2. Lecturer of Medical Biochemistry
HEMOGLOBINOPATHIES
Dr. Dalia Abdel-Wahab
Lecturer of Medical Biochemistry
and Molecular Biology

3. Intended learning outcomes (ILOs):
Studying this chapter should enable you to:
Define hemoglobinopathies
List different types of hemoglobinopathies
Explain the biochemical basis of sickle cell anaemia
Explain the biochemical basis of Hemoglobin C disease & Methemoglobinemias
Explain the biochemical basis of Thalassemias
Identify the biochemical basis of β-Thalassemias
Identify the biochemical basis of α-Thalassemias

4. HEMOGLOBINOPATHIES
Hemoglobinopathies are family of genetic disorders caused by production of a structurally abnormal hemoglobin molecule, synthesis of insufficient quantities of normal hemoglobin, or, rarely, both.

5. Different types of HEMOGLOBINOPATHIES
Qualitative hemoglobinopathy result from production of hemoglobin with an altered amino acid sequence
Sickle cell anemia (Hb S), hemoglobin C disease (Hb C), hemoglobin SC disease (Hb S + Hb C)
Quantitative hemoglobinopathy as thalassemias are caused by decreased production of normal hemoglobin

6. Glutamic Acid (polar negatively charged)
Sickle cell anemia
Sickle cell anemia is an Autosomal Recessive disease in which a mutation occurs at 6 th position in the two β- chains:
Glutamic Acid (polar negatively charged)
is changed into
Valine (non charged)

7. Sickle cell anemia
Being Autosomal Recessive disease, Symptoms occurs mainly in homozygous individuals (100% HBS )
Heterozygous individuals (trait) present symptoms only in Hypoxic conditions (50% HB A and 50% HBS)

8. Sickle cell anemia
Sickle cell anemia is characterized by lifelong episodes of pain (“crises”), chronic hemolytic anemia with associated hyperbilirubinemia and increased susceptibility to infections, usually beginning in early childhood

9. This type of hemoglobin is called Hemoglobin S
Sickle cell anemia
This type of hemoglobin is called Hemoglobin S

10. HbS Polymerizes to form long filaments This causes sickling of cells

11. Factors that increase sickling
They are all factors in favors of deoxygenated form of Hb:
Acidosis
Hypoxia
Increase CO2
Increase 2,3 BPG

12. Factors that increase sickling
The replacement of the charged glutamate with the nonpolar valine forms a protrusion on the β-globin that fits into a complementary site on the β chain of anoth hemoglobin molecule in the cell.
At low oxygen tension, deoxyhemoglobin S polymerizes inside the RBC, forming a network of fibrous polymers that stiffen and distort the cell, producing rigid, misshapen erythrocytes.

13. Sickle cell anemia
Sickle cell anemia offers advantage against malaria infection due to short life span of RBCs (10-15 days)

14. Hb electrophoresis at alkaline pH
Normal
Trait
Anemia
Hb A
Hb S + -

15. Other types of hemoglobinopathies
Hb M:
substitution of proximal histidine by tyrosine causing oxidation of Fe++ to Fe+++ forming methemoglobin
cannot bind oxygen
“chocolate cyanosis” (a brownish-blue coloration of the skin and mucous membranes) and chocolate-colored blood
Due to tissue hypoxia causing anxiety, headache, and dyspnea

16. Hb C:
Substitution of two glutamate residues in the  chain by lysine casing mild hemolytic anemia
This substitution causes Hb C to move more slowly toward the anode than Hb A or Hb S. Why?

17. “Decreased rate of synthesis of
Thalassemias
“Decreased rate of synthesis of
globin chains”

18. There is defect in one or more of the 4 copies of -globin gene.
-Thalassemias
There is defect in one or more of the 4 copies of -globin gene.
This results in decrease synthesis of -globin chains or their complete absence

19. Types of -Thalassemias
Silent carrier: one -globin gene is defective
-Thalassemia trait: two -globin genes are defective
Hb H disease: three -globin genes are defective
Hydrops fetalis: the four genes are defective (intrauterine fetal death occurs)

20. -Thalassemias
Caused by a defect in one or in the two copies of -globin chains.
There is decrease rate of synthesis of -globin chains.
 or  chains will increase.

21. Types of -Thalassemias
Thalassemia minor= -Thalassemia trait
These are heterozygous individuals who inherit only one defective gene from one of their parents
2) Thalassemia major:
Homozygous individuals who inherit two defective copies for the gene from both parents. They present with hemolytic anaemia.

22. MCQ
Sickle cell anemia is caused by a mutation in hemoglobin that causes: 1) a change from a non-charged amino acid to a charged amino acid. 2) a change from a charged amino acid to a non-charged amino acid. 3) loss of a post-translational modification of an amino acid. 4) a failure to reduce Fe3+ to Fe2+. 5) dissociation of hemoglobin to dimers.

23. MCQ
Thalassemia is caused by: 1) Absence or decrease of Hb S. 2) Presence of excessive amount of Hb A2. 3) Presence of an abnormal hemoglobin. 4) Defect in the synthesis of one or more of the polypeptide chains of hemoglobin.