THALASSEMIABurden of the disease

And Molecular Pathogenesis

MODERATOR- DR SANTOSH KR MONDAL (ASSOCIATE PROFESSOR) DEPARTMENT OF PATHOLOGY, MEDICAL COLLEGE, KOLKATA.

BY-URMIMALA BHATTACHARJEE(5TH SEMESTER)

• Group of congenital anaemias.• Deficient synthesis of one or more globin

subunits of normal human hemoglobin• According to the chain whose synthesis is

impaired, the thalassemias are called α-,β-,γ-,δ-,δβ- or εγδβ- thalassemias.

Geographic Distribution

Found in high frequency in a broad belt extending from the Mediterranean basin, the Middle East, Indian Subcontinent, Burma, South-east Asia and the islands of the Pacific.

THALASSEMIA BELT

• World-wide 15 million people have clinically apparent thalassemia disorders.

• There are 240 million carriers of β-thalassemia in the world.

• In India, 30 million people are β-thalassemia carrier with a mean prevalence of 3.3%.

(INDIAN PEDIATRICS, Vol. 44, September 17, 2007, page 647)

• Every year 100,000 children with thalassemia major are born world over, of which 10000 are born in India.

(INDIAN PEDIATRICS, Vol. 44, September 17, 2007, page 647)

• Carrier rate for β-thalassemia varies from 1-3% in South India to 3-15% in North India.

• Higher carrier rate is especially noticed in the tribal population all over India.

(INDIAN PEDIATRICS, Vol. 44, September 17, 2007, page 647)

in tribal population

What about West Bengal?

• Thalassemia trait prevalent in the population of the state in the magnitude of 11.25%.

• Prevalence among close relatives of cases is 55.26%.

• Prevalence among scheduled tribes and Muslims is predominantly more.

(JIMA, 2006 Jan;104(1):11-5. Prevalence of thalassaemia trait in the state of West Bengal, Sur D, Mukhopadhyay SP. Source- National Institute of Cholera and Enteric Diseases, Kolkata 700010.)

• General population has a prevalence of 3.6% (males) and 5.95% in antenatal mothers.

• High prevalence rate is associated with illiterates (19.23%) than literates (5.55%).

• Highest prevalence rate 20.47% is associated with age group of 0-9 years.

(JIMA, 2006 Jan;104(1):11-5. Prevalence of thalassaemia trait in the state of West Bengal, Sur D, Mukhopadhyay SP. Source- National Institute of Cholera and Enteric Diseases, Kolkata 700010.)

Molecular PathogenesisOf

Thalassemia.

Mutations causing α-thalassemia

a. Deletion α-thalassemiab. Non-deletion α-thalassemia.

Deletion α-thalassemia

α + type• Single α globin gene

deletion. -α4.2 kb (leftward deletion) -α3.7 kb(rightward deletion) -α3.5kb α[α]5.3 Region containing α1 gene.

α 0 type• Deletion of both α1 and α2

globin gene. -[α]5.2 -[α]20.5 HS40 deletion alone

keeping α1 and α2 sites intact.

Non-deletion α-thalassemia

• Hb Constant Spring(α 142 TAASCAA, StopSGlu)• Hb Icaria (α 142 Lys)• Hb Koya Dora (α 142 Ser)• Hb Seal Rock (α 142 Glu)• Hb Paksé (α 142 Tyr).

1.Due to modification of stop codon.

(Continued…)

• Hb Heraklion (α 137 ProS0)• Hb Agrinio (α 29 LeuSPro)

2. Mutation in α-globin gene

Mutations causing β-thalassemia

• Non-deletion β-thalassemia• Deletion β-thalassemia

Non-deletion β-thalassemia

• Occurs due to:-1. Single nucleotide substitution2. Oligonucleotide insertions/deletions

Non-deletion β-thalassemia

• Mutations altering β-gene transcription1. Promoter mutation-affecting conserved

motifs in 5’ flanking sequence if β gene (TATA box.)

2. 5’-UTR mutation

• Mutation involving RNA processing1. Splice junction mutation-Eg.- Mutation at

position 5 of IVS-1(G C)2. Consensus splice mutation3. Cryptic splice site mutation in introns4. Cryptic splice mutation in exons5. Poly A and other 3’-UTR mutation

• Mutations involving m-RNA translation1. Initiation codon mutation2. Nonsense codon mutation3. Frameshift mutation

Deletion β-thalassemia

• 619-bp deletion removing 3’ end of β-globin gene.

• This mutation is very common in Punjab and Sind.

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