Thalessemia

Pathogenesis Genetically determined Heterogenous group of disorder Reduced synthesis of one or more types of normal haemoglobin polypeptide chains

Demographics: Thalassemia Found most frequently in the Mediterranean, Africa, Western and Southeast Asia, India and Burma

Normal Haemoglobin HbA - α2β2 HbA2 - α2δ2 HbF – α2γ2

Each goblin chain have separate genetic control α –thalassaemia affect α-chain synthesis β –thalassaemia affect β -chain synthesis

β-Thalassaemia β Chain synthesis Hb-A γ and δ chain Hb-A = α2β2 An absence or deficiency of β-chain synthesis of adult HbA β Chain synthesis Hb-A γ and δ chain Hb-A = α2β2

Pathophysiology of β-Thalassaemia mutation in β-gene Complete or partial absence of β-chain Decreased adult HbA α-chain synthesis remain normal Free complementary α-chain – unstable and precipitate within normoblasts as insoluble inclusions Cell membrane damage & impaired DNA synthesis apoptosis i.e. ineffective erythropoeisis

On the basis of synthetic ability β-genes are designated as β gene – can synthesize normal amount of β-chain β+ gene – can synthesize reduced amount of β-chain β0 gene – cannot synthesize β-chain

β-thalassaemia intermedia β-thalassaemia major Mutation of normal β-gene β0-gene  absence HbA  increased HA2 and HbF genotype – β0β0 β-thalassaemia intermedia ↑HbA2 ↑HbF ↓HbA Genotype β+ β+ or β0 β β-thalassaemia minor HbA normal HbF normal

Symptoms Inadequate production + ineffective erythropoiesis + haemolysis Anaemia hemolysis hyperbillirubinemia jaundice To compensate anaemia extramedullary haemopoiesis in liver,spleen  Hepatosplenomegaly ↑Erythropoiesis marrow expansion & thinning of cortex of skull bone Thalassaemia facies/bone pain Iron overload—increased absorption and transfusions  Endocrine disorders, Cardiomyopathy, Liver failure

management Regular blood transfusions Iron chelation-desferroxamine SC infusion/oral Splenectomy Monitor for complications of iron overload-LFT,ECHO,Thyroid functions,growth (pituitary can be damaged)

Normal Thalassaemia

α-Thassaemia An absence or deficiency of α-chain synthesis due to delation of α-genes.

Pathogenesis of α-Thalassaemia In normal individual HbA, HbA2 and HbF need α-chain for their formation. 4 genes of α-chain, each pair on short arm of chromosome 16 In α-thalassaemia, delation of α-genes reduction or absence of synthesis of α-chain depending on number of α-gene deletion.

↓α-chain synthesis free γ-chain in the fetus & β-chain in infant of 6 months, and continue in the rest of life. Complementary 4γ and 4β are aggregated  Hb Bart (4γ ) and HbH (4β ), respectively.

Variants of α-Thalassaemia Silent carrier Delation of single α-gene Genotype α/αα Asymptomatic Absence of RBC abnormality Thalasaemia trait Delation of 2 α-genes Genotype --/αα Asymptometic, minimal or no anaemia Minimal RBC abnormalities

Hb H disease Hydrops fetalis Delation of 3 α-genes Genotype --/- α 75% reduction of α-chain small amount of HbF, HbA, & HbA2 Fetus can survive Severe anaemia Hydrops fetalis Delation of all α-genes Genotype --/-- Absence of α-chain synthsis Only Hb Bart (γ4) is produced Incompatible with life

Inheritance Autosomal recessive Inc incidence in consanguineous marriages Can be prevented by detecting carriers

Laboratory Diagnosis of Thalassaemia

Laboratory Findings Hb – low RBC count – Markedly decreased MCV, MCH, MCHC – reduced Blood picture-abn RBC Hb electrophoresis –can demonstrate the types of Hb present

Peripheral Blood Film Normal

Thalassaemia slides

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