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Thalassemia: From DNA to Clinical Practice
Noppadol Siritanaratkul, MD
Division of HematologyDepartment of MedicineFaculty of Medicine Siriraj Hospital
2 October 2009
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Hematology-Siriraj HospitalThalassemia: From DNA to Clinical Practice
Check up at the Private hospital: claimed to be the most expensive hospital in Thailand
Hb 11.3 g/dL Hct 35%
Hb analysis: Hb A = 97%Hb A2 = 2.2 %Hb F 0.1%
Married and pregnant ~ 7 months
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Hematology-Siriraj HospitalThalassemia: From DNA to Clinical Practice
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Hematology-Siriraj HospitalThalassemia: From DNA to Clinical Practice
โรงพยาบาลเอกชนแห่งหนึง
เรียนอาจารย์ทีเคารพ
หนูขอเรียนปรึกษาเรืองผลเลือดของคู่สามีภรรยาดังนี
สามี Hb 12.9 g/dL, MCV 60 fL, OF test POSITIVE, Hb typing ปกติ
PCR for αthal (SEA) negative
ได้กิน FBC และ Folic acid มาตลอด 1 ปี
ภรรยา Hb 13.2 g/dL, MCV 92 fL, DCIP negative, Hb typing A2A, A2 = 2.3%
อาจารย์กรุณาช่วยให้คําแนะนําและ/หรือการตรวจเพิมเติมแก่คู่สมรสนีด้วยนะคะ
ขอแสดงความนับถือ
พญ. Anonymous Doctor
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Hematology-Siriraj HospitalThalassemia: From DNA to Clinical Practice
β globin locus: chromosome 11
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Hematology-Siriraj HospitalThalassemia: From DNA to Clinical Practice
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Hematology-Siriraj HospitalThalassemia: From DNA to Clinical Practice
IVS1 IVS2
1
A schematic representation of and globin genes
141
146
AAA
1
Exon1
Exon2 Exon3
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Hematology-Siriraj HospitalThalassemia: From DNA to Clinical Practice
Thalassemia (ธาลัสซีเมีย)
Inherited disorders of globin synthesis
in which the production of globin
chains is partially or completely
suppressed.
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Hematology-Siriraj HospitalThalassemia: From DNA to Clinical Practice
Excess chains
Heme
AHSP
precipitationα-Inclusion
bodies
Hb A
Chromosome 16
α-Gene cluster
Chromosome 11
-Gene cluster
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Hematology-Siriraj HospitalThalassemia: From DNA to Clinical Practice
Molecular mechanisms of -thalassemia
Point mutations:– ATA Box: -28 AG– CACCC box: -86 CG– Cap site: +1 AC– Initiation codon: ATGAGG– Splice site: IVS1-1 GT– Cleavage and Polyadenylation: AATAAA AATAGA– Consensus sequence: IVS1-5 GC
Mutations creating alternative splice sites– In introns: IVS2-654 CT– In exons: Codon19 AG Hb Malay
Codon26 GA Hb E
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Hematology-Siriraj HospitalThalassemia: From DNA to Clinical Practice
Molecular mechanisms of -thalassemia
Mutations producing nonfunctional mRNA
– Nonsense mutation: Codon 17 ATCodon 26 GT
– Frameshift muations: Codon 41/42 (-TTCT)Codon 71/72 +A
Deletions: 0.6 kb deletions, 27 kb deletion
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Hematology-Siriraj HospitalThalassemia: From DNA to Clinical Practice
Parenchyma Reticuloendothelial macrophages
Gut
Transferrin
NTBI
TransfusionsErythron
Iron distribution and turnover with transfusion therapy
Hershko C et al. Ann NY Acad Sci 1998;850:191–201, permission pending
NTBI=non-transferrin bound iron
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Hematology-Siriraj HospitalThalassemia: From DNA to Clinical Practice
Andrews NC. N Engl J Med 1999;341:1986–1995
Body iron dynamics during iron overload
NTBI is produced when serum transferrin is saturated
– LPI is a component of NTBI that is redox active
LPI is toxic:
– Haber Weiss reaction
O2. - + H2O2 O2 + OH- + HO
– Catalyzed by iron in two steps (Fenton reaction)
Fe3+ + O2·- Fe2+ + O2
Fe2+ + H2O2 Fe3+ + OH- + HO·
NTBI=non-transferrin bound iron; LPI=labile plasma iron
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Hematology-Siriraj HospitalThalassemia: From DNA to Clinical Practice
Consequences of Iron-Mediated ToxicityIncreased free iron
Hydroxyl radical generation
Lipid peroxidation
TGF-b1
Collagensynthesis
Fibrosis
Organelle damage
Lysosomal fragilityEnzyme leakage
Cell death
Porter J. Hematol/Oncol Clinics. 2005;19:S7. Cohen AR. In: Disorders of Hemoglobin: Genetics, Pathophysiology & Clinical Management. Cambridge University Press, 2001:979-1027.
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Hematology-Siriraj HospitalThalassemia: From DNA to Clinical Practice
Complications of iron overload
Liver cirrhosis/ fibrosis/cancer
Non-transferrin-bound iron circulates in the plasma
Excess iron promotes the generation of free
hydroxyl radicals, propagators of oxygen-related tissue damage
Insoluble iron complexes are deposited in body tissues and end-organ
toxicity occurs
Diabetes mellitus
Growth failure
Capacity of serum transferrin to bind iron is exceeded
Iron overload
Cardiac failure
Infertility
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Hematology-Siriraj HospitalThalassemia: From DNA to Clinical Practice
Iron overload oxidative damage
Cardinal features of thalassemia
Accumulation of unpaired globin chains Rbc membrane injury
Overall accelerated production of ROS deplete cellular antioxidants
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Unpaired globin chains
DegradationDenaturation
Methemoglobin
Hemichromes
Inclusion body
Band 3clustering
IgG , C binding
Immune removal
Fe
Heme
Phosphatidyl-serine exposure
Activation of prothrombinase
complex
Hemin
Sp. band3crosslinking
Globin chains
Abnormal spectrin
association
Fragmentationdeformability
Mechanical removal
Lipid peroxidation
H2O2 O2- OH˙
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High oxygenaffinity of RBCs
Selective survival ofHb F-containing cells
Fetal hemoglobin
(tissue hypoxia)(tissue hypoxia) Transfusion
DeathDeathCardiac failureCardiac failureCirrhosisCirrhosisEndocrine deficienciesEndocrine deficienciesNEJ Med 1999;341(2):99
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Hematology-Siriraj HospitalThalassemia: From DNA to Clinical Practice
Diabetes1Pancreas
Gonads
Cirrhosis, carcinoma1LiverCardiomyopathy1HeartHypoparathyoidism1ParathyroidHypothyroidism1Thyroid
Hypogonadotrophic hypogonadism1Pituitary
ConsequencesOrgan
Joints Arthropathy2
Skin Pigmentation2
Hypogonadotrophic hypogonadism1
1. Taher A, et al. Semin Hematol. 2007;44:S2.2. Brittenham G. In Hoffman R, et al, ed. Hematology: Basic Principles and Practice, 4th ed.
Philadelphia, PA: Churchill Livingstone, 2004.
Organ Systems Affected by Iron Overload
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Hematology-Siriraj HospitalThalassemia: From DNA to Clinical Practice
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Hematology-Siriraj HospitalThalassemia: From DNA to Clinical Practice
Extramedullary hematopoiesis
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Hematology-Siriraj HospitalThalassemia: From DNA to Clinical Practice
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Hematology-Siriraj HospitalThalassemia: From DNA to Clinical Practice
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Hematology-Siriraj HospitalThalassemia: From DNA to Clinical Practice
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Hematology-Siriraj HospitalThalassemia: From DNA to Clinical Practice
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Hematology-Siriraj HospitalThalassemia: From DNA to Clinical Practice
Hemoglobinopathies (ฮีโมโกลบินผิดปรกต)ิ
Hb Q – Mahidol (Thailand) 1: GAC CAC (- 4.2)
Hb Constant Spring 2 : CD142 TAA CAA
Hb Pakse 2 : CD142 TAA TAT
Hb Suan-Dok 2 : CD109 CTG CGG
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Hematology-Siriraj HospitalThalassemia: From DNA to Clinical Practice
Hemoglobinopathies (ฮีโมโกลบินผิดปรกต)ิ
Hb E :CD26 GAG AAG
Hb C :CD 6 TAA CAA
Hb Malay :CD19 AAC AAG
Hb J Bangkok (Korat) :CD56 GGC GAA
Hb Tak :CD147 +AC
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Hematology-Siriraj HospitalThalassemia: From DNA to Clinical Practice
Hemoglobin E
Mutation CD26 GAG AAG (GluLys)
Activate alternate splice site atCD25moderate reduction of normal spiced mRNA
Hb Malay CD19 AAC AGC (AsnSer) also activates cryptic splice site at CD17
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Hematology-Siriraj HospitalThalassemia: From DNA to Clinical Practice
Prevalence of Thalassemia & Hemoglobinopathies in Thailand
thal 1 Bangkok 3.5%
Chiangmai 14.7%
thal 2 Bangkok 16%
Chiangmai 19%
thal Bangkok 3%
Chiangmai 9%
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Hematology-Siriraj HospitalThalassemia: From DNA to Clinical Practice
Prevalence of Thalassemia & Hemoglobinopathies in Thailand
Hemoglobin E Bangkok 13%
North eastern 50%
Hemoglobin CS 4%
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Hematology-Siriraj HospitalThalassemia: From DNA to Clinical Practice
33
อุบัติการของโรคธาลัสซีเมียทีพบบ่อยในประเทศไทย
โรค ทารกทีคลอด(ต่อปี)จํานวนผู้ป่วยทีมีชีวิต
อยู่ทั งหมด
Hb Bart’sอาการรุนแรงทีสุด
1,250 0
ธาลัสซีเมียเบต้าอาการรุนแรงปานกลาง
3,875 103,750
ธาลัสซีเมียชนิดHอาการไม่รุนแรง
7,000 420,000
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Hematology-Siriraj HospitalThalassemia: From DNA to Clinical Practice
Thalassemia syndromes
thalassemia syndromes
thalassemia syndromes
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Hematology-Siriraj HospitalThalassemia: From DNA to Clinical Practice
Deletions in the -globin gene cluster
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Hematology-Siriraj HospitalThalassemia: From DNA to Clinical Practice
Prevalence of (- - SEA) -thal
Regions heterozygote(%)
Northern Thailand 14.0
Central Thailand 3.7
Hong Kong 4.5
Northern Taiwan 3.5
Southern China 5.0-8.8
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Hematology-Siriraj HospitalThalassemia: From DNA to Clinical Practice
Deletions cause – thal2
121
3.7
4.2
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Hematology-Siriraj HospitalThalassemia: From DNA to Clinical Practice
Clinical types of thalassemia
Asymptomatic : heterozygote
Symptomatic
mild - Hb H disease
- Homozygous CS
severe - Hb Bart’s hydrops fetalis
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Hematology-Siriraj HospitalThalassemia: From DNA to Clinical Practice
12
12
12
12
1CS
thal 1 trait
thal 2 trait
Hb H disease
Hb Bart’s hydrops fetalis
Normal
thal 2 homozygote
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Hematology-Siriraj HospitalThalassemia: From DNA to Clinical Practice
Hb Bart’s Hydrops Fetalis
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Hematology-Siriraj HospitalThalassemia: From DNA to Clinical Practice
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Hematology-Siriraj HospitalThalassemia: From DNA to Clinical Practice
Absence of all -globin genes
Decreased Hb synthesis Hb Bart’s 80-90% Hb Portland 10-20%
Anemia Tissue Hypoxia
Enlarged Placenta Heart Failure ExtramedullaryHematopoiesis
Maternal complications
Congenital anomalies
Hepatosplenomegaly
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Hematology-Siriraj HospitalThalassemia: From DNA to Clinical Practice
Maternal Complications
Mean gestation at delivery 31 wk
Malpresentation of fetus 37%
Cesarean section 14 – 17%
Postpartum complications:
life-threatening hypertension
retained placenta, hemorrhage
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Hematology-Siriraj HospitalThalassemia: From DNA to Clinical Practice
Hemoglobin H disease
Compound heterozygote
- thal1/ thal2 (- - - thal1/ CS (- -CS
mild anemia Hb 8 - 10 g/dL
hepatosplenomegaly
newborn : Hb Bart’s 20 - 40%
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Hematology-Siriraj HospitalThalassemia: From DNA to Clinical Practice
Hemoglobin H disease
Acute hemolysis following infections
Numerous Inclusion bodies ( 4) Hb analysis : Hb H, Hb Bart’s
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Hematology-Siriraj HospitalThalassemia: From DNA to Clinical Practice
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Hematology-Siriraj HospitalThalassemia: From DNA to Clinical Practice
Clinical types of thalassemia
Asymptomatic : thalassemia trait
Thalassemia intermedia
- HbE / thal
- + thal/ + thal
Thalassemia major
- 0 / 0 thalassemia
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Hematology-Siriraj HospitalThalassemia: From DNA to Clinical Practice
Type Position mutation
- thalassemia Codon 17 AT
IVSI-1 GT
Codon 35 CA
Codon 41 – C
Codon 41/42 – TCTT
Codon 71/72 + A
3.4 kb deletion
+- thalassemia – 87 CG
– 28 AG
– 29 AG
IVSI-5 GC
IVSII-654 CT
Codon 126 TG
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Hematology-Siriraj HospitalThalassemia: From DNA to Clinical Practice
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Hematology-Siriraj HospitalThalassemia: From DNA to Clinical Practice