Tgp chi THONG TIN YDlfOC Sd 9 ndm 2010
SANG LOG Sff SINH
Hoang Van Sdn*
Sang Igc sd sinh (NBS - newborn screening) la mgt phddng hddng quan trgng, nham phat hien sdm nhieu benh di truyen va bam sinh td trddc khi co trieu chdng, de'dda ra phddng phap dieu tri kip thdi ngay tdkhi tre mdi ra ddi, nham han che hoac xdly cac hau qua cua benh, nhd vay se cd hieu qua hdn nhieu so vdi dieu tri luc trieu chdng da the hien.
Cd rat nhieu benh di truyen va bam sinh, mdt sd benh da dUdc ehan doan va cd phUdng phap dieu trj. Tren ed sd phdng benh la chfnh, nhieu nUde da dUa ra nhiJng ehUdng trinh chan doan trUde sinh va sang lpc tre sd sinh. Nhieu nUde phat trien da tien hanh tU lau cac chUdng trinh sang lpc sd sinh, mdt sd nUdc da thanh luat bat budc tiit ca cae tre khi sinh ra deu phai xet nghiem mdt vai benh thudc chUdng trinh sang lpc sd sinh qude gia.
I. CHUaNG TRINH SANG LOC SQ SINH 1. Benh du'dc sang Igc
ChUdng trinh sang lpc sd sinh phai dap ling cac tieu chuan chii yeu sau (Wilson va Jungner, To chUc Y te The gidi (WHO) 2008):
- Benh tat &\i(iz sang lpc nam trong sd nhiJng benh ed tan suiit khdng qua thiip va neu ehan doan dUdc sdm thi se ed ldi cho dUa tre.
- Cd phUdng phap dieu trj, tU van thieh hdp.
- Cd phUdng phap xet nghiem thieh hdp.
Tan suiit mac benh bam sinh di truyen cd the khae nhau theo chiing tde, dja dU, nhUng eung ed nhieu benh cd tan suat khdng khae nhau nhieu d cae nUdc.
Bao cao nam 2005 eiia Hdi Di truyen Y hpc Hoa Ky (American college of medical genetics - ACMG) eho thay tan suat eiia 10 benh hay gap tai My nhUsau:
Bang 1: Tan suat benh bam sinh, di Tt
1 2 3 4 5 6 7 8 9 10
T;
gde F l/40(
bam thieu dehy hayc chau Hai.
thieu trinh (Huy Cdnc rd:
chiir dan
Ten benh Suy giap bam sinh Xd nang
Thieu mau hong cau liem Tang san thUdng than bam sinh Phenylxeton - nieu
Beta - thalassemia Galactose - huyet Thieu biotinidase Acid propionic - huyet Acid glutaric - huyet typ 1
an suat nay ed khae mdt chiit d ngU 'hi, riit cao vdi thieu mau hdng eau ). Bao cao khdng ndi den mdt sd sinh di truyen khae, trong do cd
enzym glucose-6-phos drogenase (G-6-PD) la mdt benh va jap nhat tren the gidi, dac biet d eae Phi, nhieu nUde chau A, vung Dja "
Thdng ke eho thay ed tdi 400 trieu enzym nay d mUe dp khae nhau.
nghien cUu eiia mdt sd tae gia Viet nh Cdng Chanh, Hoang Van Sdn, Nc ) Khanh,...) each day tren 30 nam d tan suat thieu G-6-PD khae nhau g toe, thap d ngUdi kinh, eao d m tdc it ngUdi tai Viet Nam.
truyen d Hoa Ky Loaibenh Roi loan ndi tiet
Dot bien gen Roi loan te bao mau Roi loan ndi tiet
Roi loan chuyen hda acid amin Rdi loan te bao mau
Roi loan chuye'n hda hydrat carbon Rdi loan chuyen hda acid hQ'u cd Rdi loan chuyen hda acid hCfu cd Roi loan chuyen hoa acid hQ'u cd di My
liem:
benh benh phate 0 loai nUde Trung ngUdi Cdng Nam 3uyin a neu
theo dt sd
DUa tren tinh hinh thU benh, dieu kien ky thuat, cac nUdc dUa ra nhiJng ch sd sinh khae nhau. Nhin cl ed hai benh dUdc sang lpc bam sinh, benh xd nang. ( dau chUdng trinh sang lpc CLTU benh suy giap bam (Nguyin Thu Nhan, Nguye Van Sdn, Phan Sy An). Nh nhd sU dung eae ky thuat phd ky (tandem mass spec hpe) da phat hien dUde truyen mdi, nhUng vi tan thiip, td chUe va kinh phf ci' phat hien chUa dap li'ng (
Tan suat mac benh 1/5000 1/5000 1/5000 1/25000 1/25000 1/50000 1/50000 1/75000 1/75000 1/75000 : te (tan suiit mac tai chinh, td chUe), Jdng trinh sang lpc lung, tren the gidi, phd bien: suy giap
? Viet Nam, da bat cd tinh chat nghien sinh tU nam 1998 n Thj Hoan, Hoang
iJng nam gan day, hien dai nhU khdi :trometry, chip sinh nhieu rdi loan di sueit tim dUdc raft lUa thieh hdp, benh :ac tieu chuan chii
*PGS.TS., Hpi Hda sinh Y hpc Viet Nam
Tgp chi THONG TIN YDU'OC So 9 ndm 2010
yeu neu tren, do do chUa dUa cac rdi loan do vao chUdng trinh sang Igc sd sinh.
2. Ky thuat sang Igc
Phd bien nhiit la lay mau d gdt chan tre sd sinh, lify mau day rdn khi tre mdi Ipt Idng.
Ngoai ra, cdn lay nUdc tie'u sd sinh. 6 nhieu nUdc dang phat trien, lay mau d gdt chan khd dUdc cae ba me hUdng Ung. Can thuyet phuc de lam viee nay, vi day la phUdng phap cd Uu die'm hdn lay mau day rdn, nhiit la khi dung ky thuat xet nghiem khdi pho thi lay mau day rdn it cd gia trj. Thdi gian liiy mau: cang sdm cang tdt khi dUa tre dUdc sinh ra, ed the lay trong vdng 48-72 gid ke tU khi sinh.
Thiim mau (vai gipt) vao mdt loai giiiy chat IUdng eao, thudng la giay Whatman 903, hoac thiim vao tam thU (card) chuyen dung (ban san) nhu tam thU Guthrie (sang lpc phenylxeton- nieu). Oe khd giiiy hoac tiim thU d nhiet dp phdng rdi dUa tdi phdng xet nghiem hoac giii qua dudng bUU dien, qua dUdng van chuye'n.
Lay mUde tieu sd sinh bang each thiim nUde tieu vao loai giify tham rieng, dat trong ta Idt. Tuy cd nhiJng bao eao ndi rang sang lpc
phenylxeton-nieu bang nUde tieu khdng ehinh xae bang djnh IUdng phenylalanin trong mau nhUng khi dung ky thuat khdi phd de xet nghiem thi dung nUde tieu lai cd nhiJng thuan ldi nhiit djnh.
Sau khi lay mau hoac nUde tieu, phai chuye'n ngay benh pha'm den phdng xet nghiem de tien hanh sang Ipe bang cac ky thuat tUdng Ung. Cac ky thuat khdi phd va chip sinh hpc la nhiJng ky thuat mdi, ed the phat hien nhieu benh ciing mdt liic. L/de tinh cd 25 rdi loan bam sinh ve chuye'n hda mdi 6\Jdc phat hien gan day.
Ky thuat sang lpc la bUde dau, neu cho ket qua dUdng tfnh thi can phai tien hanh cae xet nghiem tiep theo de xae djnh ehan doan.
I I . SANG LOC BENH LY
Bang 2 neu eac benh dUde sang lpc phd bien tren the gidi hien nay. Tuy theo tan suiit mae theo dja dU hoac ehiing tde, ehUdng trinh sang lpc d eac nUde ed khae nhau. Thi du:
thieu G-6-PD phd bien d Ddng Nam A, Dja Trung Hai, nhUng lai ft d Au My. Xd nang phd bien d Au My, lai ft d A-Phi.
Bang 2: Cac benh dUdc sang loc phd Benh
Suy giap bam sinh
Xd nang
Thieu G-6-PD
Phenylxeton- nieu Tang san thUdng than bam sinh Galactose- huyet
Tan suat mac 1/3000-1/4000
1/2500-1/5000
1/50-1/5000
1/12000-1/14000
1/12000-1/18000
1/50000
dien hien nay
Nguyen nhan
Roi loan td'ng hdp hormon giap trang gay thieu hormon nay, hoac khang the truyen tU me sang
Dot bien gen CI=TR (cystic fibrosis transmembrane conductance regulator) gay rdi loan van chuye'n clorua qua mang bieu mo.
Di truyen lan lien ket tren nhiem sac the X, Hemoglobin de bj oxy hoa gay huyet tan
Dot bien gen phenylalanin hydroxylase (PAH) lam tang phenylalanin
Di truyen lan, thieu enzym 21- hydroxylase gay thieu Cortisol, giam san xuat mineralocorticoid
Di truyen lan, thieu enzym galactose-1- phosphat uridyl transferase
Bleu Men Thieu nang tri tue va the lUc
Suy tuy tang hay nhiem triing phoi, ho man tinh Thieu mau; tang bilirubin sd sinh; huyet tan lien quan den sU dung thuoc Cham phat trien tinh than va van dong; nao nhd, co qiat
l^at nUdc, mat muoi, cd the chet sau khi sinh. Gay gia day thi tre em, chuyen gidi d tre gai
Thieu nang tri tue; gan to, suy gan, vang da
1. Suy giap bam sinh
Day la mdt benh ndi tiet vao loai phd bien nhiit trong cac benh tuyen giap, sau bUdu cd.
Benh gay thie'u nang tri tue va the lUc, phat trie'n cd the kem, gay lun, dan ddn. 6 giai doan sd sinh, tre khd thd, tim tai, vang da, an kem. Neu dieu trj sdm sau khi phat hien dUdc
qua xet nghiem sang Ipe va xet nghiem khang djnh, sU dung hormon tuyen giap ngay trong tUan l i dau sau khi sinh, se ngan ngUa hoac cai thien dUde tinh trang benh, nhiit la cham phat trie'n tri tue sau nay.
Xet nghiem sang lpc suy giap bam sinh bang each djnh IUdng TSH lay d mau gdt chan tre sd sinh la
Tgp chi THONG TIN YDlfOC Sd 9 ndm 2010
phUdng phap phd bien. 6 Viet Nam, tU nam 1998-2001, eac tae gia Nguyin Thu Nhan, Nguyin Thj Hoan, Hoang Van Sdn, da tien hanh chUdng trinh sang lpc benh nay, dung mau cudng rdn, djnh IUdng TSH cho 4860 tre sd sinh, chUa phat hien dUdc trUdng hdp nao bj benh.
Tuy nhien, day mdi la chUdng trinh thi die'm.
Mdt sd tae gia: Kemfers, Lanting, Van Heijst (2006) Rose, Brown (2006), da phdi hdp djnh IUdng TSH, T4, thyrotropin, thyroxine-binding globulin (TBG) de sang Ipe suy giap d tre sd sinh. Cung ed y kien cho rang cac xet nghiem phdi hdp nay cho ket qua dUdng tinh gia nhieu hdn khi chi djnh IUdng TSH. Delange, Travers, Guttikonda, Norton (2006) IUu y: tinh trang thieu iod la mdt nguyen nhan quan trpng dan den suy giap bam sinh. Do do, can quan tam den viec bao dam dii iod eho ngUdi me cd thai.
2. Benh xd nang
Benh nay phd bien d eac nUdc Au - My hdn d eac nUde PhUdng Dong, gay ra do eac dot bien d gen CFTR, ed tdi tren 1500 dot bien.
NhUng chi cd vai dot bien chinh gay benh d 70% sd benh nhan. Benh gay suy tuy tang d 85-90% benh nhan, 50% benh nhan ed nhiJng bieu hien d phd'i, the hien rd nhiit la ho, tai phat nhieu lan, nhiim trung phd'i nhieu lan dan tdi man tfnh. Benh cdn gay vd sinh d ca nam va niJ, nhieu trUdng hdp khdng cd tinh trung.
Neu phat hien sdm va dieu trj bang vat ly trj lieu, bang khang sinh sdm thi benh se dUde cai thien rd ret. Tuy nhien, benh nhan thUdng chet d tud'i thanh nien. Neu dieu trj sdm va tfch cUc, thdi gian sdng se keo dai hdn.
Chan doan sang Ipe sd sinh dUa tren xet nghiem clorua trong md hdi. Neu IUdng clorua vUdt qua 60mmol/l, tu'c la ed benh. Clorua dudi 40mmol/l gap d ngUdi mang gen benh, khi dd can kie'm tra anh em, hp hang. Sau khi sang Ipe can djnh IUdng trypsin phan Ung mien djch (IRT- immunoreactive trypsin) de xae djnh ehan doan (Hammond, Abman, 1991; Massie, Clements, 2005). Cac tac gia Sarles, Berthezene, Le Louarn (2005) edn de nghj phdi hdp xet nghiem IRT vdi protein lien ket tuy. Trong nhiJng trUdng hdp phUe tap, cd the sU dung ky thuat phan tU, tim eae dot bien ciia CFTFi (Parad, Comeau, 2005).
3. Phenylxeton-nieu
Benh gay ra do sU dot bien gen Phenylalanin hydroxylase (PAIH) khien nd khdng chuye'n dUde phenylalanin thanh tyrosin de thai ra khdi cd the. Phenylalanin tieh tu
trong mau va dUde bai xuiit vdi IUdng bat thudng ra nUde tieu, mdt sd dUdc chuyen thanh acid phenylpyruvie, acid nay lai chuyen hda thanh eac acid phenylaeetie, phenyllactic, phenylpyruvie va bai xuat ra nUde tieu. Do dd, cd ten benh phenylxeton-nieu. Benh khdng cd trieu chUng gi, den khi xuiit hien eae trieu ehUng than kinh, phan xa, hieu ddng, cham phat trie'n tinh than, co giat, thi da eham. Do dd, xet nghiem sang lpc tre sd sinh la rat quan trpng. Xet nghiem Guthrie do Robert Guthrie dUa ra nam 1960 nham mue dieh nay va xet nghiem Guthrie ehinh la xet nghiem sang lpc dau tien eho tre sd sinh tren the gidi. Khi ket qua dUdng tinh, eho tre an che dp it phenylalanin that sdm, se han che dUdc riit nhieu tinh trang eham phat trie'n than kinh va van ddng sau nay vi phenylalanin tae hai den sU phat trien eiia nao. LUdng phenylalanin trong mau vUdt 200Mmol/l ehUng td ed benh. Theo ddi benh nhan sau nay bang each djnh IUdng eac acid amin trong mau. Gan day, ngUdi ta edn dung ky thuat khdi phd MSMS de djnh IUdng phenylalanin, nhanh va chfnh xae hdn. Cac tac gia Kure, Hou, Ohura, Iwamoto, Suzuki (1999), Blau, Eriandsen (2004) da chUng minh tetrahydrobiopterin dap Ung dUde tinh trang thieu PAH, ed the dung de dieu trj benh nay.
4. Tang san thu'dng than bam sinh Day la benh di truyen lan, gay ra do dot bien gen CYP21 khien cho khdng tdng hdp dUdc enzym 21-hydroxylase (21-OH). Thieu enzym nay, nen 17-hydroxyprogesterone (17- OHP) khdng chuye'n thanh Cortisol va deoxyeortieosteron khdng chuyen thanh aldosteron, giam san xuat mineralocorticoid, lam cho thUdng than bj suy. Cortisol giam lam tang tiet ACTH, khien cho eae tien chat trUdc cho tac tang len, androgen tang len gay nam tfnh hda. Cd hai the: mat mudi va nam hda ddn thuan. Mat mudi cd the cd nhiJng cdn kich phat chet ngUdi. Nam hda d tre gai, gia day thi d tre trai eung nhU tre gai, eham phat trie'n cd the. Khi dUde ehan doan sdm, viee dieu trj bang hormon nhU hydroeortison,... se han che bdt eae tae hai, nhiit la hien tUdng mait mudi trong thdi gian sd sinh, tranh dUde tU vong.
Chan doan sang lpc sd sinh dUa tren djnh IUdng 17-Hydroxyprogesterone bang ky thuat miin djch, eho ket qua eao (IUdng 17-OHP d tre em binh thUdng <50ng%). Theo White (2009), the nhe ciia benh khd phat hien dUdc bang ky thuat sang lpc vi 17-OHP khdng tang
Tgp chi THONG TIN YDlfOC So 9 ndm 2010
trong thdi gian sd sinh. Khi ket qua nghi ngd, can lam nghiem phap kich thfch vd thUdng than bang Synacthen de xae djnh cha'n doan (New, Lorenzen, Lerner, Kohn, 1983). Cung can chii y: tre sinh non thang, sinh ra nhe can cung cd 17-OHP cao, gay khd khan cho chan doan. Gan day, cac tae gia Janzen, Peter, Sander, Sehwarz, Liu, Randall (2007-2009) da dung ky thuat sac ky Idng phdi hdp khdi phd MS/MS de djnh IUdng 17-OHP, dUa ra nhiJng ket qua va ehan doan tang san thUdng than
bam sinh ehinh xae hdn. , 5. Galactose-huyet
Benh nay do thieu enzym Galaetose-1- phosphat uridyl transferase (GALT) nen galactose khdng 6\S(ic chuyen thanh glucose va U dpng trong mau ciing vdi galactose-1- phosphat, ddng thdi cung tim thiiy trong nUdc tieu benh nhan. Galaetose-1-phosphat iJ dpng trong te bao, can thiep vao nhieu qua trinh chuye'n hda. Khi mdi sinh ra, dUa tre ed ve binh thudng. NhUng khi bat dau eho bii siJa, tre ndn, chan an, vang da va khdng phat trie'n binh thudng. Gan to ra, bat dau phii, cd ed trUdng. Neu khdng dUdc dieu trj, tre se kem phat trien ca the lUc va tinh than. Do dd, can sang lpc dUa tre khi mdi sinh bang each djnh IUdng GALT va galactose-1-phosphat trong hong cau lay d cudng rdn: ndng dp GALT rift thap, galactose-1-phosphat tang cao chUng td mac benh (Diepenbrock, Heckler, Schiekling, Engelhard, 1992). Cae tae gia Fieicioglu, Thomas,Yager, Gallagher (2008) neu len: cac the GALT nhe, nhU the Duarte, van cd hoat dp GALT thiip, nhuhg cae the' nay khdng can dieu trj.
Khi chan doan rift sdm nhd sang Ipe tre sd sinh, thi thUe hien che dp dinh dUdng hoan toan khdng cd sUa va cac san pha'm ciia sUa va dung s(Ja td'ng hdp khdng ed galactose va lactose sudt ddi. NhU vay, tre cd the phat trie'n binh thudng, nhUng trf tue van kem. Dieu quan trpng la tranh dUdc tU vong sdm eho tre.
Schweitzer-Krantz, Waggoner, Buist (2003) cung neu: tuy dUde ehan doan sdm va dieu trj, mdt sd tre v i n kem phat trie'n the lUc va tinh than va d niJ gidi nhieu khi bi vd sinh vi suy giam budng trUng.
6. Thieu enzym G-6-PD
Day la mdt benh di truyen lan lien ket tren nhilm sac the X, the hien d nam gidi va niJ
gidi ddng hdp tU. Nam gidi da den cd tan suat mac benh riit eao, tdi 10%. Benh eung phd bien d Odng Nam A, Dja Trung Hai. 6 Viet Nam, mdt sd dan tde it ngUdi eung ed tan suiit mac eao (ngUdi H'Mdng, Cham, Ede,...), ngUdi kinh cd tan suat benh thiip hdn nhieu. Khi phat hien dUdc benh nay, thudng khdng diing thudc dieu trj, chii yeu khuyen eao benh nhan tranh khdng dung cac thudc oxy-hda nhU cac thudc chUa sdt ret (chloroquine, primaquine), aspirin, salicylate, phenacetin, sulfamid, probenecid, vitamin K,... hoac khdng an loai dau Fava, vi eac loai nay gay thieu mau huyet tan do thieu enzym G-6-PD, dan tdi oxy-hda hemoglobin va mang hdng eau. Khi bj huyet tan, benh nhan se vang da, thieu mau, xuiit hien the' Heinz trong mau.
Hoat dp binh thUdng eiia G-6-PD trong hdng eau: 5-15 U/gHb. Khi benh nhan thieu mau, dieu trj bang eac thude ehdng thieu mau.
T A I LIEU THAM KHAO
1. Andermann A., Blancquaert I., Beauchamp S., Dery V.: Revisiting Wilson and Jungner in the genomic age: a review of screening criteria over the past 40 years. Bull World Health Organ 2008, 86, pp.317-319.
2. Castellani C , Souther K.W., Brownlee K., et al: European best practice guidelines for cystic fibrosis neonatal screening. J Cyst Fibros 2009, 8, pp.153-173
3. Grody W.W., Howeli R.R.:The fate of newborn sereening spots. Pediatr Res 2010, 67, pp.237.
4. James J.P.: Newborn Screening. Clin Biochem Rev 2010, 31, pp.57-68
5. Kaplan M., Hammerman C : The need for neonatal glucose-6-phosphate dehydrogenase screening: a global perspective. J Perinatol 2009, • 29 (suppl 1), PP.S46-52.
6. Kugelman A., Riskin A., Bader D., Koren I.:
Pitfalls in screening programs for congenital hypothyroidism in premature newborns. Am J Perinatol 2009, 26, pp.383-385.
7. Misuma H., Wada H., Kawakami M., et al: Galadnse and galadDse-l-phosphate spot test ft)r galadnsemia screening. Qin Chim Ada 1981, HI, pp.27-32.
8. Poilitt R.3.: Newborn blood spot screening: new opportunities, old problems. J Inherit Metab Dis 2009, 32, pp.395-399
9. White P.O.: Neonatal screening for congenital adrenal hyperplasia. Nat Rev Endocrinol 2009, 5, pp.490-498.
10. Wiicken B., Wiley V.: Newborn screening.
Pathology 2008, 40, pp 104-115
11. Williams R.A., Mamotte C D . , Burnett J.R.:
Phenylketonuria: an inborn error of phenylalanine metabolism. Clin Biochem Rev 2008, 29, PP.31-41.S'
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