sickle cell anemia and thalassemias ; their genetic causes, effects and consequences;

2. HEMOGLOBINOPATHIES
Hemoglobinopathy :-genetic defect that results
in abnormal structure of one of
the globin chains of the hemoglobin
molecule. Hemoglobinopathies are inherited
single-gene disorders.

3. NORMAL HUMAN
HAEMOGLOBINS
Haemoglobin Structural
formula
Adult Hb-A 2 2 97%
Hb-A2 2 2 1.5-3.2%
Fetal Hb-F 2 2 0.5-1%
Embryonic Hb-Gower 1 2 2
Hb-Gower 2 2 2
Hb-Portland 2 2

6. TWO MAJOR DISORDERS OF HB SYNTHESIS
1. Qualitative hemoglobinopathies: caused by
mutations that lead to the transcription of
structurally abnormal hemoglobins, such as
HbS, HbC,HbE
2. Quantitative hemoglobinopathies : caused
by mutations that lead to the reduced synthesis
of normal globin chains.eg,Thalassemias

7. SICKLE CELL DISEASE
(HBS)
 sickle cell anemia is an autosomal
recessive disease that result from the
substitution of valine for glutamic acid
at position 6 of beta-globulin chain.
 Patient who are homozygous for the
HbS have sickle cell disease
 Patient who are heterozygous for HbS
gene have sickle cell trait.

8. CAUSE OF SICKLING
Deoxygenation of heme moiety of sickle
hemoglobin leads to hydrophobic interaction
between adjacent sickle hemoglobin that
aggregate into larger polymers.
 HbS undergoes innumerable cycles of
deoxygenation induced polymerisation and
oxygenation induced depolymerisation until it’s
membrane is irreversibly injured.
 Fate:1.chronic hemolysis
2.microvascular obstruction.
 These red blood cell have a life span of only 10-
20 days.

9. THALASSEMIAS
 Heterogeneous group of inherited autosomal
recessive disorders caused by mutations that
decreases the synthesis of alpha or beta globin
chain.
 On the basis of type of globin chain affected it is of
two types:-
 1.Beta thalassemia:-impaired synthesis of b
globin chain
 2.Alpha thalassemia:- impaired synthesis of a
globin chain.

10. MUTATIONS IN B-GLOBIN GENE
Mutations associated with β-thalassemia are of two
categories:-
1. Βo :-no β globin chains are synthesized
2. β+ :- reduced β globin chain synthesis
DIFFERENT WAYS OF MUTATION
1. Aberrant RNA splicing: It is of two types:
*Mutation in normal rna splicing: causes βo thalassemia
*Ectopic splicing: causes β+ thalassemia.
1. Mutation in promoter: mutation in β-globin promoter
gene,lower transcription causing β+ thalassemia
2. Chain terminator mutation: creates stop
codon/nonsense codon within exon, causes βo
thalassemia

11. GENOTYPE OF Β THALASSEMIA
 Thalassemia major
– Homozygous for β-Thalassemia genes
– Genotype β0 / β0 or β+ / β+
 Thalassemia minor
– Heterozygous with one thalassemia gene and
one normal gene β0 / β or β+ / β
 Thalassemia intermedia
– Genetically heterogeneous group with milder
variant of β0 /β0 or β+ / β+ and severe form of
heterozygous thalassemia β0 / β or β+ / β

12. β THALASSEMIA MAJOR
-Severe microcytic,hypochromic anemia with target cells and
anisopoikilocytosis
-Marrow expansion and crew cut app. In skull x-ray
-skeletal deformities and chipmunk facies
Requires frequent blood transfusion and it leads to iron overload and 2˚
hemochromatosis
-Increased HbF is seen
Thalassemia minor
- b chain is underproduced, asymptomatic
-Diagnosis is confirmed by increased HbA2 on electrophoresis
Thalassemia intermediate
-mild to moderate disorder depending on amount of β globin production.
Expression of disorder is between thalassemia major and minor.

13. α- THALASSEMIA
-Caused mainly by deletions of α-globin chains.
on the basis of number of alpha globin genes affected it is
categorized into 4 categories:-
1. Silent carrier state: deletion of single alpha gene
Genotype: α_/αα
- asymptomatic,can only be diagnosed by DNA studies.
2. THALASSEMIA TRAIT: deletion of two alpha genes
Genotype: _ _/αα
_asymptomatic,mild or no anemia.
3.HAEMOGLOBIN H DISEASE
Genotype:_ _/_α
severe anemia and RBC abnormalities but less than that of
β-thalassemia major.

14. 4.BART’S HB/ HYDROPS FETALIS
-All the 4 alpha globin genes are deleted.
-Genotype: _ _ / _ _.
-Baby is born with hydrops fetalis, which is edema and
ascites due to the accumulation of serous fluid in fetal
tissue as a result of anemia.