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GENETIC/METABOLIC EFFECT OF IRON METABOLISM & RARE ANEMIAS
3rd Pan-European Conference on Haemoglobinopathies & Rare Anaemias
Limassol, 24 – 26 October 2012
Clara CamaschellaUniversità Vita-Salute San Raffaele IRCCS San Raffaele, Milano, Italy
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DISCLOSURE
Clara Camaschella
Università Vita-Salute - IRCCS San Raffaele, Milano
NO DISCLOSURE
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Iron for erythropoiesis
Daily iron needs for Hb synthesis of maturing erythroblasts: 25 mg
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Advances in iron metabolism research….
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Systemic iron regulation
(Hentze et al, Cell 2010)
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(Traglia et al, J Med Genet, 2011)
Iron and hepcidin levels in Val Borbera individuals
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Hepcidin inhibition in iron deficiency, hypoxia and erythropoiesis expansion
(Hentze et al, Cell 2010)
Proposed inhibitors:
Epo, Hif1-alpha, s-HJV,GDF15/TWSG1TMPRSS6/Matriptase 2
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1. Defects of iron absorptionIRIDA - OMIM #206200
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(Finberg et al, Nat Genet 2008, Sem Hematol 2009)
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TMPRSS6/Matriptase-2: the hepcidin inhibitor
CN TM CUB LCUB LL SERINE PROTEASESEA
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…)
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Y1
41
CL
16
6fs
I21
2T
Q2
29
fsW
24
7fs
R2
71
Q
C5
10
S
S5
61
XS
57
0fs
E4
86
D
S3
04
L
A1
18
D
Y3
35
XY
39
3X
G4
42
R
E4
61
fs
D5
21
NE
52
2K
Ma
sk
R5
99
X
A6
05
fs
K6
36
fs
P6
86
fs
R7
74
C
Mutations associated with IRIDA
L6
74
F
(Silvestri et al Blood 2009De Falco et al, Hum Mut 2010)
K2
53
EQ
G6
03
R
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Hepcidin activation in IRIDA: molecular mechanism
HEPC
SMADs
BMP
BMPR
m-HJV
TMPRSS6
serum ironHEPC
SMADs
BMP
BMPR
m-HJV
TMPRSS6
serum iron
IRIDA IDA
(Silvestri et al, Cell Met 2008;8:502-11.)
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Hepcidin: the key iron regulator
hepcidin
Fe
Liver
macrophagesenterocytes
Fe
Fe
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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*
IRIDA: hematological data
(Camaschella and Poggiali Curr Op Ped, 2010)
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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)
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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)
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2. Defects of TfRC cycle
1.Defects of transferrin (the ligand)
1.Defects of TfRC are not described!
2.Defects of TfRC components: DMT1, STEAP3
(Camaschella C, Br J Haematol, in press)
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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)
Hpx miceSimilar phenotype
Splicing mutations of transferrin
Hepcidin low/undetectable
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Hypotransferrinemia: lesson from patients
Iron-deficienterythropoiesis
transferrin
Microcytic anemia
100% Tf saturation
NTBILiver, pancreas iron overload
Transferrin (and TFR cycle) are indispensable for erythropoiesisbut not for liver iron uptake (NTBI)
hepcidin
Hepcidin suppression by the iron-deficient erythropoiesis increases iron absorption
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DMT1 deficiency (OMIM #206100)
mk mouse and Belgrade ratsevere iron-deficient anemia due to G185R homozygous Dmt1 mutationDmt1 -/- mice even more severe
Patients with homozygous or compound heterozygous DMT1 mutations Microcytic hypochromic anemia and liver iron overload (less severe than atransferrinemia)
(Iolascon et al, J Pediatr. 2008;152:136-9)
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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 oflow hepcidin levels
Partial response of anemia to erythropoietin treatment
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A novel type of hypochromic anemia associated with a nonsense mutation in the STEAP3 gene
(Grandchamps et al, Blood 2011)
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Atransferrinemia
DMT1 mutations
IRIDA IDA
Hb low low low low
MCV low low low low
Fe low high low low
Tf Low/absent low high high
Tf sat high high low low
ferritin high high normal/high low
hepcidin low low high low
Differential diagnosis of iron-related inherited anemias
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Perl’s staining Anti-MT-ferritin(Courtesy of R. Invernizzi, Pavia)
3. Defects of iron utilization: sideroblastic anemias
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Mitochondrial iron metabolism
(modified from Blood 105;1867-1874, 2005)
Heme
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Defects of heme synthesis
X-linked sideroblastic anemia (OMIM #300751)
The commonest form
Deficiency of ALAS2 reduced heme synthesis
Affects males (rarely females) - Variable severity
Piridoxin (Vitamin B6)-responsive (some cases)
Autosomal recessive sideroblastic anemia (OMIM 301310)
Phenotype more severe than XLSA
Mutations in SLC25A38, an erythroid mitochondrial aminoacid transporter: involved in mitochondria glycine transport (?)
Piridoxin unresponsive
(Guernsey et al, Nat Genet. 2009;41:651-3)
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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 deficiencyThe human counterpart of zebrafish shiraz shows sideroblasticanemia and iron overload due to an homozygous splicingmutation of GLRX5 (a gene of Fe/S cluster)
(Camaschella et al Blood 2007)
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GLRX5-mutant patient follow up
Hb
g/d
L
Fer
ritin
ng/
mL
Correlation Hb/ferritin: r = -0.79
start transfusions; stop transfusions: start DFO: stop DFO
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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 edsGeneReviews University of Washington, Seattle)
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ACERULOPLASMINEMIA: pathogenesis
liver iron overload
Low serum FeIncreased Fe absorption
Mild “iron deficiency”anemia
FPN
CP
Fe2+
(
(
Fe3+
ferroxidase activity -- cellular iron efflux !
Acp -/- mouse
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Aceruloplasminemia: diagnosis
Microcytic/normocytic anemia
High serum ferritin, low transferrin saturationLow serum copper (< 10g/dL; nv 70-125g/dL)(Low ferroxidase plasma activity)
Undosable Ceruloplasmin (Cp gene mutations)
MRI of liver, pancreas and basal ganglia(striatum thalamus and dentate nucleus)
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How to recognize an atypical microcytosis
1. Refractory (or partially refractory) microcytic anemiaDMT1 deficiency: no response to i.v. iron
2. Iron parameters not congruous: high transferrin saturation and high serum ferritin
high serum ferritin and low transferrin saturation
3. Ringed sideroblasts (any percentage)
4. Familial cases
5. (High hepcidin) TMPRSS6 mutations
(Camaschella C Br J Haematol, in press)
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Disorder Gene OMIM n
Defect of iron absorption IRIDA TMPRSS6 #206200 Defects of iron transport/erythroid uptake
Hypotransferrinemia TF #209300DMT1 mutations DMT1 #206100STEAP3 mutations STEAP3
Defects of cellular iron utilizationSideroblastic anemiaX-linked sid. anemia ALAS2 +301300X-linked sid. anemia/ataxia ABCB7 #30131AR sideroblastic anemia SLC25A38 #205950
GLRX5Defects of iron recycling Aceruloplasminemia CP #604290
Inherited iron-metabolism related anemias
Camaschella C, Br J Haematol, 2012 online
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E-RARE project on microcytic anemias (ERARE-115, HMA-IRON)
Carole Beaumont (France)
Clara Camaschella (Italy)
Martina Muckenthaler (Germany)
Mayka Sanchez (Spain)
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Acknowledgements
Vita-Salute University & San Raffaele Scientific Institute
Antonella Nai, Alessia PaganiLaura Silvestri
Alessandro CampanellaMarco Rausa
University of NaplesAchille Iolascon Luigia De Falco
University of VeronaDomenico Girelli Natascia Campostrini
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Fifth Meeting of the International BioIron Society
BioIron 2013: April 14 – 18, 2013University College London UK
www.bioiron.org