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Hemoglobinopathies

Hemoglobinopathies. Dr Pupak Derakhshandeh, PhD Ass Prof of Medical Science of Tehran University. Hemoglobinopathies. Disorders of Hemoglobin. Disorders of Hemoglobin. 5 % of world population: carrier for genes, important disorders of hemoglobin. Structure and function of hemoglobin.

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Hemoglobinopathies

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  1. Hemoglobinopathies Dr PupakDerakhshandeh, PhD Ass Prof of Medical Science of Tehran University

  2. Hemoglobinopathies Disorders of Hemoglobin

  3. Disorders of Hemoglobin 5 % of world population: carrier for genes, important disorders of hemoglobin

  4. Structure and function of hemoglobin • Oxygen carrier • In vertebrate: red blood cells • Four subunits: • 2α- and 2-chains

  5. Hemoglobin

  6. Each Subunits • Globin: Polypeptide chain • Heme : Prosthetic group (Iron-Containing pigment) Heme + Oxygene • Oxygene transporting

  7. Normal adult hemoglobin HbA: • 2α globin chain (141 AA) • 2  globin chain (146 AA) • α22 • Equal length

  8. Normal adult hemoglobin HbA2: • 2α globin chain • 2 dglobin chain • a 2 d2

  9. Normal adult hemoglobin HbF: • 2α globin chain • 2 γglobin chain • α2γ2

  10. Normal adult hemoglobin

  11. Globin genes synthesis Lessons from the thalasemia. Nature Reviews, Genetics, volume2, 2001

  12. Thalassemia Onset: Childhood Hypo chromic / Microcytic anemia Low level of MCV / MCH Mean corpuscular volume (MCV) Mean corpuscular hemoglobin (MCH) -Thal: Elevated HbA2 (α2d2) HbF (α2γ2) α-Thal: Normal HbA2, HbF

  13. Thalassemia Minor

  14.  Thalassemia major

  15.  Thalassemia major

  16. Thalassemia 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.

  17. Hematological values &a-Thalassemia a a a a s Molecular diagnosis of hemoglobin disorders, Clin. Lab. Haem. 2004, 26, 159–176

  18. Thalassemia Major

  19. an inherited form of hemolytic anemiared blood cell (hemoglobin) abnormalitiesthe most severe form of anemiathe oxygen depletion in the bodybecomes apparent within the first 6 months of life Thalassemia major

  20. 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

  21. Diesease • Autosomal recessive • Deficiency: Synthesis of α/- globin • Origin: Mediteranean, African, Iranian, Indian, Southeast Asian • Resistant to malaria

  22. Prevalence of -Thalassemia • ~ 1.5 % in Africans and African Americans • ~ 30 % in Sardinia

  23. Pathogenesis of -Thalassemia • In adequate Hb production • Reduced MCV/MCH • Unbalanced accumulation of a globin subunits • Ineffective Erythrocyt • 200 different mutations • In Iran over 70 mutations !

  24. Prenatal diagnosis • I. ARMS-PCR (22 common mut.) • II. PCR-RFLP (9 inf. RFLPs) • III. RDB (60 mut.) • IV. Sequencing

  25. ARMS-PCR

  26. PCR-RFLP 1 2 3 M 4 5 6 7

  27.  globin mutations • Transcriptional mutations (+) • In promotor regulatory elements • -101(silent) • -92 (silent) • -88 • -30

  28.  globin mutations 2. RNA-Processing (º) • Splice junction • IVSI-1 Cd30 • IVSI-2 • IVSI-3’ end del 25bp • IvsI-130 • Consensus splice sites (º/ +) • IVSI-5 • IVSI-6 • IVSII-844

  29.  globin mutations • Cryptic splice sites in Introns (+) • IVSI-110 • IVSII-745 • Cryptic splice sites in exons • Cd 26 (HbE) • Cd 121 (HbD panjab/O Arab)

  30. -Thalassemia major • Onset: 6 months • Severe hemolytic anemia • Hb level< 7 g/dl • Skin: pale • Growth retardation • don’t eat or sleep well • Hepatosplenomegaly • Bone marrow expansion: • Make more red cells • Expantion in face and skull • Spleen: destroy of young red cell • 80% of untreated patients: † by 5 y. • Treatment: Cardiac/Hepatic: † by 30 y. • Transfusion +Chelation > 30y.

  31. a-Thalassemia

  32. Peripheral Blood Smear (1) MCV a MCH a Normochrome Normocyte

  33. Peripheral Blood Smear (2) MCV MCH Hypochrome Microcyte

  34. Defected globin chains

  35. Prevalence of α-Thalassemia • 0.01 % in non malarial areas • ig. UK, Japan • ~ 49 % in Southwest Pacific Islands

  36. α globin mutations • Deletions: 80-85 % of αThalassemia • Del: 3.7 kb (most frequent) • Del: 4.2 kb • α2 InsI-5bp deletion (αHph1α) • α2 InCd T>C (αNco1α) • αºVariant: • --MED • --CAL • --SEA

  37. a-Thalassemia Trait -a/aa • 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.

  38. a-Thalassemia Alpha1 thalassemia minor (--/aa) • Hemoglobin is within the reference range. • Reticulocyte count is within the reference range. • MCV is 65-75 fL. • MCH is 22 pg.

  39. Hemoglobin 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.

  40. HbH 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.

  41. HbH disease • Functional αglobin: 1 • α: globin ratio : 0.3 • Hb level: 7-9 g/dl • Genotype: --/-α • HbH Inclusion (Heinz body): Many • Moderate anemia • Hepatosplenomegaly • Galstones, infection, folic acid deficiency

  42. Hydrops fetalis • Hemoglobin is 4-10 g/dL. • MCV is 110-120 fL. • The peripheral blood smear shows severe hypochromia, and nucleated red blood cells.

  43. Hydrops fetalis • Functional αglobin: 0 • α: globin ratio : 0.0 • Genotype: --/-- • HbH Inclusion (Heinz body): Present • Severe anemia • Heart defect/fatal in utero/ shortly after birth

  44. haemoglobinopathies Reduced synthesis of globin chains (Thalassaemia) Synthesis of a structurally abnormal Hb variant

  45. a-globin genes cluster Chromosome16p13.3 Exon I Intron I Exon II Intron II Exon III Blood,Vol 91, No 7 (April 1), 1998: pp 2213-2222

  46. Alpha-Thalassemia inheritance Autosomal recessive

  47. 1)alpha-globin gene deletions approximately 90% of mutations 2)alpha-globin point mutations approximately10% of mutations a-Thalassemia mutations

  48. a-thalassemias phenotype a+ or a-thalassemia 2 - non-functional one a-globin gene (-a) ao ora-thalassemia 1 - non-functional both a-globin genes(--)

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