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Hepatic but not brain iron is rapidly chelated by deferasirox in aceruloplasminemia due to a novel gene mutation.

ABSTRACT: BACKGROUND & AIMS: Aceruloplasminemia is a rare autosomal recessive neurodegenerative disease associated with brain and liver iron accumulation which typically presents with movement disorders, retinal degeneration, and diabetes mellitus. Ceruloplasmin is a multi-copper ferroxidase that is secreted into plasma and facilitates cellular iron export and iron binding to transferrin. RESULTS: A novel homozygous ceruloplasmin gene mutation, c.2554+1G>T, was identified as the cause of aceruloplasminemia in three affected siblings. Two siblings presented with movement disorders and diabetes. Complementary DNA sequencing showed that this mutation causes skipping of exon 14 and deletion of amino acids 809-852 while preserving the open reading frame. Western blotting of liver extracts and sera of affected patients showed retention of the abnormal protein in the liver. Aceruloplasminemia was associated with severe brain and liver iron overload, where hepatic mRNA expression of the iron hormone hepcidin was increased, corresponding to the degree of iron overload. Hepatic iron concentration normalized after 3 and 5months of iron chelation therapy with deferasirox, which was also associated with reduced insulin demands. During short term treatment there was no clinical or imaging evidence for significant effects on brain iron overload. CONCLUSIONS: Aceruloplasminemia can show an incomplete clinical penetrance but is invariably associated with iron accumulation in the liver and in the brain. Iron accumulation in aceruloplasminemia is a result of defective cellular iron export, where hepcidin regulation is appropriate for the degree of iron overload. Iron chelation with deferasirox was effective in mobilizing hepatic iron but has no effect on brain iron.

SUBMITTER: Finkenstedt A

PROVIDER: S-EPMC2987498 | biostudies-literature | 2010 Dec

REPOSITORIES: biostudies-literature

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Hepatic but not brain iron is rapidly chelated by deferasirox in aceruloplasminemia due to a novel gene mutation.

Finkenstedt Armin A Wolf Elisabeth E Höfner Elmar E Gasser Bethina Isasi BI Bösch Sylvia S Bakry Rania R Creus Marc M Kremser Christian C Schocke Michael M Theurl Milan M Moser Patrizia P Schranz Melanie M Bonn Guenther G Poewe Werner W Vogel Wolfgang W Janecke Andreas R AR Zoller Heinz H

Journal of hepatology 20100804 6

<h4>Background & aims</h4>Aceruloplasminemia is a rare autosomal recessive neurodegenerative disease associated with brain and liver iron accumulation which typically presents with movement disorders, retinal degeneration, and diabetes mellitus. Ceruloplasmin is a multi-copper ferroxidase that is secreted into plasma and facilitates cellular iron export and iron binding to transferrin.<h4>Results</h4>A novel homozygous ceruloplasmin gene mutation, c.2554+1G>T, was identified as the cause of acer ...[more]

PMID: 20801540

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Project description:BACKGROUND:The myelodysplastic syndrome (MDS) comprises a diverse group of haematopoietic stem cell disorders. Due to symptomatic anaemia, most people with MDS require supportive therapy including repeated red blood cell (RBC) transfusions. In combination with increased iron absorption, this contributes to the accumulation of iron resulting in secondary iron overload and the risk of organ dysfunction and reduced life expectancy. Since the human body has no natural means of removing excess iron, iron chelation therapy, i.e. the pharmacological treatment of iron overload, is usually recommended. However, it is unclear whether or not the newer oral chelator deferasirox leads to relevant benefit. OBJECTIVES:To evaluate the effectiveness and safety of oral deferasirox for managing iron overload in people with myelodysplastic syndrome (MDS). SEARCH METHODS:We searched the following databases up to 03 April 2014: MEDLINE, EMBASE, The Cochrane Library, Biosis Previews, Web of Science, Derwent Drug File and four trial registries: Current Controlled Trials (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov), ICTRP (www.who.int./ictrp/en/), and German Clinical Trial Register (www.drks.de). SELECTION CRITERIA:Randomised controlled trials (RCTs) comparing deferasirox with no therapy, placebo or with another iron-chelating treatment schedule. DATA COLLECTION AND ANALYSIS:We did not identify any trials eligible for inclusion in this review. MAIN RESULTS:No trials met our inclusion criteria. However, we identified three ongoing and one completed trial (published as an abstract only and in insufficient detail to permit us to decide on inclusion) comparing deferasirox with deferoxamine, placebo or no treatment. AUTHORS' CONCLUSIONS:We planned to report evidence from RCTs that evaluated the effectiveness of deferasirox compared to either placebo, no treatment or other chelating regimens, such as deferoxamine, in people with MDS. However, we did not identify any completed RCTs addressing this question.We found three ongoing and one completed RCT (published as an abstract only and in insufficient detail) comparing deferasirox with deferoxamine, placebo or no treatment and data will hopefully be available soon. These results will be important to inform physicians and patients on the advantages and disadvantages of this treatment option.

Dataset Information

Hepatic but not brain iron is rapidly chelated by deferasirox in aceruloplasminemia due to a novel gene mutation.

Publications

Hepatic but not brain iron is rapidly chelated by deferasirox in aceruloplasminemia due to a novel gene mutation.

Similar Datasets

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