HEMOGLOBINOPATHIES
DR BILAL KARIM
ASSISTANT PROFESSOR
BIOCHEMISTRY
HEMOGLOBINOPATHIES
• Sickle Cell Anemia (Hemoglobin S Disease)
• Hemoglobin C Disease
• Hemoglobin SC Disease
• Methemoglobinemias
• Thalassemias (Alpha & Beta)
SICKLE CELL ANEMIA
• An autosomal recessive disorder that occurs in individuals who
have inherited two mutant genes (one from each parent) that
code for the synthesis of β globin chain.
• Blood cells of heterozygotes contain both HbS and HbA.
SICKLE CELL ANEMIA
• HbS contains two normal α globin chains and two mutant β
globin chains.
• Glutamate is replaced by valine at position 6 in β globin chain.
SICKLE CELL ANEMIA
• During electrophoresis at alkaline pH, HbS moves more slowly
towards anode than does HbA due to absence of negatively
charged glutamic acid residues in two β chains.
SICKLE CELL ANEMIA
• At low O₂ tension, deoxyhemoglobin S polymerizes inside the RBC,
forming a network of fibrous polymers that stiffen and distort the cell,
producing rigid, misshapen RBC.
• Sickle cells frequently block the flow of blood through narrow
capillaries.
• The interruption of oxygen supply leads to localized anoxia in the
tissue, causing pain and eventually death of cells in the vicinity of
blockage.
SICKLE CELL ANEMIA
• Characterized by
Episodes of pain
Chronic hemolytic anemia and associated hyperbilirubinemia
Increased susceptibility to infections
SICKLE CELL ANEMIA
• Variables that reduce O₂ affinity of HbS also increase sickling.
• These variables include
1. Decreased pO₂
2. Increased pCO₂
3. Decreased pH
4. Increased concentration of 2, 3-BPG
5. Dehydration
SICKLE CELL ANEMIA
• Therapy involves adequate hydration, analgesics , aggressive
antibiotic therapy if infection is present & transfusion.
• Hydroxyurea (hydroxycarbamide), an antitumor drug, is
therapeutically useful because it increases circulating levels of
HbF, which decreases RBC sickling.
• Stem cell transplantation is possible.
HEMOGLOBIN C DISEASE
• Glutamate is replaced by lysine at position 6 in β globin chain.
• HbC moves more slowly towards anode than HbA or HbS does.
• Patient has a relatively mild, chronic hemolytic anemia.
HEMOGLOBIN SC DISEASE
• Some β globin chains have sickle cell mutation whereas other β
globin chains carry mutation found in HbC disease.
• Doubly heterozygous.
• Differs from sickle cell anemia in that symptoms such as
painful crisis are less frequent & less severe.
METHEMOGLOBINEMIAS
• Oxidation of heme iron in hemoglobin from Fe⁺² to Fe⁺³ forms
methemoglobin, which cannot bind O₂.
• Oxidation is caused by certain drugs or reactive oxygen species.
METHEMOGLOBINEMIAS
• A deficiency of NADH-cytochrome b5 reductase (also called
NADH-methemoglobin reductase), the enzyme responsible for
the conversion of methemoglobin (Fe⁺³) to hemoglobin (Fe ⁺²),
leads to the accumulation of methemoglobin.
METHEMOGLOBINEMIAS
• Characterized by chocolate cyanosis due to dark colored
methemoglobin.
• Symptoms are related to degree of tissue hypoxia and include
anxiety, headache & dyspnea.
• Coma & death can occur in rare cases.
• Treatment is with methylene blue, which is oxidized as Fe ⁺³ is
reduced.
THALASSEMIAS
• Synthesis of either α or β globin chain is defective and Hb
concentration is reduced.
• A thalassemia can be caused by a variety of mutations,
including entire gene deletions, or substitutions or deletions of
one to many nucleotides in the DNA.
TYPES OF THALASSEMIAS
• β – Thalassemias
• α – Thalassemias
ALPHA GLOBIN GENE FAMILY
• There are two genes for α globin chain, each located on
chromosome 16.
• This family also contains zeta gene that is expressed early in
development as α globin like component of embryonic
hemoglobin.
BETA GLOBIN GENE FAMILY
• There is a single gene for β globin chain located on
chromosome 11.
• This family also has additional four β globin like genes
1. ε gene that is expressed in early development
2. 2 γ genes that are expressed in HbF
3. δ gene for HbA₂
β - THALASSEMIAS
• Synthesis of β globin chains is decreased or absent.
• However, α globin chain synthesis is normal.
• Increase in HbA₂ and HbF also occurs.
β - THALASSEMIAS
• There are two copies of β globin gene (one on each of
chromosome 11).
• Therefore, if one gene is defective, the patient is having β
thalassemia trait (β thalassemia minor).
• If both genes are defective, the patient is having β thalassemia
major (Cooley anemia).
β - THALASSEMIAS
• These patients require regular transfusions of blood which may
lead to iron overload.
• The only curative option available is hematopoietic stem cell
transplantation.
α - THALASSEMIAS
• Synthesis of α globin chain is decreased or absent.
• There are four copies of α globin gene (two on each of
chromosome 16).
• If one gene is defective, the individual is a silent carrier of α
thalassemia.
• If two genes are defective, the individual is designated as having
α thalassemia trait.
α - THALASSEMIAS
• If three genes are defective, the individual has hemoglobin H
(β4) disease, a hemolytic anemia of variable severity.
• If all four genes are defective, hemoglobin Bart (γ4) disease
with hydrops fetalis & fetal death occurs, because α chains are
required for synthesis of HbF.
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