1. Dr. Shumaila Asim Lecture #6
Hemoglobinopathies
Dr. Shumaila Asim
Lecture #6

2. Hemoglobinopathies Disorders of hemoglobin caused by:
Synthesis of structurally abnormal Hb
Synthesis of insufficient quantities of normal Hb
Combination of both

3. HEMOGLOBINOPATHIES Sickle cell anemia (Hb S)
Hemoglobin C disease (Hb C)
Hemoglobin SC disease (Hb S+ Hb C)
Thalasemia

4. Hemoglobinopathies Sickle cell (HbS) disease
Caused by a single mutation in b-globin gene
Glutamic acid at position 6 in HbA is replaced by valine
The shape of RBCs become sickled
Causes sickle cell anemia

6. Hemoglobinopathies Hemoglobin C disease:
Caused by a single mutation in β-globin gene
Glutamic acid at position 6 in HbA is replaced by lysine
Causes a mild form of hemolytic anemia

7. Hemoglobinopathies Methemoglobinemia:
Caused by oxidation of Hb to ferric (Fe3+) state
Methemoglobin cannot bind oxygen
Caused by certain drugs, reactive oxygen species and NADH-cytochrome b5 reductase deficiency
Chocolate cyanosis: brownish-blue color of the skin and blood

8. Hemoglobinopathies Thalassemia:
Genetic blood disorder resulting in a mutation or deletion of the genes that control globin production.
Normal hemoglobin is composed of 2 alpha and 2 beta globins
Mutations in a given globin gene can cause a decrease in production of that globin, resulting in deficiency
aggregates become oxidized  damage the cell membrane, leading either to hemolysis, ineffective erythropoiesis, or both.
2 types of thalassemia: alpha and beta.

9. Demographics
The thalassemia gene may be maintained in the human population, in part because of the greater immunity of heterozygous individuals against malaria and is found in parts of the world where malaria is common
These include Southeast Asia, China, India, Africa, and parts of the Mediterranean.

10. Alpha Thalassemia
mutation of 1 or more of the 4 alpha globin genes on chromosome 16
severity of disease depends on number of genes affected
results in an excess of beta globins

11. Silent Carriers (heterozygotes +/-)
3 functional alpha globin genes
No symptoms, but thalassemia could potentially appear in offspring

12. Alpha Thalassemia Trait
2 functional globin genes
results in smaller blood cells that are lighter in colour
no serious symptoms, except slight anemia

13. Hemoglobin H Disease Second most severe form alpha thalassemia.
Usually caused by presence of only one gene producing alpha chains (--/-a). 
Results in accumulation of excess unpaired gamma or beta chains. Born with 10-40% Bart's hemoglobin (γ4).   Gradually replaced with Hemoglobin H (β4). In adult, have about 30-50% Hb H.
γ β4

14. Hemoglobin H Disease
Live normal life; however, infections, pregnancy, exposure to oxidative drugs may trigger hemolytic crisis.
RBCs are microcytic, hypochromic with marked poikilocytosis.  Numerous target cells.
Hb H vulnerable to oxidation.  Gradually precipitate in vivo to form Heinz-like bodies of denatured hemoglobin.  Cells been described has having "golf ball" appearance, especially when stained with brilliant cresyl blue.

15. Alpha Thalassemia Major
no functional globin genes
death before birth (embryonic lethality)

16. Bart’s Hydrops Fetalis Syndrome
Most severe form.  Incompatible with life.  Have no functioning alpha chain genes (--/--).
Baby born with hydrops fetalis, which is edema and ascites caused by accumulation serous fluid in fetal tissues as result of severe anemia.  Also see hepatosplenomegaly and cardiomegaly.
Predominant hemoglobin is Hemoglobin Bart, along with Hemoglobin Portland and traces of Hemoglobin H.
Hemoglobin Bart's has high oxygen affinity so cannot carry oxygen to tissues.  Fetus dies in utero or shortly after birth. At birth, see severe hypochromic, microcytic anemia with numerous NRBCs.
Pregnancies dangerous to mother.  Increased risk of toxemia and severe postpartum hemorrhage.

17. Beta Thalassemia mutations on chromosome 11
hundreds of mutations possible in the beta globin gene, therefore beta thalassemia is more diverse
results in excess of alpha globins

18. Beta Thalassemia Trait
slight lack of beta globin
smaller red blood cells that are lighter in colour due to lack of hemoglobin
no major symptoms except slight anemia

19. Beta Thalassemia Intermedia
lack of beta globin is more significant
bony deformities due to bone marrow trying to make more blood cells to replace defective ones
causes late development, exercise intolerance, and high levels of iron in blood due to reabsorption in the GI tract
if unable to maintain hemoglobin levels between 6 gm/dl – 7 gm/dl, transfusion or splenectomy is recommended

20. Beta Thalassemia Major
complete absence of beta globin
enlarged spleen, lightly coloured blood cells
severe anemia
chronic transfusions required, in conjunction with chelation therapy to reduce iron (desferoxamine)

21. Myoglobin A globular hemeprotein in heart and muscle
Stores and supplies oxygen to the heart and muscle only
Contains a single polypeptide chain forming a single subunit with eight a-helix structures
The interior of the subunit is composed of nonpolar amino acids

22. Structure of myoglobin

23. Myoglobin The charged amino acids are located on the surface
The heme group is present at the center of the molecule
Myoglobin gives red color to skeletal muscles
Supplies oxygen during aerobic exercise

24. Myoglobin in disease
Myoglobinuria: Myoglobin is excreted in urine due to muscle damage (rhabdomyolysis)
May cause acute renal failure
Specific marker for muscle injury
Less specific marker for heart attack