HEMOGLOBINOPATHY

1. HEMOGLOBINOPATHY Prof.Dr.Arzu SEVEN

2. HEMOGLOBINOPATHY • Mutations in the genes that encode the α or β subunits of Hb potentially can affect its biological function • More than 800 known mutant human Hbs are both extremely rare and benign, with no clinical abnormalities • When a mutation compromises bilogic function hemoglobinopathy

4. Diagnosis of hemoglobinopathies • The mobility of a protein during elecrophoresis or chromatography is determined by its charge and interaction with matrix

5. 3 commonly used techniques • Electrophoresis in agar gel at pH:6.2 • IEF (using polyacrylamide gel) • Ion exchange chromatography

6. Sickling disorders=sickle cell disease HbS • Inherited, single point mutation in the gene encoding β_globulin • Glu Val • A surface-localized charged AA is replaced by a hydrophobic (nonpolar) residue • At low PO2 deoxy HbS can polymerize to form long, insoluble fibers

7. Sickle shape erythrocytes vulnerable to lysis • HbS, when deoxygenated, is less soluble it forms long, filamentous polymers that readily precipitate characteristic sickle shape

8. In homozygous individual (HbS/HbS) the complex process of nucletion γ polymerization occurs readily • In heterozygous individual (HbA/HbS) sickle cell trait asymptomatic

9. Sickled erythrocytes block blood flow especially in the spleeen γ joints cells lose water, become fragile, have shorter life span hemolysis γ anemia

10. Intermittent episodes of hemolytic anemia • Acute vasoocclusive crises, impaired growth ,increased susceptibility to infections, multiple organ damage • Heterozygosity is associated with an increased resistance to malaria, specifically growth of the infectious agent plasmodium falciparum in erythrocytes (selective advantage)

13. HbC (glu lys) • Copolymerize (interact) with HbS • when both are present, causing a sickling disorder resembling homozygous HbS disease • HbA ,F and most Hb variants do not copolymerize with HbS they prevent severe sickling disorders when they are present with HbS

14. When HbS trait is inherited together with β°_thalasemia trait severe sickling disorders • α_thalassemia are protective against severe sickling

15. Met Hbemia (Hb M) • Heme iron is ferric can neither bind nor transport O2 • Inherited due to metHb reductase deficiency (autosomal recessive) • Acquired by ingestion of certain drugs (sulfonamides) γ chemicals

16. HbM: Histidin F8 tyr (congenital) Fe makes a tight ionic complex with phenolate anion of tyrosine • If α chain is affected: T state, O2 affinity Bohr effect (-) • If β chain is affected:R_T switching Bohr effect(+) +3

17. Infants are particulary vulnerable to metHbemi because HbF is more sensitive to oxidants compared to Hb A >%10 of Hb is in metHb cyanosis • Diagnosis:electrophoresis ,characteristic absorption spectrum of metHb • Therapy:ingestion of methylene blue or ascorbic acid

18. Unstable Hb Hemolytic Anemia • More than 100 Hb variants show instability of either α or β globulin chain • Due to a substituon of a polar (or hydrophilic) AA for a nonpolar (or hydrophobic) AA that lines the pocket where heme is located • Köln Hbpati compensated hemolytic anemia • Zürich Hbpati sulfonamide_induced hemolysis

19. Thalassemias • Hereditory disorders characterized by a reduction in the synthesis of one type of globulin chain • α thalassemia: mutations in α-globulin genes(unequal crossing- over γ large deletions) reduction in α chain synthesis

20. βthalassemia: a very wide variety of mutations in β_globulin gene including deletions, nonsense γ frameshift mutations reduction in β chain synthesis

21. Thalasemia major: • Severe anemia • Hypochromic microcytic RBC • Signs of accelerated hemolysis and regeneration (hyperbilirubiemia) • Hepato-splenomegali • Growth retardation • Bony abnormalities

22. Thalassemia minor: • Common γ mild condition • Hypochromia • Mild microcytosis of RBC • Mild elevation of RBC • Slight/no anemia

23. Thalassemia trait: • Heterozygout state