haemoglobinopathies - svenska...
TRANSCRIPT
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Haemoglobinopathies
Henrik Birgens, MD Department of Haematology L
Herlev Hospital University of Copenhagen
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Haemoglobinopathies Due to resistance against malaria, carrier states of hereditary haemoglobinopathies are the most common monogeneic disorders in the world WHO has calculated, that about 7 per cent of the worlds population carry a haemoglobinopathy gene Each year 300.000 -400.000 children are born with a serious haemoglobin disorder Weatherall & Clegg. Bulletin of the WHO 2001;79:704
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Center for Haemoglobin Disorders at Herlev Hospital
Field of activity: 1. Diagnostic 2. Prenatal diagnosis 3. Genetic Councelling 4. Advising and education of health care
persons 5. Treatment of patients with
haemoglobinopathies Videncenter for Hæmoglobinsygdomme
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Hemoglobin
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Hæmoglobinopathies
Kvalitative mutations: Mutations leding to a change in an amino acid (missense): Examples: Hb S, Hb C, Hb D Hb Volga, Hb Philadelphia + approx. 600 others
Kvantitative mutations: Mutations leading to reduced synthesis of globin chains (deletions, nonsense, frameshift, promotor mutations and mutations involving splicing. Examples: α-thalassæmia, β-thalassæmia, δβ-thalassæmia, Hb Lepore, Hb E
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Embryo ζ2,ε2 Ηb Gower I α2,ε2 Ηb Gower II ζ2,γ2 Portland I ζ2,β2 Portland II
Fetus α2,γ2 Hb F
Adult α2,β2 Hb A
HS-40 ζ α2 α1
5’ 3’
LCR
ε Gγ Aγ δ β
5’ 3’
Chromosome 16
Chromosome 11
α2,δ2 Ηb Α2
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Geografic Distribution of the Haemoglobinopathies
HB, 2007
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Geografic Distribution of the Haemoglobinopathies
HB, 2007
Migration
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Geografic origin of immigrants to the Nordic countries during the recent
decade
In the period 1995-1999, the net annual immigragion to Norway: 18.000 Denmark: 16.000 Sweden: 53.000 Finland: 10.000
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β-Thalassemia
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Screening for Haemoglobinopathies
HB,2007
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Screening for Haemoglobinopathies
HB,2007
1998
Ny i 2008
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Screening for Haemoglobinopathies
HB,2002
β-thalassaemia: Homozygous β-thalassaemia, β-thalassaemia/ haemoglobin E disease
α-thalassaemia: Homozygous α0-thalassaemia
Sickle cell disease: Hb SS disease, Hb S/β-.thalassaemia
Diagnosis
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• Tillväxtretardation, muskelatrofi, fettreduktion
• Hyperplastisk expanderande märg – Facies thalassemica. – Psudotumörer i rörben o kotpelare. – Generell osteoporos - patolog. frakturer
• Ökad plasmavolym pga extramedullär hematopoes och hepatosplenomegali
• Hypersplenism (hemolys, leukopeni, trombocytopeni) • Gallsten • Ökad järnresorption i tarmen
b-Thalassemia major b-Thalassemia major Beta-Thalassemia major
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β-thalassæmia major
HB,2002
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β-thalassæmia major
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α-Thalassemia
Normal
α+, silent carr.
α+, homozyg.
α0, trait HbH (β4) Hb Bart (χ4)
Synonym α-thal. 2 α-thal. 1 α-thal. 1
Fung. Gener
4 3 2 2 1 0
α/β-ratio 1.0 0.8 0.6 0.6 0.3 0 Genotyp αα/
αα -α/αα -α/-α --/αα --/-α --/--
MCV 90 +/-5
81 +/- 7 69 +/-4 69 +/-4 65 +/-7 110/120
Hb u.a. u.a. mild anemi
mild anemi
mod/svår hemolytisk anemi, splenomegali, akut hemolytisk kris
död in utero/neonat.
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Sickle cell anemia
HB,2002
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Screening for haemoglobinopathies
HB,2007
All from the Mediterranean countries, Iran and Iraq with MCV < 78 fl.
All from Africa, including afroamericans, the Middle East, the Indian subcontinent, Southeast Asia and Polynesia.
Screening of pregnant immigrants:
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0
20
40
60
80
100
120
140
160
180
200
Antal
<55 55-59 60-64 65-69 70-74 75-78 >78
MCV (fl)
Beta-ThalassæmiAlfa0-Thalassæmi
Distribution of mean cellular volume in carriers for β-thalassaemia in Denmark
(n=485) and α0-thalassaemia (n=110)
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13
15
17
19
21
23
25
27
29
31
50 55 60 65 70 75 80 85
MCV (fl)
MC
H (p
g)
Relationship between MCV and MCH in carriers of β-thalassaemia (+),
α+-thalassaemia (°) or α0-thalassaemia (•)
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Screening for Haemoglobinopathies
HB,2007
1995: 2,8 % (14/205) 1996: 4,2 % (25/578) 1998: 4,2 % (16/381)
The frequency of serious beta-globin allels among pregnant immigrants in Copenhagen County
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1 3 2
1 30 30(3) 104 105 146
C ATG GT AG GT AG TAA P
5’UTR 3’UTR 5’ 3’ 130 bp 850 bp
IVS I IVS II
Nonsense and frameshift mutations (β0
Mutations affecting splicing of RNA from introns (β0 and β+)
Mutation affecting initiation of translation (β0)
CACCC
CCAAT
TATA
Promoter
Promoter mutations (β+)
Mutations affecting RNA cleavage (β+)
Mutations affecting transcription (β+)
)
Mutations in ß-thalassaemia
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-α3.7 -α4.2 --MED --SEA -(α)20.5
--FIL --THAI
ζ2 α2 α1 3’ 5’
Iran, Irak,Indien, Sydøst asien, Indonesien, Afrika }
Middelhavet Sydøstasien
Middelhavet Sydøstasien Sydøstasien
Geografi ψζ1 ψα2 ψα1 θ1
0 10 kb 20 kb 30kb
HB 2002
α-thalassaemia deletions
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Haemoglobinopathy Diagnostic Laboratory Methods:
Screening: High-pressure liquid chromatography (HPLC) Isoelectric focusing Unknown mutations in the β-globin gene: PCR followed by sequencing Denaturing gradient gel electrophoresis (DGGE Mutations in the α-globin gene: Deletions: GAP-PCR (multiplex) Small mutations: PCR followed by sequencing HB/1999
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Normal
HbA
HbA
2
Heterozygot β-thalassæmi
HbA
HbA
2
Heterozygot HbS
HbA
HbA
2
HbS
Hæmoglobin Lepore
HbF
HbA
HbL
epor
e H
bA2
Haemoglobinopathies HPLC
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Haemoglobinopathies
HB, 2002
Isoelectric focusing
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A new thalassaemic nonsense mutation in the b-globin gene (codon 37;tgg > tag) in an Afghanistani
family
Mother
Father
Child
Kornblit B, Taaning P, Birgens H. Hemoglobin 2005; 29: 209-13
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ψζ1 ζ2 ψζ2 ψα1 α2 α1 θ1
THAI(F)
FIL(F) 20,5(F)
MED(F)
a/SEA(F) a(R) 20,5(R) MED(R)
FIL(R) THAI(R)
SEA(R)
a0-Thalassæmi PCR multiplex
-(α)20,5 -(α)20,5 / Lane 1 Lane 2 αα/αα Lane 3 -(α)20,5 / - -MED
Lane 4 --SEA /--SEA
Lane 5 αα/ -(α)20,5
Lane 6 αα / --MED
Lane 7 αα / --SEA
Lane 8 αα / --FIL
Lane 9 αα / --THAI
HB/2003
Inter-HVR
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β-thalassæmia
HB,2002
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(Indien)CD8-9 +G, beta012%
(Medit)IVSI 110 G>A, beta+11%
(Medit)IVSII 1G>A, beta011%
(Medit)CD39 C>T, beta09%
(Medit)IVSI 1G>A, beta07%
(Medit)CD5 -CT, beta05%
(Medit)IVS I 6T>C, beta+5%
(Asiea)CD41-42 -TCTT, beta04%
(Medit)CD8 -AA, beta03%
(Medit)CD15 G>A, beta03%
(Asia)CD17 A>T, beta02%
(Iran)CD36-37 -T, beta01%
Andre14%
(Medit)IVSI 5G>C, beta013%
Distribution of 245 mutations in the β-globin gene associated with β-thalassaemi in the Danish immigrant population
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-α3.7 -α4.2 --MED --SEA -(α)20.5
--FIL --THAI
ζ2 α2 α1 3’ 5’
Iran, Irak,Indien, Sydøst asien, Indonesien, Afrika }
Middelhavet Sydøstasien
Middelhavet Sydøstasien Sydøstasien
Geografi ψζ1 ψα2 ψα1 θ1
0 10 kb 20 kb 30kb
HB 2002
a-thalassaemia deletions
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α-Thalassemia
HB,2002
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α-Thalassemia SEA Deletion
Prevalence of (--SEA) α-Thalassemia Deletion in Southeast Asia.
Region Proportions of Population who are Heterozygous Carriers (%)
Hong Kong 4,5 Northern Taiwan 3,5 Southern China 5,0-8,8 Northern Thailand 14,0 Central Thailand 3,7
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SEA73%
MED20%
20,54%
FIL1%
THAI2%
Distribution of various α0-thalassaemia alleles in 109 patients with α0-thalassaemia and 32 patients with HbH
disease in the Danish immigrant population
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Thalassemia in 165 immingrants with MCV < 80 fl
Total 165 samples: β-thalassemia: 30 (18.2 %)
β-thalassemia minor 29; β-thalassemia intermedia 1
α-thalassemia: 39 (23.6 %) αα/-α3.7 27; -α3.7/-α3.7 5; αα,-SEA 2; αα/-MED 2; αα/-(α)20.5 1; αα/αααanti 3.7 1; -α4.2/-(α)20.5 1
3 pts have α and β thalassemia simultaneously
Videncenter for Hæmoglobinsygdomme
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Sickle cell anemia
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The Procedure for Screening of Haemoglobinopathy in Pregnants of relevant etnic origin in Copenhagen
Primary Health Care, General Practitioner
The Laboratory of General Practitioners in Copenhagen The pregnant comes from a mediterran- ean country, Iran or Iraq
MCV < 78 MCV > 78
The pregnant comes from Africa, the Middle east, the Indian subcontinent, or Southeast Asia
Haemoglobin analysis (HPLC)
The sample is stopped
If the sample shows heterozygosity for beta-thalassaemia, alpha0-thalassaemia, Hemoglobin S or hemoglobin E
All samples
Blood sample
A direct contact from the laboratory to the GP con- cerning a blood sample from the fa- ther
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Chorion villus sampling
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Far. Cd5 -CT
Foster. Cd5 -CT 1 2 3 4 5 6
Lane 1 hetero controle Lane 2 mother Lane 3 fetus Lane 4 fetus Lane 5 mother Lane 6 normal controle
Prenatal diagnosis
619 bp deletion
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HB,2002
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Beta-thalassaemia Homozygous: 4 Heterozygous: 2 Normal: 1 Sickle cell disease Homozygous: 1 Normal: 1 Alpha-thalassaemia Homozygous SEA: 1 Heterozygous 3.7: 1 Normal: 1
Number and results of CVS performed at Herlev Hospital in the period 2002-2007