Thalassemia

Content

•       Thalassemia

•       Classification

•       Pathophysiology

•       Clinical features

•       Treatment

Objective

At the end of this PDF Note, students will be able to

•       Define  thalassemia

•       Explain the type of thalassemia

•       Describe the pathophysiology, clinical signs and symptoms, and treatments for the alpha and beta forms of thalassemia. 

Thalassemia

•       Thalassemia are a heterogenous group of genetic disorders of Hb synthesis characterized by a lack or decreased synthesis of globin chains

•       Two major types of thalassemia:

–      Alpha (α) – Caused by defect in rate of synthesis of alpha chains.

–      Beta (β) – Caused by defect in rate of synthesis in beta chains.

•       Alpha thalassemia usually caused by gene deletion;  Beta thalassemia usually caused by mutation.

•       Results in microcytic, hypochromic anemias of varying severity

BASICS – 3 Types of Hb

1. Hb A – 2α and 2β chains forming a tetramer

•       97% adult Hb

•       Postnatal life Hb A replaces Hb F by 6 months

2. Fetal Hb – 2α and 2γ chains

•       1% of adult Hb

•       70-90% at term. Falls to 25% by 1^st month and  progressively

3. Hb A2 – Consists of 2 α and 2 δ chains

•       1.5 – 3.0% of adult Hb

INHERITANCE

•       Autosomal recessive

•       Beta thal – point  mutations
on  chromosome 11

•       Alpha thal – gene  deletions on  chromosome 16

Classification of thalassemia

•       If synthesis of α chain is suppressed – level of all  3 normal Hb A (2α ,2β),A2 (2α,2δ), F(2α ,2γ) reduced

–  alpha thalassemia

•       If β chain is suppressed- adult Hb is suppressed – beta thalassemia

α-thalassemia

Hb H (β₄)

Hb-Bart’s (₄)

β-thalassemia

•       β⁺ thal : reduced synthesis of β globin chain,  heterozygous

•       β ⁰ thal : absent synthesis of β globin chain,  homozygous——     Hb A – absent

Hb F (α₂₂)

Hb A₂ (α₂ δ₂)

Classification of β Thalassemia

CLASSIFICATION	GENOTYPE	CLINICAL SEVERITY
β thal    minor/trait	β/β+, β/β0	Silent
β thal    intermedia	β+ /β+, β+/β0	Moderate
β thal    major	β0/ β0	Severe

Classification OF α-Thalassemia

No. Of genes  present	Genotype	Clinical classification
4 genes	αα/αα	Normal
3 genes	αα/- α	Silent carrier
2 genes	– α/- α     or         αα/- –	α thalassemia trait
1 gene	–α/- –	Hb H Ds
0 genes	– -/- –	Hb Barts / Hydrops  fetalis

 

α-Thalassaemia Molecular Pathogenesis

•       Defective synthesis of α-globin chains: HbA, HbA2 and HbF

1. Four α-gene deletion: Hb Bart’s hydrops foetalis

2. Three α-gene deletion: HbH disease

3. Two α-gene deletion: α-thalassaemia trait

4. One α-gene deletion: α-thalassaemia trait (carrier)

β–Thalassaemia Molecular Pathogenesis

•       β-thalassaemias are caused by decreased rate of β-chain synthesis resulting in reduced formation of HbA in the red cells.

 i)  Transcription defect

ii)  Translation defect

iii)   mRNA splicing defect

3 Types of β-Thalassaemia

1)      Homozygous form

2)      β-Thalassaemia intermedia

3)      Heterozygous form

Pathophysiology

•       Since ẞ chain synthesis reduced –

•       1. Gamma and delta δ₂ chain combines with normally produced α chains ( Hb
F (α₂₂) , Hb A₂  (α₂
δ₂) – Increased production of Hb F and Hb A₂

•       2. Relative excess of α chains → α tetramers forms  aggregates →precipitate in red cells → inclusion  bodies → premature destruction of maturing  erythroblasts within the marrow (Ineffective  erythropoiesis) or in the periphery  (Hemolysis)→ destroyed in spleen

Anemia result from lack of adequate Hb A

→ tissue hypoxia→↑EPO production →

↑ erythropoiesis in the marrow and  sometimes extramedullary → expansion  of medullary cavity of various bones

Liver spleen enlarge → extramedullay

hematopoiesis

Clinical Features (Thal Major)

INFANTS:

•       Age of presentation: 6-9 mo (Hb F replaced by Hb A)

•       Progressive pallor and jaundice

•       Cardiac failure

•       Failure to thrive, gross motor delay

•       Feeding problems

•       Bouts of fever and diarrhea

•       Hepatosplenomegaly

BY CHILDHOOD:

•       Growth retardation

•       Severe anemia-cardiac dilatation

•       Transfusion dependant

•       Icterus

•       Changes in skeletal system

Clinical Features (Thal Intermedia)

•       Moderate pallor, usually maintains Hb >6gm%

•       Anemia worsens with pregnancy and infections (erythroid stress)

•       Less transfusion dependant

•       Skeletal changes present, progressive splenomegaly

•       Growth retardation

•       Longer survival than Thal major

Clinical Features (Thal Minor)

•       Usually ASYMPTOMATIC

•       Mild pallor, no jaundice

•       No growth retardation, no skeletal  abnormalities, no splenomegaly

•       MAY PRESENT AS IRON DEFICIENCY ANEMIA (Hypochromic microcytic anemia)

•       Unresponsive/ refractory to Fe therapy

•       Normal life expectancy

Prevention of Thalassaemia

•       antenatal diagnosis

•       amniocentesis and foetal DNA studied by PCR amplification technique for presence of genetic mutations of thalassaemias

•       Treatment- blood transfusions (4-6 weekly), chelation therapy, folic acid supplement, Bone marrow transplantation

Summary

•       Thalassemia are a heterogenous group of genetic disorders of Hb synthesis characterized by a lack or decreased synthesis of globin chains

–      Alpha (α) – Caused by defect in rate of synthesis of alpha chains.

–      Beta (β) – Caused by defect in rate of synthesis in beta chains.