirastu M et al.. 1993 Mapping, cloning and genetic characterization of the region containing the Wilson disease gene. Nat Genet 5, 338-342.Google Scholar
  31. Roetto A, Bosio S, Gobbi MDe et al. 2001 Molecular characterization of aceruloplasminemia in an Italian patient. In: Powell LW et al. (eds), Bioiron 2001 (abstract) P26.Google Scholar
  32. Schapira AHV. 1999 Mitochondrial involvement in Parkinson's disease, Huntington's disease, hereditary spastic paraplegia and Friedreich's ataxia. Biochim Biophys Acta 1410, 159-170.Google Scholar
  33. Schewe T, Albracht SPJ, Ludwig P. 1981 On the site of action of the inhibition of the mitochondrial respiratory chain by lipoxygenase. Biochim Biophys Acta 636, 210-217.Google Scholar
  34. Takahashi Y, Miyajima H, Shirabe S et al. 1996 Characterization of a nonsense mutation in the ceruloplasmin gene resulting in diabetes and neurodegenerative disease. Hum Mol Genet 5, 81-84.Google Scholar
  35. Tanzi RE, Petrukhin K, Chernov L et al. 1993 The Wilson disease gene is a copper transporting ATPase with homology to the Menkes disease gene. Nat Genet 5, 344-350.Google Scholar
  36. Vulpe C, Levinson B, Whitney S et al. 1993 Isolation of a candidate gene for Menkes disease and evidence that it encodes a copper transporting ATPase. Nat Genet 3, 7-13.Google Scholar
  37. Yamaguchi Y, Heiny ME, Gitlin JD. 1993 Isolation and characterization of a human liver cDNA as a candidate gene for Wilson disease. Biochem Biophys Res Commun 197, 271-277.Google Scholar
  38. Yazaki M, Yoshida K, Nakamura A et al. 1998 A novel splicing mutation in the ceruloplasmin gene responsible for hereditary ceruloplasmin deficiency with hemosiderosis. J Neurol Sci 156, 30-34.Google Scholar
  39. Yoshida K, Furihata K, Takeda S et al. 1995 A mutation in the ceruloplasmin gene is associated with systemic hemosiderosis in humans. Nature Genet 9, 267-272.Google Scholar
  40. Yoshida K, Kaneko K, Miyajima H et al. 2000 Increased lipid peroxidation in the brains of aceruloplasminemia patients. J Neurol Sci 175, 91-95.Google Scholar

Copyright information

© Kluwer Academic Publishers 2003

Authors and Affiliations

  • Hiroaki Miyajima
    • 1
  • Yoshitomo Takahashi
    • 1
  • Satoshi Kono
    • 1
  1. 1.First Department of MedicineHamamatsu University School of Medicine, Hamamatsu University School of MedicineHamamatsuJapan

Personalised recommendations