Non transfusion dependent thalassemia

1. Non-Transfusion-
Dependent Thalassemia
Dr. Govind Kendre
Department of hematology,
Seth G.S. medical college & KEM hospital,
Parel,Mumbai

2. Hemoglobin structure

3. Heme

4. Chromosomal organization of the globin genes

5. Globin gene clusters

6. β globin gene

7. Types of mutation
• Point mutation - Substitutions (silent, missense, nonsense)
• Frame shift mutation -Insertion
-Deletion
• Duplication
• Repeat expansion

8. Types of mutation

9. Frameshift mutation

10. Hb mutations count…..
• α1 – 267 mutations
• α2 – 314 mutations
• β – 732 mutations
• δ – 79 mutations
• λA – 50 mutations
• λG – 56 mutations

11. Various types of mutations in β globin gene

12. Common mutations in β thalassemia
Racial Group Description
Mediterranean IVS-1, position 110 (G → A)
Codon 39, nonsense (CAG → TAG)
IVS-1, position 1 (G → A)
IVS-2, position 745 (C → G)
IVS-1, position 6 (T → C)
IVS-2, position 1 (G → A)
Black -34 (A → G)
-88, (C → T)
Poly(A), (AATAAA → AACAAA)
Southeast Asian Codons 41/42, frameshift (-CTTT)
IVS-2, position 654 (C → T)
-28 (A → T)
Asian Indian IVS-1, position 5 (G → C)
619-bp deletion
Codons 8/9, frameshift (++G)
Codons 41/42, frameshift (–CTTT)
IVS-1, position 1 (G → T)

13. Genotype-phenotype associations in
β- and α-thalassemia

14. α thalassemia mutations & genotypes

15. Inherited Hb disorders
Structural Hb
variants
Defective
chain synthesis

16. Thalassemia belt
Attributed to - consanguinous marriages & malaria prevalence

17. Thalassemia Syndromes
• Occurs because of diversity & high prevalence of Hb mutations
Simultaneous
inheritance of 2 diff
thal mutations
Coinheritance of
thal with structural
Hb variants

18. Thalassemia Syndromes
No Transfusions
Occasional
Transfusions
Regular
Transfusions
for Symptoms
Regular
Transfusions
for Survival
Trait Intermedia Major

20. NTDT
Non transfusion-dependent thalassemia (NTDT) is a group of
thalassemias for which patients do not require regular red cell
transfusions for survival
They may require occasional or even frequent transfusions in certain
clinical settings & for defined period such as for growth failure,
pregnancy, infections
There are 3 NTDTs
β-Thalassemia intermedia
Mild/moderate Haemoglobin E β-thalassemia
α thalassemia intermedia (HbH disease)
2 Seperate entity with similar transfusion requirement
Haemoglobin S β-thalassemia
Haemoglobin C β thalassemia

21. NTDT

22. Genetic & environmental modifiers of
phenotype
• β-Thalassemia intermedia
•Broad diversity of mutations
•Variable degree of α/β chain imbalance
Primary
modifiers
•Coinheritance of α thal
•Genes modifying γ chain production
Secondary
modifiers
•Polymorphisms affecting specific complication
of disease (iron absorption,bili metabolism,
bone metabolism, cardiovascular disease)
Tertiary
modifiers

23. Hb E /β thalassemia
•Type of β thal mutation
Primary
modifiers
•Coinheritance of α thal
•Genes modifying γ chain production
Secondary
modifiers
•Inherited variability in function of gene for UDPG transferase
•Advancing age affecting EPO productin in response to anemia
•P.Vivax infection
Tertiary
modifiers

24. Mahidol score

25. α thalassemia
• Limited studies
• Different sizes of α globin gene
deletions
• 7 forms of non deletional HbH
disease
Primary
modifiers
• Co-inheritance of β thal trait
• Role of α Hb stabilising protein
Secondary
modifiers

26. Pathophysiology

27. Iron overload
Increased intestinal absorption
Inappropriately low hepcidin level
Ineffective erythropoiesis

28. Regulators of hepcidin production
Growth differentiation factor-15
Twisted gastrulation factor-1
Hypoxia inducible transcription factors
Transmembrane protease serine-6 (TMPRSS6)

29. Characteristics of iron overload in NTDT
• Low ferritin level d/t increased labile plasma iron pool
• Liver iron 5mg/gm dry wt is considerable morbidity risk factor
• Cardiac iron overload not a major concern

30. Hypercoagulability & vascular disease
Thrombosis risk upto 20% in spleenectomised
Other risk factors - advancing age
-Total Hb <9gm%
-Platelet count > 5 lakh
-nRBCs >300х10®6/L
Silent cerebral ischaemia upto 60%

31. Thrombosis

32. Pulmonary hypertension
Decreased arginine & NO production d/t hemolysis
Chronic anemia & hypoxia
Iron overload
Spleenectomy
Hypercoagulability
Microthrombotic disease of pulmonary circulation

33. Skin ulcers
• Thin skin
• Decreased oxygenation

34. THANK YOU
THANK YOU