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Thalassemia Syndromes
Dr.CSBR.Prasad, M.D.,
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• They are QUANTITATIVE defects in globin chain synthesis
• Heme synthesis is normal
Thalassemias
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Porphyrias
Name some diseases involving heme synthesis?
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Cooley’s anemia
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Usual types of HGBs in adults
• Different types of HGBs seen in adults
– Hb A (α2 β2) (97%)
– Hb A2 (α2 δ2) (1.5-3.5%)
– Hb F (α2 γ2) (<1%)
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Fetal hemoglobin - HbF
• The main oxygen transport protein in the fetus during the last seven months of development in the uterus and
• After birth HBF levels gradually fall reaching adult levels by the age of 6-9 months
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Oxygen dissociation curve
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Facial abnormalities
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Organomegaly
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Hemoglobin
• HbA (α2β2)
• FOUR α-globin genes on chr 16
• TWO β-globin gene on chr 11
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Globin genes
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Thalassemia
• Inherited genetic disorder of globin chain synthesis of HbA (α2β2)
• AR
• Decreased synthesis may involve α or β globin chain
α-Thalassemias [↓ α-chain]
β-Thalassemias [↓ β-chain]
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Normal HGB
• Hb A - α2β2
• α : β = 1:1 (+/- 0.05)
• Disproportionate synthesis is associated with relative excesses of the other
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Figure 1. The two chromosomes #11 have one beta globin gene each (for a total of two genes). The two chromsomes #16 have two
alpha globin genes each (for a total of four genes).
Hemoglobin protein has two alpha subunits and two beta subunits. Each alpha globin
gene produces only about half the quantity of protein of a
single beta globin gene. This keeps the production of protein subunits equal.
Thalassemia occurs when a globin gene fails, and the
production of globin protein subunits is thrown out of
balance.
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Thalassemia
• Low HGB levels
• Relative excess of unimpaired chains form insoluble inclusions Hemolysis
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β-Thalassemia
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β-Thalassemia
• ↓ Synthesis of structurally normal β globin chain with unimpaired synthesis of α globin chain
• β globin chain is coded by two globin genes located on Ch 11
• α globin chain is coded by two pairs of globin genes located on Ch 16
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β-Thalassemia
• β0 Thalassemia – Total absence of β globin chain in homozygous state
• β+ Thalassemia – reduced β globin chain synthesis in homozygous state
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β-Thalassemia
• More than 100 different causative MUTATIONS • Point mutations – most common • Promoter region mutations
– Reduces transcription rate by 75-80% - Β+ Thalassemia
• Chain terminator mutation – Premature chain termination - Β0Thalassemia
• Splicing mutation – More common cause of Β+ Thalassemia
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β-Thalassemia
• Thalassemia major – Homozygous for β-Thalassemia genes – Genotype β0 / β0 or β+ / β+
– Severe tranfusion dependent anemia
• Thalassemia minor – Heterozygous with one thalassemia gene and one normal
gene β0 / β or β+ / β
• Thalassemia intermedia – Genetically heterogenous group with milder variant of β0 /
β0 or β+ / β+ and severe form of heterozygous thalassemia β0 / β or β+ / β
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Thalassemia major
• Mediterranean, Africa and south east Asia • Manifest 6-9 months after birth • Hb – 3-6 gm/dl • PBS
– Anisocytosis - microcytes, – poikilocytosis, target cells, basophilic stippling, fragmented
RBC, NRBCs – Reticulocytosis – ↑ ↑ Hb F – Hb A2 - N, ↑, ↓
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Transfusion dependent anemia
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Hereditary - AR
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Microcytic hypochromic RBCs
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Target cells
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NRBs and Punctate basophilia
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Thalassemia major
• Morphology
• Bone marrow hyperplasia – “CREW CUT” appearance on skull X ray
• Splenomegaly – upto 1500 gms
• Hemosiderosis and secondary hemochromatosis – due to repeated blood transfusion and ↑ absorption of dietary iron – affects heart, liver and pancreas
• Early death in untreated cases
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“CREW CUT” appearance
on skull X ray
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Thalassemia minor
• More common
• Heterogenous carrier of β0 or β+ gene
• Asymptomatic / mild anemia
• PBS – Microcytic hypochromic RBCs, basophilic stippling
• ↑ Hb A2 ; 4-8% (N 2.5%)
• DD – Iron deficiency anemia
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α Thalassemia
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Demographics: Thalassemia
• Found most
frequently in the
Mediterranean, Africa,
Western and
Southeast Asia, India
and Burma
• Distribution parallels
that of Plasmodium
falciparum
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Classification & Terminology
Alpha Thalassemia
• Terminology
• Silent carrier
• Minima
• Minor
• Intermedia
• Major
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Symbolism Alpha Thalassemia
• Greek letter used to designate globin
chain:
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Symbolism Alpha Thalassemia
/ : Indicates division between genes
inherited from both parents:
/
• Each chromosome 16 carries 2 genes. Therefore the
total complement of genes in an individual is 4
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Symbolism Alpha Thalassemia
- : Indicates a gene deletion:
-/
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Classification & Terminology
Alpha Thalassemia
• Normal /
• Silent carrier - /
• Minor -/-
--/
• Hb H disease --/-
• Barts hydrops fetalis --/--
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Symbolism Other Thalassemia
• Greek letter used to designate globin
chain:
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Symbolism Other Thalassemia
+: Indicates diminished, but some
production of globin chain by gene:
+
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Symbolism Other Thalassemia
0 :Indicates no production of globin chain by
gene:
0
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Symbolism Other Thalassemia
Superscript T denotes nonfunctioning gene:
T
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Classification & Terminology
Beta Thalassemia
• Normal /
• Minor /0
/+
• Intermedia 0/+
• Major 0/0
+/+
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Special Cases Thalassemia
• Hb Lepore: fusion seen in some types
of thalassemia
• Hb Constant Spring
• chain with 31 additional amino acids
• --/cs
• Hereditary persistence of fetal hemoglobin
(HPFH)
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Special Cases: Thalassemia
• Hb H
• 4 tetramer
• Associated with --/- thalassemia
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Special Cases: Thalassemia
• Hb Barts & hydrops fetalis
• Barts is a 4 tetramer
• Associated with --/--
• Lethal
• High concentrations are capable of sickling
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Different types of HGBs seen in adults
• Hb A (α2 β2) 97%
• Hb A2 (α2 δ2) (1.5-3.5%)
• Hb F (α2 γ2) <1%
• Adult HbH (β4)
• Neonate Barts (γ4)
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α Thalassemia
• Reduced or absent synthesis of α globin chains
• Excess of non α chain –ß, γ, δ
– Hb A (α2 β2)
– Hb A2 (α2 δ2)
– Hb F (α2 γ2)
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α Thalassemia
• New born – formation of γ4 tetramer – Hb Barts
• Adults – ß4 tetramer – HbH
• Free ß, & γ chains are more soluble than α chains – hemolysis is less severe
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α Thalassemia
• Sevearity varies depending on number of α globin genes affected
• DELETION of α- globin genes are more common
• Hydrops fetalis -/- -/-
• HbH disease -/- -/ α
• α Thalassemia trait -/- α/ α (asian)
-/ α -/ α ( black african) • Silent carrier -/ α α/ α
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Figure 3. People of Asian ancestry often have two alpha globin genes deleted on the same chromosome #16. The parents each
have the mild thalassemia that results with two functioning alpha globin genes. The
offspring that inherits the double deletion from one parent and the single from the
other will have Hemoglobin H disease (Scenario 1). The offspring who inherits no alpha genes from the parents dies in utero
(Scenario 2; hydrops fetalis).
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Figure 4. People of African ancestry usually
have only one alpha globin gene deleted per
chromosome. The parents each have the mild thalassemia that
results with two functioning alpha globin genes. The
offspring can, at most, inherit the relatively mild condition of the
parents.
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Hb H disease
• Tetramer of β globin chain
• High affinity for oxygen
• Unstable HbH form precipitates
• Resemble β-Thalassemia intermedia
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HBH inclusions
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HPLC pattern of a patient with HbH disease. The peaks of the different hemoglobins are indicated
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Hydrops fetalis
• Hb barts – tetramer of γ globin chains
• ζ2 γ2 -Severe tissue anoxia
• Pallor, generalised edema, massive hepatosplenomegaly
• High mortality
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Hydrops fetalis
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Other causes for Hydrops fetalis
• Rh incompatibility
• Hypoplastic left heart syndrome
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Common mechanism
• Alfa thal- Deletion
• Beta thal – Mutation
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Gamma gene can be induced to function by some drugs
• What is the clinical implication of this finding?
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END
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Dr.CSBR.Prasad, M.D.,
Associate Professor of Pathology,
Sri Devaraj Urs Medical College,
Kolar-563101,
Karnataka,
INDIA.