1 Chromosomes Dr Pupak Derakhshandeh, PhD Ass Prof Medical Science of Tehran University.
Hemoglobinopathies. Hemoglobinopathies Disorders of Hemoglobin Dr. Pupak Derakhshandeh.
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Transcript of Hemoglobinopathies. Hemoglobinopathies Disorders of Hemoglobin Dr. Pupak Derakhshandeh.
HemoglobinopatHemoglobinopathieshies
HemoglobinopatHemoglobinopathieshies
Disorders of Disorders of HemoglobinHemoglobin
Dr. Pupak DerakhshandehDr. Pupak Derakhshandeh
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
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
HemoglobinHemoglobin
Each SubunitsEach Subunits
Globin: Polypeptide chainGlobin: Polypeptide chain Heme : Prosthetic groupHeme : Prosthetic group
(Iron-Containing (Iron-Containing pigment)pigment)
Heme + OxygeneHeme + OxygeneOxygene transportingOxygene transporting
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
Normal adult Normal adult hemoglobinhemoglobin
HbFHbF::
22 αα globin chain globin chain 2 2 γγ globin chain globin chain αα22γγ22
Normal adult Normal adult hemoglobinhemoglobin
Hemoglobin in the Hemoglobin in the OntogenesisOntogenesis
ThalassemiThalassemiaa Onset: ChildhoodOnset: Childhood
Hypo chromic / Microcrystal Hypo chromic / Microcrystal anemiaanemia
Low level of MCV / MCHLow level of MCV / MCHMean 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
Thalassemia Thalassemia MinorMinor
Thalassemia MinorThalassemia Minor
• Thalassemia minor is an inherited form of hemolytic anemia that is less severe than thalassemia major.
• This blood smear from an individual with thalassemia shows small (microcytic), pale (hypochromic), variously-shaped red blood cells.
• These small red blood cells (RBCs) are able to carry less oxygen than normal RBCs.
Thalassemia Thalassemia MajorMajor
an inherited form of hemolytic anemia
red blood cell (hemoglobin) abnormalities
the most severe form of anemia
the oxygen depletion in the body becomes apparent within the first 6 months of life
Thalassemia major
If untreated, death usually results within a few years
Note the small, pale (hypochromic), abnormally-shaped red blood cells associated with thalassemia major
The darker cells likely represent normal RBCs from a blood transfusion
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
Prevalence of Prevalence of αα--ThalassemiaThalassemia
0.01 % in non malarial 0.01 % in non malarial areasareas
ig. UK, Japanig. UK, Japan ~ 49 % in Soutwest ~ 49 % in Soutwest
Pasific Pasific IslandsIslands
Defected globin Defected globin chainschains
Prevalence of Prevalence of --ThalassemiaThalassemia
~ 1.5 % in Africans and ~ 1.5 % in Africans and African AmericansAfrican Americans
~ 30 % in Sardinia~ 30 % in Sardinia
Pathogenesis Pathogenesis of of -Thalassemia-Thalassemia
In adequate Hb production Reduced MCV/MCH
Unbalanced accumulation of globin subunits Ineffective Erythrocyt
200 different mutations In Iran about 60 mutations
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
-Thalassemia-Thalassemia Trait -
– Hemoglobin is with in the reference range.
– Reticulocyte count is within the reference range.
– Mean corpuscular volume (MCV) is 75-85 fL.
– Mean corpuscular hemoglobin (MCH) is 26 pg.
a-Thalassemiaa-Thalassemia Alpha1 thalassemia minor (--/)
– Hemoglobin is within the reference range.
– Reticulocyte count is within the reference range.
– MCV is 65-75 fL.– MCH is 22 pg.
Hemoglobin H diseaseHemoglobin H disease
Peripheral smear from a patient with hemoglobin H disease showing target cells, microcytosis and hypochromia. Morphological abnormalities are similar to those observed in beta thalassemia. In alpha2 thalassemia (silent trait) only mild microcytosis is observed.
HbH diseaseHbH disease•Hemoglobin H disease
– Hemoglobin is 7-10 g/dL.– Reticulocyte count is 5-10%.– MCV is 55-65 fL.– MCH is 20 pg.– The peripheral blood smear shows
small misshapen red cells, hypochromia, microcytosis, and targeting.
– Brilliant cresyl blue stain demonstrates hemoglobin H inclusion bodies.
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
Hydrops fetalisHydrops fetalis
–Hemoglobin is 4-10 g/dL. –MCV is 110-120 fL. –The peripheral blood smear shows severe hypochromia, and nucleated red blood cells.
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
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.
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.
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
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
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)
-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..
Thalassemia majorThalassemia major
Thalassemia majorThalassemia major
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
Sickle Cell disorderSickle Cell disorder
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)
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
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
ARMS-PCRARMS-PCR
1 2 3 4 5 6 7 8 9 10 11 12 13
PCR-RFLPPCR-RFLP1 2 3 M 4 5 6 7
The combination of The combination of hemoglobinopathieshemoglobinopathies
Doesn't cause any health Doesn't cause any health problem:problem: αα+ + Thalassemia / Thalassemia / αα+ + ThalassemiaThalassemia
HbH disease:HbH disease: ααº º Thalassemia / Thalassemia / αα+ + ThalassemiaThalassemia
Hydrops fetalis:Hydrops fetalis: ααº º Thalassemia / Thalassemia / ααº º ThalassemiaThalassemia
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
Thalassemia / Thalassemia / ThalassemiaThalassemia
Caused severe Caused severe health health problem!problem!
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
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
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
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
Prenatal Diagnosis Prenatal Diagnosis (PND)(PND)
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