Fourth European Symposium on Rare Anaemias. Vita-Salute University - San Raffaele Scientific Institute, Milano

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1 Fourth European Symposium on Rare Anaemias Clara Camaschella Vita-Salute University - San Raffaele Scientific Institute, Milano Sofia, Bulgaria, November 19-20, 2011

2 The iron cycle Hepcidin (Jordan et al,jbc 2009) Liver secreted peptide Active peptide: 25 C-terminal aa cleaved from a 84 aa precursor Hairpin structure Acute phase reactant (Andrews, NEJM1 999) (Ganz, Blood 2003) Hepcidin: the key iron regulator Fe Liver hepcidin Fe Fe enterocytes macrophages

3 Systemic iron regulation (Hentze et al, Cell 2010) Disorders of hepcidin deficiency Genetic disorders Hereditary hemochromatosis type 1,2,3 due to mutations of HFE, Hepcidin and HJV, TFR2 Acquired disorders Acquired disorders secondary iron overload in iron loading anemias

4 Disorders of hepcidin excess Genetic disorders Iron-refractory iron deficiency anemia Acquired disorders Anemnia of chronic diseases Microcytosis - Hypochromia Reduced size and reduced Hb content of red blood cells, as inferred by erythrocyte t indexes: MCH < 26 pg (normal values pg) MCV < 80 fl (normal values fl) MCHC < 30 g/dl (normal values g/dl) Peripheral blood smear

5 Microcytic anemia: relevance Most common form of anemia worldwide: Iron deficiency anemia ( heme) Thalassemia syndromes ( globin) Inherited microcytic anemias Disorder Gene OMIM n Defects of iron transport Hypotransferrinemia TF # DMT1 mutations DMT1 # Defects of cellular iron utilization Sideroblastic anemia X-linked sid. anemia ALAS AR sideroblastic anemia SLC25A38 # GLRX5 X-linked sid. anemia/ataxia i ABCB7 #30131 Defect of iron absorption IRIDA TMPRSS6 # Defects of iron recycling (Aceruloplasminemia CP #604290)

6 Iron for erythropoiesis Daily iron needs for Hb synthesis of maturing erythroblasts: 25 mg (A)Hypo-transferrinemia Hpx mice Autosomal recessive, extremely rare First description 1961 Plasma transferrin nearly absent Severe microcytic anemia since birth Liver iron overload Low urinary hepcidin levels (Responsive to plasma infusions) Similar phenotype Splicing mutations of TF Liver hepcidin RNA low/absent

7 Hypotransferrinemia: lesson from patients hepcidin transferrin 100% Tf saturation NTBI Liver, pancreas iron overload Microcytic anemia Iron-deficient erythropoiesis Hepcidin suppression by the iron-deficient erythropoiesis increases iron absorption

8 New rare disorders of iron utilization: DMT1 deficiency DMT1: Transporter of divalent metal cations: Mn 2+ Cu 2+ Zn 2+ Fe 2+ Duodenal cell: luminal non heme iron transporter Erythroblasts: endosomal transferrin cycle DMT1 deficiency (OMIM #206100) mk mouse and Belgrade rat severe iron-deficient anemia due to G185R homozygous Dmt1 mutation Dmt1 -/- mice even more severe Patients with homozygous or compound heterozygous DMT1 mutations Microcytic hypochromic anemia and liver iron overload (Iolascon et al, J Pediatr. 2008;152:136-9)

9 Figure 1. Response of hematologic parameters to darbepoetin Pospisilova, D. et al. Blood 2006;108: Copyright 2006 American Society of Hematology. Copyright restrictions may apply. Reduced iron supply to erythropoiesis Suppression of hepcidin production Increased duodenal iron absorption (Andrews, NEJM, 1999)

10 Differential diagnosis of iron-related inherited anemias Atransferrinemia DMT1 IDA mutations ti Hb low low low MCV/MCH low low low Fe low high low Tf Low/absent low high Tf sat high high low ferritin high high low hepcidin low low low Genetic defects of iron absorption IRIDA: iron refractory-iron deficiency anemia (OMIM #206200) Inappropriately high hepcidin production (Ganz, T. et al. Blood 2008;112: )

11 Inappropriate hepcidin activation: IRIDA Autosomal recessive disorder due to TMPRSS6 (matriptase 2) mutations IRIDA = iron refractory iron deficiency anemia Moderate anemia, severe microcytosis Extremely low iron and transferrin saturation Normal serum ferritin High serum (and urinary) hepcidin levels Refractory to oral and partially refractory to iv iron (Finberg et al, Nat Genet 2008, Sem Hematol 2009) Hepcidin activation in IRIDA: molecular mechanism IDA IRIDA m-hjv BMP m-hjv BMP TMPRSS6 BMPR TMPRSS6 BMPR SMADs SMADs HEPC serum iron HEPC serum iron (Silvestri et al, Cell Met 2008;8: )

12 IRIDA: hematological data (32 published cases) Mean±SD Hb g/dl (at presentation) 7.7±1.3 Hb g/dl (at diagnosis) 9.21±1.8 MCV fl 55.47±7.6 Transferrin saturation % 5.03±2.3 Ferritin ng/ml 126±82 Serum hepcidin nm 257±157* Urin. hepcidin ng/mg creat 4113±3089* Differential diagnosis of iron-related inherited anemias Atransferrinemia DMT1 Tmprss6 mutations mutations Hb low low low MCV/MCH low low low Fe low high low Tf Low/absent low high Tf sat high high low ferritin high high normal/high hepcidin low low high

13 Disorders of mitochondrial iron metabolism: sideroblastic anemias Perl s staining Anti-MT-ferritin (Courtesy of R. Invernizzi, Pavia) Mitochondrial iron metabolism Heme (modified from Blood 105; , 2005)

14 Defect of heme synthesis X-linked sideroblastic anemia The commonest form Deficiency of ALAS2 reduced heme synthesis Affects males (rarely females) - Variable severity Piridoxin (Vitamin B 6 )-responsive (some cases) Autosomal recessive sideroblastic anemia Phenotype identical to XLSA Mutations in SLC25A38, an erythroid specific mitochondrial aminoacid transporter: involved in glycine transport into mitochondria? Non piridoxin responsive (Guernsey et al, Nat Genet. 2009;41:651-3 Kannengiesser et al. Haematologica 2011;96:808-13) Defects of Fe/S clusters biogenesis X-Linked SA with Ataxia (OMIM A syndrome described d in Few families worldwide Mild sideroblastic anemia - Late onset of ataxia missense mutations of ABCB7, a transporter involved in Fe/S cluster biogenesis 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)

15 How to suspect an atypical microcytic anemia Microcytic anemia since childhood (or birth) Iron parameters not congruous: microcytosis + high transferrin saturation and high serum ferritin high serum ferritin and low transferrin saturation Ringed sideroblasts (any percentage) Refractory (or partially refractory) microcytic anemia High hepcidin (Tmprss6 mutations) Familial cases Decisional tree for the candidate gene strategy Increased ring sideroblasts Normal e-alas sequence ataxia Signs of mitochondrial dysfunction No signs of mitochondrial dysfunction ABC7 GRX 5 Enzymes of the ISC assembly No obvious candidate Microcytic hypochromic anemia with no ring sideroblasts Low/normal No response to oral iron Response to i.v. iron DMT1 isoform IA Dctyb Hephaestin Ferroportin stfr No response to iron TfR (expression defect) IRP2 elevated DMT1 Steap3 Sec15l1 Mitoferrine TfR (non functional mutant)

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

17 Fifth Meeting of the International BioIron Society BioIron 2013: April 14 18, 2013 University College London UK A novel type of congenital hypochromic anemia associated with a nonsense mutation in the STEAP3/TSAP6 gene Three siblings of Pakistani origin with transfusion-dependent hypochromic, poorly regenerative anemia and iron overload. A nonsense heterozygous mutation (p.cys100stop) in STEAP3, inherited from the father, no mutation in the mother Example of combination of a mutated allele and a weakly expressed allele (Grandchamp B et al online)

18 Phenotype similar to non-syndromic congenital sideroblastic anemia