Horm Metab Res. 2015 Apr;47(4):303-8.

Aceruloplasminaemia: a family with a novel mutation and long-term therapy with deferasirox

Uwe Lindner1, Detlef Schuppan2, Lothar Schleithoff3, Joerg-Olaf Habeck4, Tine Grodde5, Klaus Kirchhof6, Ulrich Stoelzel1

  1. Department of Internal Medicine II, Gastroenterology, Hepatology, Endocrinology, Metabolic Disorders, Oncology, Klinikum Chemnitz gGmbH, Chemnitz, Germany.
  2. Molecular and Translational Medicine, Department of Internal Medicine I, Johannes Gutenberg-University of Mainz Medical School, Mainz, Germany
  3. MVZ Labor PD Dr. Volkmann und Kollegen, Karlsruhe, Germany 4. Center of Histopathology, Chemnitz, Germany 5.Institute of Diagnostic Radiology, Klinikum Chemnitz gGmbH, Chemnitz, Germany 6. Institute of Diagnostic and Interventional Radiology and Neuroradiology, Klinikum Chemnitz gGmbH, Chemnitz, Germany



Ceruloplasmin is a member of the multicopper oxidase family that plays a major role in the transport of iron in the body. Aceruloplasminaemia (ACP) is a rare disease and is clinically identified by iron overload in liver, pancreas, brain and other organs and by microcytic anaemia. So far, the iron chelator deferasirox was given for therapy only up to 6 months due to side effects. Here, we describe a novel mutation leading to ACP and report for the first time a long term therapy i.e. two years with deferasirox.

ACP was diagnosed in three siblings using clinical and biochemical characteristics, HFE and ceruloplasmin mutational analysis, liver biopsy, brain-, liver-, and heart- MRI. For iron depletion a starting dose of deferasirox 7.5 mg/kg/day was increased to 15 mg/kg/day and maintained at 4-7.5 mg/kg/day with a patient follow-up for two years.

A novel homozygous mutation of the ceruloplasmin gene on chromosome 3 (3q23-q25, exon 12, G708S) was found. Iron was selectively and successfully removed by long-term therapy with deferasirox, as confirmed by follow-up liver biopsies, normalisation of serum ferritin concentrations, and improved glucose metabolism. Unexpectedly, iron depletion ameliorated anaemia.

Low-dose deferasirox is an effective and safe long-term treatment option for patients with ACP.

PMID: 25089372



Ceruloplasmin (EC is an enzyme of the multi-copper oxidase family and plays an important role in the iron metabolism of the human body. After ferroportin-mediated iron transport from the intracellular space into the extracellular space, cerulopasmin functions as a ferroxidase and converts ferrous (Fe2+) in ferric (Fe3+) iron, thus enabling the binding of ferric iron to transferrin (Roeser et al. 1970). In combination with ferroportin, ceruloplasmin is essential for the cellular export and mobilization of iron from tissue storages (De Domenico et al. 2007). The bluish plasma protein ceruloplasmin consists of 1046 amino acids and contains 95% of copper in the blood. Despite the high copper content, the protein has no essential importance for the copper metabolism and transport. Each ceruloplasmin can bind six copper atoms which are necessary for the enzyme function of ceruloplasmin (Hellman and Gitlin 2002).

Aceruloplasminemia (OMIM 604290) is a rare disorder characterized by excessive intracellular iron accumulation in the liver, pancreas, heart, brain, and other organs. Redox-active iron is cytotoxic, which results in diabetes mellitus, retinal degeneration and neurodegenerative diseases (Harris et al. 1998, Xu et al. 2004). Aceruloplasminemia leads to an intracellular iron retention and a low extracellular transferrin saturation, resulting in a hypochromic microcytic anemia (Harris et al. 1998, Fleming and Ponka 2012).

For the treatment of aceruloplasminemia iron depletion is essential. Phlebotomy as the most effective way to relieve the body of excess iron is contraindicated in anemia. Therefore, iron-binding chelators are used for the treatment of aceruloplasminemia.

In this work, a new missense mutation G708S of the ceruloplasmin gene was discovered in aceruloplasminemia. A computerized simulation model of this mutation predicts a loss of function of ceruloplasmin (http://www.ensembl.org) (Flicek et al. 2013). This homozygous mutation G708S, first described in this study for aceruloplasminemia, is immediately adjacent to the type I – copper binding site M709 of ceruloplasmin. Non-incorporation of copper into apo-ceruloplasmin is caused by mutations in this region (Hellman et al. 2002, Kono 2013).


Figure 1-cMRT ACP World Biomedical Frontiers

Figure 1. T2-weighted cranial MRI of study patient 1 with decreased signal in the basal ganglia, indicating pathologically high iron accumulation.


Until now, using the iron chelator deferasirox for treatment of aceruloplasminemia was limited to a maximum time of six months due to adverse reactions. In this study, the safety and efficacy of a long-term treatment with the iron chelator deferasirox over a period of two years was demonstrated for the first time. Due to the side effects of using deferasirox with an initial dose of 15 to 20 mg/kg/day for the treatment of aceruloplasminemia, and the findings from a Phase 1/2 trial in which this iron chelator was used for the treatment of hereditary hemochromatosis, a low-dose long-term therapy of aceruloplasminemia with deferasirox was initiated in the present work.

The results of this study show clearly the feasibility of long-term treatment with deferasirox for eliminating intracellular iron in hereditary aceruloplasminemia. Moreover, successful treatment of anemia with a two-year iron chelation therapy regimen in patients with aceruloplasminemia has not been reported previously. A possible explanation is a less toxic iron inducing improved erythropoiesis (Camaschella 2013).

We were able to demonstrate for the first time that both insulin resistance and impaired insulin secretion are involved in the development of a glucose metabolism disorder in aceruloplasminemia. The administration of deferasirox finally results in an improvement of glucose metabolism. Furthermore, we demonstrated that in aceruloplasminemia this improvement of glucose metabolism by iron depletion with deferasirox was caused by enhanced insulin sensitivity rather than amelioration of beta-cell function which has also been reported for the first time.

Therapy with deferasirox over two years resulted in no visible reduction of accumulated iron in the brain in aceruloplasminemia. It requires further investigations to determine whether an even longer therapy with deferasirox is able to reduce this iron accumulation in the central nervous system or whether new iron chelators with improved passage of the blood-brain barrier can effectively be applied in the future.



  1. Roeser HP, Lee GR, Nacht S, Cartwright GE. The role of ceruloplasmin in iron metabolism. J Clin Invest 1970; 49: 2408-2417
  2. De Domenico I, Ward DM, di Patti MC, Jeong SY, David S, Musci G, Kaplan J. Ferroxidase activity is required for the stability of cell surface ferroportin in cells expressing GPI-ceruloplasmin. EMBO J 2007; 26: 2823-2831
  3. Hellman NE, Gitlin JD (2002) Ceruloplasmin metabolism and function. Annu Rev Nutr. 22:439-458.
  4. Harris ZL, Klomp LW, Gitlin JD. Aceruloplasminemia: an inherited neurodegenerative disease with impairment of iron homeostasis. Am J Clin Nutr 1998; 67: 972-977
  5. Xu X, Pin S, Gathinji M, Fuchs R, Harris ZL. Aceruloplasminemia: an inherited neuro-degenerative disease with impairment of iron homeostasis. Ann N Y Acad Sci 2004; 1012: 299-305
  6. Fleming RE, Ponka P. Iron overload in human disease. N Engl J Med 2012; 366: 348-359. Hellman NE, Gitlin JD (2002) Ceruloplasmin metabolism and function. Annu Rev Nutr. 22:439-458.
  7. Flicek P, Ahmed I, Amode MR, Barrell D, Beal K, Brent S, Carvalho-Silva D, Clapham P, Coates G, Fairley S, Fitzgerald S, Gil L, García-Girón C, Gordon L, Hourlier T, Hunt S, Juettemann T, Kähäri AK, Keenan S, Komorowska M, Kulesha E, Longden I, Maurel T, McLaren WM, Muffato M, Nag R, Overduin B, Pignatelli M, Pritchard B, Pritchard E, Riat HS, Ritchie GR, Ruffier M, Schuster M, Sheppard D, Sobral D, Taylor K, Thormann A, Trevanion S, White S, Wilder SP, Aken BL, Birney E, Cunningham F, Dunham I, Harrow J, Herrero J, Hubbard TJ, Johnson N, Kinsella R, Parker A, Spudich G, Yates A, Zadissa A, Searle SM (2013) Ensembl 2013. Nucleic Acids Res. 41:D48-55.
  8. Hellman NE, Kono S, Mancini GM, Hoogeboom AJ, De Jong GJ, Gitlin JD (2002) Mechanisms of copper incorporation into human ceruloplasmin. J Biol Chem. 277:46632-46638.
  9. Kono S (2013) Aceruloplasminemia: an update. Int Rev Neurobiol. 110:125-151.
  10. Camaschella C (2013) Treating Iron Overload. N Engl J Med. 368:2325-2327.


Corresponding author:

Prof. Ulrich Stölzel Department of Internal Medicine II, Gastroenterology, Hepatology, Metabolic Disorders, Endocrinology, Oncology Klinikum Chemnitz, Academic Teaching Hospital of the Universities of Leipzig and Dresden, Germany 09116 Chemnitz, Flemmingstr. 2 Tel.:       +49 371 33333232

Fax:   +49 371 33333224 Email: u.stoelzel@skc.de


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