TAP CHl NGHI6N CCPU Y HQC •
C H A N D O A N DI T R U Y E N T R U d e SINH BENH BETA THALASSEMIA TAI BENH VIEN NHI TRUNG UONG
Ly T h j Thanh H d \ N g u y i n T h j Phu'O'ng M a t \ Ngo Di6m Ngoc^
N g u y i n T h j Tdn S i n h ^ , T r i n Danh Cu-dng^, Le A n h Tudn' 'Khoa Di truyin Ti bdo vd Sinh hpc phdn td- - B$nh Vipn Nhi Tmng wong 'B^nh vidn Bach Mai. Hd NOi: 'Tmng Tdm Chin dodn tru&c sinh b$nh vipn Phu sdn Trung uung Chin dodn tmPv sinh cho nhung bd mp thuOc cdc gia dlnh cd tiin su' bdnh beta thalassemia dang tri thdnh vin di cip thiit nhim ndng cao chit Iwpng xd hpi vd gidm gdnh ndng cho gia dinh ngw&i bpnh.
Nghi6n ciiv nhdm phdt liiin cdc ddt biin gen p globin (Hbb) cho thai phu cd nguy ca smh con bi beta thalas- semia thi n$ng Kit qud cho thiy trong 09 ddt biin dope sang lpc- CD17(AAG-TAG). 15%. CD41/42 (-TCTT) 15%. HbE (G > A) 6.7% cd tin suit gdp cao nhit, 15 thai nhi bj beta thalassemia the ndng. 35 thai nhi klidng mang dpi biin gen, hodc Id nguoi Idnh mang gen bdnh. Phdt hiin cdc dpt biin tren gen Hbb bdng ky thudt ARMS-PCR vd ky thudt giai trinh tif gen Hbb cd y nghla quan trpng trong chin dodn trw&c sint]
bdnh beta thalassemia
Tu khoa; Beta thalassemia, C h i n do^n trudc sinh, ARMS-PCR, Multiplex ARMS-PCR
I. DAT VAN O^
Beta thalassemia Id b6nh di truyen Idn nhiem sde the (NST) thudng do d6t bien gen beta globin n l m tr6n cdnh ngdn n h i l m sde t h i I I , gdy giam hodc mat tong hap chu6i p glo- bin Tai Vi6t Nam, ty 16 ngudi mang gen beta thalassemia Id 1,5 - 25% [91 Beta thalassemia Id mpt trong nhirng bPnh huyet s l e t i pho bien nhat, phdn b i khdp t h i gidi [7] O Vipt Nam, theo Nguyin C6ng Khanh, bPnh beta thalassemia Id nguySn nhdn hdng 6 l u gdy t h i i u mdu, tan mdu ndng d tre em [3] Ty 16 ngudi mang gen bpnh phdn b i trong ea nude vd khac nhau tuy tiimg dia phuang, tung nh6m ddn tpc Ddc bipt, ty 16 mang gen b6nh r l t cao d cdc ddn tOc it ngudi n h u Mdng (25%), Catu (14%), Tdy (11%), Pake (8,33%) [9]
Cho d i n nay, cP khoang han 200 d6t bien
Dia Chilian h$ Ly Thi Thanh H6 - Khoa Di truySn vd Smh hoc phSn tu' - B^nh vi4n Nhi Trung uung
Email lythanhha@gmait com Ngdynh$n 27/11/2013 Ngay dupe chip Ihu&n 15/3/2013
3d, 6 u a c tim t h l y tren gen p globm (Hbb) [9], x i p vdo 2 nh6m nhPm gdy mdt hodn todn s6 lupng chuPi p globin, lam m l t chire n ^ g cua gen p gdy p° globin vd nhpm Idm giam s i lupng ehuPi p globin gay p* globm- Cdc dot bien ndy mang tinh ddc trung vd phdn bo vdi ty 16 khde nhau d tirng dan t6c.
Viing gen p globin ndm tren cdnh ngan n h i l m s i c the 11 {11 p i 5 5), ddi 1600bp, g i m 3 exon vd 2 intron M6t nghien ciru tren quin t h i ngudi Vi6t Nam cua M L Saovaros Svasti cho t h l y ed 9 dpt b i l n gdy ra 95% cae trudng hdp P thalassemia, g i m . CD17(AAG-TAG), CD41/42(-TCTT), -28(A>G), CD71/72(+A), IVS1-1(G>T). IVS1-5(G>C), IVS2-654(C>T), CD95 (+A) vd CD26 (GAG>AAG) gay benh h u y i t sde to E, la mdt the p thalassemia dac biet [9]
Dya vdo bieu hien lam sdng, benh beta thalasemia chia lam 3 the chinh' the nhe, t h i trung gian, the ndng Benh nhan t h i nhe di hpp t u vdl m6t d6t b i l n tr6n gen Hbb gay thieu mdu nhuac sde the hien tren xet
• TAP CHI NGHIEN CU'U Y HOC nghiem. t h u d n g khong c6 bieu hien idm sdng.
c a the phdt tnen binh t h u d n g . Benh nhdn the nang hay c6n goi la the Cooley, dong hap tir h o l e dl hap tu kep hai dot b i i n khde nhau se bj t h i l u mdu ndng, phy thuoc vdo viec truyin mau vd thai sdt s u i t ddi
Beta thalassemia la bPnh di t m y l n Idn tren n h i l m sde the t h u d n g Ty le m l c benh Id nhu nhau d ca hai gidi nam vd nir B i va me Id mang gen di hap t u v d i mpt ddt bien, nguy ea trong mdt l l n smh thai nhi Id ngudi Idnh mang gen benh la 50%. thai nhi Id ngudi hodn todn khoe manh khPng mang gen bPnh Id 25%, thai nhi m l c b6nh beta thalassemia the ndng la 25% Benh nhdn the ndng phai 3woe truyin hong e l u thay t h i vd thai s i t s u i t 6di 6e c6 cudc s i n g binh thudng Neu viee 6 i i u tn tren khong d y a c thuc hien thi benh nhan eP n h i i u b i l n Chung nhu lach to, gan to, nhiem sdt d tim, gan, t u y i n npi tiit, b i l n dang xuang ldm anh hudng xau d i n tinh trang sire khde, t h i c h i t va ddi song eua ngydi b6nh Dieu trj benh beta thalassemia la mpt viec khP khan va ton -(e-^ khong phai chi doi vdi nhirng nuac cP ngudn lyc kmh t i va y t i kem. ma ca vdl nhOng nude eo ngudn lye manh Mot giai phap phong benh beta thalassemia t i t n h l t 66 la t h u c hien chan dodn trude sinh eho cac gia dlnh cd nguy c a sinh con bi benh beta thalassemia the ndng Vi vdy de tai ndy dupe t i i n hanh vdi m u c t i e u Ap dung ky thuat Multiplex ARMS-PCR, ARMS-PCR va giai trinh t u gen trong chan doan tnroe smh benh beta thalassemia
II. 0 6 l TU'P'NG VA PHU'ONG PHAP
1. Doi tup'ng
60 thai phu (16 - 18 tuan thai) eua 60 gia dmh cP con ddu dd d u a e c h i n doan m l c beta thalassemia tai benh vien Nhi Trung u a n g .
duae thu thap tir 6/2008 den 12/2011 Cac gia dinh ndy d i u Id ngudi dan t6e Kmh hiPn dang s i n g tai cdc tinh m i l n Bdc
2. Phu'O'ng phap
2.1. Mau benh pham: Mdu bpnh p h l m yeu c l u dung trong xet nghiem chan dodn trudc smh la 15 ml dich 6i dung trong i n g v6 triing Quy trinh choc ^ u t dich nude Pi duae t i i n hdnh tai Trung tam chan doan trudc sinh - benh vi6n Phu san Trung uang
2.2. Nudi cay te bdo dich 6i: Dich Pi dwac nuPi c l y trong dung dich amniomax fluid - la mdi trudng nupi e l y dac hi6u chi eho t l bdo dich 6i Sau khi nu6i c l y tir 10 den 14 ngdy, cac t l bdo dich Pi duae thu hoach va rira sach b l n g dung dieh PBS I X .
2.3. Tach chiit DNA tO- ti bao dich 6i:
Cac t i bdo dich Pi duae tach chilt DNA b l n g kit tdeh DNA eua Qia^en - Diic (QiaAmp DNA mini kit)
2.4. Sang Ipc cac dot bien thw&ng gap bang ky thuat mutiplex ARMS-PCFU ARt\/!S- PCR: ky thuat mutiplex ARMS-PCR va ARMS- PCR d u o c sir dung trong c h i n doan sau smh cho bP, me vd con d i u d l sang loe cdc dot bien thudng gdp 9 ddt bien thudng gap duae chia thdnh 6 nh6m vd duae sang Ipc l l n luot nhu bang 1 theo nghien ciru eua Huang L6 (2000) tren quan the ngudi D6ng Nam A [6]
Dot b i l n d u a e phat hien qua multiplex ARMS- PCR. d u a e xdc dmh k i i u gen b l n g ARMS- PCR Rieng dot b i l n CD26 cua HbE duoc phat hien true tiep b l n g ARMS-PCR neu c6 HbE duang tinh vdi dien di huyet sde to Chan doan trudc smh chf d u a e thyc hien tren nhirng gia dinh da b i i t k i l u dot bien
2.5. Giai trinh tip gen Hbb va phan tich kit qua: trong trudng hop khPng tim thly d6t b i i n sau khi sdng lpc 9 dot b i l n thudng gap
TCNCYH 81 (1) - 2013
TAP C H ! NGHIEN CLPU Y HQC
b l n g ky thudt mutiplex ARMS-PCR/ ARMS- PCR eho b i , mp vd con d i u , chiing t6i t i i p tyc dimg kJ thudt giai trinh t y gen d i tim cdc dpt b i i n khde Ky thudt ndy sir dyng d i tim cdc d6t b i i n n l m ngodi 9 66t b i l n thudng gdp trPn, dupe thyc hi6n tr6n mdy ABI 3130 tpi khoa Di truyin vd Sinh hpc phdn tir - b^nh
vi6n Nhi Trung u a n g . Ky thudt ndy diing trong c h i n dodn trude sinh vd sau sinh
K i t qua d u p e phdn tich b l n g p h l n m i m Chromas vd Chromas Pro, sau dP dupe dua I6n Ngdn hdng gen (Gene Bank) d l so sanh vdi trinh t y c h u i n .
B a n g 1 . Cdc d a n g d p t b i l n g e n H b b va m 6 i d ^ c h i 6 u
B u d c sang loe Loai d o t bien Mdi dac hipu Mdi c h u n g Dp ddi (bp) CD17(AAG-TAG)
CD41/42 (-TTCT) -28 (A>G) IVS1-1 (G>T)
CD17M CD41/42M -28M IVS1-1M
240 439 107 281 2
3 4 5 6
IVS1-6(G>C) CD71/72+A IVS2-654(C>T) Cd95 (+A) CD26 (G>A)
IVS1-5M CD71/72M IVS2-654M C D 9 5 M HbE-WI
T h a l B T h a l C T h a l F T h a l B BT-B
286 241 382 163 271
III. K ^ T Q U A
Tir thang 6/2008 d i n 12/2011, cP 60 gia 6inh c6 t i i n sir smh eon ddu mde beta thalassemia bao gom b l me va con 6 l u , 3woc t i i n hanh x6t nghipm di t r u y i n xdc dmh dot b i i n tren gen Hbb tai Khoa Dl truyin vd Smh hpc phdn t u benh vi6n Nhi Trung u a n g
B a n g 2. Ket q u a e h i n d o a n t r u ' d c s i n h c u a gia d i n h c d t i l n su*
s i n h c o n d d u m l c beta t h a l a s s e m i a
Sd dot bien tim thay 0 1 2
tren gen Hbb S6 gia d i n h 23 22 15
K i t luan Thai nhi hoSn toan blnh thu'ang
Thai nhi mang gen benh 0 i n h chi thai nghen
— • TAP CHI NGHIEN CU'U Y HpC Bang 3. Ty le cac alen dot b i l n trong c h i n doan tru'dc sinh tren gen Hbb
Oot bien
CD17 CD41M2
HbE CD71/72
IVS1-1
•28 IVS1-5 IVS2-654
CD9S
Cac dpt bien diem hiem gSp khac
Tan s u i t
18/120 18/120 8/120 5/120 2/120 1/120 0/120 0/120 0/120 0/120
Hinh 1 . Multiplex A R M S - P C R sang Ipc b u d e 1 d mot gta dinh c d con d i u t i i n sir bj beta thalassemia t h i nang
M Marker lOObp G i i n g 1 Mau chirng binh thudng G i i n g 2 M l u chirng m l c dot b i l n CD17 vd CD41/42 G i i n g 3 Mdu DNA ciia me (bi dot b i i n GDI 7). G i i n g 4 Mdu DNA ciia b i (bi 66t bilnCD41/42) G i l n g 5 M l u DNA ciia con ddu (bi dPt b i i n CD17+CD41/42)
Hinh 2. A R M S - P C R xac djnh kieu gen trong chan doan tru-dc sinh G i i n g 1^ Mdu chirng eiia ngudi binh thudng G i i n g 2 DNA cua ngudi di hap tir 1 66t biln Giing 3 DNA ciia me hodc b i G i i n g 4 DNA eiia thai nhi G i i n g 5- Mdu chung khong chira DNA
TCNCYH81 (1)-2013
TAP CHI NGHIEN CU'U Y HQC •
M.
Khong dot taien(b)
Di hop tir dot bien -138C>T
H i n h 3a. T r i n h tu> g e n H b b k h d n g b i d p t b i l n c u a t h a i n h i Hinh 3 b . T r i n h tie g e n Hbb m a n g d o t b i l n d i e m c u a t h a i p h u I V . B A N L U A N
6* 60 gia dlnh d u a e Idm c h i n doan trudc sinh benh beta thalassemia, 120 trudng hap la b i hoae me d i u cd k i l u gen di hap vdi 1 ddt b i l n , 15 thai nhi cP kieu gen di hap tir k6p 2 dot b i l n khde nhau hodc 66ng hap tir vdi m6t d6t b i i n trong 9 ddt bien sang Ipc, d u a e k i t ludn m l c beta thalassemia t h i ndng 22 thai nhi cd k i i u gen di hap t u vdi mpt dpt b i l n la ngudi ldnh mang gen bPnh 23 thai nhi khPng bi d6t b i i n ndo trPn gen Hbb Id ngudi blnh thudng khong mang gen bpnh N h y vdy, trong t i n g so 60 gia dlnh Idm c h i n dodn trudc smh, 37 trudng hpp mang it n h l t mpt alen dpt b i l n trpn gen Hbb Do beta thalassemia the ndng c6 k i i u gen Id'dong hap tir vdi m6t dpt b i i n hodc di hpp tir kpp vdi hai dpt bien tir hat alen khac nhau, nSn ty 1$ d6t b i l n cua tirng alen co y nghTa quan trpng vi6c tham gia c d e h i gdy b6nh
Alen dPt b i i n c6 ty 16 cao n h l t C D 1 7 (AAG-TAG)' 15%, CD41/42 (-TCTT) 15%, HbE (G>A) 6.7% Ty IP ndy cung t u a n g duang vdi ty 16 alen dPt bien cua ngudi mang gen beta thalassemia d ngudi Vi6t Nam trong nghiPn ciru ciia Bin Van Vi6n vd cs [1]
Trong so 60 trudng hdP lam chan doan trudc sinh, c6 1 trudng hpp gia dinh, ngypi bo dl hpp tir vdi dot b i i n CD41/42 (-TCTT), ngudi me khdng mang dpt bien ndo trong 9 dpt b i l n t h u d n g gdp tren Ooi vdi trudng hpp ndy, ch6ng t6i da giai trinh t y gen Hbb ciia ngudi mp de tim cdc dot bien khde Dot bien d u o c tim t h l y la 66t b i i n d i i m HBB c- 138C>T Giai trinh t y gen Id ky thudt chiing toi dang t r i l n khai sau ARMS-PCR, Id tidu chuin vdng 3e sdng loe t i t ca cdc 66t b i i n da biit vd dpt b i l n mdi trpn gen
Thdi gian thich hdP 3e tien hdnh chan dodn trudc sinh Id khi thai nhi duae 16-18 t u i n tuoi Thdi d i i m ndy d u p e xem Id tuang 6 i i mupn d mpt so nude trinh dp y hoc phdt trien, do n g y d i mp nguy ea cao duoc tiin hdnh t r u d c smh d t u i n thai thir 8-10 vdi ky thudt smh t h i l t gai rau Tuy nhien, o Viet Nam, ky thu6t ndy chua d u p e cdc dan vi san khoa dp dyng, do dP. chpc hut dich 6i td phuang phdp dyy n h l t d u a e dp dung Mau dich 6i sau khi thu thdp, 6u'dc nudi c l y trong mdi trudng ddc hi6u eua te b6o 6i trong khoang thdi gian tir 10 ngdy, vdi muc dieh nhdn rdng dong t i bdo oi, vd lopi trir t i bdo mdu cua ngydi me.
TCNCYH 81 (1) - 2013
• TAP CHI NGHIEN CUU Y HQC Id nguy6n nhdn gdy anh hudng d i n mirc dp
chinh xdc ciia k i t qua. Do do, thdi gian tra k i t qua e h i n doan t r u d c smh cho b6nh beta tha- lassemia th6ng t h u d n g sau 14 ngdy k i tir thdi d i l m choc 6i Trong s6 60 gia dinh dupe ldm Chan dodn trudc sinh, c6 15 gia 61nh md thai nhi 6 y a c k i t ludn mde beta Thalassemia t h i ndng Chung t6i dd k i t hap vdi bdc sy ldm sdng, cting nhu cde dan vi san khoa trong viee t u v l n di t r u y i n d6i vdi cdc gia dinh ndy
V. K^T LUAN
Trong 9 d6t bien sdng loe, alen 66t bien eP ty 16 cao n h l t Id CD17(AAG-TAG) 18/120, CD41/42(-TCTT) 18/120: va HbE (GAG >
AAG) 8/120
Ky thuat ARMS-PCR vd ky thudt giai trinh t u gen id nhO'ng ky thudt di t r u y i n hipn dai, nhanh eh6ng, co 66 chinh xdc cao
TAI LIEU THAM KHAO
1. Biii Van Vien, Duo-ng Ba Tryc, Nguyen Cong Khanh (1999). Nhan xet budc d i u c a s d dl t r u y i n phan tir va m i i quan h6 gitra k i l u gen vdi mirc 36 t h i i u mau va t h i tieh h i n g c l u trong benh HbE/b Thalassemia Tap chi Nhi khoa, S; 12 - 7.
2. Hoang Van Ngpc (2007). Nghien ciru thuc trang benh (3 thalassemia vd m6t s6 y i u t i Ii6n quan d tre em ddn tde Tdy vd Dao tai huyen Dmh H6a - tinh Thai Nguyen Ludn vdn thae sy
3. Nguyen Cong Khanh (1993). T i n s u i t b6nh hemoglobin d Viet Nam V hoc Vi$t Nam, 8: 11 - 6 .
4 Nguyin K h I c Han Hoan (2010). C h i n dodn di t r u y i n phdn t u bpnh beta thalassemia tpi b6nh vipn Tir DQ, Bdo cdo khoa hpc.
Trw&ng Dai hoc Y dwQC Thdnh phd Hd Chl Mmh Thdnh pho Ho Chi Minh
5. L6 Thj Hao (2001), Nghi6n ciru irng dyng ky thudt di truyin phan t u phdt hi6n d6t b i l n gen gdy benh beta thalassemia tai Viet Nam, Bdo cdo khoa hoc, Trudng Dai hoc Y d u o c Thdnh p h i HP Chi Mmh
6. H.M.Aderson, H.M.Ranney (1990).
"Southeast Asian Immigrant The new Thallas- semia in Amencans", Seminars in Hematol- ogy, 27 (3), 239 - 246
7. HH Jr Kazazian, CE Dowling, PC Wa- ber et al (1986). The spectrum of beta- thalassemia genes in China and Southeast Asia The American Society of Hematology 68: 964 - 966
8. Imran-ud-din Khattak, Sania Tanwwer Khattak, Jehanzeb Khan (2006). Heterozy- gous beta thalassemia in patients of children Vi/ith beta thalassemia major Gamal Journal of Medical Sciences July-Dec 2006. 4, 2
9. M.L. Saovaros Svasti, Tran Minh Hieu, Thongperm munkongdee et al.(2002). Mo- lecular analysis of beta thalassemia in South Vietnam American Journal of Hematology 71 8 5 - 8 8
Summary
PRENATAL DIAGNOSIS FOR BETA THALASSEMIA USING MOLECULAR TESTING AT THE NATIONAL PEDIATRICS HOSPITAL
Prenatal diagnosis for fetuses with high risk of major beta thalassemia is one of the most strategies of public health. The objective of the study was to find mutations on Hbb gen for for fetuses with high risk of major beta thalassemia The result showed that a rate of 9 common mutations was found, including 3 highest common mutations at CD17{AAG-TAG ) at 15 %,
TCNCYH 81 (1) - 2013
TAP CHi NGHIEN CU'U Y HQC ' CD41/42(-TCTT) at 15 %, and HbE (G>A) at 6,7% 15 fetuses were found to be beta thalassemia
major, 35 fetuses were not found to be beta thalassemia major, In conclusion, using ARMS-PCR technique to find mutations on Hbb gene not only is important for prenatal diagnosis, but is very useful and helpful for preventive public health.
Key w o r d s Beta thalassemia, Prenatal d i a g n o s i s , ARMS-PCR, Multiplex ARMS-PCR
U'NG DUNG KY THUAT SINH HOC PHAN TU' TRONG PHAT HIEN DOT BI^N GEN a GLOBIN CUA BENH a THALASSEMIA
Ngd D i l m Ngpc^*, Ly Thj Thanh Ha^", Du-o-ng Ba Tru-c^, Bui Van Vien^
T r i n T h j Thanh Huo-ng'
^Khoa Dl tmyin vd Sinh hpc phdn tif - Bpnh Vipn Nhi Tmng wong
^Khoa Huyet hpc ldm sang - Bpnh Vipn Nhi Trung uong
^Bp mdn Y Sinh hpc Oi truyin - Tru&ng Dpi Hpc YHa Npi Alpha (a) thalassemia la bpnh di truyin Idn tren nhiem sde the thw&ng, dac trung b&i sw suy giam ho$c thieu hut tdng hpp chuoi a globin trong phdn tw hemoglobin. Nghien cim nhim phat hipn dpt biin gen a globin a cac benh nhan a thalassemia bdng ky thupt sinh hpc phan tw Kit qud cho thiy ngwai HbH mang kiiu gen (--^Ai/HbCs) 9/15ngua, (--SE/V-a3.7). 5d5nguoi, (--SEA/HbQs) 1/15ngua Ngw&i mang gen benh dl hap tie (Het) dot bien (-- SEA). 64 1%, Het HbCs. 25 6%. Het a3.7 51%. Ap dung ky thuat multiptex-PCR.
C-ARIVS-PCR da phdt hien cac ddt biin thw&ng gap tren gen a globin. Day la ca sa de chin doan benh a thalassemia, dac bipt trong chin doan trw&c sinh
Tu khoa: a thalassemia, C-ARMS-PCR, multiptex-PCR
I. DAT
VANDt
a thalassemia la mot trong cae benh di truyin pho b i i n n h l t tren t h i gidi va la nguyen nhan gay t h i l u mau tan mdu hdng dau d tre em, do d6t b i i n gen a globin tren nhiem s l e t h i s6 16 (16p13 3), gdy nen tinh trpng suy giam hodc m l t chire nang tong hop chudi a globin [1]. T i n s u i t bPnh a thalassemia phdn bo khac nhau tuy theo tirng quoc gia, chiing t6c, va tiiy theo s u phdn bo ciia ngudi mang gen benh a""-thalassemia vd a°-thalassemia Dia Chilian he Ngo Diem Ngpc ~ Khoa Di truyen va Smh hoc phan tu; benh Vv$n Nhi Trung uong
Email ngo_ngoc_diem@yahoo com Ngaynh$n 26/11/2012 Ngay dupe chap thuan 15/3/2013
[2], Tai Trung Qudc, t i n s u i t nay la 5 - 15%
ddn s i , tai Hong Kong Id 4 % [3], tai Thailand Id 15 - 30% [4], tai Lao 16 4 3 % [5]
Ngudi blnh t h u d n g c6 tong so 4 gen a globin, n l m tr6n hai n h i l m s i c t h i s i 16 tuong dong, trong 66 mdi n h i l m s i c t h i s i 16 cd 2 gen a globin (oa/oo) N l u mpt gen bi dot b i i n (dl hpp t u a''-thalassemia; -a/aa), duoc gpi id ngudi mang gen benh, kh6ng eo bieu hien Idm sdng. N l u dPt b i l n xay ra d hai gen tren m6t n h i l m sde t h i (di hap tir a"- thalassemia; - / a o ) , hodc tren hai nhilm sic the (ddng hpp tir oMhalasemia; -a/-a), se co b i l u hien lam sang va h u y i t hoc nhe hoae rat nhe, N i u d6t bien xay ra d ba gen (-/-a), se gdy benh h u y i t s i c to H (HbH) vdi bieu hiPn nhu mot thalassemia the trung gian. N i u mlt
TCNCYH81 (1)-2013
