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HemoglobinopatHemoglobinopathieshies
Dr PupakDr Pupak Derakhshandeh, PhDDerakhshandeh, PhDAss Prof of Medical Science Ass Prof of Medical Science
of Tehran Universityof Tehran University
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HemoglobinopatHemoglobinopathieshies
Disorders of Disorders of HemoglobinHemoglobin
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Disorders of Disorders of HemoglobinHemoglobin
5 % of world population: 5 % of world population: carrier for genes, carrier for genes, important disorders of important disorders of hemoglobinhemoglobin
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Structure and Structure and function of function of hemoglobinhemoglobin
Oxygen carrierOxygen carrier In vertebrate: red In vertebrate: red blood blood cellscells
Four subunits: Four subunits: 22αα- and 2- and 2-chains-chains
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HemoglobinHemoglobin
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Each SubunitsEach Subunits
Globin: Polypeptide chainGlobin: Polypeptide chain Heme : Prosthetic groupHeme : Prosthetic group
(Iron-Containing (Iron-Containing pigment)pigment)
Heme + OxygeneHeme + OxygeneOxygene transportingOxygene transporting
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Normal adult Normal adult hemoglobinhemoglobin
HbAHbA::
22 αα globin chain (141 AA) globin chain (141 AA) 2 2 globin chain (146 AA) globin chain (146 AA) αα2222
Equal lengthEqual length
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Normal adult Normal adult hemoglobinhemoglobin
HbA2HbA2::
22 αα globin chain globin chain 2 2 globin chain globin chain
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Normal adult Normal adult hemoglobinhemoglobin
HbFHbF::
22 αα globin chain globin chain 2 2 γγ globin chain globin chain αα22γγ22
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Normal adult Normal adult hemoglobinhemoglobin
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Globin genes synthesisGlobin genes synthesis
Lessons from the thalasemia. Nature Reviews, Genetics, volume2, 2001Lessons from the thalasemia. Nature Reviews, Genetics, volume2, 2001
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ThalassemiThalassemiaa
Onset: ChildhoodOnset: Childhood Hypo chromic / Microcytic Hypo chromic / Microcytic anemiaanemia Low level of MCV / MCHLow level of MCV / MCH
Mean corpuscular volume (MCV)Mean corpuscular hemoglobin (MCH)
-Thal: Elevated HbA-Thal: Elevated HbA2 2 ((αα2222))
HbF (HbF (αα22γγ22)) αα-Thal: Normal HbA-Thal: Normal HbA22, HbF, HbF
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Thalassemia Thalassemia MinorMinor
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Thalassemia majorThalassemia major
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Thalassemia majorThalassemia major
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Thalassemia MinorThalassemia Minor
• Thalassemia minor is an inherited Thalassemia minor is an inherited form of hemolytic anemia that is form of hemolytic anemia that is less severe than thalassemia majorless severe than thalassemia major..
• This blood smear from an individual This blood smear from an individual with thalassemia shows small with thalassemia shows small ((microcyticmicrocytic)), pale , pale ((hypochromichypochromic)), , variouslyvariously--shaped red blood cellsshaped red blood cells..
• These small red blood cells These small red blood cells ((RBCsRBCs) ) are able to carry less oxygen than are able to carry less oxygen than normal RBCsnormal RBCs. .
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Hematological values &a-Thalassemia
Hematological values &a-Thalassemia
Molecular diagnosis of hemoglobin disorders, Clin. Lab. Haem. 2004, 26, 159–176
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Thalassemia Thalassemia MajorMajor
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an inherited form of hemolytic an inherited form of hemolytic anemiaanemia
red blood cell red blood cell ((hemoglobinhemoglobin)) abnormalitiesabnormalities
the most severe form of anemiathe most severe form of anemia
the oxygen depletion in the bodythe oxygen depletion in the body becomes apparent within the first becomes apparent within the first 6 months of life6 months of life
Thalassemia major
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If untreated, death usually results If untreated, death usually results within a few yearswithin a few years
Note the small, pale Note the small, pale ((hypochromichypochromic)), abnormally, abnormally--shaped red blood cells associated shaped red blood cells associated with thalassemia majorwith thalassemia major
The darker cells likely represent The darker cells likely represent normal RBCs from a blood normal RBCs from a blood transfusiontransfusion
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DieseaseDiesease Autosomal recessive Autosomal recessive Deficiency: Synthesis of Deficiency: Synthesis of
αα//- - globinglobin Origin: Mediteranean, Origin: Mediteranean,
African, African, Iranian, Indian, Iranian, Indian, Southeast Southeast AsianAsian
Resistant to malariaResistant to malaria
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Prevalence of Prevalence of --ThalassemiaThalassemia
~ 1.5 % in Africans and ~ 1.5 % in Africans and African AmericansAfrican Americans
~ 30 % in Sardinia~ 30 % in Sardinia
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Pathogenesis Pathogenesis of of -Thalassemia-Thalassemia
In adequate Hb productionIn adequate Hb production Reduced MCV/MCHReduced MCV/MCH
Unbalanced accumulation of Unbalanced accumulation of globin subunitsglobin subunits Ineffective ErythrocytIneffective Erythrocyt
200 different mutations200 different mutations
In Iran over 70 mutations In Iran over 70 mutations !!
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Prenatal diagnosisPrenatal diagnosis
I. ARMS-PCR (22 common I. ARMS-PCR (22 common mut.)mut.)
II. PCR-RFLP (9 inf. RFLPs)II. PCR-RFLP (9 inf. RFLPs)
III. RDB (60 mut.)III. RDB (60 mut.)
IV. SequencingIV. Sequencing
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ARMS-PCR
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PCR-RFLPPCR-RFLP1 2 3 M 4 5 6 7
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globin mutationsglobin mutations
1.1. Transcriptional mutations Transcriptional mutations ((++))
In promotor regulatory In promotor regulatory elementselements -101(silent)-101(silent) -92 (silent)-92 (silent) -88-88 -30-30
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globin globin mutationsmutations
2.2. RNA-Processing ( RNA-Processing (ºº)) Splice junctionSplice junction
IVSI-1 Cd30IVSI-1 Cd30 IVSI-2 IVSI-2 IVSI-3’ end del 25bpIVSI-3’ end del 25bp IvsI-130IvsI-130
Consensus splice sites Consensus splice sites ((º/ º/ ++)) IVSI-5IVSI-5 IVSI-6IVSI-6 IVSII-844IVSII-844
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globin mutationsglobin mutations
Cryptic splice sites in Introns Cryptic splice sites in Introns ((++)) IVSI-110IVSI-110 IVSII-745IVSII-745
Cryptic splice sites in exonsCryptic splice sites in exons Cd 26 (HbE)Cd 26 (HbE) Cd 121 (HbD panjab/O Arab)Cd 121 (HbD panjab/O Arab)
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-Thalassemia -Thalassemia majormajor
Onset: 6 monthsOnset: 6 months Severe hemolytic anemiaSevere hemolytic anemia Hb level< 7 g/dlHb level< 7 g/dl Skin: paleSkin: pale Growth retardationGrowth retardation don’t eat or sleep welldon’t eat or sleep well HepatosplenomegalyHepatosplenomegaly Bone marrow expansion:Bone marrow expansion:
Make more red cellsMake more red cells Expantion in face and skullExpantion in face and skull Spleen: destroy of young red cellSpleen: destroy of young red cell 80% of untreated patients: † by 5 y.80% of untreated patients: † by 5 y. Treatment: Cardiac/Hepatic: † by 30 y.Treatment: Cardiac/Hepatic: † by 30 y. Transfusion +Chelation > 30yTransfusion +Chelation > 30y..
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--ThalassemiaThalassemia
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Peripheral Blood Smear Peripheral Blood Smear (1)(1)
Peripheral Blood Smear Peripheral Blood Smear (1)(1)
Normochrome Normocyte Normochrome Normocyte Normochrome Normocyte Normochrome Normocyte MCV MCV MCH MCH MCV MCV MCH MCH
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Peripheral Blood Smear Peripheral Blood Smear (2)(2)
Peripheral Blood Smear Peripheral Blood Smear (2)(2)
Hypochrome MicrocyteHypochrome Microcyte MCV MCV
MCH MCH
MCV MCV
MCH MCH
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Defected globin Defected globin chainschains
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Prevalence of Prevalence of αα--ThalassemiaThalassemia
0.01 % in non malarial 0.01 % in non malarial areasareas
ig. UK, Japanig. UK, Japan ~ 49 % in Southwest ~ 49 % in Southwest
Pacific Pacific IslandsIslands
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αα globin globin mutationsmutations
Deletions: 80-85 % of Deletions: 80-85 % of ααThalassemiaThalassemiaDel: 3.7 kb (most frequent)Del: 3.7 kb (most frequent)Del: 4.2 kbDel: 4.2 kb
αα22 InsI-5bp deletion ( InsI-5bp deletion (ααHph1Hph1αα))
αα22 InCd T>C ( InCd T>C (ααNco1Nco1αα))
α১ Variant:Variant:--MED--MED--CAL--CAL--SEA--SEA
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-Thalassemia-Thalassemia Trait -
– Hemoglobin is with in the reference Hemoglobin is with in the reference range.range.
– Reticulocyte count is within the reference Reticulocyte count is within the reference range.range.
– Mean corpuscular volume (MCV) is 75-85 Mean corpuscular volume (MCV) is 75-85 fL.fL.
– Mean corpuscular hemoglobin (MCH) is Mean corpuscular hemoglobin (MCH) is 26 pg.26 pg.
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a-Thalassemiaa-Thalassemia Alpha1 thalassemia minor (--/)
– Hemoglobin is within the reference Hemoglobin is within the reference range.range.
– Reticulocyte count is within the Reticulocyte count is within the reference range.reference range.
– MCV is 65-75 fL.MCV is 65-75 fL.– MCH is 22 pg.MCH is 22 pg.
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Hemoglobin H diseaseHemoglobin H disease
Peripheral smear from a patient with hemoglobin H Peripheral smear from a patient with hemoglobin H disease showing target cells, microcytosis and disease showing target cells, microcytosis and hypochromia. Morphological abnormalities are similar to hypochromia. Morphological abnormalities are similar to those observed in beta thalassemia. In alpha2 those observed in beta thalassemia. In alpha2 thalassemia (silent trait) only mild microcytosis is thalassemia (silent trait) only mild microcytosis is observed.observed.
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HbH diseaseHbH disease•Hemoglobin H disease
– Hemoglobin is 7-10 g/dL.Hemoglobin is 7-10 g/dL.– Reticulocyte count is 5-10%.Reticulocyte count is 5-10%.– MCV is 55-65 fL.MCV is 55-65 fL.– MCH is 20 pg.MCH is 20 pg.– The peripheral blood smear shows The peripheral blood smear shows
small misshapen red cells, small misshapen red cells, hypochromia, microcytosis, and hypochromia, microcytosis, and targeting.targeting.
– Brilliant cresyl blue stain Brilliant cresyl blue stain demonstrates hemoglobin H demonstrates hemoglobin H inclusion bodies.inclusion bodies.
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HbH diseaseHbH disease
Functional Functional αα globinglobin : 1: 1 αα:: globin ratio : 0.3 globin ratio : 0.3 Hb level: 7-9 g/dlHb level: 7-9 g/dl Genotype: --/-Genotype: --/-αα HbH Inclusion (Heinz body): ManyHbH Inclusion (Heinz body): Many Moderate anemiaModerate anemia HepatosplenomegalyHepatosplenomegaly Galstones, infection, folic acid Galstones, infection, folic acid
deficiencydeficiency
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Hydrops fetalisHydrops fetalis
– Hemoglobin is 4-10 g/dL. Hemoglobin is 4-10 g/dL. – MCV is 110-120 fL. MCV is 110-120 fL. – The peripheral blood smear The peripheral blood smear shows severe hypochromia, shows severe hypochromia, and nucleated red blood and nucleated red blood cells.cells.
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Hydrops fetalisHydrops fetalis
Functional Functional αα globinglobin : 0: 0 αα:: globin ratio : 0.0 globin ratio : 0.0 Genotype: --/--Genotype: --/-- HbH Inclusion (Heinz body): HbH Inclusion (Heinz body):
PresentPresent Severe anemiaSevere anemia Heart defect/fatal in utero/Heart defect/fatal in utero/
shortly after birthshortly after birth
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haemoglobinopathies
haemoglobinopathies
• Reduced synthesis of globin chains Reduced synthesis of globin chains (Thalassaemia)(Thalassaemia)
• Synthesis of a structurally abnormal Synthesis of a structurally abnormal Hb Hb variantvariant
Thalassaemia
β-thalassemia
( over 200 point mutations)
a-thalassemia
(over 80 deletions & point mutations)
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a-globin genes cluster
a-globin genes cluster
Chromosome16p13.3
Blood,Vol 91, No 7 (April 1), 1998: pp 2213-2222
Exon I Exon II Exon III Intron I Intron II
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Alpha-Thalassemia inheritance
Alpha-Thalassemia inheritance
Autosomal Autosomal recessiverecessiveAutosomal Autosomal recessiverecessive
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1)1) alpha-globin alpha-globin gene deletionsgene deletions approximately approximately 90%90% of mutations of mutations
2)2) alpha-globin alpha-globin point mutationspoint mutations approximatelyapproximately 10%10% of mutations of mutations
-Thalassemia mutations-Thalassemia mutations
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a-thalassemias phenotype
a-thalassemias phenotype
++ or or --thalassemia 2thalassemia 2 - non-functional one - non-functional one -globin gene -globin gene (-(-))
o o oror --thalassemia 1 thalassemia 1 - non-functional both - non-functional both -globin genes-globin genes (--)
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a+-Thalassemiaa+-Thalassemia
Archives of Iranian Medicine, Vol 4, No 4, October 2001
Rightward
Leftward
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a0-Thalassemiaa0-Thalassemia
Blood,Vol 91, No 7 (April 1), 1998: pp 2213-2222
> 300 kb> 300 kb
Southeast AsiaSoutheast Asia
PhilippinesPhilippines
ThailandThailand
ChineseChinese
MediterraneanMediterranean
Greece, TurkeyGreece, Turkey
~~30 kb30 kb
~~20 kb20 kb
~~23 kb23 kb
(cd51(cd511)1)
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a-globingenes
affected
production a-globin chains
Genotype Outcome
0 100% Normal, healthy
1 75% Silent carrier, healthy
2 50%
or
Carrier, a-thalassaemia trait, Mild hypochromic microcytic anemia
3 25%--/- Hemoglobin H disease, mild
to severe hemolytic anemia
4 0%- -/- - Hemoglobin Bart's, hydrops
fetalisHaemoglobinopathies and clotting disorders. Vol. 36, No. 10, October 2007
Outcome of deletions a-globin genesOutcome of deletions a-globin genes
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HbH DiseaseHbH Disease
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Method detection a-Thalassemia
mutations
Method detection a-Thalassemia
mutations
Salting out DNA extractionSalting out DNA extraction -- human whole bloodhuman whole blood
PCR-Based Strategies PCR-Based Strategies - Gap-PCR- Gap-PCR - Multiplex Gap-PCR- Multiplex Gap-PCR
DNA Sequencing DNA Sequencing
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Gap-PCRGap-PCRGap-PCRGap-PCR
Molecular diagnosis of hemoglobin disorders, Clin. Lab. Haem. 2004, 26, 159–176
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Primers Multiplex PCR (2)Primers Multiplex PCR (2)
Chong SS, et al. Single tube multiplex-PCR screen for common deletional determinants Of a-thalassemia. Blood 2000;95:360–362.
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Primers DNA SequencingPrimers DNA Sequencing
Name Sequence 5'-3'
1M13S
135´ - CGA CGT TGT AAA ACG ACG GCC AGT CGC CAG CCA ATG AGC GCC - 3´
2 S6 5´ - TCC ATT GTT GGC ACA TTC CG - 3´
3 S8 5´ - TGT CCA CGC CCA TGC TGG CAC - 3´
American Journal of Hematology 74:99–103 (2003)
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Hba1 SequenceHba1 Sequence
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Hba2 SequenceHba2 Sequence
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Gap-PCRGap-PCR
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MED MutationMED Mutation1.1. Positive controlPositive control
2.2. Marker 200bpMarker 200bp
3.3. Negative controlNegative control
Cycle Temperature Time
1 94 5 minute
35
94 30 second
60 30 second
72 120 second
1 72 7 minute
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Multiplex PCR
Multiplex PCR
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Multiplex PCRMultiplex PCR
Cycle Temperature Time
1 94 5 minute
35
94 60 second
60 60 second
72 120 second
1 72 7 minute
1) Smart taq DNA Polymerase 2) AMS Buffer 3) DMSO (5-10%)
4) Mgcl2 (50 mM) (2 mM)
5) dNTP (10mM) (0.2 mM)
6) Primers (10pm) (0.3 µl)
7) ddH20 8) Template
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ResultResult
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Multiplex PCR (1)Multiplex PCR (1)
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Multiplex PCR (2)Multiplex PCR (2)
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Multiplex PCR (3)Multiplex PCR (3)
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Multiplex PCR (4)Multiplex PCR (4)
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Patient samplesPatient samplesMale RBC : 5.81MCV :75.9MCH :25.6HbA2 :2.6
Female RBC : 5.41MCV :75.8MCH :25.0HbA2 :2.7
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Patient samplePatient sample
HbHHbH
-a-a3.73.7/-(a)/-(a)20.520.5
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Mutations in Khorasan province
Mutations in Khorasan province
6 (6.2%)
41 (36.3%)65 (57.5%) Deletion
Without Deletion
Point mutation
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Sequencing Sequencing
Khorasan provinceKhorasan province - 2: 7 sample (4 point mutation)
- 1: 7 sample (2 point mutation)
Khoozestan provinceKhoozestan province - 2: 4 sample (4 point mutation)
- 1: 7 sample ( all normal)
950 bp PCR Product950 bp PCR Product
S8 PrimerS8 Primer
2 S6 Primer 2 S6 Primer
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Normal Seq.
AATAAA
Mutant Seq.
AAAAAA
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NormalNormal
2 IVSII-552 IVSII-55
CCGGC>CC>CTTCC
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NormalNormal
2 IVS II-242 IVS II-24
TTCCT>TT>TTTTT
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Khorasan & Khoozestan province
Khorasan & Khoozestan province
RBC Hb Hct MCVMCV MCHMCHHbA
2
5.53 + 0.51
13.52 + 1.45
41.73 + 3.61
73.96 + 6.09
24.48 + 2.23
2.96 + 1.21
MED 0 0 0 0 0 0
5.68 + 0.43
14.07 + 1.14
42.98 + 3.49
75.45 + 5.23
25.31 + 1.25
2.66 + 0.5
5.74 + 0.56
13.1 + 0.94
41.25 + 3.97
71.9 + 2.89
22.9 + 1.54
2.83 + 1.57
5.81 + 0.64
13.97 + 1.57
42.23 + 3.75
71.2 + 2.38
23.47 + 0.76
2.37 + 0.55
5.73 + 0.7
14.33 + 1.52
43.45 + 2.78
75.9 + 4.49
24.95 + 0.59
2.28 + 0.56
0 0 0 0 0 0
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Relationship of MCV to mutationsRelationship of MCV to mutationsRelationship of MCV to mutationsRelationship of MCV to mutations
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Relationship of MCH to mutationsRelationship of MCH to mutations
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TreatmentTreatment Blood transfusion (3-4 weeks for Blood transfusion (3-4 weeks for
life)life)Iron accumulation in bodyIron accumulation in body
Remove the iron: Desferal:Remove the iron: Desferal:Infused under the skin (8-12 h/6 Infused under the skin (8-12 h/6
times a week)times a week) Bone marrow transplantationBone marrow transplantation
A sib brother or sisterA sib brother or sisterHLA matchedHLA matched
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TreatmentTreatment• Avoid iron supplementation. It contributes to
iron overload • Administer folate supplementation to provide
adequate amounts of the vitamin for increased utilization resulting from the hemolytic process and high bone marrow turnover rate.
• Provide prompt attention to infection, especially in children who have had a splenectomy.
• Administer blood transfusions only if necessary.• If chronic transfusion is needed (hemoglobin H
disease), iron chelation therapy should be considered to avoid iron overloading.
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Surgical CareSurgical CareHemoglobin H disease
– Perform a splenectomy if transfusion requirements are increasing.
– Surgical or orthodontic correction may be necessary to correct skeletal deformities of the skull and maxilla due to erythroid hyperplasia.
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Sickle Cell disorderSickle Cell disorder
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Sickle Cell disorderSickle Cell disorder
Stuck the red cell in the vesselsStuck the red cell in the vessels In children: Spleen, chest, In children: Spleen, chest,
wrists,ankleswrists,ankles In adults: hips and shouldersIn adults: hips and shoulders Anemia (Hb 7-8 g/dl)Anemia (Hb 7-8 g/dl) Infections (take antibiotics)Infections (take antibiotics) Painful crises (6-18 months)Painful crises (6-18 months) Swollen and inflamed (hand/food Swollen and inflamed (hand/food
syndrome)syndrome)
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What are the What are the Complications?Complications?
• pain episodes • increased infections • bone damage • yellow eyes or jaundice • early gallstones • lung blockage • kidney damage and loss of body water in
urine • painful erections in men (priapism) • blood blockage in the spleen or liver
(sequestration) • eye damage • low red blood cell counts (anemia) • delayed growth
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The combination of The combination of hemoglobinopathieshemoglobinopathies
Doesn't cause any health Doesn't cause any health problem:problem: αα+ + Thalassemia / Thalassemia / αα+ + Thalassemia (-a/-a)Thalassemia (-a/-a)
HbH disease:HbH disease: ααº º Thalassemia / Thalassemia / αα+ + Thalassemia (--/-a)Thalassemia (--/-a)
Hydrops fetalis:Hydrops fetalis: ααº º Thalassemia / Thalassemia / ααº º Thalassemia (--/--)Thalassemia (--/--)
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Doesn't cause any Doesn't cause any health problemhealth problem
αα+ / º + / º
Thalassemia/Thalassemia/ThalassemiaThalassemia αα+ / º + / º Thalassemia / HbCThalassemia / HbC αα+ / º + / º Thalassemia / HbDThalassemia / HbD αα+ / º + / º Thalassemia / HbEThalassemia / HbE αα+ / º + / º Thalassemia / HbO ArabThalassemia / HbO Arab αα+ / º + / º Thalassemia / HbSThalassemia / HbS
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Thalassemia / Thalassemia / ThalassemiaThalassemia
Caused severe Caused severe health health problem!problem!
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Other Other combinationscombinations
HbC / HbC / Thalassemia (no problem)Thalassemia (no problem) HbD / HbD / Thalassemia (no problem)Thalassemia (no problem) HbE / HbE / Thalassemia (serious anemia)Thalassemia (serious anemia) Hbs / Hbs / Thalassemia (intermediate-Thalassemia (intermediate-
severe)severe) HPFH* / HPFH* / Thalassemia (no problem)Thalassemia (no problem)
*Heriditary persistance of fetal hemoglobin*Heriditary persistance of fetal hemoglobin
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Doesn't cause any Doesn't cause any health problemhealth problem
HbC / HbCHbC / HbC HbC / D, E, O Arab, HPFHHbC / D, E, O Arab, HPFH
HbD / HbDHbD / HbD HbD / C, E, O Arab, HPFHHbD / C, E, O Arab, HPFH
HbE / HbEHbE / HbE HbE / C, D, O Arab, HPFHHbE / C, D, O Arab, HPFH
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Doesn't cause any Doesn't cause any health problemhealth problem
HbO Arab / HbO ArabHbO Arab / HbO Arab HbO Arab/ C, E, D, HPFHHbO Arab/ C, E, D, HPFH HPFH / HPFHHPFH / HPFH
HbH / HbH / Thalassemia !Thalassemia ! Thalassemia major/Thalassemia major/αα+/º +/º
Thalassemia! Thalassemia! Thalassemia major / HbC, DThalassemia major / HbC, D
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serious serious anemiaanemia
HbH / HbH / αα+/º +/º ThalassemiaThalassemia HbS / HbS / Thalassemia Thalassemia HbS / HbCHbS / HbC HbS / HbDHbS / HbD HbS / HbEHbS / HbE HbS / O ArabHbS / O Arab
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Prenatal Diagnosis Prenatal Diagnosis (PND)(PND)
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ThankS forThankS for
YourYour
AttentionAttention