1 / 35

GENETIC/METABOLIC EFFECT OF IRON METABOLISM & RARE ANEMIAS

GENETIC/METABOLIC EFFECT OF IRON METABOLISM & RARE ANEMIAS 3rd Pan-European Conference on Haemoglobinopathies & Rare Anaemias Limassol, 24 – 26 October 2012 Clara Camaschella Università Vita-Salute San Raffaele IRCCS San Raffaele, Milano, Italy. DISCLOSURE. Clara Camaschella

ann
Download Presentation

GENETIC/METABOLIC EFFECT OF IRON METABOLISM & RARE ANEMIAS

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. GENETIC/METABOLIC EFFECT OF IRON METABOLISM & RARE ANEMIAS 3rd Pan-European Conference on Haemoglobinopathies & Rare Anaemias Limassol, 24 – 26 October 2012 Clara Camaschella Università Vita-Salute San Raffaele IRCCS San Raffaele, Milano, Italy

  2. DISCLOSURE Clara Camaschella Università Vita-Salute - IRCCS San Raffaele, Milano NO DISCLOSURE

  3. Iron for erythropoiesis Daily iron needs for Hb synthesis of maturing erythroblasts: 25 mg

  4. Advances in iron metabolism research….

  5. Systemic iron regulation (Hentze et al, Cell 2010)

  6. Iron and hepcidin levels in Val Borbera individuals (Traglia et al, J Med Genet, 2011)

  7. Hepcidin inhibition in iron deficiency, hypoxia and erythropoiesis expansion Proposed inhibitors: Epo, Hif1-alpha, s-HJV, GDF15/TWSG1 TMPRSS6/Matriptase 2 (Hentze et al, Cell 2010)

  8. 1. Defects of iron absorptionIRIDA - OMIM #206200 (Finberg et al, Nat Genet 2008, Sem Hematol 2009) Iron refractory iron deficiency anemia: Autosomal recessive disorder due to TMPRSS6 (matriptase-2) mutations Moderate anemia since childhood, severe microcytosis Extremely low iron and transferrin saturation Normal serum ferritin Inappropriately high hepcidin levels Refractory to oral and partially refractory to iv iron

  9. TMPRSS6/Matriptase-2: the hepcidin inhibitor N C SEA SERINE PROTEASE TM CUB CUB L L L Matriptase-2 is encoded by TMPRSS6 gene on chr 22 RNA expression: liver (kidney, olfactory epithelium) Protein: 811 amino acid type II transmembrane serine protease synthesized as an inactive zymogen (TTPS family: enteropeptidase, hepsin,corin, matriptase 1…)

  10. Mutations associated with IRIDA R271Q K253EQ W247fs Q229fs S570fs S561X L166fs C510S Y141C I212T E486D R774C P686fs Y335X A605fs K636fs L674F E461fs G603R G442R A118D D521N E522K R599X Y393X Mask S304L (Silvestri et al Blood 2009 De Falco et al, Hum Mut 2010)

  11. Hepcidin activation in IRIDA: molecular mechanism IRIDA m-HJV BMP TMPRSS6 m-HJV BMPR BMP SMADs TMPRSS6 BMPR HEPC  serumiron SMADs HEPC  serumiron IDA (Silvestri et al, Cell Met 2008;8:502-11.)

  12. Fe Hepcidin: the key iron regulator Liver hepcidin Fe Fe enterocytes macrophages

  13. IRIDA: hematological data (Camaschella and Poggiali Curr Op Ped, 2010)

  14. How to diagnose IRIDA • Evidence of microcytic anemia since the first months of life • Moderate degree of anemia, more severe in children (increased requests) • Familial cases (autosomal recessive) • Discrepancy between ferritin and Tf saturation levels • Exclude celiac disease and other absorption disorders • (Normal/high serum hepcidin in the presence of IDA and normal CRP) • Refractory to oral (control dose, type of iron and compliance) and partially refractory to iv iron • DNA sequence of TMPRSS6 gene (common SNP excluded)

  15. How to treat IRIDA • Oral iron ineffective (at least two cycles) • I.V. iron: partial or slow response • Epo: a single case reported with positive results (Ramsey et al, Hum Mol Genet 2009).Iron must be added • A recent report suggest some effect of ascorbic acid: • Cau M, Galanello R, Giagu N, Melis MA. Responsiveness • to oral iron and ascorbic acid in a patient with IRIDA. • (BCMD 2011)

  16. 2. Defects of TfRC cycle • Defects of transferrin (the ligand) • Defects of TfRC are not described! • Defects of TfRC components: DMT1, STEAP3 (Camaschella C, Br J Haematol, in press)

  17. Autosomal recessive, extremely rare Plasma transferrin nearly absent Severe microcytic anemia and liver iron overload Low urinary hepcidin levels Responds to plasma infusions Atransferrinemia (OMIM #209300) Hpxmice Similar phenotype Splicing mutations of transferrin Hepcidin low/undetectable

  18. hepcidin Hepcidin suppression by the iron-deficient erythropoiesis increases iron absorption Hypotransferrinemia: lesson from patients transferrin 100%Tf saturation Iron-deficient erythropoiesis NTBI Liver, pancreas iron overload Microcytic anemia Transferrin (and TFR cycle) are indispensable for erythropoiesis but not for liver iron uptake (NTBI)

  19. DMT1 deficiency (OMIM #206100) Patients with homozygous or compound heterozygous DMT1 mutations Microcytic hypochromic anemia and liver iron overload (less severe than atransferrinemia) mk mouse and Belgrade rat severe iron-deficient anemia due to G185R homozygous Dmt1 mutation Dmt1 -/- mice even more severe (Iolascon et al, J Pediatr. 2008;152:136-9)

  20. Lesson from DMT1 human mutants DMT1 is essential in erythropoiesis DMT1 is not essential for liver iron uptake DMT1 is not essential for duodenal iron absorption (alternative pathways?heme absorption?) Increased iron absorption occurs because of low hepcidin levels Partial response of anemia to erythropoietin treatment

  21. A novel type of hypochromic anemia associated with a nonsense mutation in the STEAP3 gene (Grandchamps et al, Blood 2011)

  22. Differential diagnosis of iron-related inherited anemias

  23. 3. Defects of iron utilization: sideroblastic anemias Perl’s staining Anti-MT-ferritin (Courtesy of R. Invernizzi, Pavia)

  24. Mitochondrial iron metabolism Heme (modified from Blood 105;1867-1874, 2005)

  25. Defects of heme synthesis X-linked sideroblastic anemia(OMIM #300751) The commonestform Deficiency of ALAS2 reduced heme synthesis Affectsmales (rarelyfemales) - Variableseverity Piridoxin(Vitamin B6)-responsive (some cases) Autosomal recessive sideroblastic anemia (OMIM 301310) Phenotype more severe than XLSA Mutations in SLC25A38, an erythroid mitochondrialaminoacidtransporter: involved in mitochondriaglycinetransport(?) Piridoxinunresponsive (Guernsey et al, Nat Genet. 2009;41:651-3)

  26. Defects of Fe/S clusters biogenesis X-Linked SA with Ataxia (OMIM 301310) A syndrome described in 1985. Few families worldwide Mild sideroblastic anemia - Late onset of ataxia missense mutations of ABCB7, a transporter involved in Fe/S export from mitochondria GLRX5 deficiency The human counterpart of zebrafish shiraz shows sideroblastic anemia and iron overload due to an homozygous splicing mutation of GLRX5 (a gene of Fe/S cluster) (Camaschella et al Blood 2007)

  27. GLRX5-mutant patient follow up Ferritin ng/mL Hb g/dL Correlation Hb/ferritin: r = -0.79 start transfusions; stop transfusions: start DFO: stop DFO

  28. 4. Defects of iron recycling:aceruloplasminemia AR (OMIM #604290) - Mutations of Ceruloplasmin (Cp) Iron overload in liver, RE cells, pancreas, basal ganglia. Clinical triad in midlle age: 1. Diabetes 2. Neurological disease (ataxia,dementia), 3. Retinal degeneration (Miyaijma H. in: Pagonet al eds GeneReviews University of Washington, Seattle)

  29. ( ( Acp -/- mouse  ferroxidase activity -- cellular iron efflux ! liver iron overload Low serum Fe Increased Fe absorption FPN Fe2+ Mild “iron deficiency” anemia CP Fe3+ ACERULOPLASMINEMIA: pathogenesis

  30. Aceruloplasminemia: diagnosis Microcytic/normocytic anemia High serum ferritin, low transferrin saturation Lowserumcopper (< 10mg/dL; nv 70-125mg/dL) (Low ferroxidase plasma activity) Undosable Ceruloplasmin (Cp gene mutations) MRI of liver, pancreas and basalganglia (striatumthalamus and dentate nucleus)

  31. How to recognize an atypical microcytosis • Refractory (or partiallyrefractory) microcytic anemia • DMT1 deficiency: no response to i.v. iron • Ironparametersnotcongruous: • high transferrin saturation and high serum ferritin • high serum ferritin and low transferrin saturation • 3. Ringed sideroblasts (anypercentage) • Familialcases • (High hepcidin) TMPRSS6mutations (Camaschella C Br J Haematol, in press)

  32. Inherited iron-metabolism related anemias DisorderGene OMIM n Defect of iron absorption IRIDA TMPRSS6 #206200 Defects of iron transport/erythroid uptake Hypotransferrinemia TF #209300 DMT1 mutations DMT1 #206100 STEAP3 mutationsSTEAP3 Defects of cellular iron utilization Sideroblastic anemia X-linked sid. anemia ALAS2 +301300 X-linked sid. anemia/ataxia ABCB7 #30131 AR sideroblastic anemia SLC25A38#205950 GLRX5 Defects of iron recycling Aceruloplasminemia CP #604290 Camaschella C, Br J Haematol, 2012 online

  33. E-RARE project on microcytic anemias • (ERARE-115, HMA-IRON) • Carole Beaumont (France) • Clara Camaschella (Italy) • Martina Muckenthaler (Germany) • Mayka Sanchez (Spain)

  34. Acknowledgements Vita-Salute University & San Raffaele Scientific Institute Antonella Nai, Alessia Pagani Laura Silvestri Alessandro Campanella Marco Rausa University of Naples Achille Iolascon Luigia De Falco University of Verona Domenico Girelli Natascia Campostrini

  35. Fifth Meetingof theInternational BioIron Society  BioIron 2013: April 14 – 18, 2013 University College London UK www.bioiron.org

More Related