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Genetic Forms of Iron Deficiency Anaemia

Genetic Forms of Iron Deficiency Anaemia. Photis Beris, MD Professor of Clinical Haematology Department of Internal Medicine Geneva University Hospital Geneva, Switzerland. Genetic Forms of Iron Deficiency Anaemia. Mutations in the gene encoding DMT1

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Genetic Forms of Iron Deficiency Anaemia

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  1. Genetic Forms of Iron Deficiency Anaemia Photis Beris, MD Professor of Clinical Haematology Department of Internal Medicine Geneva University HospitalGeneva, Switzerland

  2. Genetic Forms of Iron Deficiency Anaemia • Mutations in the gene encoding DMT1 • Mutations in the gene encoding glutaredoxin 5 • Hypotransferrinaemia or atransferrinaemia • Deficiency of ceruloplasmin • IRIDA (Iron-Refractory, Iron-Deficiency Anaemia)

  3. Iron Deficiency AnaemiaOverview of Iron Homeostasis With permission from Andrews NC. Blood. 2008;112:219-230.

  4. Genes Involved in Hereditary Iron Deficiency Anaemia With permission from Andrews NC. Blood. 2008;112:219-230. 1. Andrews NC. Blood. 2008;112:219-230. 2. Finberg KE, et al. Nat Genet. 2008;40:569-571.

  5. Mutations in the Gene Encoding DMT1 Haematologic and Biologic Data of the 3 Described Families with Microcytic Anaemia Secondary to DMT1 Mutations MCV = mean corpuscular volume; MCHC = mean corpuscular haemoglobin concentration. 1. Beaumont C, et al. Blood. 2006;107:4168-4170. 2. Priwitzerova M, et al. Blood. 2004;103:3991-3992. 3. Iolascon A, et al. Blood. 2006;107:349-354.

  6. DMT1 Mutations Lead to Microcytic Anaemia, Low (Normal) Ferritinaemia, and Liver Iron Overload Iron absorption in the duodenum continues because the absorption of heme iron is not disturbed. In fact, in meat-eating humans it is estimated that about 2/3 of absorbed iron comes from heme. Thus, in humans, a mutation in DMT1 protein may primarily affect iron utilisation and not absorption, leading to severe microcytic iron deficiency anaemia with increased iron stores. Mims MP, et al. Blood. 2005;105:1337-1342.

  7. Mutations in the Gene Encoding Glutaredoxin 5 Non-erythroid cells Case Report 44-year-old man Hb 88.6g/L, MCV 59fL, TF% 52 Ferritin 1100 mg/L BM: erythroid hyperplasia,28% ringed sideroblasts The patient had a homozygous mutation that interferes with intron 1 splicing and drastically reduces glutaredoxin (GLRX5) RNA Erythroid cells GLRX5 has an essential role in the synthesis of Fe/S clusters DFO = desferrioxamine; hb = haemoglobin; MCV = mean corpuscular volume; BM = bone marrow; Fe/S = iron-sulfur. With permission from Camaschella C, et al. Blood. 2007;110:1353-1358.

  8. Hypotransferrinaemia or Atransferrinaemia Caucasian woman 20 years of age with: • Hb 106 g/L; MCV 75.3 fL; iron serum 15 µg/dL; serum total iron binding capacity 23 µg/dL; ferritin >2500 µg/L • Liver biopsy marked haemosiderosis; LIC 37 mg/g dry weight • DNA sequencing revealed a 10 bp deletion followed by9-bp insertion (maternal) and a Ala >Pro mutation at position 477 (paternal chromosome) • Treatment consisted of monthly plasma infusions 500 mL + bleeding. 10 years later, Hb 120g/L; ferritin: normal Beutler E, et al. Blood. 2000;96:4071-4074.

  9. Hypotransferrinaemia or Atransferrinaemia Pathophysiology • Atransferrinaemia results in reduced delivery of iron to the erythroblasts and development of iron deficiency anaemia (hypochromic–microcytic). This triggers a massive but futile iron absorption leading to iron overload outside of the erythron1 • Hereditary atransferrinaemia has been reported in 7 families2 Andrews NC. Blood. 2008;112:219-230. Beutler E, et al. Blood. 2000;96:4071-4074.

  10. Deficiency of CeruloplasminCase Presentation • 56-year-old Italian man • Hb 98 g/L; MCV 62.5 fl; MCHC 307 g/L • Serum iron 2.96 µmol/L; ferritin 423 µg/L • Ceruloplasmin 0.2 ng/mL • Insulin-dependent diabetes mellitus since the age of 40 • CRP, fibrinogen: no evidence of inflammatory disease • Liver biopsy showed iron overload • DNA sequencing of CP gene: Gly >Arg at codon 631 (homozygous state) Hb = haemoglobin; MCV = mean corpuscular volume; MCHC = mean corpuscular haemoglobin concentration; CRP = C-reactive protein. DiRaimondo D, et al. Intern Emerg Med. 2008 Apr 12. [Epub ahead of print] PMID: 18408989

  11. Deficiency of Ceruloplasmin • Ceruloplasmin (CP), a copper-containing ferroxidase, cooperates to export iron with ferroportin 11 • CP deficiency results in low serum iron (= iron deficiency anaemia) with concomitant deposition in the brain, liver, pancreas, basal ganglia, and other organs1,2 • The constant feature of aceruloplasminaemia is a moderate degree of anaemia, associated with low serum iron and high ferritin1 • Differential diagnosis1 – Anaemia of chronic diseases – Wilson’s disease – Hypotransferrinaemia or atransferrinaemia • Treatment: chelation therapy; oral zinc sulfate3; no benefit from phlebotomy1 1. DiRaimond D, et al. Intern Emerg Med. 2008 Apr 12. [Epub ahead of print] PMID: 18408989. 2. Miyajima H. Neuropathology. 2003;23:345-350. 3. Kuhn J et al. Brain Dev. 2007;29:450-453.

  12. IRIDA (Iron-Refractory, Iron-Deficiency Anaemia) The Mask Mouse “…a chronically iron-deficient mouse with an unusual pattern of hair loss over the trunk but not the head (the mask phenotype) due to a homozygous recessive genetic mutation. Mask mice were shown to express inappropriately high levels of hepcidin mRNA in the liver, even when fed an iron-deficient diet. Using positional cloning techniques, Dr. Beutler’s group was able to ascribe the mask phenotype to a splicing error in the TMPRSS6 gene, which encodes a membrane-bound serine protease.”1,2 1. Coghill JM, Ma A. Available at: http://www.hematology.org/client_files/meeting/2007/newsdaily/HepcidinAdventureEarnsRaveReviewsatPlenary.pdf 2. Du X, et al. Science. 2008;320:1088-1092.

  13. Mutation in TMPRSS6 (Matriptase-2),Suppressor of Hepcidin Gene Expression, in Familial Iron Deficiency Anaemia Photograph: With permission from Du X. Science. 2008;320:1088-1092. Graphic (top right): With permission from Ramsay AJ, et al. Front Biosci. 2008;13:569-579. Graphic (bottom): With permission from Finberg KE, et al. Nat Genet. 2008;40:569-571.

  14. IRIDA (Iron-Refractory, Iron-Deficiency Anaemia) Generation of mutant mice TMPRSS6-/- providedevidence that matriptase-2 is an essential regulator of iron homeostasis. In fact, in mice as well as in humans, mutations in the TMPRSS6-/- gene lead to severe iron deficiency anaemia. This state is characterized by reduced ferroportin expression (shown in the mice model) and both animals and humans have high hepcidin levels. Folgueras AR, et al. Blood. 2008 Jun 3. [Epub ahead of print] PMID: 18523150.

  15. IRIDA (Iron-Refractory, Iron-Deficiency Anaemia)Case-Reports 1.Guillem F, Blood 2008 Jul 2. [Epub ahead of print] PMID: 18596229. 2. Melis MA, et al.Haematologica. 2008 Jul 4. [Epub ahead of print] PMID: 18603562. 3. Finberg KE, et al. Nat Genet. 2008 May;40(5):569-71.

  16. IRIDA (Iron-Refractory, Iron-Deficiency Anaemia)Case-Reports Treatment • Oral iron administration is ineffective • Response to parenteral iron administration is partial • Anaemia becomes less severe in adulthood as a consequence of the greater availability of the limited amount of available iron to erythropoiesis Melis MA, et al. Haematologica. 2008 Jul 4. [Epub ahead of print] PMID: 18603562.

  17. Differential Diagnosis of Microcytic Anaemia • Thalassaemia syndromes • Certain haemoglobinopathies (Hb C) • True (classical) iron deficiency secondary to blood loss, iron-poor diet, increased iron needs, Helicobacter pylori infection or gastric pathology • Anaemia of chronic inflammatory diseases • Certain forms of sideroblastic anaemia • Genetic forms of iron deficiency anaemia

  18. Diagnostic Approach—Genetic Forms of Iron Deficiency Anaemia • Look for consanguinity (recessive transmission) • Is the anaemia associated with massive iron accumulation? If yes, then do detailed evaluation of CNS to distinguish between aceruloplasmia (CNS damage present) and the other forms with iron overload • If presence of basophilic stippling and double erythroid population in peripheral blood, then do bone marrow aspiration to look for the presence of ring sideroblasts

  19. Diagnostic Approach—Genetic Form of Iron Deficiency Anaemia • Was the anaemia detected at birth or early in life? If yes, then look for a mutation in the DMT1 or the TMPRSS6 gene • Does the patient have microcytosis with high serum iron values? If yes, then a DMT1 mutation is highly suspected • If no, then look for a TMPRSS6 mutation. Hepcidin levels are also very helpful as hepcidin is normal or increased in the TMPRSS6 mutation despite low serum iron

  20. Main Biologic and Clinical Differences in Genetic Forms of Iron Deficiency Anaemia

  21. Conclusions • Iron deficiency anaemia is an acquired disease with an estimated 3 billion people affected and represents a major public health problem worldwide1 • Recent advances in iron metabolism led to the recognition of new entities of iron deficiency anaemia in nonbleeding and “high cost diet”nourished individuals • Apparently rare, these genetic forms of iron deficiency anaemia should be recognized by haematologists, as they are refractory to classical oral or intravenous iron administration 1. Andrews NC. Blood. 2008;112:219-230.

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