Download Hemglobinopathies

Hemoglobinopathies
Dr. Shumaila Asim
Lecture #6
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Hemoglobinopathies
• Disorders of hemoglobin caused by:
– Synthesis of structurally abnormal Hb
– Synthesis of insufficient quantities of
normal Hb
– Combination of both
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HEMOGLOBINOPATHIES
1. Sickle cell anemia (Hb S)
2. Hemoglobin C disease (Hb C)
3. Hemoglobin SC disease (Hb S+ Hb C)
4. Thalasemia
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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
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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
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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
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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.
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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.
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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
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Silent Carriers (heterozygotes +/-)
• 3 functional alpha globin genes
• No symptoms, but thalassemia could
potentially appear in offspring
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Alpha Thalassemia Trait
• 2 functional globin genes
• results in smaller blood cells that are lighter in
colour
• no serious symptoms, except slight anemia
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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.
γ4
β4
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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.
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Alpha Thalassemia Major
• no functional globin genes
• death before birth (embryonic lethality)
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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.
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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
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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
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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
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Beta Thalassemia Major
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•
•
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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)
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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
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Structure of myoglobin
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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
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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
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