1. Thalassemia
The thalassemias are a heterogeneous group of inherited disorders caused by mutations that decrease the rate of synthesis of α- or β-globin chains.
Quantitative abnormality of globin chain synthesis
A diverse collection of molecular defects
Inherited as autosomal codominant conditions.
As a consequence there is a deficiency of hemoglobin, with additional secondary red cell abnormalities caused by the relative excess of the other unaffected globin chain.
Found most frequently in the Mediterranean, Africa, Western and Southeast Asia, India and Burma
Distribution parallels that of Plasmodium falciparum

2. Types  Thalassemia Symbol
Greek letter used to designate globin chain: 
β-Thal is common in blacks, Greeks, and Italians.
β chains are encoded by a single β-globin gene located on chromosome 16.
/  (Normal)
+ (diminished, but some production of globin chain by gene)
0 (No production of globin chain )
Alpha Thalassemia
Symbols
Greek letter used to designate globin chain: 
α-Thal is common in Southeast Asians and in blacks.
The α chains are encoded by two α-globin genes, which lie in tandem on chromosome 11
Each chromosome carries 2 genes. Therefore the total complement of  genes in an individual is 4
/ - Normal
- ( Indicates a gene deletion)
-/
-/-
--/
--/-
--/--

3. α-Thalassemias
The α-thalassemia disorders are characterized by reduced or absent synthesis of α-globin chains.
There are normally four α-globin genes.
The severity of α-thalassemia varies greatly depending on the number of α-globin genes affected.
The anemia stems both from lack of adequate hemoglobin and the effects of excess unpaired non-α chains (β, γ, δ).
Thus, in the newborn with α-thalassemia, excess unpaired γ-globin forms γ4-tetramers known as hemoglobin Barts,
In adults excess β-globin chains form β4 tetramers known as HbH.
Since free β and γ chains are more soluble than free α chains and form fairly stable homotetramers, hemolysis and ineffective erythropoiesis are less severe than in β-thalassemias.

4. α-Thalassemias - DELETIONS
Clinical Nomenclature
Genotype
Disease
Molecular Genetics
Hydrops fetalis
Electrophoresis shows Hb Barts
--/--
Fatal in utero
HbH disease
Severe hemolytic anemia
Hb electrophoresis detects HbH.
--/-α
Moderately severe anemia
Gene deletions spanning one or both α-globin loci
α- thalassemia trait
Decreased MCV, Hb, and Hct, Increased RBC Normal RDW, serum ferritin,Hb electrophoresis.Tear drop RBCs in PBS
--/αα(Asian) or
-α/-α(black African
Mild anemia with an increased RBC count
Silent carrier
-α/αα
Asymptomatic, normal red cells

5. Clinical and Genetic Classification of Thalassemia
β-Thalassemias - β-globin Mutations
Clinical Nomenclature
Genotype
Disease
Molecular Genetics
Thalassemia major
Homozygous or compound heterozygous
β0/β0,
β0/ β+, or
β+/β+)
Severe, requires blood transfusions regularly
MUTATIONS
Defects in transcription, processing, or translation of mRNA, resulting in (β0) or (β+)
β -thalassemia trait
β/ β+ or
β/β0
Asymptomatic, with mild microcytic anemia, or microcytosis without anemia
SAME AS ABOVE
β0, in which no β-globin chains are produced; and
β+, in which there is reduced (but detectable) β-globin synthesis.

6. Molecular Pathogenesis : The β-globin gene and some sites at which point mutations giving rise to β-thalassemia have been localized.
Mutations that lead to aberrant mRNA processing are the most common cause of β-thalassemia.
Mutations in promoter region lead to reduced globin gene transcription. Because some
β-globin is synthesized, such alleles are designated β+.
Mutations in the coding
sequences are associated
with serious consequences.
Eg: A single-nucleotide
change in one of the exons
leads to the formation of a
termination, or "stop" codon,
which interrupts translation
of β-globin mRNA &
completely prevents the
synthesis of β-globin. Such
alleles are designated β0
If the mutation alters the normal splice junctions
splicing does not occur, and all of the mRNA formed is abnormal.
Unspliced mRNA is degraded within the nucleus
no β-globin is made. β0
mutations at locations away from the normal intron-exon splice junction create new sites that are substrates for the action of splicing enzymes at abnormal locations-within an intron,
Because normal splice sites remain intact, both normal and abnormal splicing occur, and normal β-globin mRNA is decreased but not absent.
β+ globin

7. Pathogenesis of β-thalassemia major
2 Major effects
Decreased β globin
Red cell hemolysis
Inadequate HbA
Decreased MCHC
Hypochromic microcytic anemia
Unpaired α chain forms insoluble aggregates
Precipitates within the RBC
Membrane damage-
Extravascular hemolysis – (splenomegaly)
erythroblasts are also damaged – ineffective erythropoeisis
Increased iron absorption
Iron overload

9. Lab diagnosis MCV, MCH are reduced
Bilirubin level is usually slightly raised
Haptoglobin depleted
Peripheral blood smears
Thalassemia minor
Red cells appear small (microcytic), pale (hypochromic), and regular in shape.
Presence of extraordinarily hypochromic, often wrinkled and folded cells (leptocytes) containing irregular inclusion bodies of precipitated α-globin chains.
Target cells are often seen, a feature that results from the relatively large surface area-to-volume ratio, which leads Hb to collect in a central, dark-red "puddle.“
Thalassemia major
microcytosis and hypochromia are much more pronounced,
Reticulocytosis.
Nucleated red cells (normoblasts) are also seen
Bone marrow
Striking hyperplasia of erythroid progenitors .The expanded erythropoietic marrow completely fill the intramedullary space of the skeleton, invade the bony cortex, impair bone growth, and produce skeletal deformities.
Hemoglobin electrophoresis :
Reveals absence or almost complete absence of HbA with almost all the circulating Hb being HbF

10. Clinical features β-Thal minor (β/β+)
(1) Mild anemia is most often due to DNA splicing defects.
(2) Severe anemia is due to a nonsense mutation with formation of a stop codon.
β-Thal minor (β/β+)
(1) Mild microcytic anemia
(2) Mild protective effect against falciparum malaria
(3) Decreased MCV, Hb, and Hct
(4) Increased RBC count
(5) Normal RDW, serum ferritin
(6) Hb electrophoresis
(a) Decreased HbA (2α/2β) β-Thal minor: (b) Increased HbA2 (2α/2δ) and HbF (2α/2γ)
(7) There is no treatment.
Do not treat with iron; danger of iron overload.

11. (1) Mild microcytic anemia
Thal minor (β/β+)
(1) Mild microcytic anemia
(2) Mild protective effect against falciparum malaria
RBC life span is shorter than normal.
(3) Decreased MCV, Hb, and Hct
(4) Increased RBC count
(5) Normal RDW, serum ferritin
(6) Hb electrophoresis
(a) Decreased HbA (2α/2β)
(b) Increased HbA2 (2α/2δ) and HbF (2α/2γ)
(7) There is no treatment.
Do not treat with iron; danger of iron overload.

12. β-Thal major (Cooley's anemia; β0/β0)
Severe hemolytic anemia β-Thal major: β0/β0
a .RBCs with α-chain inclusions are removed by macrophages in
the spleen - increase in unconjugated bilirubin (jaundice)
b. The ineffective erythropoietic precursors consume nutrients and produce growth retardation and a degree of cachexia
(2) Extramedullary hematopoiesis : The extramedullary hematopoiesis and the hyperplasia of the mononuclear phagocytes result in prominent splenomegaly, hepatomegaly, and lymphadenopathy
(3) Increased RDW and reticulocytes
(4) Hb electrophoresis
(a) No synthesis of HbA
(b) Increase in HbA2 and HbF β-Thal major: no HbA; ↑ HbA2, HbF
(5) Long-term transfusion requirement
Danger of iron overload (called hemosiderosis)

13. Microcytic Hypochromic
Target cells