Title: Thalassemia ??.???? ?????????????
1Thalassemia??.???? ?????????????
2Thalassemia
- common genetic disease
- variable severity
- difficult to diagnosis and councelling
- decrease prevalence by PND
3Thalassemia
- ???????????????????????? ?????????????????????????
??????????????????????????????? ??????? ????
????????? ???????????????????????????????
????????????????????????????? ????????????????????
??????????????????????? - ??????????????????????????
- thalassemia minor
- thalassemia intermedia
- thalassemia major
4???????????????????
- ???????? (thalassemia trait, trait)
- ??????????
- ???????????????
- ??????? (thalassemia disease, disease)
- ?????????????????
- ????????????????????
5?????????????????
- Chronic hemolytic anemia
- Pallor and jaundice
- Thalassemic facies
- Hepatosplenomegaly
- Hemochromatosis
- Skin, heart, endocrine glands
6?????????????????
- Bone change
- Endocrine dysfunction
- Growth retardation
- Delayed secondary sexual development
- Hemolytic crisis
7???????????
- ????? ????????????
- ??? ?????? ??? ?????????
- CBC anemia, low MCV, characteristic RBC
morphology - Hb typing
- DNA analysis a thal
8????????????
- Transfusion-transmitted infections
- Bone expansion
- Endocrine dysfunction
- Hypopituitarism, hypothyroidism, diabetes
millitus, short stature, delayed puberty - Pulmonary hypertension and embolism
9????????????
- Hemosiderosis/cirrhosis of liver
- Extramedullary hematopoiesis
- Arthropathy
- Osteopenia
- Venous thrombosis
- Cardiomyopathy
10?????????????????????
- ?????????????????????????????? ???????????????????
????????????? - ???????????????????????? ?????????????
????????????? - ?????????????????????????????
- ????????????????? ferritin ??????? ???? ??./??.
??????????????????? ????????????????????
11??????????????? Thalassemia
- ???????????
- ????????????????????
- ??????????
- ???????????????????
12????????????
- ?????????? ??? ??? ????????? ??????? ??????????
- ??? ?????????????????????
- ???????????????????????????
- ?????????? ? ????? ?????????? ? ??? ??? ?
????????? - ????????????????????????????????????? ??????????
13- Heterozygote ?????????????????????????????????????
???????? ???????????????? trait - Homozygote ????????????????????????????
??????????????????????????????? - Double heterozygote ???????????????????? a ???
ß???????????????????? -
14- ß0-thal ??????????????????????????????????? ß
globin chain ??? - ß-thal ???????????????? ??????????? ß globin
chain ??????? - HbE ???? Hb ?????????? ????????????????? ß-thal
- a-thal1 ??? alpha globin gene ????2???????????????
???????????????????????????? - a-thal2 ??? alpha globin gene 1???????????????????
???????????????????????? - HbCS ???? Hb ?????????? ????????????????? a-thal2
15a-thalassemia
- aa/aa normal
- -a/aa a thal-2 trait
- --/aa a thal-1 trait
- -a/-a homozygous a thal-2
- --/-a Hb H disease
- --/-- Hb Barts disease
16Hb Constant Spring
- ???????????????????????????????????????????? a
thal - ??????????????????????????? ?? ???
- ?????????? a thal 2
- --/aCSa Hb H disease with constant spring
17b-thalassemia
- b/b normal
- b0/b b thal trait
- b0/b, b0/b, b/b b thal major
- b0/bE, b/bE b thal/E disease
18a and b thalassemia
- AE Barts disease
- --/-a, Hb E trait
- EF Barts disease
- --/-a, homozygous Hb E
19Thalassemia minor
- Heterozygote
- Homozygous a-thal2
- Homozygous HbE
- a/ß thal double hetrozygote
- ??????????????
20Thalassemia intermedia
- ???????????? ??????????????????????????
?????????? Hb 8-10g/dl ?????????????
?????????????? ?????????? ????????????????????????
???????? - ß-thal/HbE ???????
- EA Barts
- homozygous Hb CS
- HbH
21Thalassemia major
- Hb Barts hydrops fetalis
- Homo. ß-thalassemia
- ß-thal/HbE ???????
22Hb Barts hydrops fetalis
- ????????????????????????????????????
??????????????????????? Hb ??? - ?????????????????????????????????? ????
???????????????? ??????????????????????????????
??????????????????
23Hemoglobin Barts hydrops fetalis
24Homo. ß-thalassemia??? ß-thal/HbE
- ?????? Hb 3-4 g/dl ????????????????????
?????????????????????????????????
???????????????? ??? ??????????????????????? - 6-10 ????????????????
- 30-40 ?? ????????????????? ???????????? ???????
??????? - ?????????????????????????????? ?????????????????
????????????????????????????? Stem cell
???????????????????? ????????????????????????
???????????????????????????????????????????????
25Hemoglobinopathy
- ß-chain (ß0, ß)
- ß-trait
- E trait
- ß/E disease
- ß-thal homo.
- HbE homo.
- a-chain (a-thal1, a-thal2)
- a-trait
- HbH(a-thal1/a-thal2 or a-thal1/HbCS)
- Hb Barts hydrops fetalis
- ??????
- EA Barts disease (HbHHbE heterozygote)
- EF Barts disease (HbHHbE homo.or ß0 thal/HbE)
26important diseases for PND
- ß-thal/E disease
- ß-thal. homozygote
- Hb Barts hydrops fetalis
?????????????????????-?????
27??????????????
- OF ???? MCV ?????? ß-thal ??? a-thal1
- DCIP ?????? HbE
28female
male
¼ ¼
¼
¼
29female(ß tr.)
male(E tr.)
¼ normal ¼ ß tr.
¼ E tr.
¼ ß/E Dz
30male (ß/E Dz)
female (E tr.)
¼ ß tr. ¼ ß/E Dz.
¼ E tr. ¼ EE
homo.
31Punnett Square
?thal ?N
?N ?N / ?thal ?N / ?N
?E ?E / ?Thal ?E / ?N
F
M
32????? ????
ß-trait E trait
a-thal1 trait HbH
a-thal2 trait HbH
E trait E trait
ß-trait HbCS trait
ß/E disease EF Barts disease
E trait EA Barts disease
ß-trait/ a-thal1 trait EA Barts disease
ß-thal homo. HbE homo.
Hb Barts HbH
PND
v
v
X
X
X
v
X
v
?
33???????? Hb typing ?????????? HPLC
Hb typing Hb F Hb A2(E)
Normal(A2A) 0.5 0.7 2.6 0.4
a-thal trait (A2A) 0.5 0.74 2.3 0.47
ß-thal trait (A2A) 1.5 1.43 5.5 1.26
HbE trait (EA) 1.2 0.86 27.8 7.5
ß-thal/HbE (EF) 31.1 14.5 61.2 13.6
Homo HbE E(F) 4.3 2.7 90.2 4.9
EA Barts EA(Barts) 2.6 1.4 14.9 1.6
EF Barts EF(Barts) 10.2 6.73 79.7 8.7
HbH(A2A Barts H) 0.6 0.61 1.6 1.21
34?????????????????
- ??????????? ? ?? ??????????
- Hb A a2b2 97
- Hb A2 a2d2 lt3.5
- Hb F a2g2 lt1
- ???????????
- Hb F ????????????
35red cell indices and Hb typing
normocyte
microcyte
Thal.Dz. ß-thal Homo ß-thal/HbE HbH EA Barts EF
Barts
HbA2A
HbA2A DxNormal a-thal2 tr.
Hb ACS DxHb CS
HbEA
Hb EE DxHbE Homo
HbA2 Determination
HbE Determination
HbA2gt3.5 Dx ß-thal tr.
HbA2lt3.5
HbE25-30 DxHbE a-thal2/HbE
HbElt21
Hbgt10g/dl Dx a-thal1/HbE
Hblt10g/dl Dx iron def. iron def. on top of
thal tr.
Hbgt10g/dl Dx a-thal1 tr.
Hblt10g/dl DxHbE tr. with iron def.
a-thal1/HbE with iron def.
36OF
pos.
neg.
DCIP
DCIP
pos. Dx HbE tr.
neg. Dx a-thal1 tr ß-thal tr.
ß-thal homo iron def.
pos. Dx HbE tr. HbE homo
ß-thal/HbE HbH Others
neg. Dx normal a-thal2 tr.
HbCS tr.
Clinical RBC morphology ß-thal homo
HbA2 Determination
-Clinical -Rbc morphology -Hb typing -Inclusion
body (HbH) -F cell stain (ß-thal/HbE)
HbA2gt3.5 Dx ß-thal tr.
HbA2lt3.5 Dx a-thal1 tr. iron def.
Repeated study after iron supplementation X 3 mo.
37a-thal1 trait ?????? iron def. ??????
- a-thal1 trait ???? MCV ??? ?????????????? (Hb
12-13 g/dl)
38??????????? a-thal1
39???????????????? a-thal1
- case OF ve or MCVlt 80 ??? Hb typing ????
- E homo ??? ß / E disease ????? ??? a-thal1
??????? - ß-thal trait ????? ??? a-thal1 ???????
- E trait ????? HbE 20-25 ????? ??? a-thal1
??????? - E trait ????? HbE lt 20 ??????? AE Barts ????
EF Barts ????????? a-thal1
40???????????
- Homo E ???????? Hb E gt 80 ??? MCV gt 60
- Homo E ????? Hb E lt80 ??? MCV lt 60
- ????????? ß / Hb E disease
41??? OF -ve ???? MCV gt 80????????? a-thal1 trait
?????? ?
42??????????? a-thal1 trait ??????? DNA mapping
43Prenatal diagnosis (PND)
- ?????????????????
- ?????????????????????????????????????????????
?????????????? - ????????????????? ????????????????????????
- ?????????????? ??????????????????????
44???????????????????????????????
- Hb Barts hydrops fetalis
- Beta thal / beta thal
- Beta thal / Hb E disease
45?????????????????
- Ultrasound
- Amniocentesis
- Fetal blood sampling
- Chrorionic villus sampling
46Ultrasound
- ???????????????????????????????
??????????????????????????? - ?????????????????????????? ???????????????
Hydrops fetalis ?????????? 20-24 ??????? - ??????????????????????? ?? ??????????????????
??????????????????????????????????????
47??????????????????? ????????????? (Ultrasound)
- ??????????????????????????????????? Hb Barts
hydrops fetalis - ?? fetal ascites, cardiomegaly, skin edema,
dilated umbilical vein - ????? pericardial effusion ???? pleural effusion
- ???????????????? ???????????????????
48??????????????????? ????????????? (Ultrasound)
- ??????? second trimester (14-28 weeks) ??????????
32 ??????? - ???????? confirm ??????????????????????
??????????????? - ?? maternal complication ???? preclampsia,
eclampsia, placenta previa
49Prenatal Diagnosis Ultrasound (Ascites)
50Fetal hydrops
- Immune hydrops (??????????????????? ???????? Rh
blood group) - Non-immune hydrops
- Hemoglobin Barts hydrops fetalis
- ???????????? ????????????
- ????????????????????????? ???? ???????
- ?????????????? chromosome ???? malformations
??????? - TTTS (Twin-to-twin transfusion syndrome)
- ???
51Earliest ultrasound detection
- Overt features of hydrops fetalis are found in
only one-third of affected pregnancies at 17-18
weeks - Fetal cardiomegaly is a sensitive marker
- 18-21 weeks, in 484 pregnancies at risk, C/T
ratio of gt 0.5 carries a sensitivity and
specificity of 95 and 96.1 (Tongsong T et al.
2000) - 12-14 weeks, C/T ratio of gt 0.5 provided a
sensitivity and specificity of 65 and 100 (
TVS, detected 43 affected pregnancies in 135
at-risk women at 12-14 weeks with no false
positive) Lam YH et al 1997 and 1999
52???????????????????????????????????????????????
- ?????????????? (Amniocentesis)
- ??????????????????????????? (Cordocentesis, fetal
blood sampling FBS, percutaneous umbilical
blood sampling PUBS) - ?????????????? (Chorionic villus sampling, CVS)
53Amniocentesis
- ???????????????????? 16-18 ???????
?????????????????????? Ultrasound guide
?????????????????????? - ????????????? ?? fetal loss 0.5
- ????????????????????? ???????????????????????
??????????????????????? ??????????????????????????
????
54?????????????? (amniocentesis)
- ????????? 16-20 ???????
- amniotic fluid 5 ml
- fetal loss rate lt1
- DNA study
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56?????????????? (amniocentesis)
57Fetal blood sampling
- ?????????????????????? Ultrasound guide
??????????????????????????? 17 ??????? - ?? fetal loss 2.5
- ??????????????????????????????????????????????????
?????? ????????????????????????
58Prenatal Diagnosis???????????????? Fetal blood
sampling
59??????????????????????? (Fetal blood sampling)
- ????????? 18-22 ???????
- hemoglobin study, DNA study
- ?? confirm ????????????
- fetal loss rate 2.5
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63Chrorionic villus sampling (CVS)
- ???????????????????????????????????
???????????????????????????????? - ?? fetal loss lt1
64?????????????? (chorionic villus sampling, CVS)
- ????????? 10-13 ???????
- DNA study
- fetal loss rate lt1
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67?????????????????????????????
???? ????????? ?????????? ??????????
Amniocentesis 16-20 0.5 DNA study
CVS 10-13 0.5-1 DNA study
cordocentesis 18-22 2.5 DNA study ??? Hb typing
68??????????????????????????
??????????????????????????????????????????????
????????????????
???????????????????????????????????? ?????
????????? ?????????? ???????? ???????????????????
?????
??????????????????????????
???????????????????????
ANC ?????? high risk pregnancy clinic
???????????????????????? ????????????????????????
????? ????????????????????????????????????? ?
69??????????????????????????
????????? Hb Barts hydrops fetalis
First trimester
Second trimester
Serial U/S ANC at high risk pregnancy clinic
CVS for DNA study
Cordocentesis for hemoglobin typing
Specimen to lab ???????????
70??????????????????????????
???????????????????????????? - globin
chain
???????????????? ????? mutation characterization
???? mutation
??????? mutation
- DNA study ???
- 1st trimester CVS ????
- 2nd trimester cordocentesis
- 2nd trimester amniocenthesis
Hemoglobin typing ??? 2nd trimester
cordocentesis
Specimen to lab ???????????
71??????????????????????????
Post-diagnosis counselling
Unaffected fetus
Affected fetus
F/U high risk pregnancy clinic
Choices
Termination of pregnancy
Continue pregnancy
???? ???? specimen ???? confirm
Abortion committee ???? ????
specimen ???? confirm
72??????? PND
- ?????????????????????????????? Thalassemia
?????????? ???????????????????????????????????????
???????????????????????????? ?????????????????????
?? 24 ??????? (?????? Hb Barts
?????????????????????????????????????????????)
73????????????????????????
74Preimplantation Embryo in vivo
75Preimplantation Embryo
76Embryo biopsy
77????
- ??? Thalassemia ???????????????????????????
????????????????????? ????????????????????????????
????????????????????????????? ????????????????????
????????? ????????????????????????????????????????
?????????????? - ?????????????????????????????????????????????
?????????????? - ????????????????? ??????????????
?????????????????????? ???????????????????????? - ??????????????????????? ????????????????????????
???????????????? counseling ????