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65629490-Genetica-Curs.pdf

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TRANSMITEREA INFORMAĠ,(, (5(',7$5( % 75$160,7(5($ ,1)250$ğ,(, *(1(7,&( '( /$ 2 &(/8/Ă /$ &(/8/(/( Ä),,&(´ ÌQ FHOXOHOH VRPDWLFH PDWHULDOXO JHQHWLF GXEODW vQ LQWHUID]ă VH GLVWULEXLH vQ PRG HJDO úL WRWDO celulelor fiice, prin procesul GH GLYL]LXQH PLWRWLFă 5H]XOWă GRXă FHOXOH QRL ÄILLFH´ LGHQWLFH GLQ SXQFW GH YHGHUH JHQHWLF DWkW vQWUH HOH FkW úL FX FHOula ÄPDPă´ GLQ FDUH SURYLQ 3URFHVHOH SULQ FDUH R FHOXOă vúL UHSOLFă PDWHULDOXO JHQHWLF vO GLYLGH HJDO úL vO WUDQVIHUă FHOXOHlor fiice se GHVIăúRDUă vQWU-R RUGLQH SURJUHVLYă SUHFLV UHJODWă FH IRUPHD]ă FLFOXO FHOXODU Controlul ciclului celular GHFLGH vQ XOWLPă LQVWDQĠă GDFă R FHOXOă vúL YD FRQWLQXD SURJUHVLD SULQ FLFOX YD FUHúWH úL VH YD GLYLGH VDX YD VXIHUL R GLIHUHQĠLHUH Vau va trece într-o stare de UHSDXV SUROLIHUDWLY 3LHUGHUHD FRQWUROXOXL FLFOXOXL YD JHQHUD R FUHúWHUH FHOXODUă DQRUPDOă FHOXOH WXPRUDOH GHIHFWH GH GH]YRltare) VDX YD GXFH OD PRDUWH FHOXODUă SURJUDPDWă DSRSWRVLV 6H SRW SURGXFH GH DVHPHQHD erori în segreJDUHD FURPRVRPLORU vQ PLWR]ă FDUH YRU JHQHUD DQRPDOLL FURPRVRPLFH 3HQWUX DFHVWH UDĠLXQL FXQRDúWHUHD SURFHVHORU FH DOFăWXLHVF FLFOXO FHOXODU SUH]LQWă R LPSRUWDQĠă GHRVHELWă SHQWUX vQĠHOHJHUHD XQRU PHFDQLVPH SDWRJHQLFH JHQHUDWRDUH GH EROL 1. CICLUL CELULAR. &LFOXO FHOXODU UHSUH]LQWă VXFFHVLXQHD GH HYHQLPHQWH ELRFKLPLFH úL PRUIRORJLFH FDUH VH SURGXF vQ YLDĠD XQHL FHOXOH GLQ PRPHQWXO IRUPăULL úL SkQă OD VIkUúLWXO GLYL]LXQLL VDOH &LFOXO FHOXODU DUH GRXă PDUL SHULRDGH interfaza úL diviziunea (figura 5.6). Interfaza UHSUH]LQWă SHULRDGD FXSULQVă vQWUH GRXă GLYL]LXQL VXFFHVLYH vQ FDUH VH GHVIăúRDUă WRDWH DFWLYLWăĠLOH VSHFLILFH XQHL celule. Evenimentul cel mai important al interfazei este sinteza de ADN (replicarea), prin care se GXEOHD]ă FDQWLWDWHD GH PDWHrial genetic (4C). Ea se produce într-R SHULRDGă OLPLWDWă D LQWHUID]HL GHQXPLWă faza S 'DWRULWă DFHVWXL SURFHV LQWHUID]D SRDWH IL VXEGLYL]DWă vQ WUHL HWDSH VXFFHVLYH faza G1 SUHVLQWHWLFă faza S GH VLQWH]ă úL faza G2 SRVWVLQWHWLFă VDX SUHPLWRWLFă. 'LYL]LXQHD FHOXODUă sau faza M PLWRWLFă HVWH DOFăWXLWă GLQWU-R VHULH GH SURFHVH VHFYHQĠLDOH SULQ FDUH PDWHULDOXO JHQHWLF $'1 UHSOLFDW vQ LQWHUID]ă VH GLVWULEXLH HJDO úL WRWDO VHJUHJDUH FURPDWLGLDQă IRUPkQG GRL QXFOHL GLVWLQFĠL LDU FHOXOD VH vmparte vQ GRXă FHOXOH ILLFH FLWRNLQH]ă); acestea vor fi identice cu celula din care au provenit (vezi capitolul 1, figura 1.1.B). Prin replicarea ADN-XOXL úL GLYL]LXQH VH DVLJXUă WUDQVPLWHUHD ILGHOă D LQIRUPDĠLHL JHQHWLFH vQ VXFFHVLXQHD JHQHUDĠLLORU FHOXOare. 'XUDWD FLFOXOXL FHOXODU SRDWH YDULD PXOW vQWUH GLIHULWH ĠHVXWXUL GDWRULWă YDULDELOLWăĠLL ID]HL *1 FHOăODOWH ID]H ILLQG UHODWLY FRQVWDQWH FD GXUDWă 3HQWUX R GXUDWă PHGLH GH RUH GXUDWHOH DSUR[LPDWLYH DOH ID]HORU VXQW *1 = 10 ore, S = 9 ore, G2 RUH 0 RUă PERIOADA )$=$ ù, DURATA (ore) EVENIMENTE CANTITATE ADN ASPECT LA MICROSCOPUL ELECTRONIC ,QWHUID]ă G1 (10 h) 6LQWH]ă LQWHQVă GH $51 úL Proteine 2C 2n cromosomi monocromatidieni S (9h) 6LQWH]ă GH $'1 úL KLVWRQH 4C G2 (4h) Sinteza proteinelor fusului de diviziune Sinteza IDFWRUXOXL GH GHFODQúDUHDO PLWR]HL 4C 2n cromosomi bicromatidieni GHVSLUDOL]DĠL Diviziune M (1h) 3URID]ă 0HWDID]ă $QDID]ă 4C 4C &URPRVRPL ELFURPDWLGLHQL FRQGHQVDĠL (vizibili la microscopul optic) 7HORID]ă 2C 2C Cromosomi monocromatidieni 1.1. FAZELE CICLULUI CELULAR MITOTIC a. Faza G1 Faza G1 vQ HQJOH]ă gap LQWHUYDO ODFXQă JRO GHRDUHFH QX L VH FXQRúWHD VHPQLILFDĠLD UHSUH]LQWă ID]D GH VWDUW D FLFOXOXL FHOXODU pentru celulele stimulate (de IDFWRUL GH FUHúWHUH Vă VH GLYLGă (tabelul 5.1). Fiecare cromosom (puternic despiralizat) este monocromatidian, ILLQG DOFăWXLW GLQWU-R VLQJXUă PROHFXOă GH $'1. Cantitatea de material genetic este 2C molecule de ADN sub forma a 2n (46) cromosomi despiralizaĠL ÌQ SULPD SDUWH D ID]HL *1 (G1A), se produce o VLQWH]ă LQWHQVă GH VXEVWDQĠH $51 SURWHLQH) QHFHVDUH FUHúWHULL úL IXQFĠLRQăULL FHOXOHL 6H DFXPXOHD]ă $51 úL SURWHLQH SkQă OD R FRQFHQWUDĠLH SUDJ QXPLWă SXQFW GH UHVWULFĠLH 5 GXSă FDUH FHOXOHOH WUHF vQ subfaza G1B, fiind FRQGLĠLRQDWH Vă LQWUH vQ ID]D 6 úL Vă VH GLYLGă (figura 5.6). 1 ÌQ DQXPLWH FRQGLĠLL OLSVD IDFWRULORU GH FUHúWHUH SUH]HQĠD XQRU LQKLELWRUL DL VLQWH]HL SURWHLQHORU HWF FHOXOHOH DIODWH vQ subfaza G1A pot trece într-R ID]ă GH activitDWH PHWDEROLFă UHGXVă QXPLWă ID]D G0 sau G1Q (de la "quiescence" - UHSDXV OLQLúWH vQ FDUH UăPkQ YLDELOH úL SRW VXSUDYLHĠXL WLPS vQGHOXQJDW 'DFă DFHVWH FRQGLĠLL UHVWULFWLYH GLVSDU FHOXOHOH *0 pot reveni în G1 úL DSRL pot progresa spre faza S, deoarece vúL SăVWUHD]ă FDSDFLWDWHD GH GLYL]LXQH )D]HOH *1 úL *0 VXQW GRXă VWăUL IL]LRORJLFH GLVWLQFWH DOH celulei. Unele celule aflate în subfaza G1$ VXE LQIOXHQĠD XQRU LQGXFWRUL DL GLIHUHQĠLHULL SăUăVHVF GHILQLWLY FLFOXO FHOXODU úL WUHF vQ ID]D G1D, ce corespunde FHOXOHORU GLIHUHQĠLDWH HOH QX VH PDL GLYLG úL PRU GXSă XQ DQXPLW WLPS b. Faza S )D]D 6 vQ HQJOH]ă synthesis"- VLQWH]ă VH FDUDFWHUL]HD]ă SULQ sinteza de ADN UHDOL]DWă SULQ UHSOLFDUHD VHPLFRQVHUYDWLYă úL sinteza de histone (vezi capitolul 5.A). ÌQ DFHDVWă ID]ă FDQWLWDWHD WRWDOă GH $'1 & WUHEXLH Vă ILH UHSOLFDWă FRPSOHW GDU QXPDL R VLQJXUă GDWă VH SURGXFH DVWIHO R dublare D FDQWLWăĠLL GH PDWHULDO JHQHWLF & FRQGLĠLH REOLJDWRULH SHQWUX GHVIăúXUDUHD GLYL]LXQLL FHOXODUH 1XPăUXO GH FURPRVRPL UăPkQH GDU ILHFDUH FURPRVRP YD IL ELFURPDWLGLDQ DOFăWXLW GLQ GRXă FURPDWLGH LGHQWLFH "surori"), deci va FRQĠLQH GRXă PROHFXOH GH $'1 Replicarea ADN în faza S este DVLQFURQă XQHOH VHJPHQWH GH $'1 ERJDWH vQ SHUHFKL GH ED]H *-& VH UHSOLFă precoce, la începutul fazei S, iar alte segmente (bogate în perechi de baze A-7 VH UHSOLFă tardiv OD VIkUúLWXO ID]HL 6 ,QIRUPDĠLL SUHFLVH GHVSUH 1 Poziŗia punctului de oprire G1 este incertĈ, fie aproape de faza S, fie la mijlocul fazei G1 1
Transcript

TRANSMITEREA INFORMAĠ,(,��(5(',7$5(�� %��75$160,7(5($��,1)250$ğ,(,��*(1(7,&(� '(��/$��2��&(/8/Ă��/$��&(/8/(/(��Ä),,&( ́

ÌQ�FHOXOHOH��VRPDWLFH��PDWHULDOXO�JHQHWLF�GXEODW�vQ�LQWHUID]ă��VH�GLVWULEXLH�vQ�PRG�HJDO�úL�WRWDO celulelor fiice, prin procesul GH�GLYL]LXQH�PLWRWLFă��5H]XOWă�GRXă�FHOXOH�QRL��ÄILLFH´���LGHQWLFH�GLQ�SXQFW�GH�YHGHUH�JHQHWLF��DWkW�vQWUH�HOH��FkW�úL�FX�FHOula �ÄPDPă´��GLQ�FDUH�SURYLQ��3URFHVHOH�SULQ�FDUH�R�FHOXOă�vúL�UHSOLFă�PDWHULDOXO�JHQHWLF��vO�GLYLGH�HJDO�úL�vO�WUDQVIHUă�FHOXOHlor fiice se GHVIăúRDUă�vQWU-R�RUGLQH�SURJUHVLYă��SUHFLV�UHJODWă��FH�IRUPHD]ă�FLFOXO�FHOXODU��Controlul ciclului celular GHFLGH�vQ�XOWLPă�LQVWDQĠă�GDFă�R�FHOXOă�vúL�YD�FRQWLQXD�SURJUHVLD�SULQ�FLFOX��YD�FUHúWH�úL�VH�YD�GLYLGH��VDX�YD�VXIHUL�R�GLIHUHQĠLHUH�Vau va trece într-o stare de UHSDXV�SUROLIHUDWLY��3LHUGHUHD�FRQWUROXOXL�FLFOXOXL�YD�JHQHUD�R�FUHúWHUH�FHOXODUă�DQRUPDOă��FHOXOH�WXPRUDOH��GHIHFWH�GH�GH]YRltare) VDX�YD�GXFH�OD�PRDUWH�FHOXODUă�SURJUDPDWă��DSRSWRVLV���6H�SRW�SURGXFH�GH�DVHPHQHD�erori în segreJDUHD�FURPRVRPLORU�vQ�PLWR]ă�FDUH�YRU�JHQHUD�DQRPDOLL�FURPRVRPLFH��3HQWUX�DFHVWH�UDĠLXQL��FXQRDúWHUHD�SURFHVHORU�FH�DOFăWXLHVF�FLFOXO�FHOXODU�SUH]LQWă�R�LPSRUWDQĠă�GHRVHELWă�SHQWUX�vQĠHOHJHUHD�XQRU�PHFDQLVPH�SDWRJHQLFH�JHQHUDWRDUH�GH�EROL�

1. CICLUL CELULAR.

&LFOXO�FHOXODU�UHSUH]LQWă�VXFFHVLXQHD�GH�HYHQLPHQWH�ELRFKLPLFH�úL�PRUIRORJLFH�FDUH�VH�SURGXF�vQ�YLDĠD�XQHL�FHOXOH��GLQ�PRPHQWXO�IRUPăULL�úL�SkQă�OD�VIkUúLWXO�GLYL]LXQLL�VDOH��&LFOXO�FHOXODU�DUH�GRXă�PDUL�SHULRDGH��interfaza úL�diviziunea (figura 5.6). Interfaza UHSUH]LQWă�SHULRDGD�FXSULQVă�vQWUH�GRXă�GLYL]LXQL�VXFFHVLYH��vQ�FDUH�VH�GHVIăúRDUă�WRDWH�DFWLYLWăĠLOH�VSHFLILFH�XQHL�celule. Evenimentul cel mai important al interfazei este sinteza de ADN (replicarea), prin care se GXEOHD]ă�FDQWLWDWHD�GH�PDWHrial genetic (4C). Ea se produce într-R�SHULRDGă�OLPLWDWă�D�LQWHUID]HL��GHQXPLWă�faza S��'DWRULWă�DFHVWXL�SURFHV��LQWHUID]D�SRDWH�IL�VXEGLYL]DWă�vQ�WUHL�HWDSH�VXFFHVLYH��faza G1 �SUHVLQWHWLFă�� faza S �GH�VLQWH]ă��úL�faza G2 �SRVWVLQWHWLFă�VDX�SUHPLWRWLFă�. 'LYL]LXQHD�FHOXODUă sau faza M ��PLWRWLFă���HVWH�DOFăWXLWă�GLQWU-R�VHULH�GH�SURFHVH�VHFYHQĠLDOH�SULQ�FDUH�PDWHULDOXO�JHQHWLF��$'1���UHSOLFDW�vQ�LQWHUID]ă��VH�GLVWULEXLH�HJDO�úL�WRWDO �VHJUHJDUH�FURPDWLGLDQă��IRUPkQG�GRL�QXFOHL�GLVWLQFĠL��LDU�FHOXOD�VH�vmparte vQ�GRXă�FHOXOH�ILLFH��FLWRNLQH]ă); acestea vor fi identice cu celula din care au provenit (vezi capitolul 1, figura 1.1.B). Prin replicarea ADN-XOXL�úL�GLYL]LXQH�VH�DVLJXUă�WUDQVPLWHUHD�ILGHOă�D�LQIRUPDĠLHL�JHQHWLFH vQ�VXFFHVLXQHD�JHQHUDĠLLORU�FHOXOare. 'XUDWD�FLFOXOXL�FHOXODU�SRDWH�YDULD�PXOW�vQWUH�GLIHULWH�ĠHVXWXUL��GDWRULWă�YDULDELOLWăĠLL�ID]HL�*1��FHOăODOWH�ID]H�ILLQG�UHODWLY�FRQVWDQWH�FD�GXUDWă��3HQWUX�R�GXUDWă�PHGLH�GH����RUH��GXUDWHOH�DSUR[LPDWLYH�DOH�ID]HORU�VXQW��*1 = 10 ore, S = 9 ore, G2 ���RUH��0� ���RUă�� PERIOADA )$=$�ù,�

DURATA (ore) EVENIMENTE CANTITATE

ADN ASPECT LA MICROSCOPUL ELECTRONIC

,QWHUID]ă G1

(10 h) 6LQWH]ă�LQWHQVă�GH�$51�úL Proteine

2C 2n cromosomi monocromatidieni

S (9h)

6LQWH]ă�GH�$'1�úL�KLVWRQH 4C

G2

(4h) Sinteza proteinelor fusului de diviziune Sinteza IDFWRUXOXL�GH�GHFODQúDUHDO�PLWR]HL

4C 2n cromosomi bicromatidieni GHVSLUDOL]DĠL

Diviziune M (1h)

3URID]ă 0HWDID]ă $QDID]ă

4C 4C

&URPRVRPL�ELFURPDWLGLHQL�FRQGHQVDĠL�(vizibili la microscopul optic)

7HORID]ă 2C 2C Cromosomi monocromatidieni

1.1. FAZELE CICLULUI CELULAR MITOTIC a. Faza G1

Faza G1 �vQ�HQJOH]ă�gap – LQWHUYDO��ODFXQă��JRO�– GHRDUHFH�QX�L�VH�FXQRúWHD�VHPQLILFDĠLD��UHSUH]LQWă�ID]D�GH�VWDUW�D�FLFOXOXL�FHOXODU��pentru celulele stimulate (de IDFWRUL�GH�FUHúWHUH��Vă�VH�GLYLGă�(tabelul 5.1). Fiecare cromosom (puternic despiralizat) este monocromatidian, ILLQG�DOFăWXLW�GLQWU-R�VLQJXUă�PROHFXOă�GH�$'1. Cantitatea de material genetic este 2C molecule de ADN sub forma a 2n (46) cromosomi despiralizaĠL��ÌQ�SULPD�SDUWH�D�ID]HL�*1 (G1A), se produce o VLQWH]ă�LQWHQVă�GH�VXEVWDQĠH��$51��SURWHLQH) QHFHVDUH�FUHúWHULL�úL�IXQFĠLRQăULL�FHOXOHL� 6H�DFXPXOHD]ă�$51�úL�SURWHLQH�SkQă�OD�R�FRQFHQWUDĠLH�SUDJ��QXPLWă�SXQFW�GH�UHVWULFĠLH��5���GXSă�FDUH�FHOXOHOH�WUHF�vQ subfaza G1B, fiind FRQGLĠLRQDWH� Vă�LQWUH�vQ�ID]D�6�úL�Vă�VH�GLYLGă�(figura 5.6).1 ÌQ�DQXPLWH�FRQGLĠLL��OLSVD�IDFWRULORU�GH�FUHúWHUH��SUH]HQĠD�XQRU�LQKLELWRUL�DL�VLQWH]HL�SURWHLQHORU�HWF����FHOXOHOH�DIODWH�vQ subfaza G1A pot trece într-R�ID]ă�GH�activitDWH�PHWDEROLFă�UHGXVă��QXPLWă�ID]D G0 sau G1Q (de la "quiescence" - UHSDXV��OLQLúWH���vQ�FDUH�UăPkQ�YLDELOH�úL�SRW�VXSUDYLHĠXL�WLPS�vQGHOXQJDW��'DFă�DFHVWH�FRQGLĠLL�UHVWULFWLYH�GLVSDU��FHOXOHOH�*0 pot reveni în G1 úL�DSRL�pot progresa spre faza S, deoarece vúL�SăVWUHD]ă�FDSDFLWDWHD�GH�GLYL]LXQH��)D]HOH�*1 úL�*0 VXQW�GRXă�VWăUL�IL]LRORJLFH�GLVWLQFWH�DOH�celulei. Unele celule aflate în subfaza G1$��VXE�LQIOXHQĠD�XQRU�LQGXFWRUL�DL�GLIHUHQĠLHULL��SăUăVHVF�GHILQLWLY�FLFOXO�FHOXODU�úL�WUHF�vQ�ID]D�G1D, ce corespunde FHOXOHORU�GLIHUHQĠLDWH��HOH�QX�VH�PDL�GLYLG�úL�PRU�GXSă�XQ�DQXPLW�WLPS�

b. Faza S )D]D�6��vQ�HQJOH]ă��synthesis"- VLQWH]ă��VH�FDUDFWHUL]HD]ă�SULQ�sinteza de ADN �UHDOL]DWă�SULQ�UHSOLFDUHD�VHPLFRQVHUYDWLYă��úL�

sinteza de histone (vezi capitolul 5.A). ÌQ�DFHDVWă�ID]ă�FDQWLWDWHD�WRWDOă�GH�$'1���&��WUHEXLH�Vă�ILH�UHSOLFDWă�FRPSOHW�GDU�QXPDL�R�VLQJXUă�GDWă��VH�SURGXFH�DVWIHO�R�dublare D�FDQWLWăĠLL�GH�PDWHULDO�JHQHWLF���&���FRQGLĠLH�REOLJDWRULH�SHQWUX�GHVIăúXUDUHD�GLYL]LXQLL�FHOXODUH��1XPăUXO�GH�FURPRVRPL�UăPkQH�����GDU�ILHFDUH�FURPRVRP�YD�IL�ELFURPDWLGLDQ��DOFăWXLW�GLQ�GRXă�FURPDWLGH�LGHQWLFH��"surori"), deci va FRQĠLQH�GRXă�PROHFXOH�GH�$'1� Replicarea ADN în faza S este DVLQFURQă��XQHOH�VHJPHQWH�GH�$'1��ERJDWH�vQ�SHUHFKL�GH�ED]H�*-&��VH�UHSOLFă�precoce, la începutul fazei S, iar alte segmente (bogate în perechi de baze A-7��VH�UHSOLFă�tardiv��OD�VIkUúLWXO�ID]HL�6��,QIRUPDĠLL�SUHFLVH�GHVSUH�

1 Poziŗia punctului de oprire G1 este incertĈ, fie aproape de faza S, fie la mijlocul fazei G1 1

VLQWH]D�UHSOLFDUHD�$'1�SRW�IL�REĠLQXWH�ILH�SULQ�DXWRUDGLRJUDILH��FX�DMXWRUXO�XQXL�L]RWRS�UDGLRDFWLY��GH�UHJXOă�WLPLGLQă�WULWLDWă�73H), ILH�SULQ�XWLOL]DUHD�EURPRGHR[LXULGLQHL��%UG8���XQ�DQDORJ�DO�WLPLQHL��(OH�VH�YRU�vQFRUSRUD�vQ�PROHFXOD�QRX�VLQWHWL]DWă��PDUFkQd-o radioactiv, în primul caz, sau modificându-L�FRQILJXUDĠLD��vQ�DO�GRLOHD�FD]� Uneori, în faza S a ciclului celular mitotic se produce un "schimb egal de material genetic între cromatidele surori" (SCE – vQ�HQJOH]ă�´VLVWHU�FKURPDWLGH�H[FKDQJH´���&DVHWD����� c. Faza G2 Faza G2 VH�FDUDFWHUL]HD]ă�SULQ�VLQWH]D�XQRU�SURWHLQH�VSHFLILFH�úL�D�XQRU�PLFL�FDQWLWăĠL�GH�$'1 (necesare în procesul de "corectare" a erorilor de replicare). Fiecare cromosom este bicromatidian (cantitatea de ADN este 4C), dar despiralizat. Spre VIkUúLWXO�ID]HL�*2 VH�DFWLYHD]ă��VLQWHWL]HD]ă�XQ "IDFWRU�GH�GHFODQúDUH�DO�PLWR]HL" �03)���FH�GHWHUPLQă�Fondensarea filamentelor de FURPDWLQă�vQ�FURPRVRPL�úL�IRUPDUHD�IXVXOXL�GH�GLYL]LXQH��

2�GHPRQVWUDĠLH�HOHJDQWă�D�H[LVWHQĠHL�03)�HVWH�IHQRPHQXO�GH��FRQGHQVDUH�SUHPDWXUă�D�FURPRVRPLORU�� realizat prin fuziunea XQHL�FHOXOH�vQ�GLYL]LXQH��PHWDID]ă��FX�R�FHOXOă�vQ LQWHUID]ă�(figura 5.7.); se produce rapid o condensare precoce a ILODPHQWHORU�GH�FURPDWLQă�LQWHUID]LFă��FDUH�vQ�PRG�RELúQXLW��VXQW�SXWHUQLF�GHVSLUDOL]DWH�úL�GHFL�LQYL]LELOH�OD�PLFURVFRSXO�RSWLF��LDU�PHPEUDQD�QXFOHDUă�VH�GH]DVDPEOHD]ă�

În lipsa factorului de condensare celulele se opresc în faza G2 úL�SRW�DEDQGRQD�FLFOXO�FHOXODU��IRUPkQGX-se celule tetraploide (4n cromosomi); unele dintre ele devin celule binucleate (de exemplu cardiomiocitele adulte)(figura 5.6).

d. Faza M Faza M corespunde diviziunii mitRWLFH�úL�DUH�R�GXUDWă�GH�DSUR[LPDWLY�R�RUă��(D�vQFHSH�FX�GLYL]LXQHD�QXFOHXOXL��PLWR]ă��úL�VH�WHUPLQă�FX�GLYL]LXQHD�FLWRSODVPHL��FLWRNLQH]ă���6XEOLQLHP�GLQ�QRX�Fă��vQ�DFHDVWă�HWDSă��PDWHULDOXO�JHQHWLF�GXEODW�vQ�LQWHUID]ă�(4C molecule ADN în 46 cromosomi bicromatidieni) VHJUHJă��DGLFă�VH�GLVWULEXLH�vQ�PRG�HJDO�úL�WRWDO celulelor "fiice" (2C molecule ADN în 46 cromosomi monocromatidieni), care vor fi astfel identice cu celula din care provin. 3URFHVXO�GH��GLVWULEXĠLH��a materialului genetic prin diviziune se dHVIăúRDUă�GH�RELFHL�FX�PDUH�SUHFL]LH�DVLJXUkQG�ILGHOLWDWHD�WUDQVPLWHULL�LQIRUPDĠLHL�genetice vQ�VXFFHVLXQHD�JHQHUDĠLLORU�GH�FHOXOH��(O�SRDWH�VXIHUL�vQVă�úL�HURUL��FDUH�YRU�JHQHUD�DQRPDOLL�FURPRVRPLFH�

�����(92/8ğ,$�&(/8/(LOR REZULTATE PRIN DIVIZIUNE CHOXOHOH�UH]XOWDWH�GXSă�GLYL]LXQH�SRW�HYROXD�vQ�WUHL�GLUHFĠLL��SUROLIHUDUH��GLIHUHQĠLHUH úL�WUHFHUHD�vQ�stadiul de repaus.

a. Proliferarea. &HOXOHOH�SDUFXUJ�XQ�QRX�FLFOX�úL�VH�GLYLG�UHSHWDW��DFHVWH��FHOXOH�FLFOLFH��DOFăWXLHVF�compartimentul proliferativ al RUJDQLVPXOXL�úL�VH�JăVHVF�vQ�ĠHVXWXULOH�HPEULRQDUH��PăGXYD�KHPDWRJHQă��VWUDWXO�ED]DO�DO�HSLGHUPXOXL��HWF��

E��'LIHUHQĠLHUHD�� &HOXOHOH�SăUăVHVF�GHILQLWLY�FLFOXO�FHOXODU�úL�VH�WUDQVIRUPă�vQ�celule specializate��FX�DQXPLWH�VWUXFWXUL�úL�IXQFĠLL��FDUH�nu se mai divid úL�PRU�GXSă�XQ�WLPS�GHWHUPLQDW��'H�H[HPSOX��QHXURQLL��FHOXOHOH�PXVFXODUH��JUDQXORFLWHOH��KHPDWLLOH�PDWXUH��HWF�

c. Stadiul de repaus. 8QHOH�FHOXOH��GH�H[HPSOX��FHOXOHOH��VWHP��VDX�VXúă��OLPIRFLWHOH�ú�D���SăUăVHVF�FLFOXO�FHOXODU�vQ�ID]D�*1 úL�Uămân în faza G0, DYkQG�R�DFWLYLWDWH�PHWDEROLFă�PDL�UHGXVă��GDU�SăVWUkQGX-úL�FDSDFLWDWHD�GH�GLYL]LXQH��$FHVWH�FHOXOH�IRUPHD]ă�compartimentul neproliferativ��ÌQ�FRQGLĠLL�VSHFLDOH��HOH�UHDFĠLRQHD]ă�OD�DQXPLĠL�VWLPXOL�GLQ�PHGLX��IDFWRUL�GH�FUHúWHUH��XQLL�KRUPRQL��VXEVWDQĠH�PLWRJHQH�HWF���úL�SRW�UHLQWUD�vQ�FLFOXO�GH�GLYL]LXQH��8Q�H[HPSOX�HGLILFDWRU�vO�UHSUH]LQWă�DFWLYDUHD�OLPIRFLWHORU�7�GLQ�VkQJHOe SHULIHULF�VXE�DFĠLXQHD�ILWRKHPDJOXWLQLQHL��3+$���HOH�VH�WUDQVIRUPă�vQ�OLPIREODVWH��FHOXOH�WLQHUH��FDUH�VH�GLYLG�LQWHns. Acest fenomen este utilizat pentru studiul cromosomilor prin culturi de limfocite (vezi capitolul 2.D.3).

1.3 CONTROLUL CICLULUI CELULAR.

Progresia RUGRQDWă�úL�GHVIăúXUDUHD�QRUPDOă�D�FLFOXOXL�FHOXODU�VXQW�UHDOL]DWH�SULQ�UHDFĠLL�ELRFKLPLFH��vQ�care multiple kinaze ciclin-dependente (CDK)(1-7) sunt activate, prin fixarea unor proteine numite cicline (A-H). 'XSă�activare, fiecare complex proteic CDK-FLFOLQă�IRVIRULOHD]ă DQXPLWH�SURWHLQH�VHSHFLILFH��QHFHVDUH�SHQWUX�UHDFĠLLOH�FDUH�DX�ORF�vQWU-o anuPLWă�ID]ă�D�FLFOXOXL��$SRL��complexul CDK-FLFOLQă�SRDWH�IL�inactivat GHWHUPLQkQG�WUHFHUHD�OD�ID]D�XUPăWRDUH�D�FLFOXOXL�FHOXODU��LQDFWLYDUHD�VH�SRDWH�IDFH�ILH�SULQ�GHJUDGDUHD�SURWHROLWLFă�D�FLFOLQHL��GH�FăWUH�FRPSOH[XO�SURWHDVRPLORU��vQ�XUPD�XELTXLWLQăULL) ILH�SULQ�LQWHUYHQĠLD�XQRU�PROHFXOH�inhibitoare CKI2 (proteine KIP: P21, P27 sau proteine INK: P15, P16).

,QWHUDFĠLXQHD�GLQWUH�DFWLYDUHD�úL�LQDFWLYDUHD�DFWLYLWăĠLORU�&'.��vQ�GLIHULWH�PRPHQWH�FKHLH, DVLJXUă�SURJUHVLD�QRUPDOă�úL�reglarea ciclului celular. FiHFDUH�ID]ă�D�FLFOXOXL�DUH�XQ�FRQWURO�VSHFLILF�(figura 5.9), realizat: � în G1 de complexul CDK4-ciclina D, � OD�WUDQ]LĠLD�*��6�GH�FRPSOH[XO�CDK 2-FLFOLQă�(, � în faza S de complexul CDK 2-FLFOLQă�$, � LDU�vQ�ID]HOH�*��úL�0�GH�FRPSOH[XO�Cdc2-FLFOLQă�%. 7UDQ]LĠLD�GH�OD�R�ID]ă�OD�DOWD�D�FLFOXOXL�FHOXODU�HVWH�FRQWURODWă�SULQ�PHFDQLVPH�VSHFLILFH��FDUH�DFĠLRQHD]ă�vQ�DQXPLWH�SXQFWH�GH�FRQWURO�úL�YHULILFă�GDFă�anumite procese sunt terminate înaintea începerii altora VDX�GDFă�QX�H[LVWă�DOWHUăUL ale componentelor ´PDúLQăULLORU´�GH�UHSOLFDUH�úL�VHJUHJDUH�FURPDWLGLDQă��ÌQ�FD]XO�LGHQWLILFăULL�XQRU�GHYLHUL�GH�OD�QRUPDO�VDX�GHIHFWH�VH�EORFKHD]ă�progresia celulei în ciclul celular (prin inactivarea CDK��úL�VH�LQGXFH�´UHSDUDUHD´�VDX��GDFă�DFHDVWD�QX�HVWH�SRVLELOă��DSRSWR]D�(moarWHD�FHOXODUă�SURJUDPDWă���3ULQ�DFHVWH�PHFDQLVPH�VH�DVLJXUă�FUHúWHUHD�QRUPDOă�úL�VH�HOLPLQă�GHIHFWHOH��FDUH�QX�YRU�WUHFH�DVWIHl la celulele fiice. 3H�SDUFXUVXO�FLFOXOXL�FHOXODU�VH�SURGXF�XUPăWRDUHOH�HYHQLPHQWH�FRUHODWH�FX�UHJODUHD�FLFOXOXL�

2 Moleculele CKI (de le Cyclin-dependentKinase Inhibitors�� VXQW� GH� GRXă� IHOXUL��KIP (de la kinase inhibitory proteins) care DFĠLRQHD]ă� SH�multiple complexe CDK-FLFOLQă� úL� INK (de la Inhibitors of CDK�� FDUH� DFĠLRQHD]ă� VSHFLILF� SH� FRPSOH[XO�CDK-ciclina D 2

ƒ În faza “de staUW´�*��FHOXOHOH�UHDFĠLRQHD]ă�OD�VWLPXOL�H[WHUQL��PLWRJHQL��IDFWRUL�GH�FUHúWHUH��IRUPkQGX-se complexul CDK4-FLFOLQă�'��FDUH�IRVIRULOHD]ă�úL�GHFL�DFWLYHD]ă�GLIHULWH�SURWHLQH�FH�IXQFĠLRQHD]ă�vQ�DFHDVWă�ID]ă��3ULQWUH�DFHVWHD��XQ�URO�LPSRUWDQW�îl are proteina RB3��FDUH��GXSă�IRVIRULODUH��HOLEHUHD]ă�XQ�factor activator (E2F) DO�WUDQVFULSĠLHL�JHQHORU�FH�IXQFĠLRQHD]ă�vQ�ID]D�6�úL�UHDOL]HD]ă�UHSOLFDUHD�$'1��

ƒ ,QWUDUHD�vQ�ID]D�6�HVWH�GHWHUPLQDWă�GH�XQ�VHPQDO�DFWLYDWRU��FRPSOH[XO CDK2-FLFOLQă�(. Formarea acestui comple[�HVWH�vQVă�EORFDWă�GH�inhibitorul P27 al CDK��WUHFHUHD�vQ�ID]D�6�LPSOLFă�GHFL�PDL�vQWkL�GHJUDGDUHD�SURWHROLWLFă�D��P27 (prin sistemul XELTXLWLQă-proteasomi)

ƒ În punctul de control G1�6�DUH�ORF��R�YHULILFDUH�D�SDUDPHWULORU�GH�HYROXĠLH�QRUPDOă�D�FHOXOHL��RULFH�DOWHUDUH�D�$'1��GHSOHĠLH�GH�R[LJHQ���PHWDEROLĠL���HQHUJLH�VDX�SHUWUXUEDUH�IL]LRORJLFă�GHFODQúHD]ă�VLQWH]D�proteinei TP53 (“gardianul” genomului uman)4 FDUH�DFWLYHD]ă�WUDQVFULSĠLD�JHQHL�FH�FRGLILFă�proteina P21, un inhibitor al complexelor CDK-FLFOLQă�SUHFXP�úL�DO�3&1$�(antigenul nuclear al celulelor proliferante)5. Celulele sunt oprite în G1, oferindu-li-VH�WLPS�GH�FRUHFĠLH��(figura 5.10); GDFă�DOWHUăULOH��vQ�VSHFLDO�FHOH�GLQ�VWUXFWXUD�$'1��QX�VXQW�UHSDUDWH��FHOXOD�YD�IL�GLUHFĠLRQDWă�VSUH�DSRSWR]ă�

ƒ ProgUHVLD�XOWHULRDUă�SULQ�ID]D�6�úL�UHSOLFDUHD�$'1�VXQW�UHJODWH�GH�FăWUH�CDK2-ciclina A6. ƒ ÌQ�ID]D�*���OD�SXQFWXO�GH�FRQWURO�*��0��VH�GHFLGH�GDFă�FHOXOD�LQWUă�vQ�PLWR]ă��DFHVW�OXFUX�HVWH�GHWHUPLQDW�GH�DFWLYDUHD�EUXVFă�

a complexului Cdc27-FLFOLQă�%�(numit anterLRU�úL�factorul MPF, de la “Mitosis Promoting Factor´���&HOXOHOH�FX�DEHUDĠLL�FURPRVRPLFH�VDX�GHIHFWH�DOH�DSDUDWXOXL�PLWRWLF�VXQW�RSULWH�Vă�LQWUH�vQ�PLWR]ă��SULQ�DFĠLXQHD�TP53 úL�P21��FDUH�EORFKHD]ă�formarea complexului Cdc2-ciclina B).

ƒ În cursul mitozei, îQ�PHWDID]ă��PDL�H[LVWă�XQ�SXQFW�GH�FRQWURO�0�vQ�FDUH�GLYL]LXQHD�VH�RSUHúWH�úL�HVWH�YHULILFDWă�alinierea SHUIHFWă�D�FURPRVRPLORU��vQDLQWHD�VHSDUăULL�FURPDWLGHORU�VXURUL��$FĠLXQHD�HVWH�UHDOL]DWă�GH�FăWUH�R�SURWHLQă�LQKLELWRDUH�,66; GHJUDGDUHD�SURWHROLWLFă��D DFHVWHL�SURWHLQH��GHWHUPLQDWă�GH�XELTXLWLQă��GHFODQúHD]ă�DQDID]D��SULQ�VHSDUDUHD�FURPDWLGHORU�

ƒ /D�VIkUúLWXO�PLWR]HL�DUH�ORF�GHJUDGDUHD�EUXVFă�D�FLFOLQHL�% �SURGXVă�GH�FăWUH�XELTXLWLQă��úL�LQDFWLYDUHD�&GF���IHQRPHQH�FH�SHUPLW�FHOXOHL�Vă�WUHDFă�vQWU-R�QRXă�ID]ă�*��

3UROLIHUDUHD�FHOXODUă�HVWH�UHJODWă�SH�R�GXUDWă�OLPLWDWă�GH�factori extracelulari �KRUPRQL��IDFWRUL�GH�FUHúWHUH�HWF���SUHFXP�úL�GH�DQXPLWH�gene de proliferare VDX��PLWRJHQH���FH�FRGLILFă�FLFOLQH��UHFHSWRUL�DL�IDFWRULORU�GH�FUHúWHUH��SURWHLQH�QHFHsare sintezei de ADN, etc.). Deoarece SULQ�PXWDĠLD�úL�DFWLYDUHD�ORU�DQRUPDOă�VH�SURGXFH�R�SUROLIHUDUH�FHOXODUă�DEHUDQWă�úL�FDQFHU��DFHVWH�JHQH�QRUPDOH�PDL�VXQW�QXPLWH�úL�SURWR-RQFRJHQH��2�DOWă�FDWHJRULH�GH�JHQH��QXPLWH�antiproliferative, au rolul de a inhiED�SUROLIHUDUHD�FHOXODUă��'H�DFHHD�DFHVWH�JHQH�PDL�VXQW�QXPLWH�gene supresoare de tumori sau antioncogene. ÌQ�FDQFHU�VH�SURGXFH�R�SHUWXUEDUH�D�GHVIăúXUăULL�QRUPDOH�D�FLFOXOXL�FHOXODU��&HOXOHOH�FDQFHURDVH��SXUWăWRDUH�GH�PXWDĠLL���VFDSă��GH�VXE�controlul meFDQLVPHORU�FDUH�UHJOHD]ă�SUROLIHUDUHD�QRUPDOă��SDUFXUJ�UDSLG�úL�UHSHWDW�FLFOXO�FHOXODU��PXOWLSOLFkQGX-VH�SHUPDQHQW�úL�DQDUKLF��0XOWH�PHGLFDPHQWH�DQWLFDQFHURDVH��FLWRVWDWLFH��GHWHUPLQă��EORFDUHD��SUROLIHUăULL�FHOXOHORU��SULQ�RSULUHD�HYROXĠLHL�ORU�vQ�GLIerite faze ale ciclului celular.

2. MITOZA

0LWR]D�HVWH�R�GLYL]LXQH�FDUDFWHULVWLFă�FHOXOHORU�VRPDWLFH�DOH�RUJDQLVPXOXL��(D�DVLJXUă�FUHúWHUHD biomasei organismului, care, între VWDGLXO�GH�]LJRW�XQLFHOXODU�úL�FHO�GH�RUJDQLVP�DGXOW�QHFHVLWă��[�����GLYL]LXQL�FHOXODUH��ÌQ�XQHOH�ĠHVXWXUL��FXP�DU�IL�PăGXYD�KHPDWRJHQă�VDX�ĠHVXWXO�HSLWHOLDO��PLWR]D�VH�GHVIăúRDUă�FRQWLQXX��SH�WRW�SDUFXUVXO�YLHĠLL��DVLJXUkQG�reînnoirea FHOXODUă�GDU�úL�repararea XQRU�OH]LXQL�WLVXODUH��3ULQ�PLWR]ă��PDWHULDOXO�JHQHWLF�GXEODW�vQ�LQWHUID]ă��VH distribuie total úL�egal celulelor fiice. Mitoza HVWH�R�GLYL]LXQH�HFXDĠLRQDOă��GHRDUHFH�GLQ�FHOXOD�LQLĠLDOă��FHOXOD�³PDPă´��FX����FURPRVRPL�UH]XOWă�GRXă�FHOXOH�³ILLFH´�FDUH�Du, de asemenea, 46 cromosomi (celule diploide). Mitoza permite transmiterea cu maUH�ILGHOLWDWH�D�LQIRUPDĠLHL�JHQHWLFH în succesiunea JHQHUDĠLLORU�GH�FHOXOH��FHHD�FH�DVLJXUă��stabilitatea proceselor ereditare.

2.1. FAZELE MITOZEI

0LWR]D�HVWH�XQ�SURFHV�FRQWLQXX��FDUH�GXUHD]ă�FLUFD�R�RUă��úL�VH�GHVIăúRDUă�vQ�FLQFL�HWDSH�VXFFHVLYH��Srofaza, prometafaza, metafaza, DQDID]D�úL�WHORID]D�(figura 5.11). Fiecare din aceste faze sunt definite prin DFĠLXQHD�FURPRVRPLORU úL�GLVWULEXĠLD�FRQĠLQXWXOXL�FLWRSODVPDWLF�LDU�GHVIăúXUDUHD�ORU�HVWH�ULJXURV�FRQWURODWă�SHQWUX�D�VH�DVLJXUD�Fă�ILHFDUH�FHOXOă�ILLFă�YD�SULPL�R�FRSLH�H[DFWă�D�JHQRPXOXL�SDUHQWDO��2ULFH�HURDUH�GH�GLVWULEXĠLH�YD�JHQHUD�DQRPDOLL�FURPRVRPLFH�OD�FHOXOHOH�ILLFH�

a. Profaza /D�vQFHSXWXO�SURID]HL��vQ�FHOXOH�SRW�IL�REVHUYDWH�R�VHULH�GH�IHQRPHQH�FLWRSODVPDWLFH�úL�QXFOHDUH�� ÌQ�FLWRSODVPă��FHQWURVRPXO��XQ�RUJDQLW�FLWRSODVPDWLF�SHULQXFOHDU��VH�GLYLGH��LDU�FHL�GRL�FHQWURVRPL�UH]XOWDĠL�VH�GHSODVHD]ă�vQ�GLUHFĠLL�RSXVH��IRUPkQG�polii fusului de diviziune. 'LQ�ILHFDUH�FHQWURVRP�VH�DQVDPEOHD]ă�UDGLDU�microtubulii��FDUH�IRUPHD]ă�ILEUHOH�fusului de diviziune, ce pot fi centriolo-FURPRVRPLDOH�úL�FHQWULROR-centriolare (figura 5.12.a). De asemenea, componentele PLFURWXEXODUH�DOH�FLWRVFKHOHWXOXL�FHOXODU�VXIHUă�WUDQVIRUPăUL�HVHQĠLDOH��SULQ�GHSROLPHUL]DUH�vQ�GLPHUL�GH�Į-WXEXOLQă�úL�ȕ-WXEXOLQă�úL�reansamblarH�vQ�ILEUH�DOH�IXVXOXL�GH�GLYL]LXQH��$OWH�FRPSRQHQWH��FXP�DU�IL�PROHFXOHOH�GH�Ȗ-WXEXOLQă�úL�R�SURWHLQă�PLQRUă�- SHULFHQWULQD�IRUPHD]ă�SULQ�DQVDPEODUH�FHQWULROLL��&HQWULROLL�DX�XQ�FLFOX�SURSULX�GH�GLYL]LXQH��GXSă�ILHFDUH�PLWR]ă�ILHFDUH�FHOXOă�

3 Proteina RB HVWH�FRGLILFDWă�GH�R�JHQă�VXSUHVRDUH�GH�WXPRUL�VLWXDWă�SH���T����PXWDĠLLOH�JHQHL�5E�SRW�SURGXFH�DQXPLWH�FDQFHUH��inclusiv retinoblastoame. 4 Gena TP53 HVWH�R�JHQă�VXSUHVRDUH�GH�WXPRUL��PXWDĠLLOH�HL�VH�UHJăVHVF�ăQ�SHVWH�����GLQ�FDQFHUH 5 PCNA VWLPXOHD]ă�$'1�SROLPHUD]D�į 6 Acest complex SURGXFH�IRVIRULODUHD�SURWHLQHORU�LPSOLFDWH� vQ�GHVSLUDOL]DUHD�$'1�SUHFXP�úL�D�SURWHLQHL�53$�FDUH�VH�IL[HD]ă�vQ�SXQFWHOH� GH� RULJLQH� DOH� UHSOLFăULL�� 'XSă� GHFODQúDUHD� UHSOLFăULL� FRPSOH[XO� 53$-RULJLQH� HVWH� EORFDW� GH� FăWUH� CDK-FLFOLQD%� úL�replicarea nu se poate UHSHWD��VH�IDFH�R�VLQJXUă�GDWă��SkQD�FH�FHOXOD�QX�WUHFH�SULQ�PLWR]ă��FDUH�GHJUDGHD]ă�FRPSOH[XO�CDK-ciclina B 7 Cdc2 este o CDK VSHFLILFă��QXPLWă�DúD�GH�OD�cell division cycle mutant 2 3

ILLFă�PRúWHQHúWH�GRL�FHQWULROL��LDU�vQ�LQWHUID]D�FH�XUPHD]ă�HL�VH�GLYLG��DVWIHO�vQFkW�vQDLQWH�GH�GLYL]LXQH�YRU�IL�SDWUX�FHQWULROL��JUXSDĠL�FkWH�GRL�úL�GLVSXúL�SHUSHQGLFXODU�XQXO�SH�DOWXO� In nucleu are loc condensarea ILEUHORU�GH�FURPDWLQă FDUH�VH�VFXUWHD]ă�úL�VH�vQJURDúă��GHYLQ�LQWHQV�FRORUDWH�úL�YL]LELOH�OD�PLFURVFRSXO�RSWLF�VXE�IRUPă�GH�cromosomi. 1XFOHROLL�GLPLQXă�FD�PăULPH�úL�vQ�FHOH�GLQ�XUPă�VH�GH]LQWHJUHD]ă�� )LHFDUH�FURPRVRP�HVWH�DOFăWXLW�GLQ�GRXă�cromatide surori, deoarece materialul genetic s-a replicat (dublat) în faza S a LQWHUID]HL��(OH�VXQW�DWDúDWH�OD�QLYHOXO�centromerului��R�VWUXFWXUă�FURPRVRPLFă�HVHQĠLDOă�SHQWUX�D�DVLJXUD�GLVWULEXĠLD (segregarea) ILHFăUHL�FURPDWLGH�vQ�FHOXOHOH�ILLFH�� 5HJLXQLOH�FHQWURPHULFH�VXQW�ERJDWH�vQ�VHFYHQĠH�GH�$'1�VDWHOLW�Į�úL�FRQĠLQ�FDQWLWăĠL�FRQVLGHUDELOH�GH�KHWHURFURPDWLQă�FRQVWLWXWLYă��&RPSRQHQWD�FHQWURPHULFă�FX�URO�vQ�VHJUHJDUH�HVWH�NLQHWRFRUXO��FDUH�HVWH�VLWXDW�vQ�LQWHULRUXO�FHQWURPHUXOXL��DYknd OD�H[DPLQDUHD�SULQ�PLFURVFRSLH�HOHFWURQLFă�DVSHFWXO�XQXL�FRUSXVFXO�ILEURV�PDL�GHQs cu diametrul de 400 nm. Kinetocorul este VWUXFWXUD�GH�FDUH�VH�DWDúD]ă�FkWH�R�ILEUă�D�IXVXOXL�GH�GLYL]LXQH��/RFXO�XQGH�VH�IRUPHD]ă�NLQHWRFRUXO�HVWH�GLFWDW�GH�R�VHFYHQĠă�VSHFLILFă�GH�$'1�GH�FLUFD�����SE��GLVSXVă�vQWU-R�]RQă�UH]LVWHQWă�OD�DFĠLXQHD�QXFOHD]HORU��$FHVWH�VHFYHQĠH�VXQW�VLPLODUH�OD�WRĠL�cromosomii, deoarece experimental s-D�FRQVWDWDW�Fă�SULQ�VFKLPEDUHD�ORU�UHFLSURFă�vQWUH�QHRPRORJL��IXQFĠLD�GH�VHJUHJDUH�VH�SăVWUHD]ă��6HFYHQĠD�GH�FLUFD�����SE�GLQ�]RQD�NLQHWRFRUXOXL�FXSULQGH�WUHL�WLSXUL�GH�PRWLYH��D) CDE-,��IRUPDWă�GLQ���SE��GLVSXVă�OD�FDSăWXO��¶�DO�VHFYHQĠHL�NLQHWRFRULFH�úL�FRQVHUYDWă�FX�PLFL�YDULDĠLL��E��&'(-,,��IRUPDWă�GLQ���-���SE�FH�FRQĠLQ�vQ�SURSRUĠLH�GH�SHVWH�����$7��OD�HXFDULRWHOH�VXSHULRDUH�SUH]LQWă�VHFYHQĠH�VFXUWH�UHSHWLWLYH��FH�SHUPLW�FkWHva distorsiuni considerabile ale GXEOXOXL�KHOL[���GLVSXVă�vQ�PLMORFXO�VHFYHQĠHL�NLQHWRFRULFH��F��&'(-,,,��IRUPDWă�GLQ����SE��GLVSXVă�OD�FDSăWXO��¶�úL�vQDOW�FRQVHYDWă��,PSRUWDQĠD�DFHVWRU�VHFYHQĠH�HVWH�VXJHUDWă�GH�FRQVHFLQĠHOH�PXWDĠLLORU�OD�DFHVW�QLYHO��$VWIHO��PXWDĠLLOH�vQ�&'(-,�úL�CDE-,,��GXF�OD�SLHUGHUHD�SDUĠLDOă�D�IXQFĠLHL�FHQWURPHUXOXL��vQ�WLPS�FH�PXWDĠLLOH�SXQFWLIRUPH�GLQ�SRUĠLXQHD�FHQWUDOă�D�&'(-III GXF�OD�SLHUGHUHD�WRWDOă�D�IXQFĠLHL�FHQWURPHUXOXL��'H�DVHPHQHD��SHQWUX�IXQFĠLD�FHQWURPHUXOXL�HVWH�LPSRUWDnt un complex proteic de 240 kD, format din trei polipeptide, denumit Cbf-,,,��FX�URO�GH�OHJDUH�D�VHFYHQĠHL�&'(-,,,��0XWDĠLLOH�vQ�XQD�GLQ�FHOH�WUHL�JHQH�FDUH�FRGLILFă�SROLSHSWLGHOH�&EI-,,,�EORFKHD]ă�VHJUHJDUHD�FURPDWLGHORU�VXURUL���� &URPDWLGHOH�FRQĠLQ�vQ UHJLXQHD�FHQWURPHUXOXL�R�VHFYHQĠă�VSHFLILFă�GH�$'1�UHSHWLWLY��XQGH�VH�DVDPEOHD]ă�FRPSOH[H�proteice specializate, numite kinetocori (figura 5.12.b). )LHFDUH�FURPDWLGă�DUH�XQ�NLQHWRFRU��OD�FDUH�VH�YD�IL[D�XQ�PLFURWXEXO��FH�OHDJă�FHQWURPHUXO�ILHFăUXL�FURPRVRP�GH�SROLL�IXVXOXL�GH�GLYL]LXQH��$WDúDUHD�FURPDWLGHORU�HVWH�HVWH�UH]XOWDWXO�LQWHUYHQWLHL�XQRU�complexe proteice numite coezina si condensina.

b. Prometafaza 3URPHWDID]D�vQFHSH�FX�GH]DQVDPEODUHD�PHPEUDQHL�QXFOHDUH��GDWRUDWă�GLVRFLHULL�laminei nucleare în VXEXQLWăĠL�GH�ODPLQLQă. Simultan cu GH]DVDPEODUHD�PHPEUDQHL�QXFOHDUH��DUH�ORF�úL�GH]LQWHJUDUHD�UHWLFXOXOXL�HQGRSODVPDWLF�úL�D�DSDUDWXOXL�*ROJL�vQ�PLFL�YH]LFROH�membranare, prin mecanisme insuficient clarificate. Dezintegrarea membranei nucleare este urmată�GH�GHSODVDUHD�IXVXOXL�PLWRWLF�vQ�DULH�pe care a ocupat-R�QXFOHXO��8QLL�PLFURWXEXOL�VH�DWDúHD]ă�OD�NLQHWRFRULL�ILHFăUXL�FURPRVRP��OHJkQG�FHQWURPHUXO�ILHFăUXL�FURPRVRP�GH�polii fusului de diviziune, ceea ce permite deplasarea cromosomilor spre ecuatorul celulei.

c. Metafaza În metafaza propriu-]LVă��FURPRVRPLL�ELFURPDWLGLHQL�VH�DOLQLD]ă�LQGHSHQGHQW�unul de altul la ecuatorul fusului de diviziune, în DFHODúL�SODQ��IRUPkQG�DúD-numita SODFă�PHWDID]LFă8.

d. Anafaza $QDID]ă�vQFHSH�EUXVF�FX�VHSDUDUHD�FURPDWLGHORU�VXURUL��VLPXOWDQ�OD�WRĠL�FURPRVRPLL��úL�PLúFDUHD�ORU�VSUH�SROLL�RSXúL�DL�IXVXOXL�GH�diviziune. Prin acest proces GH�GLVMXQFĠLH��VHJUHJDUH��FURPDWLGLDQă��ILHFDUH�FURPRVRP�ELFURPDWLGLDQ�IRUPHD]ă�GRL�FURPRVRPL�PRQRFURPDWLGLHQL��'XSă�VHSDUDUH��FURPRVRPLL PRQRFURPDWLGLHQL�VXQW��vQ�DFHODúL�WLPS��WUDúL�VSUH�SROLL�IXVXOXL�GH�GLYL]LXQH�SULQ�VFXUWDUHD�depolimerizarea) fibrelor centriolo-cromosomiale, respectiv prin alungirea (polimerizarea) fibrelor centriolo-centriolare.9 Deplasarea cromosomilor spre poli se face VLPXOWDQ��FX�DFHHDúL�YLWH]ă��$VWIHO��VH�SURGXFH�vPSăUĠLUHD�WRWDOă�úL�HJDOă�a materialului genetic între celulele fiice.

e. Telofaza 6H�FDUDFWHUL]HD]ă�SULQ�HYHQLPHQWH�RSXVH�FHORU�GLQ�SURID]ă��FURPRVRPLL�VXIHUă�XQ�SURFHV�de decondensare úL�despiralizare, fusul GH�GLYL]LXQH�VH�GH]DVDPEOHD]ă���VH�UHIDF�PHPEUDQHOH�FH�GHOLPLWHD]ă�QXFOHXO��UHWLFXOXO�HQGRSODVPLF�úL�DSDUDWXO�*ROJL��ÌQFHSH�GLYL]LXQHD�FLWRSODVPHL��FLWRNLQH]ă��SULQ�DFĠLXQHD�FRQWLQXXă�D�XQXL�LQHO�FRQWUDFWLO�GH�DFWLQă��FDUH�SURGXFH�GLYL]LXQHD�FLWRSlasmei, FHOH�GRXă�FHOXOH�ILLFH�VH�VHSDUă��ILHFDUH�FRQĠLQkQG��Q�FURPRVRPL�PRQRFURPDWLGLHQL�FX�DVSHFW�LQWHUID]LF�úL�R�FDQWLWDWH�DSUR[LPativ HJDOă�GLQ�PDVD�FLWRSODVPDWLFă��

2.2. REGLAREA MITOZEI

'HVIăúXUDUHD�PLWR]HL�HVWH�ULJXURV�FRQWURODWă��SULQ���SXQFWH�GH�FRQWURO��GH�FăWUH�FHOXOD�ÄPDPă´�SHQWUX�D�VH�DVLJXUD�Fă�ILHFDUH�FHOXOă�ÄILLFă´�YD�SULPL�R�FRSLH�H[DFWă�D�JHQRPXOXL�SDUHQWDO�úL�R�FDQWLWDWH�DSUR[LPDWLY�HJDOă�GLQ�PDVD�FLWRSODVPDWLFă��2ULFH�HURDUH�Ge GLVWULEXĠLH�YD�JHQHUD�DQRPDOLL�FURPRVRPLFH�OD�FHOXOHOH�ILice. /D�WUDQ]LĠLD�*2�0�H[LVWă�XQ�punct de control (1) FUXFLDO��vQ�FDUH�VH�GHFLGH�GDFă�FHOXOD�LQWUă�vQ�PLWR]ă��DVXSUD�FăUXLD�DFĠLRQHD]ă�&GF��úL�FLFOLQD�%��$FWLYDUHD�EUXVFă�D�complexului Cdc2-FLFOLQă�% �QXPLW�úL�03)�GH�OD�M-phase promoting factor) GHWHUPLQă LQLĠLHUHD�PLWR]HL�� 03)�DFĠLRQHD]ă�SULQ�DFWLYDUHD�XQRU�SURWHLQ-NLQD]H�VDX�SULQ�IRVIRULODUHD�GLUHFWă�D�XQRU�SURWHLQH�UHVSRQVDELOH�SHQWUX�PRGLILFDULOH�DVRFLDWH�PLWR]HL��3ULQWUH�SURWHLQHOH�ĠLQWă�VH�QXPDUD�condensinele FDUH�VXQW�UHVSRQVDELOH�GH�GHFODQúDUHD�coQGHQVăULL�FURPRVRPLORU��laminele D�FăURU�IRVIRULODUH�GHWHUPLQă�IUDJPHQWDUHD�PHPEUDQHL�QXFOHDUH��proteinele GM130 D�FăURU�IRVIRULODUH�LQGXFH�GHJUDGDUHD�DSDUDWXOXL�*ROJL�úL�D�UHWLFXOXOXL�HQGRSODVPDWLF�úL�proteinele asociate microtubulilor care induc formarea fususlui de diviziune.

8 6ă�UHDPLQWLP�Fă�Petafaza este stadiul optim pentru studiul cromosomilRU��GHRDUHFH�DFHúWLD�VXQW�FRQWUDFWDĠL��ELQH�LQGLYLGXDOL]DĠL�PRUIRORJLF�úL�GLVSXúL�vQWU-un singur plan. 9 )XQFĠLD� PLFURWXEXOLORU� SRDWH� IL� GHPRQVWUDWă� SULQ� WUDWDPHQW� FX� FROFKLFLQă�� FDUH� LQKLEă� IRUPDUHD� ORU� úL� vPSLHGLFă� DUDQMDUHD�cromosomilor în plan ecuatoriDO��SUHFXP�úL�PLJUDUHD�ORU�DQDID]LFă� 4

'DFă�H[LVWă�R�DOWHUDUH�FURPRVRPLFă�VDX�XQ�GHIHFW�DO�DSDUDWXOXL�PLWRWLF�HVWH�DFWLYDWă�SURWHLQD�73����FDUH�LQGXFH�VLQWH]D�SURWHinei 21, un inhibitor al CDK��FH�EORFKHD]ă�FHOXOD�vQ�*2. 'XSă�FH�ILHFDUH�FURPRVRP�V-a aliniat în placa metDID]LFă�SURFHVXO�VH�RSUHúWH��FLUFD���-30 minute) într-un nou punct de control (2), SHQWUX�D�VH�YHULILFD�GDFă�WRĠL�FURPRVRPLL�VXQW�SHUIHFW�DOLQLDĠL vQDLQWHD�VHSDUăULL�FURPDWLGHORU�VXURUL�(figura 5.13). 'DFă�WRWXO�HVWH�ÄSHUIHFW´�DWXQFL�VH�GHFODQúHD]ă�GHJUDGDUHD�SURWHROLWLFă�D�SURWHLQHORU��coezina si condensina��FH�DWDúHD]ă�FHOH�GRXă�FURPDWLGH�OD�QLYHOXO�FHQWURPHUXOXL��VXE�DFĠWLXQHD�XQXL�FRPSOH[�SURWHLF�FX�DFWLYLWDWH�HQ]LPDWLFă�QXPLW�VHSDUD]ă care a fost activat GH�FăWUH�FRPSOH[XO�GH�SURPRYDUH�DO�DQDID]HL��SULQ�vQGHSDUWDUHD�DúD-numitei securine��R�FRPSRQHQWă�LQDFWLYDWRDUH��$FHVWH�IHQRPHQH�SHUPLW�VHSDUDUHD�FURPDWLGHORU�VXURUL�úL�LQLĠLHUHD�DQDID]HL� ÌQ�DQDID]ă�H[LVWă�punctul de control (3) al mitozei când se produce inactivarea complexului Cdc2-FLFOLQă�%��SULQ�dHJUDGDUHD�SURWHROLWLFă�EUXVFă�D�FLFOLQHL�%��GH�FăWUH�XELTXLWLQă��úL�LQDFWLYDUHD�&GF�� fapt ce va permite celulei terminarea mitozei úL�trecerea într-R�QRXă�ID]ă�*��

2.3. ERORI DE DIST5,%8ğ,(��$��0$7(5,$/ULUI GENETIC ÎN M,72=Ă Principalele erori de dLVWULEXĠLH�D�PDWHULDOXOXL�JHQHWLF�vQ�PLWR]ă�VXQW��QHGLVMXQFĠLD�FURPDWLGLDQă��vQWkU]LHUHD�DQDID]LFă�úL�FOLYDUHD�WUDQVYHUVDOă�D�FHQWURPHUXOXL��(OH�JHQHUHD]ă�DQRPDOLL�FURPRVRPLFH�vQ�ĠHVXWXULOH�VRPDWLFH��YH]L�FDSLWROHOH���%���úL����&�

D���1HGLVMXQFĠLD��FURPDWLGLDQă 1HGLVMXQFĠLD�FURPDWLGLDQă�DSDUH�DWXQFL�FkQG�FHOH�GRXă�FURPDWLGH�DOH�XQXL�FURPRVRP�QX�VH�VHSDUă în timpul anafazei mitozei, ci UăPkQ�XQLWH�úL�PLJUHD]ă�vPSUHXQă�vQ�XQD�GLQ�FHOH�GRXă�FHOXOH�ILLFH��&RQVHFLQĠD�DFHVWHL�HURUL�HVWH�DSDULĠLD�XQRU�FHOXOH�DQRUPale: una cu un cromosom în plus (2n+1) = WULVRPLFă (47 cromosomi) alta cu cromosomul respecWLY�OLSVă���Q-1) = PRQRVRPLFă (45 cromosomi).

E����ÌQWkU]LHUHD����DQDID]LFă ÌQWkU]LHUHD�DQDID]LFă�FRQVWă�vQ�migrarea cu întârziere a unui cromosom monocromatidian, FDUH�vQ�PRPHQWXO�IRUPăULL�PHPEUDQHORU�QXFOHDUH�YD�UăPkQH�vQ�DIDUD�QXFOHLORU�FHOXOHORU�ILLFH��(O�IRUPHD]ă�XQ�³micronucleu” FDUH�GLVSDUH�OD�XUPăWRDUHD�GLYL]LXQH��5H]XOWă�FORQH�FHOXODUH�FX��Q-���Q��DGLFă�������FURPRVRPL��3UH]HQĠD�PLFURQXFOHLORU��FH�VH�IRUPHD]ă�GLQ�FURPRVRPL�FDUH�QX�DX�PLJUDW�úL�FDUH�QX�DX�IRVW�LQFOXúL�vQ�QLFL�XQXO�GLQ�QXFOHLL�ILL���LQGLFă�WXOEXUăUL�DOH�GHVIăúXUăULL�PLWR]HL��FH�SRW fi produse de cauze externe. De aceea testul micronucleilor este utilizat pentru studiul efectelor cromosomice pURGXVH�GH�UDGLDĠLLOH�LRQL]DQWH�VDX�DOĠL�IDFWRUL�PXWDJHQL.

F��&OLYDUHD��WUDQVYHUVDOă��D��FHQWURPHUXOXL Clivarea WUDQVYHUVDOă�D�FHQWURPHUXOXL�SURGXFH�LVRFURPRVRPL��³FURPRVRPL�FX�EUDĠH�HJDOH´��DOFăWXLĠL�QXPDL�GLQ�EUDĠH�VFXUWH��S��VDX�QXPDL�GLQ�EUDĠH�OXQJL��T)(figura 5.14)��$FHúWLD�VXQW�DQRUPDOL��GHRDUHFH�DX�GXSOLFDWH�JHQHOH�GH�SH�EUDĠXO�SUH]HQW�úL�OH�OLSVHVF�JHQHOH�GH�SH�EUDĠXO�SLHUGXW��ÌQ�SDWRORJLD�XPDQă�DX�IRVW�GHVFULúL�PDL�IUHFYHQW�LVRFURPRVRPL�;S�VDX�;T�vQ�GLVJHQH]LLOH�JRQDGDOH sau i(12p) în sindromul Pallister-.LOOLDQ��FX�DQRPDOLL�FRQJHQLWDOH�PXOWLSOH�úL�UHWDUG�PLQWDO�

G���$EVHQĠD��FLWRNLQH]HL &HOXOHOH�VRPDWLFH�GXSă�GXSOLFDUHD�$'1-XOXL�vQ�LQWHUID]ă�DX��Q�FURPRVRPL�ELFURPDWLGLHQL���&���'DFă�DUH�ORF�PLWR]D�GDU�QX�VH�SURGXFH�FLWRNLQH]D�UH]XOWă�R�FHOXOă�tetraSORLGă FX��Q�FURPRVRPL�PRQRFURPDWLGLHQL���&���$FHVW�SURFHV��QXPLW�úL�HQGRPLWR]ă, se REVHUYă��vQ�PRG�IL]LRORJLF��vQ�SURFHVXO�GH�UHJHQHUDUH�KHSDWLFă�

H���&RQVHFLQĠHOH��HURULORU��PLWRWLFH (URULOH�GH�GLVWULEXĠLH�D�PDWHULDOXOXL�JHQHWLF�vQ�PLWR]ă�GHWHUPLQă�DSDULĠLD�XQRU�DQRPDOLL�GH�QXPăU�úL�VWUXFWXUă�DOH�FURPRVRPLORU�vQ�FHOXOHOH�ILLFH��(OH�YRU�DYHD�FRQVHFLQĠH�DVXSUD�HYROXĠLHL�FHOXOHORU��LQIOXHQĠkQG�YLDELOLWDWHD�úL�FDSDFLWDWHD�GH�PXOWLSOLFDUH��$FHúWL�SDUDPHWUL�GHSLQG�PDL�DOHV�GH�FURPRVRPXO�DIHFWDW�úL�WLSXO�GH�DQRPDOLH�FURPRVRPLFă��WULVRPLH�VDX�PRQRVRPLH��SURGXVă��'DFă�FHOXOHOH�UH]XOWDWH�VXQW�YLDELOH�úL�VH�PXOWLSOLFă�XOWHULRU��UH]XOWă�R�FORQă �JUXS�GH�FHOXOH�FH�DX�R�SDUWLFXODULWDWH�FRPXQă�úL�SURYLQ�SULQ�mitoze repetate dintr-R�FHOXOă�LQLĠLDOă�PRGLILFDWă��LDU în organism apar mozaicuri cromosomice (figura 5.15). Se întâlnesc mai frecvent în sindromul Turner (25% cazuri), sindromul Down (2-���EROQDYL��úL�VLQGURPXO�.OLQHIHOWHU��YH]L�FDSLWROXO����&� $SDULĠLD�XQRU�FORQH�FHOXODUH�DQRUPDOH�OD�XQ�RUJDQLVP��SULQ�RULFDUH�GLQ�HURULOH�DPLQWLWH��GHWHUPLQă�HIHFWH�GLIHULWH�vQ�UDSRUW�cu momentul ontogenetic în care s-D�SURGXV�DFFLGHQWXO��úL�GHFL�FX�SURSRUĠLD�FHOXOHORU�DQRUPDOH�FDUH�VH�IRUPHD]ă���3HUWXUEDUHD�SUHFRFH�úL�DSDULĠLD�XQXL�QXPăU�PDUH�GH�FHOXOH�DQRUPDOH�vQ�SULPHOH�VWDGLL�GH�Gezvoltare DUH�FRQVHFLQĠH�QHJDWLYH�PDMRUH��DQRPDOLL�FRQJHQLWDOH��DVXSUD�IHQRWLSXOXL�SXUWăWRULORU�GH�DQRPDOLL�FURPRVRPLFH��YH]L�FDSLWROXO����&���8Q�DOW�IDFWRU�FH�LQIOXHQĠHD]ă�HIHctele IHQRWLSLFH�DOH�FORQHORU�DQRUPDOH�HVWH�GLVWULEXĠLD�ORU�vQ�GLIHULWH�ĠHVXWXUL. A fost descris, de exemplu, un PR]DLFLVP��OLPLWDW�OD�SODFHQWă, cu XQ�IăW�HXSORLG��YH]L�FDSLWROXO������� &��75$160,7�(5($��,1)250$ğ,(,��*(1(7,&(� '(���/$���3Ă5,1ğ,���/$���'(6&(1'(1ğ, 7UDQVPLWHUHD�LQIRUPDĠLHL�JHQHWLFH�vQ�VXFFHVLXQHD�JHQHUDĠLLORU�GH RUJDQLVPH�HVWH�XQ�SURFHV�FRPSOH[�FDUH�VH�GHVIăúRDUă�vQ�GRXă�HWDSH��IRUPDUHD�JDPHĠLORU��FHOXOH�VH[XDOH�PDWXUH�FX�XQ�QXPăU�KDSORLG��GH�FURPRVRPL�����OD�RP��úL�IHFXQGDUHD�ORU��FDUH�UHIDFH�la ]LJRW�QXPăUXO�GLSORLG�GH����GH�FURPRVRPL��FDUDFWHULVWLF�VSHFLHL�XPDQH�úL�UHDOL]HD]ă�R�VWUXFWXUă�JHQHWLFă�QRXă��XQLFă�úL�FRQVWDQWă��LQGLYLGXDOLWDWHD�JHQHWLFă��FDUDFWHULVWLFă�YLLWRUXOXL�LQGLYLG��$PEHOH�HWDSH�VH�HIHFWXHD]ă�GH�RELFHL�FX�PDUH�SUHFL]LH�GDU�XQHRri se SRW�SURGXFH�HURUL�FDUH�JHQHUHD]ă�DQRPDOLL�JHQHWLFH�

1. GAMETOGENEZA *DPHWRJHQH]D�DUH�ORF�vQ�JRQDGH��SULQ�PHLR]ă�- XQ�WLS�VSHFLDO�GH�GLYL]LXQH�UHGXFĠLRQDOă�- FDUH�DVLJXUă�WUDQVPLWHUHD�LQIRUPDĠLHL�JHQHWLFH�OD�JHQHUDĠLD�XUPăWRDUH�úL�vQGHSOLQHúWH�GRXă�IXQFĠLL�PDMRUH� � 5HGXFH�OD�MXPăWDWH��Q��QXPăUXO�GH�FURPRVRPL�úL�DVLJXUă�DVWIHO��GXSă�IHFXQGDUH��PHQĠLQHUHD�FRQVWDQWă�D�QXPăUXOXL�GH�

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10 In acest context, termenul de “reproducere” este impropriu pentru că�LQGLYLGXO�FH�UH]XOWă�GXSă�IHFXQGDUH�QX�HVWH�R�UHSURGXFHUH�D�QLFL�XQXLD�GLQ�SăULQĠL� 5

UHFRPELQDUH�JHQLFă��GLQ�SURID]D�,��úL�UHFRPELQDUH�LQWHUFURPRVRPLFă��GLQ�DQDID]D ,���PHLR]D�HVWH�SULQFLSDOD�VXUVă�GH�YDULDELOLWDWH�JHQHWLFă�

1.1 CARACTERELE GENERALE ALE MEIOZEI

0HLR]D�HVWH�XQ�SURFHV�FRPSOH[�FDUH�VH�UHDOL]HD]ă�SULQ�GRXă�GLYL]LXQL�VXFFHVLYH��PHLR]D�,��GLYL]LXQHD�PHLRWLFă�SULPDUă��KHWHURWLSLFă��UHGXFĠLRQDOă��úL�PHLR]D�,,��GLYL]LXQHD�PHLRWLFă�VHFXQGDUă��KRPRWLSLFă��HFXDĠLRQDOă���QHVHSDUDWH�GH�LQWHUID]ă��GHFL�$'1�VH�UHSOLFă�QXPDL�R�VLQJXUă�GDWă�� a. Meioza I (VWH�R�IRUPă�VSHFLDOă�GH�GLYL]LXQH�FHOXODUă11��XQLFă�úL�IRDUWH�FRPSOH[ă��FX�R�GXUDWă�OXQJă��vQ�VSHFLDO�OD�RUJDQLsmele feminine. 3UH]LQWă�SDWUX�HWDSH��SURID]D�,��PHWDID]D�,��DQDID]D�,��WHORID]D�,��ILHFDUH�FX�DQXPLWH�SDUWLFXODULWăĠL�(figura 5.16.A).

������3URID]D��,��HVWH�IRDUWH�OXQJă�������GLQ�GXUDWD�PHLR]HL�,��úL�FXSULQGH�FLQFL�VWDGLL� � Leptoten. Prin condensarea fibUHORU�GH�FURPDWLQă��FURPRVRPLL�GHYLQ�YL]LELOL�FD�ILODPHQWH�VXEĠLUL�úL�OXQJL��DWDúDWH�SULQ�WHORPHUH�

OD�PHPEUDQD�QXFOHDUă��$VWIHO��GDWRULWă�OXQJLPLL�PDUL�úL�JURVLPLL�PLFL�D�FURPRVRPLORU��GHúL�FURPRVRPLL�VXQW�ELFURPDWLGLHQL��HL apar monocromatidieni la examinarea la microscopul optic.

� =LJRWHQ��&URPRVRPLL�RPRORJL��PDWHUQ�úL�SDWHUQ��VH�DSURSLH��VH�GLVSXQ�SDUDOHO�GH-a lungul cromatidelor, fenomen numit VLQDSVă�sau FRQMXJDUH�FURPRVRPLFă��VH�UHDOL]HD]ă�DVWIHO�R�DOLQLHUH��JHQă�OD�JHQă��VDX��PDL�H[DFW��R�vPSHUHFKHUH�între VHFYHQĠHOH�RPRORJH12, rezultând structuri numite ELYDOHQĠL (în realitate fiecare unitate este o WHWUDGă��GHRDUHFH�SUH]LQWă�SDWUX�cromatide). Cromosomii omologi sunt XQLĠL��OLSLĠL� în anumite regiuni, la nivelul complexului sinaptonemal, vizibil la micURVFRSXO�HOHFWURQLF��2�H[FHSĠLH�GH�OD�DFHVW�PRGHO�GH�VLQDSVă��HVWH�SUH]HQWă�OD�VH[XO�PDVFXOLQ��OD�FDUH�FURPRVRPLL�;�úL�<��QHILLQG�RPRORJL��IDF�VLQDSVă��FDS�OD�FDS���SULQWU-R�PLFă�UHJLXQH�RPRORJă���UHJLXQH�SVHXGRDXWRVRPDOă���DIODWă�OD�FDSăWXO�EUDĠHORU�VFXUWH��úL�IRUPHD]ă�SULQ�FRQGHQVDUH�R�VWUXFWXUă�VSHFLILFă�- YH]LFXOD�VH[XDOă.

� 3DKLWHQ��&URPRVRPLL�VH�VFXUWHD]ă�úL�VH�vQJURDúă��'LQ�ORF�vQ�ORF�GHYLQ�YL]LELOH�QLúWH�SXQFWH�PDL�LQWHQV�FRORUDWH�QXPLWH�cromomere��DO�FăURU�QXPăU�úL�SR]LĠLH�VXQW�FDUDFWHULVWLFH�ILHFăUui cromosom13. În faza de pahiten are loc fenomenul de vQFUXFLúDUH�FURPRVRPLFă�vQWUH�FURPRVRPLL�RPRORJL�- crossing-over - FDUH�FRQVWă�vQ��UXSHUHD��FURPDWLGHORU�QHVXURUL�exact în DFHODúL�SXQFW úL�VFKLPEDUHD�UHFLSURFă �vQFUXFLúDWă��D�XQRU�fragmente egale („reFRPELQDUH�RPRORJă´�14; astfel, un fragment de FURPDWLGă�GH�SH�XQ�FURPRVRP�PDWHUQ�VH�WUDQVIHUă SH�RPRORJXO�VăX�SDWHUQ�úL�LQYHUV��UHDOL]kQG�R�QRXă�FRPELQDĠLH�JHQLFă cu PDWHULDO�JHQHWLF�GH�OD�DPELL�SăULQĠL��YH]L�ILJXUD��������)HQRPHQXO�LPSOLFă�QXPDL�GRXă�GLQ�FHOH�SDWUX�FURPDWLGH��FDUH�YRU�FRQĠLQH�JHQH�GH�OD�DPELL�SăULQĠL��VH�UHDOL]HD]ă�DVWIHO�R�UHFRPELQDUH�JHQLFă��LQWUDFURPRVRPLFă���FDUH�UHSUH]LQWă�R�VXUVă�GH�YDULDELOLWDWH�JHQHWLFă� GDWRULWă�QRLORU�FRPELQDĠLL�GH�JHQH�FDUH�DSDU�úL�VH�WUDQVPLW�OD�GHVFHQGHQĠL��YH]i capitolul 3.A.2.2). La om se produc 1-��UHFRPELQăUL�SHU�FURPRVRP��vQ�IXQFĠLH�GH�GLPHQVLXQHD�FURPRVRPXOXL��ÌQ�PHLR]D�PDVFXOLQă�WRWDOXO�UHFRPELQăULORU�HVWH�GH�FLUFD����SHU�FHOXOă��vQ�WLPS�FH�PHLR]D�IHPLQLQă�VH�FDUDFWHUL]HD]ă�SULQWU-XQ�QXPăU�PDL�PDUH�GH�UHFRPELQăUL��DSUR[LPDWLY����SHU�FHOXOă���)UHFYHQĠD�UHFRPELQăULL�FDUH�VH�SURGXFH�vQWUH�GRXă�JHQH�VLWXDWH�SH�DFHODúL�FURPRVRP�GHSLQGH�GH�GLVWDQĠD�GLQWUH�HOH��FDOFXOXO�IUHFYHQĠHL�GH�UHFRPELQDUH�SHUPLWH�DOFăWXLUHD�KăUĠLORU�FURPRVRPLFH��FDUH�LQGLFă�ORFDOL]DUHD�JHQelor în lungul cromosomilor (vezi capitolul 3.D.1).

� 'LSORWHQ��&URPRVRPLL�RPRORJL�vQFHS�Vă�VH�VHSDUH�ORQJLWXGLQDO��FD�úL�FXP��V-DU�UHVSLQJH��UHFLSURF��&URPDWLGHOH�ORU�UăPkQ�vQ�contact la nivelul anumitor puncte ("chiasmata", pluralul de la "chiasma") care mDUFKHD]ă�ORFDOL]DUHD�FURVVLQJ-over-ului.

� 'LDNLQH]D��&URPRVRPLL�GHYLQ�PDL�VFXUĠL�úL�PDL�JURúL��RPRORJLL�VH�VHSDUă�DSURDSH�FRPSOHW��LDU�FKLDVPDWHOH�VH�REVHUYă�QXPDL�OD�capetele lor (terminalizarea chiasmatelor���ÌQ�DFHDVWă�ID]ă�VH�REVHUYă�FODU�Fă�ILHFDUH�ELYDOHQW�FRQĠLQH�SDWUX�HOHPHQWH��FURPDWLGHOH�VXURUL�VXQW�XQLWH�SULQ�FHQWURPHU��LDU�FURPDWLGHOH�QHVXURUL�VXQW�XQLWH�SULQ�FKLDVPDWHOH�OD�QLYHOXO�FăURUD�V-a produs crossing-over-ul.

����0HWDID]D��,��0HPEUDQD�QXFOHDUă�GLVSDUH�FRPSOHW�úL�VH�IRUPHD]ă�IXVXO�GH�GLYL]LXQH��%LYDOHQĠLL��IRUPDĠL�GLQ�FURPRVRPL�ELFURPDWLGLHQL��VH�IL[HD]ă�FX�FHQWURPHUXO�SH�ILODPHQWHOH�IXVXOXL�úL�VH�GHSODVHD]ă�VSUH�SODFD�PHWDID]LFă��OD�HFXDWRUXO�FHOXOHL. &HQWURPHUXO�FURPRVRPLORU�RPRORJL�VH�GLVSXQH�DOHDWRULX�GH�R�SDUWH�úL�GH�DOWD�D�SODQXOXL�HFXDWRULDO��0HWDID]D�,�HVWH�HWDSD�RSWLPă�GH�VWXGLX�D�FURPRVRPLORU�vQ�PHLR]ă�� �����$QDID]D��,�FXSULQGH�XQ�IHQRPHQ�JHQHWLF�IRDUWH�LPSRUWDQW��GLVMXQFĠLD�FURPRVRPLFă��&HL�GRL�FURPRVRPL�ELFURPDWLGLHQL�DL�ILHFăUXL�ELYDOHQW�VH�VHSDUă úL�VH�UHSDUWL]HD]ă�FkWH�XQXO�OD�ILHFDUH�FHOXOă�ILLFă��6SUH�GHRVHELUH�GH�PLWR]ă��cromatidele surori nu se despart, FL�UăPkQ�DWDúDWH�OD�QLYHOXO�FHQWURPHUXOXL��$SRL�DUH�ORF�PLJUDUHD�DQDID]LFă SULQ�GHSODVDUHD�FURPRVRPLORU��ELFURPDWLGLHQL��VLPXOWDQ�úL�FX�DFHHDúL�YLWH]ă��VSUH�SROLL�RSXúL�DL�FHOXOHL��ÌQ�ILQDO��VH�SURGXFH�R�UHGXFHUH�D�QXPăUXOXL�GH�FURPRVRPL��GH�OD��Q�OD�Q�úL�ILHFDUH�FHOXOă�YD�DYHD�QXPDL�XQ�H[HPSODU�GLQ�SHUHFKHD�GH�RPRORJL��$FHVW�IHQRPHQ�VWă�OD�ED]D�SULPHL�OHJL�D�OXL�0HQGHO��OHJHD�VHJUHJăULL� Segregarea sau separarea DOHDWRULH�D�ILHFăUHL�SHUHFKL�GH�FURPRVRPL�RPRORJL�GHWHUPLQă DVRUWDUHD�LQGHSHQGHQWă�D�omologilor��IHQRPHQ�GHQXPLW�UHFRPELQDUH�LQWHUFURPRVRPLFă��'HRDUHFH�ILHFDUH�SHUHFKH�GH�FURPRVRPL�VH�VHSDUă�LQGHSHQGHQW de FHOHODOWH�SHUHFKL�UH]XOWă�XQ�QXPăU�PDUH�GH�FRPELQDĠLL�FURPRVRPLFH�vQ�JDPHĠL��vQ�UDSRUW�GLUHFW�FX�QXPăUXO�GH�SHUHFKL�GH�cromosomi ai speciei (figura 5.17). 6H�IRUPHD]ă��23 WLSXUL�GH�JDPHĠL��GHFL�SHVWH�����PLOLRDQH�GH�JDPHĠL�GLIHULĠL��OD�ILHFDUH�GLQ�FHOH�GRXă�VH[H� $VRUWDUHD�LQGHSHQGHQWă�D�FURPRVRPLORU�RPRORJL��SULQ�IHQRPHQXO�GH�UHFRPELQDUH�FURPRVRPLFă��DVRFLDWă�FX�UHFRPELQDUHD�LQWUDFURPRVRPLFă�SULQ�FURVVLQJ-over, H[SOLFă�PDUHD�YDULDELOLWDWH�D�JDPHĠLORU��(D�FRQILUPă�FHD�GH�D�GRXD�OHJH�D�OXL�0HQGHO��referitoare la FRPELQDUHD�OLEHUă�D��IDFWRULORU�HUHGLWDUL���JHQHORU��DVWIHO�Fă�ILHFDUH�JDPHW��FDUH�UH]XOWă�vQ�XUPD�PHLR]HL��DUH�XQ�VHW�XQLF�GH�JHQH��GLIHULW�GH�DO�FHORUODOĠL��3ULQ�FRPELQDUHD��SH�ED]ă�GH�SUREDELOLWDWH��D�JDPHĠLORU�PDVFXOLQL�FX�FHL�IHPLQLQL�vQ�Srocesul de fecundare are loc formarea unor ]LJRĠL�GLIHULĠL�GLQ�SXQFW�GH�YHGHUH�JHQHWLF��LDU�LQGLYL]LL�UH]XOWDĠL�YRU�IL�XQLFDWH�JHQHWLFH�

11 ([LVWă�GRXă�GLIHUHQĠH�PDMRUH�vQWUH�PHLR]ă�úL�PLWR]ă��SULQ�meiR]ă�UH]XOWă celule haploide, care genetic sunt diferite 12 Alinierea / împerecherea cromosomilor omologi “margine” la “margine” la nivelul sinapselor HVWH�IDYRUL]DWă�GH�VHFYHQĠHOH�UHSHWLWLYH�PXOWLSOH�úL�LGHQWLFH�FD�WLS�úL�ORFDOL]DUH�GLQ�FHL�GRL�FURPRVRPL�RPologi. 13 'LVSR]LĠLD�FURPRPHUHORU�FRLQFLGH�FX�FHD�D�EHQ]LORU�*��YH]L�FDSLWROXO�Cromosomii umani) 14 0HFDQLVPXO�PROHFXODU�DO�UHFRPELQăULL�OD�RP�QX�HVWH�SUHD�FODU�GDU�VH�SUHVXSXQH�FD�LQWHUYLQH�XQ�VLVWHP�JHQLF�VLPLODU�FX�JHQHOH�„SOS” descrise la procariote, carH�SULQ�HQ]LPHOH�FRGLILFDWH�WDLH��VFKLPEă�úL�UHVXGHD]ă�IUDJPHQWHOH�GH�FURPRVRPL� 6

������7HORID]D��,��$UH�ORF�UHDVDPEODUHD�QXFOHLORU��FLWRNLQH]D�VH�UHDOL]HD]ă�IăUă�VHSDUDUHD�FRPSOHWă�D�FHOXOHORU�ILLFH��FDUH�UăPkQ�DWDúDWH�SULQWU-R�SXQWH�FLWRSODVPDWLFă��IRUPknd o GLDGă.

b. Meioza II 0HLR]D�,,�vQFHSH�LPHGLDW�GXSă�WHUPLQDUHD�PHLR]HL�,�úL�VH�DVHDPăQă�FX�R�GLYL]LXQH�PLWRWLFă�GDU�FDUH�VH�UHDOL]HD]ă�vQ�FHOXOH�FX QXPăU�KDSORLG�GH����GH�FURPRVRPL�ELFURPDWLGLHQL��GLQWUH�FDUH�XQLL�VXQW�UHFRPELQDQĠL��úL�QX�HVWH�SUHFHGDWă�GH�R�UHSOLFDUH�D�$'1��Este deci o GLYL]LXQH�KRPRWLSLFă��HFXDĠLRQDOă��(D�FXSULQGH��GH�DVHPHQHD��FHOH�SDWUX�VWDGLL��SURID]D�,,��PHWDID]D�,,��DQDID]D�,,�úL�telofaza II (figura 5.16. B).

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2�DOWă�DQRPDOLH�GH�IHFXQGDUH�HVWH�dispermia��VLWXDĠLD�IRDUWH�UDUă�vQ�FDUH�XQ�RYXO�HVWH IHFXQGDW�GH�FăWUH�GRL�VSHUPDWR]RL]L��5H]XOWă�XQ�]LJRW�WULSORLG���Q���$FHODúL�UH]XOWDW�SRDWH�IL�REĠLQXW�DWXQFL�FkQG�XQXO�GLQ�JDPHĠL�HVWH�GLSORLG��diginie sau diandrie) (vezi FDSLWROXO����%�����(YROXĠLD�XQXL�]LJRW�WULSORLG�YD�GHSLQGH�GH�RULJLQHD�VHWXOXL�KDSORLG�VXSOLPHQWDU��GDFă�HVWH�GH�SURYHQLHQĠă�PDWHUQă��GLJLQLH��DWXQFL�GH]YROWDUHD�HPEULRQDUă�HVWH�VHYHU�vQWkU]LDWă��SODFHQWD�HVWH�PLFă�úL�ILEURWLFă�LDU�HPEULRQXO�HVWH�DYRUWDW�SUHcoce; GDFă�HVWH�GH�RULJLQH�SDWHUQă��GLDQGULH��VH�YD�IRUPD�R�SODFHQWă�DQRUPDOă��PDUH�úL�SROLFKLVWLFă��FX�XQ�HPEULRQ�VODE�GH]YROWDW��PROă�KLGDWLIRUPă�SDUĠLDOă)

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2. TRANSMITEREA CARACTERELOR MONOGENICE &DUDFWHUHOH�PRQRJHQLFH�VXQW�FHOH�PDL�VLPSOH�FDUDFWHUH�JHQHWLFH�D�FăURU�SUH]HQĠă�VDX�DEVHQĠă�GHSLQGH�GH�DOHOHOH��QRUPDOH�VDX�mutante, ale unui singur locus, situat pe autosomi sau pe cromosomul ;��'HVLJXU��PDQLIHVWDUHD�FDUDFWHUXOXL�SRDWH�GHSLQGH�úL�GH�DOĠL�IDFWRUL��JHQHWLFL�VDX�GH�PHGLX��GDU�JHQHOH�UHVSHFWLYH�VXQW�QHFHVDUH�úL�VXILFLHQWH�pentru exprimarea caracterului. Ele au efecte mari úL�VH�FRQIRUPHD]ă�vQ�PRG�RELúQXLW�SULQFLSLXOXL�³R�JHQă ĺ�R�SURWHLQă�ĺ�XQ�FDUDFWHU´��GHúL��GXSă�FXP�úWLP�GHMD��PXWDĠLL�GLIHULWH�vQ�DFHHDúL�JHQă�SRW�SURGXFH�IHQRWLSXUL��EROL��GLIHULWH�VDX��LQYHUV��PXWDĠLL�vQ�JHQH�GLIHULWH�VH�SRW�PDQLIHVWD�IHQRWLpic identic �YH]L�KHWHURJHQLWDWHD�JHQHWLFă��FDSLWROXO���$���$FHVWH�FDUDFWHUH�PRQRJHQLFH�VH�PRúWHQHVF�GH�RELFHL�vQWU-un mod simplu, identic VDX�VLPLODU�FX�FHO�GHVFULV�GH�FăWUH�0HQGHO��GH�DFHHD�HOH�VH�QXPHVF�úL�FDUDFWHUH�PHQGHOLHQH� Se cunosc peste 10.000 de caractere mendeliene, normale sau patologice, listate în lucrarea de reIHULQĠă�D�OXL�9LFWRU�McKusick Mendelian Inheritance of Man �HG������������LQGLVSHQVDELOă�PHGLFLORU�JHQHWLFLHQL��9HUVLXQHD�RQOLQH���QXPLWă�OMIM HVWH�FRQWLQXX�DFWXDOL]DWă�úL�GLVSRQLELOă�SULQ�LQWHUQHW��FDVHWD�����

Bolile monogenice sunt caracterizate prin modul lor de transmitere în familie, stabilit în urma unei anamneze (istoric) IDPLOLDOH�úL�UHSUH]HQWDW�JUDILF��FX�DMXWRUXO�XQRU�VLPEROXUL�VWDQGDUG���VXE�IRUPD�XQXL�DUERUH�JHQHDORJLF��vQ�HQJOH]ă�pedigree19) (figura 5.21).

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0RGHOXO�GH�WUDQVPLWHUH�HUHGLWDUă�D�XQXL�FDUDFWHU�PRQRJHQLF�vQ�IDPLOLH�GHSLQGH�GH�GRi factori: � localizarea genei pe un autosom (caracter autosomal) sau pe cromosomii sexuali, X sau Y (caracter legat de X sau de Y); � fenotipul GRPLQDQW�VDX�UHFHVLY�GHWHUPLQDW�GH�JHQă�

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$VWIHO�H[LVWă�FLQFL�PRGHOH�GH�ED]ă�SHQWUX�WUDQVPLWHUHD�PRQRJHQLFă��DXWRVRPal dominant (AD), autosomal recesiv (AR), recesiv-legat de X (RLX), dominant-OHJDW�GH�;��'/;��úL�OHJDW�GH�<��/<���$QDPQH]D�IDPLOLDOă�SRDWH�LQGLFD�úL�DOWH�PRGHOH�GH�WUQVQPLWHUH��QHPHQGHOLHQH��GH�H[HPSOX�WUDQVPLWHUHD�PDWHUQDOă�vQ�EROLOH�PLWRFRQGULDOH���GDU�Oa acestea ne vom referi distinct, ulterior.

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20 ([FHSĠLH�IDF�JHQHOH�ÄSDVHXGRDXWRVRPDOH´�FDUH�DX�DOHOH�IXQFĠLRQDOH�DWkW�SH�;�FkW�úL�SH�< 21 6H�UHFRPDQGă�FD�DOHOHOH�FH�GHWHUPLQă�FUDFDWHUH�GRPLQDQWH�Vă�ILH�QRWDWH�FX�PDMXVFXOH�LDU�alelele FH�GHWHUPLQă�FDUDFWHUH�UHFHVLve cu litere mici��1RL�SUHIHUăP�VLPEROXULOH�A sau a��SHQWUX�JHQHOH�PXWDQWH�úL�N sau n pentru cele normale. 11

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ÌQ�DFHDVWă�VLWXDĠLH��FDUDFWHUXO�HVWH�GHWHUPLQDW�GH�R�pereche de gene alele��VLWXDWă�vQ�loci omologi, pe unul dintre autosomi. 8QD�GLQ�JHQHOH�DOHOH�VXIHUă�R�PXWDĠLH��A��úL�VH�PDQLIHVWă�IHQRWLSLF��FOLQLF��OD�KHWHUR]LJRĠL��A/n), deoarece DOHOD�QRUPDOă��n) este LQVXILFLHQWă�SHQWUX�D�FRPSHQVD�HIHFWXO�DOHOHL�PXWDQWH��&HOH�GRXă�DOHOH�$�úL�Q pot forma trei genotipuri: A/n (mai frecvent), A/A �PDL�UDU��úL�n/n��SULPHOH�GRXă�JHQRWLSXUL�YRU�GHWHUPLQD�XQ�IHQRWLS�DQRUPDO��R�ERDOă��DXWRVRPDO�GRPLQDQWă��vQ�FDUH�EDUEDĠLL�úL�femeile vor fi HJDO�DIHFWDĠL.

Teoretic, cu cele trei genotipuri se pot realiza úDVH FRPELQDĠLL�VDX�WLSXUL�GH�vQFUXFLúăUL�(tabel 5.6)��GDU�SUDFWLF��IUHFYHQĠD�lor într-R�SRSXODĠLH�GHSLQGH�GH�VHYHULWDWHD�PDQLIHVWăULL�FOLQLFH��FDUH�GHWHUPLQă�VDX�QX�VXSUDYLHĠXLUHD�SkQă�OD�YkUVWD�DGXOWă�úL�FDSDFLWDWHD�UHSURGXFWLYă��IHUWLOLWDWHD���(YLGHQW�SULPHOH�GRXă�FRPELQDĠLL�VXQW FHOH�PDL�IUHFYHQWH��D�WUHLD�HVWH�UDUă�úL��vPSUHXQă�FX�XUPăWRDUHOH�WUHL��UDULVLPH���VH�vQWkOQHVF�vQ�IDPLOLLOH�PDUL��QXPDL�SHQWUX�EROL�ÄXúRDUH´��GH�H[HPSOX��brahidactilia, hemeralopia, prognatismul��VDX�SHQWUX�FHOH�FX�GHEXW�WDUGLY��GXSă����GH�DQL�� 6ăQăWRúL (n/n��úL�EROQDYL��A/A; A/n)

&RPELQDĠLL

genotipice

parentale

*DPHĠL

'HVFHQGHQĠL

Genotipuri Fenotipuri

(indiferent de sex)

1. n/n + n/n n x n n/n WRĠL�VăQăWRúL

2. A/n + n/n (A+n) x n ½ A/n

½ n/n

½ bolnavi

ò�VăQăWRúL

3. A/n + A/n (A+n) x (A+n)

¼ A/A; ½ A/n

¼ n/n

¾ bolnavi

ó�VăQăWRúL���

(indiferent de sex)

4. A/A + n/n A x n A/n WRĠL�EROQDYL

5. A/A + A/n A x (A+n) ½ A/A; ½ A/n WRĠL�EROQDYL

6. A/A + A/A A x A A/A WRĠL�EROQDYL

'LQ�DQDOL]D�DFHVWRU�FRPELQDĠLL���vQFUXFLúăUL�UH]XOWă�R�VHULH�GH�FDUDFWHULVWLFL��UHJXOL��DOH�WUDQVPLWHULL�DXWRVRPDO�GRPLQDQWH� DoL�LQGLYL]L�VăQăWRúL��Q�Q���Q�Q��QX�SRW�DYHD�FRSLL�FX�DIHFĠLXQL�$'��ERDOD�QX�HVWH�WUDQVPLVă�SULQ�SHUVRDQH�QHDIHFWDWH�deoarece, teoretic, nu H[LVWă�SXUWăWRUL�VăQăWRúL�GH�JHQă�PXWDQWă��$FHDVWă�UHJXOă�DUH�R�H[FHSĠLH��SURGXFHUHD�XQRU�PXWDĠLL��$'��germinale noi �vQ�JDPHWRJHQH]D�XQXLD�GLQWUH�SăULQĠLL�VăQăWRúL��SRDWH�GHWHUPLQD�DSDULĠLD�XQXL�FRSLO�DIHFWDW��H[LVWă�GH�DVHPHQHD�ÄDEDWHUL´�GHWHUPLQDWH�GH�KHWHURJHQLWDWHD�JHQHWLFă�GH�ORFXV��PXWDĠLL�GLIHULWH��GRPLQDWH�úL�UHFHVLYH��SRW�GD�DFHODúL�IHQRWLS��Ge exemplu în retinLWD�SLJPHQWDUă��YH]L�FDVHWD������VDX�GH�JHQRWLSXO�XQXLD�GLQWUH�SăULQĠLL�VăQăWRúL�FDUH�HVWH�vQ�UHDOLWDWH�A/n dar alela A QX�VH�H[SULPă�GHORF�IHQRWLSLF��QRQ-SHQHWUDQĠă��VDX�VH�YD�H[SULPD�PDL�WkU]LX�GHFkW�OD�FRSLOXO�DIHFWDW��DQWLFLSDĠLH���ÌQ�DFHODúL�context sH�SRW�LQFOXGH�úL�FD]XULOH�GH�QRQ-SDWHUQLWDWH��vQ�FDUH�WDWăO�QHOHJLWLP�HVWH�A/n). 'LQ�vQFUXFLúDUHD�GLQWUH�XQ�EROQDY�KHWHUR]LJRW��A/n��úL�XQ�VăQăWRV��n/n��UH]XOWă��WHRUHWLF������EROQDYL��A/n��úL�����VăQăWRúL��n/n): Bolnav (A/n)

Ļ JDPHĠL A n n 6ăQăWRV�ĺ�JDPHĠL�� (n/n) n 50% 50% 5H]XOWDWXO�DFHVWHL�vQFUXFLúăUL�QH�SHUPLWH�Vă�IRUPXOăP�DOWH�UHJXOL�GH�ED]ă�DOH�WUDQVPLWHULL�$'��ILHFDUH�EROQDY�DUH��FHO�SXĠLQ��XQ�SăULQWH�DIHFWDW��FX�DOWH�FXYLQWH��ERDOD�HVWH�SUH]HQWă�vQ�ILHFDUH�JHQHUDĠLH úL�vQ�DUERUHOH�JHQDORJLF�DO�XQHL�IDPLOLL��VXILFLHQW�GH�PDUH��VH�REVHUYă�R�IUHFYHQĠă�UHODWLY�ULGLFDWă�D�EROQDYLORU�úL�R�WUDQVPLWHUH�YHUWLFDOă (figura 5.23). $FHVWH�FDUDFWHULVWLFL��úL�PDL�DOHV�SUH]HQĠD��FRQWLQXLWDWHD��EROLL�vQ�VXFFHVLXQHD�JHQHUDĠLLORU� VH�REVHUYă�IUHFYHQW�vQ�EROLOH�$'�PDL�SXWLQ�VHYHUH��FRPSDWLELOH�FX�UHSURGXFHUHD�úL��GHVHRUL��OD�FHOH cu debut tardiv.

%RDOD�VH�PDQLIHVWă��FX�R�IUHFYHQĠă�úL�R�VHYHULWDWH�UHODWLY�HJDOă��DWkW�OD�EăUEDĠL�FkW�úL�OD�IHPHL�LDU�JHQD�PXWDQWă��VLWXDWă�SH�XQ�DXWRVRP��SRDWH�IL�PRúWHQLWă�úL�WUDQVPLVă�FX�R�SUREDELOLWDWH�HJDOă�GH�FăWUH�DPEHOH�VH[H��GHFL�LQGHSHQGHQWă�GH sex). Toate DFHVWHD�SOHGHD]ă�SHQWUX�R�WUDQVPLWHUH�DXWRVRPDOă��ÌQ�SOXV��WUDQVPLWHUHD�WDWă�ĺ�ILX�HVWH�SRVLELOă��GHúL�DFHVW�FULWHULX�QX�HVWH�REOLJDWRULX�SHQWUX�WUDQVPLWHUHD�$'��SUH]HQĠD�OXL�H[FOXGH�DOWH�WLSXUL�GH�WUDQVPLWHUH�

Evident, de la aceste reguli exiVWă�úL�H[FHSĠLL��FDUH�FRPSOLFă�LQWHUSUHWDUHD��úL�SH�FDUH�OH�YRP�GLVFXWD�PDL�MRV��HVWH�YRUED�GH�PXWDĠLL�QRL��PR]DLFXUL�JHUPLQDOH��SHQHWUDQĠă�UHGXVă��DQWLFLSDĠLH��V�D�

$FXP�vQVă�YRP�VXEOLQLD�DOW�HOHPHQW�LPSRUWDQW��ILHFDUH�EROQDY, heterozigot �VLWXDĠLD�FHD�PDL�IUHFYHQWă�vQ�EROLOH�$'���DUH�un risc de 50% GH�D�DYHD�GHVFHQGHQĠL�DIHFWDĠL��GDFă�JHQD�DUH�R�SHQHWUDQĠă�FRPSOHWă��$FHVW�risc de 50% este valabil la fiecare VDUFLQă�(ca eveniment independent���LQGLIHUHQW�GDFă�DQWHULRU�V-D�QăVFXW�XQ�FRSLO�QRUPDO�VDX�DIHFWDW��'DU�WUDQVPLWHUHD�JDPHĠLORU��OD�

A/N

N/N

A/n

n/n

12

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În transmiterea bolilor AD sH�SRDWH�vQWkOQL�XQHRUL�VLWXDĠLD�vQFUXFLúăULL�GLQWUH�GRL�EROQDYL�KHWHUR]LJRĠL�A/n x A/n �FRPELQDĠLD���vQ�WDEHOXO������GLQ�FDUH�SRW�UH]XOWD�LQGLYL]L�DIHFWDĠL�úL�KRPR]LJRĠL��VLWXDĠLLOH���úL���GLQ�WDEHOXO�����VXQW�DSroape numai teoretice). În multe boli AD (hiSHUFROHVWHUROHPLD�IDPLOLDOă��DFRQGURSOD]LD��VLQGURPXO�0DUIDQ��ú�D.) KRPR]LJRĠLL�VXQW�PDL�JUDY�DIHFWDĠL GHFkW�KHWHUR]LJRĠLL úL�GHVHRUL�SUH]LQWă�IRUPH�OHWDOH��QHRQDWDO���GH�ERDOă��6SUH�GHRVHELUH�GH�DFHVWH�EROL�FX�VHPLGRPLQDQĠă�(A/A > A/n > n/n��H[LVWă�úL�FD]XUL�GH�EROL�FX�GRPLQDQĠă�FRPSOHWă��vQ�FDUH�A/A = A/n) iar exemplul cel mai cunoscut fiind cel al bolii Huntington��5HYHQLQG�OD�VLWXDĠLD�UDUă�D�vQFUXFLúăULL�GLQWUH�GRL�EROQDYL�KHWHUR]LJRĠL�YRP�VHPQDOD��FD�R�FDUDFWHULVWLFă�D�EROLORU�GRPLQDQWH��IDSWXO�Fă�HL�SRW�DYHD�GHVFHQGHQĠL�VăQWRúL�FDUH��vQ�EROLOH�$'��YRU�IL�úL�IHWH�����úL�EăLHĠL� 3H�ED]D�GDWHORU�GLVFXWDWH�PDL�VXV�VH�SRW�IRUPXOD�XUPăWRDUHOH�criterii privind transmiterea AD: � ILHFDUH�EROQDY�DUH�GH�RELFHL�XQ�SăULQWH�DIHFWDW� � orice bolnav transmite boala la MXPăWDWH�GLQ�FRSLLL�VăL��ULVFXO�GH�����HVWH�YDODELO�OD�ILHFDUH�VDUFLQă� � IHQRWLSXO�DQRUPDO�DSDUH�vQ�ILHFDUH�JHQHUDĠLH��FRQWLQXLWDWH�vQ�VXFFHVLXQHD�JHQHUDĠLLORU��LDU�vQ�DUERUHOH�JHQHDORJLF�VH�REVHUYă o

WUDQVPLWHUH�YHUWLFDOă� � LQGLYL]LL�VăQăWRúL�QX�WUDQVPLW�ERala;

([FHSĠLLOH�GH�OD�DFHVWH�UHJXOL�VXQW�GHWHUPLQDWH�GH��SHQHWUDQĠD UHGXVă��PXWDĠLL�QRL�VDX�PR]DLFXUL�JHUPLQDOH, debut tardiv de manifestare, non-paternitate úL��PDL�UDU��KHWHURJHQLWDWH�JHQHWLFă�úL�IHQRFRSLL;

� ERDOD�VH�PDQLIHVWă��FX�R�IUHFYHQĠă�úL�R�VHYHULWDWH�UHODWLY�HJDOă��DWkW�OD�EăUEDĠL�FkW�úL�OD�IHPHL�LDU�JHQD�PXWDQWă��SRDWH�IL�PRúWHQLWă�úL�WUDQVPLVă��FX�R�SUREDELOLWDWH�HJDOă�GH�FăWUH�DPEHOH�VH[H��GHFL�LQGHSHQGHQWă�GH�VH[��H[FHSĠLD�R�FRQVWLWXLH�EROLOH FDUH�SUHGRPLQă�VDX�VXQW�OLPLWDWH�OD�XQ�VH[��

� transmiWHUHD�WDWă�ĺ�ILX�HVWH�SRVLELOă�úL�FDUDFWHULVWLFă�HUHGLWăĠLL�$'. � GRL�EROQDYL��FX�R�DIHFĠLXQH�FRPSDWLELOă�FX�VXSUDYLHĠXLUHD�úL�UHSURGXFHUHD��SRW�DYHD�GHVFHQGHQĠL�VăQăWRúL��IHWH�úL�EăLHĠL��LDU

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3HQHWUDQĠD�VH�SRDWH�PăVXUD�FDQWLWDWLY�SULQ�GHWHUPLQDUHD�SURSRUĠLHL�KHWHUR]LJRĠLORU��A/n��FDUH�H[SULPă�IHQRWLSLF�JHQD PXWDQWă�GLQ�WRWDOXO�ÄSXUWăWRULORU�REOLJDWRULL´�GH�PXWDĠLH��ÌQ�H[HPSOXO�GLQ�ILJXUD������$�SHQHWUDQĠD�HVWH�GH�ô�GHFL�����VDX�������&XQRDúWHUHD�SHQHWUDQĠHL�HVWH�LPSRUWDQWă�vQ�VIDWXO�JHQHWLF�GHRDUHFH�ULVFXO�XQXL�EROQDY�FX�R�DIHFĠLXQH�$'�FX�SHQHWUDQĠă�UHGXVă��GH�H[HPSOX��������GH�D�DYHD�FRSLL�DIHFWDĠL�HVWH�PDL�PLF�GH������������ILLQG�����[������ �������ÌQ�DFHVW�FRQWH[W��YRP�SUHFL]D��GLQ�QRX��Fă�HVWH�IRDUWH�LPSRUWDQW�Vă�IDFHP�GLIHUHQĠD�GLQWUH�R�PXWDĠLH�FX�SHQHWUDQĠă�UHGXVă��FX�ULVF�VXILFLHQW�GH�PDUH��FKLDU�GDFă�HVWH�VXE�FHO�WHRUHWLF�GH������úL�R�PXWDĠLH�QRXă��FX�ULVF�PLF�GH�UHFXUHQĠă���vQ�DFHVW�VFRS�YRP�folosi toate mijloacele posibile de diagnostic presimptomatic.

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a adultului (ADPKD) R�SHUVRDQă�WkQăUă��FH�D�PRúWHQLW�JHQD�PXWDQWă��SRDWH�Vă�QX�SUH]LQWH�HFRJUDILF�FKLVWL�UHQDOL�YL]LELOL��FX�GLPHQVLXQL�SUHD�PLFL��GDU�HL�DU�SXWHD�IL�SXúL�vQ�HYLGHQĠă�SULQ�&7�VDX�501��ÌQWU-XQ�DQXPLW�VHQV��SHQHWUDQĠD�SRDWH�IL�FRQVLGHUDWă ÄXQ�DUWHIDFW´�GHWHUPLQDW�GH�DELOLWDWHD�QRDVWUă�GH�D�UHFXQRDúWH��FOLQLF�úL�VDX�SDUDFOLQLF��H[SUHVLD�VDX�IHQRWLSXO�JHQHL�PXWDQWH�

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&DX]HOH�SHQHWUDQĠHL�UHGXVH��LQFRPSOHWH��QX�VXQW�FODUH�GDU�LQWHUYLQ�SUREDELO�IDFWRUL�JHQHWLFL�úL�QHJHQHWLFL��FDUH�SRW�DYHD�– într-R�DQXPLWă�FRQMXQFWXUă�– XQ�HIHFW�DQWDJRQLF��ÄVXSUHVRU´��DVXSUD�PDQLIHVWăULL�XQHL�JHQH��8Q�H[HPSOX�HGLILFDWRU�HVWH�GHILFLHQĠD�în factorul V Leiden, SUH]HQWDWă�vQ�caseta 5.5��YRP�PDL�DGăXJD�IDSWXO�Fă�vQ�KLSHUFROHVWHUROHPLD�IDPLOLDOă depozitele de colesterol GLQ�SHUHĠLL�YDVHORU�VDQJXLQH��FH�GHWHUPLQă�VLPSWRPDWRORJLD�SULQFLSDOă�D�EROLL��SRW�IL�UHGXVH�GH�R�GLHWă�VDX�R�PHGLFDĠLH�DGHFYDWă�(statine); vom aminti de asemenea „bolile induse de medicamente” (farmacogenetica) – ca SRUILULD�DFXWă�LQWHUPLWHQWă sau KLSHUWHUPLD�PDOLJQă – FDUH�YRU�IL�ÄGHFODQúDWH´�QXPDL�vQ�DQXPLWH�FRQGLĠLL�GH�PHGLX��YH]L�FDSLWROXO���$����� (2). 0XWDĠLL�JHUPLQDOH�QRL��3DFLHQĠLL�DIHFWDĠL�SRW�IL�SULPXO�úL�VLQJXUXO�FD]�GH�ERDOă�$'�GLQ�IDPLOLH��vQ�DFHDVWă�VLWXDĠLH�VH�SUHVXSXQH�Fă�DSDULĠLD�EROQDYXOXL�GLQ�SăULQĠL�VăQăWRúL�úL�KRPR]LJRĠL��n/n���ILJXUD������F��HVWH�FRQVHFLQĠD�XQHL�PXWDĠLL�VSRQWDQH�QRL��QHRPXWDĠLL��DSăUXWă�vQ�WLPSXO�JDPHWRJHQH]HL��GH�RELFHL�OD�EăUEDW��DFHDVWă�LSRWH]ă�VH�YD�OXD�vQ�FRQVLGHUDĠLH�GXSă�FH�V-au eliminat FHOHODOWH�SRVLELOLWăĠL��SHQHWUDQĠD�UHGXVă��H[SUHVLYLWDWHD�YDULDELOă�úL�QRQ-paternitatea.

'H�DOWIHO��PXWDĠLLOH�QRL��VXQW�IUHFYHQWH�vQ�QXPHURDVH�EROL�$'�FDUH��GDWRULWă�JUDYLWăĠLL�KDQGLFDSXOXL�FOLQLF�VDX�UHGXFHULL�SkQă�OD�DQXODUH�D�FDSDFLWăĠLL�UHSURGXFWLYH��QX�SRW�IL�WUDQVPLVH�GH�OD�SăULQĠL�OD�GHVFHQGHQĠL��ÌQ�osteogenesis imperfecta tipul II (OMIM 166200)��ERDOă�$'�– FDUDFWHUL]DWă�SULQ�IUDJLOLWDWH�RVRDVă�– OHWDOă�SHULQDWDO��WRDWH�FD]XULOH�UHSUH]LQWă�PXWDĠLL�QRL��8Q�DOW�exemplu frecvent citat este al acondroplaziei (OMIM 100800) – un nanisP�GLVSURSRUĠLRQDW�SH�VHDPD�PHPEUHORU��IRDUWH�VFXUWH�– vQ�FDUH�VH�DSUHFLD]ă�Fă�����GLQ�FD]XUL�VXQW�SURGXVH�SULQ�QHRPXWDĠLL��ÌQ�QHXURILEURPDWR]ă DFHVWHD�UHSUH]LQWă�����GLQ�FD]XUL�� (3). Mozaicismul germinal��0XOW�PDL�UDU��PXWDĠLLOH�VH�SRW�SURGXFH�SUHFRFe în YLDĠD�HPEULRQDUă, afectând unii din precursorii JDPHĠLORU��VH�IRUPHD]ă�DVWIHO�R�VXE-SRSXODĠLH�GH�JRQRFLWH�FH�SRDUWă�PXWDĠLD, deci un mozaicism germinal care poate explica

13

DSDULĠLD�PDL�PXOWRU�FRSLL�DIHFWDĠL�GLQ�SăULQĠL�VăQăWRúL (figura 5.24.d). ConsideUDW�IRDUWH�UDU��DFHVW�PHFDQLVP�vQFHSH�Vă�ILH�SUREDW�prin analizele moleculare: de exemplu, a fost demonstrat în 6% din cazurile de copii cu osteogenesis imperfecta QăVFXĠL�GLQ�SăULQĠL�VăQăWRúL��SUHFXP�úL�vQ�DOWH�EROL��QHXURILEURPDWR]ă�VDX�XQHOH�EROL�UHFHVLve-legate de X). F���([SUHVLYLWDWHD�YDULDELOă� ([SUHVLYLWDWHD��VSUH�GHRVHELUH�GH�SHQHWUDQĠă��HVWH�R�QRĠLXQH�FDOLWDWLYă��FDUH�GHILQHúWH�JUDGXO��LQWHQVLWDWHD��QDWXUD��VHYHULWDWHD�PDQLIHVWăULL�IHQRWLSLFH�D�XQHL�JHQH�PXWDQWH�úL�SHQHWUDQWH�OD�EROQDYL�GLIHULĠL��$WXQFL�FkQG�DFHúWL�SDUDPHWUL�VXQW�GLIHULĠL�SHQWUX�H[SUHVLD�XQHL�JHQH�PXWDQWH�VH�IRORVHúWH�WHUPHQXO�GH�H[SUHVLYLWDWH�YDULDELOă��ILJXUD������E���

([SUHVLYLWDWHD�YDULDELOă�LQWHUHVHD]ă� � VSHFWUXO�GH�PDQLIHVWDUHD�D�VLPSWRPHORU�úL�GLVWULEXĠLD�ORU� � vârsta de debut a semnelor, � LQWHQVLWDWHD��VHYHULWDWHD��H[SULPăULL� � OLPLWDUHD�PDQLIHVWăULL�OD�SDFLHQĠLL�GH�XQ�DQXPLW�VH[�

(1). 6SHFWUXO�GH�PDQLIHVWDUH�DO�VLPSWRPHORU�úL�GLVWULEXĠLD�ORU� 1XPHURDVH�EROL�$'��PDL�DOHV�FHOH�FX�SOHLRWURSLH��PDQLIHVWăUL�variate în organe multLSOH��SUH]LQWă�R�H[SUHVLYLWDWH�YDULDELOă��ÌQ�FDSLWROXO���$������H[HPSOLILFDP�DFHVW�FRQFHSW�la bolnavii cu sindrom Marfan �FDVHWD�������OD�FDUH�SRW�Vă�QX�DSDUă�WRDWH�DQRPDOLLOH�FHORU�WUHL�VLVWHPH�DIHFWDWH��VFKHOHW��RFKL��DSDUDW�FDUGLRYDVFXODU��sau la care sHYHULWDWHD�FOLQLFă�HVWH�GLIHULWă��SUH]HQWăP�DFXP�XQ�DUERUH�JHQHDORJLF�LOXVWUDWLY�(figura 5.25)��vQ�FDUH�WRĠL�LQGLYL]LL�YLL�DIHFWDĠL�au DFHLDúL�PXWDĠLH vQ�JHQD�ILEULOLQHL�GDU�SUH]LQWă�R�YDULDELOLWDWH�PDUFDWă�vQ�YkUVWD�GH�GHEXW��GLVWULEXĠLD�úL�VHYHULWDWHD�VHmnelor. Un alt exemplu ilustrativ este cel al neurofibromatozei (NF1��VDX�ERDOD�9RQ�5HFNOLQJKDXVHQ��YH]L�FDSLWROXO����(����FDUH�SUH]LQWă�PDQLIHVWăUL�FXWDQDWH��PXOWLSOH�SHWH�café au lait��SLVWUXL�D[LODUL��ú�D���RIWDOPRORJLFH��QRGXOL�/LVFK�vQ�LULV��ú�D���PXVculoscheletice �VFROLR]ă��VWDWXUă�PLFă�ú�D����QHXURSVLKLDWULFH��GLILFXOWăĠL�GH�vQYăĠDUH�VDX�UHWDUG�PLQWDO��FRQYXOVLL�HWF��úL�WXPRUDOH��QHXURfibroame de GLYHUVH�PăULPL��JOLRDPH�GH�FăL�RSWLFH�VDX�61&��IHRFURPRFLWRDPH�ú�D���7RDWH�DFHVWH�PRGLILFăUL�VH�GH]YROWă la vârste diferite (primele semne ce apar la copii sunt petele multiple café au lait��úL�DX�R�PDUH�YDULDELOLWDWH�D�GLVWULEXĠLHL�VHYHULWăĠLL��

0RGXO�úL�JUDGXO��VHYHULWDWHD��GH�PDQLIHVWDUH D�XQHL�EROL�$'�GHWHUPLQDWă�GH�R�DQXPLWă�JHQă�PXWDQWă�nu poate fi prezis, QLFL�FKLDU�OD�EROQDYLL�GLQ�DFHHDúL�IDPLOLH��FDUH�DX�DFHHDúL�PXWDĠLH�JHQLFă��ÌQ�VFKLPE��FXQRDúWHUHD�vQWUHJXOXL�spectru de manifestare DO�XQHL�EROL�PRQRJHQLFH�$'�SHUPLWH�HYDOXDUHD�úL�GLDJQRVWLFXO�FRPSOHW�DO�XQXL�SDFLHQW��SUHFXP�úL�FHUFHWDUHD�XQRU�FD]XUL oligo- sau mono-VLPSWRPDWLFH��SXĠLQ�HYLGHQWH��vQ�IDPLOLH��7RDWH�DFHVWHD�YRU�LQIOXHQĠD�FDOLWDWHD�GLDJQRVWLFXOXL��FRQGXLWD�PHGLFDOă��SUHYHQĠLD�XQRU�FRPSOLFDĠLL�úL�DFXUDWHĠHD�VIDWXOXL�JHQHWLF� (2). Vârsta de debut a semnelor��2�SUREOHPă�FRUHODWă�FX�H[SUHVLYLWDWHD�YDULDELOă�HVWH�YkUVWD�GH�GHEXW�D�PDQLIHVWăULORU�XQRU�EROL�$'�SOHLRWURSH��'LYHUVHOH�VHPQH�DSDU�vQ�WLPS��OD�YkUVWH�GLIHULWH��SHQHWUDQĠă�GHSHQGHQWă�GH�YkUVWă���XQHRUL�SULPHOH�PDQLIHVWăUL ale unor boli (ca $'3.'��KLSHUFROHVWHUROHPLD�IDPLOLDOă��SROLpoza de colon, boala Huntington ú�D��DSDU�WDUGLY�OD�DGXOW��ÌQ�figura 5.26 SUH]HQWăP�exemplul clasic al coreei Huntington – R�ERDOă�GHJHQHUDWLYă�QHXURORJLFă�FDUDFWHUL]DWă�SULQ�PLúFăUL�DQRUPDOH��coree��úL�SLHUGHUHD�SURJUHVLYă�D�IXQFĠLLORU�PLQWDOH��GHPHQĠă) – în care primele semne apar, în medie la 35 de ani��3HUVRDQD�FDUH�D�PRúWHQLW�JHQD�PXWDQWă�HVWH�PXOW�WLPS�DVLPSWRPDWLFă��IăUă�Vă�úWLH�Fă�SRVHGă�PXWDĠLD�vQ�PRPHQWXO�vQ�FDUH�vúL�DOFăWXLHúWH�R�IDPLOLH�úL�GHFLGH�Vă�DLEH�FRSLL��FăURUD��evident, le poate transmitH�JHQD�DQRUPDOă���$FHVW�OXFUX�VFRDWH�vQ�HYLGHQĠă�XWLOLWDWHD�DQDPQH]HL�IDPLOLDOH�úL�LPSRUWDQĠD�XQRU�WHVWH�GH�diagnostic presimptomatic (vezi capitolul 18). ÌQ�DFHVW�FRQWH[W��YRP�PHQĠLRQD�úL�IHQRPHQXO�GH�DQWLFLSDĠLH��vQ�XQHOH�DIHFĠLXQL�$'�VHPQHOH�GH ERDOă�VH�PDQLIHVWă�vQ�JHQHUDĠLL�VXFFHVLYH�OD�R�YkUVWă�WRW�PDL�SUHFRFH�úL�FX�R�VHYHULWDWH�WRW�PDL�PDUH��0XOW�WLPS�H[LVWHQĠD�DQWLFLSDĠLHL�D�IRVW�GLVFXWDELOă�GDU�DVWă]L�VH�úWLH�Fă�HVWH�XQ�IHQRPHQ�FHUW��PDL�DOHV�vQ�EROLOH�SULQ�DPSOLILFDUHD�UHSHWLĠLLORU�WULQXFleotidice �YH]L�FDSLWROHOH���%�����úL����&���vQ�FDUH�QXPăUXO�DFHVWRU�H[SDQVLXQL�LQVWDELOH�YD�FUHúWH�vQ�VXFFHVLXQHD�JHQHUDĠLLORU�GHWHUPLQkQG�R�YkUVWă�GH�GHEXW�WRW�PDL�SUHFRFH�úL�R severitate mai mare.

(3). /LPLWDUHD�PDQLIHVWăULL�OD�SDFLHQĠLL�GH�XQ�DQXPLW�VH[��([SUHVLYLWDWHD�YDULDELOă�D�XQRU�EROL�SRDWH�Vă�VH�PDQLIHVWH�úL�SULQ�DIHFWDUHD�SUHGRPLQDQWă��VDX�FKLDU�OLPLWDWă��D�XQXL�DQXPLW�VH[��1H�UHIHUHDP�PDL�VXV�OD�FDQFHUXO�GH�VkQ�IDPLOLDO�SURGXV��SULQ�PXWDĠLD�genei BRCA2 FVUH�HVWH�IRDUWH�UDU�OD�EăUEDĠL��GDU�VXQW�úL�DOWH�H[HPSOH�GH�EROL�$'�PDQLIHVWH�OD�XQ�DQXPLW�VH[��YRP�PDL�FLWD��porfiria DFXWă�LQWHUPLWHQWă SUHGRPLQDQWă�OD�VH[XO�IHPLQLQ�VDX�SXEHUWDWHD�SUHFRFH�IDPLOLDOă OLPLWDWă la sexul masculin.

În acest ultim exemplu, pubertatea apare precoce la 4-5 ani, datorită�XQHL�PXWDĠLL�D�UHFHSWRUXOXL�SHQWUX�KRUPRQXO�OXWHLQL]DQW�FDUH��DúD�FXP�VH�REVHUYă�vQ�figura 5.27, VH�WUDQVPLWH�$'��YH]L�WUDQVPLWHUHD�WDWă�ĺ�ILX��GDU�JHQD�HVWH�QHPDQLIHVWă�OD�persoanele de sex feminin (I-1, II-1,II-���FDUH�R�PRúWHQHVF�úL�R�WUDQVPLW�OD�GHVFHQGHQĠL�

&DX]HOH�H[SUHVLYLWăĠLL�YDULDELOH VXQW�JUHX�GH�GHILQLW��6LJXU��OD�ERODQYLL�FX�DFHLDúL�DIHFĠLXQH�GDU�GLQ�IDPLOLL�GLIHULWH��SULPD�H[SOLFDĠLH�D�H[SUHVLYLWăĠLL�YDULDELOH�SRDWH�IL�KHWHURJHQLWDWHD�DOHOLFă, GHFL�H[LVWHQĠD�XQRU�PXWDĠLL�GLIHULWH��'H�H[HPSOu, în osteogenesis imperfecta PXWDĠLLOH�FDUH�DIHFWHD]ă�DPLQRDFL]LL�GLQVSUH�FDSăWXO�FDUER[LO�DO�PROHFXOHL�GH�SURFRODJHQ�YRU�GD�IRUPH�PDL�JUDYH�GH�ERDOă�GHFkW�FHOH�FDUH�DIHFWHD]ă�DPLQRDFL]LL�GLQVSUH�FDSăWXO�DPLQR�WHUPLQDO� 3HQWUX�EROQDYLL�GLQ�DFHHDúL�IDPLOLH VDX�GLQ�IDPLOLL�GLIHULWH�FDUH�DX�DFHHDúL�PXWDĠLH�FDX]HOH�IHQRPHQXOXL�VXQW��vQVă��DOWHOH��6H�LQYRFă�LQWHUDFĠLXQHD�JHQHL-ERDOă�FX�DOWH�gene modificatoare (caseta 5.6) úL�VDX�FX�XQLL�factori de mediu��R�GRYDGă�LQGLUHFWă�D�H[LVWHQĠHL�JHQHORU�PRGLILFDWRDUH�R�UHSUH]LQWă�H[SUHVLD�PDL�IUHFYHQWă�SUHGRPL��QDQWă�VDX�H[FOXVLYă�OLPLWDWă�D�XQRU�JHQH�DXWRVRPDOH�la un anumit sex. ����75$160,7(5($�$872620$/�5(&(6,9Ă Circa 1/3 din caracterele monogenice sunt transmise autosomal recesiv (AR). Cele mai frecvente boli AR în SRSXODĠLD�HXURSDHDQă�sunt KHPRFURPDWR]D�úL�ILEUR]D�FKLVWLFă�VDX�PXFRYLVFLGR]D��$OWH�DIHFĠLXQL�$5��VXUGLWDWHD�FRQJHQLWDOă��XQHOH�IRUPH���IHQLOFHWRQXULD��DWURILD�PXVFXODUă�VSLQDOă��FHFLWDWHD�UHFHVLYă��VLQGURPXO�DGUHQRJHQLWDO���VLFNOHPLD��WDODVHPLD��DOELQLVPXl oculo-FXWDQDW��HWF��0DUHD�PDMRULWDWH�D�HURULORU�vQăVFXWH�GH�PHWDEROLVP�VH�WUDVQPLW�GH�DVHPQHD�$5�

CASETA 5.6. Genele modificatoare

14

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'HúL�SH�GH�R�SDUWH�IHQRPHQH�SUHFXP�GRPLQDQĠD�LQFRPSOHWă��H[SUHVLYLWDWHD�YDULDELOă�VDX�SOHLRWURSLD�FRPSOLFă�DQDOL]D�JHQHWLFă�a caracterelor mendeliene, identificarea genelor modificatoare responsabile de asemenea fenomene se poate dovedi sursa unor noi PHWRGH�GH�GLDJQRVWLF��WUDWDPHQW�úL�SUHYHQĠLH�D�bolilor genetice.

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Tabel 5.7. TransmitereD�UHFHVLYă�DXWRVRPDOă�D�XQXL�FDUDFWHU�SDWRORJLF�

6ăQăWRúL��N/N ; N/a��úL�EROQDYL��a/a)

&20%,1$ğ,,��*(127,3,CE PARENTALE

*$0(ğ, '(6&(1'(1ğ, Genotipuri Fenotipuri

1. N/a x N/a (N + a) x (N + a) ¼ N/N ; ½ N/a ¼ a/a

ô�VăQăWRúL�GLQ�FDUH�����SXUWăWRri ¼ bolnavi, indiferent de sex.

2. N/a x N/N (N + a) x (N) ½ N/N ; ½ N/a 7RĠL�VăQăWRúL��ò�SXUWăWRUL 3. a/a x N/N (a) x (N) N/a 7RĠL�VăQăWRúL�úL�SXUWăWRUL 4. a/a x N/a (a) x (N + a) ½ N/a; ½ a/a ; ò�VăQăWRúL�úL�SXUWăWRUL��ò�EROQDYL 5. a/a x a/a (a) x (a) a/a 7RĠL�EROQDYL 'LQ�GDWHOH�SUH]HQWDWH�PDL�VXV�VH�SRDWH�IRUPXOD�R�UHJXOă�LPSRUWDQWă�D�WUDQVPLWHULL�DXWRVRPDO�UHFHVLYH��$5���GRL�SăULQĠL�VăQăWRúL��KHWHUR]LJRĠL�SHQWUX�DFHHDúL�SHUHFKH�GH�JHQH�DOHOH��SRW�DYHD�FRSLL��IHWH�úL�EăLHĠL��EROQDYL�FX�R�DQRPDOLH�$5��'H�VXEOLQLDW�IDSWXO�Fă�

22 'XSă�DGXQDUHD�GDWHORU�VH�LPSXQH�R�SUHOXFUDUH�úL�R�FRUHFĠLH�VWDWLVWLFă�SHQWUX�D�FRPSHQVD�SLHUGHUHD�GH�LQIRUPDĠLL�GHWHUPLQDWă�Ge fratriile ce provin GLQ�FăVăWRULL� vQWUH�KHWHUR]LJRĠL�úL�FDUH�QX�DX�QLFL�XQ�EROQDY��DOWIHO��SURSRUĠLD�GH�KRPR]LJRĠL�DIHFWDĠL�YD�IL�PDL�mare de 25%. 15

DPEHOH�VH[H�VXQW�DIHFWDWH�vQ�SURSRUĠLL�FYDVL-HJDOH�úL�SRW�WUDQVPLWH�DOHOD�PXWDQWă�FX�DFHLDúL�SUREDELOLWDWH��HOHPHQWH�ORJLFH�SHQWUX�ORFDOL]DUHD�DXWRVRPDOă�D�JHQHL��

'HRDUHFH�SăULQĠLL�EROQDYXOXL�VXQW�VăQăWRúL��vQ�DUERUHOH�JHQHDORJLF�(figura 5.28) VH�vQUHJLVWUHD]ă�R�GLVFRQWLQXLWDWH�D�EROLL�vQ�VXFFHVLXQHD�JHQHUDĠLLORU��Bolnavul poate fi singurul membru afectat al familiei23��GDFă�DSDU�úL�DOWH�FD]XUL��HOH�VH�JăVHVF�IUHFYHQW�vQ�DFHHDúL�IUDWULH��GkQG�DVSHFWXO�XQHL�WUDQVPLWHUL�orizontale.

5LVFXO�XQXL�FXSOX�GH�LQGLYL]L�QRUPDOL�úL�KHWHUR]LJRĠL�GH�D�DYHD�XQ�FRSLO�EROQDY��a/a��HVWH�GH�����VDX�ó��OD�ILHFDUH�VDUFLQă��FD�HYHQLPHQW�LQGHSHQGHQW��$U�IL�JUHúLW�Vă�FUHGHP�Fă�vQ�IDPLOLLOH�cu patru copii este obligatoriu ca

6ăQăWRV��N/a) Ļ

JDPHĠL N a N 6ăQăWRV�ĺ�JDPHĠL�� (N/a) a 25% bolnavi QXPDL�XQXO�Vă�ILH�DIHFWDW��VDX�PDL�UăX��GDFă�V-DX�QăVFXW�WUHL�FRSLL�VăQăWRúL�DO�SDWUXOHD va fi bolnav. Riscul de ¼ este valabil la ILHFDUH�VDUFLQă��Vă�QH�LPDJLQăP�R�ORWHULH�FX�SDWUX�ELOH��WUHL�DOEH�úL�XQD�QHDJUă��GLQ�FDUH�OD�ILHFDUH�QDúWHUH�V-DU�H[WUDJH�R�ELOă��vQDLQWHD�QDúWHULL�XUPăWRDUH�ÄELOD�VH�SXQH�OD�ORF´�úL�WUDJHUHD�VH�UHSHWă��8QHRUL�SRW�H[LVWD�IDPLOLL�FX�úDQVD�GH�D�DYHD��-4 copii QRUPDOL��DOWHRUL�VH�SRW�QDúWH�VXFFHVLY�GRL�EROQDYL�

ÌQ�DIDUD�FRPELQDĠLHL�D�GRL�KHWHUR]LJRĠL��DOWH�vQFUXFLúăUL�GLQ�FDUH�SRW�UH]XOWD�FRSLL�EROQDYL�VXQW�WUHFXWH�vQ�WDEHOXO������vQ�SR]LĠLLOH���úL����2FD]LRQDO��XQ�Eolnav (a/a��VH�SRDWH�vQFUXFLúD�FX�XQ�VăQăWRV�KHWHUR]LJRW��N/a��úL�DWXQFL�����GLQ�GHVFHQGHQĠL�DU�SXWHD�IL�DIHFWDĠL��SH�DUERUHOH�JHQHDORJLF�VH�vQUHJLVWUHD]ă�XQ�DSHFW�GH�SVHXGR-GRPLQDQĠă��ERDOD�ILLQG�SUH]HQWă�vQ�GRXă�JHQHUDĠLL�(figura 5.29). ÌQ�VIkUúLW��PXOW�mai rar, din vQFUXFLúDUHD�GLQWUH�GRL�EROQDYL��KRPR]LJRĠL�SHQWUX�DFHHDúL�PXWDĠLH�(a/a x a/a) vor UH]XOWD�QXPDL�GHVFHQGHQĠL�EROQDYL�(a/a���$FHVW�WLS�GH�XQLXQH�ÄDVRUWDWLYă´�VH�REVHUYă�vQ�FROHFWLYLWăĠL�VSHFLDOH��GHILFLHQĠL�YL]XDOL��VXU]L�ú�D��úL�SHQWUX�EROL�FH�QX�DIHFWHD]ă�FDSDFLWDWHD�UHSURGXFWLYă��'H�OD�UHJXOD�HQXQĠDWă�PDL�VXV�IDF�H[FHSĠLH�VLWXDĠLLOH�GH�KHWHURJHQLWDWH�JHQHWLFă�vQ�FDUH�EROQDYLL�FX�DIHFĠLXQL�DVHPăQăWRDUH�FOLQLF�DX�PXWDĠLL�vQ�JHQH��ORFL��GLIHULWH�(figura 5.30); întrucât SăULQĠLL�EROQDYL�QX�VXQW KRPR]LJRĠL�SHQWUX�DFHHDúL�PXWDĠLH�GHVFHQGHQĠLL�ORU�YRU�IL�GXEOX�KHWHUR]LJRĠL�úL�VăQăWRúL�

ÌQ�DIHFĠLXQLOH�DXWRVRPDO�UHFHVLYH�VH�REVHUYă�Fă�SULQWUH�SăULQĠLL�EROQDYXOXL�H[LVWă�R�PDUH�SURSRUĠLH�PDL�PDUH�GH�FăVăWRULL�vQWUH�SHUVRDQH�FDUH�DX�FHO�SXĠLQ�XQ�VWUăPRú comun (consanguinitate), în special între veri primari.

ÌQ�FRQFOX]LH��FULWHULLOH�PDMRUH�SHQWUX�GLDJQRVWLFXO�HUHGLWăĠLL�UHFHVLYH�DXWRVRPDOH�OD�RP�VXQW�XUPăWRDUHOH� � PDUHD�PDMRULWDWH�D�SHUVRDQHORU�DIHFWDWH�VXQW�XUPDúL�DL�SăULQĠLORU�DSDUHQW�VăQăWRúL�GDU�KHWHUR]LJRĠL��ULVFXO�ORU�GH�D�DYHD�XQ�FRSLO�

bolnav este 1/4, indiferent de sex; � GDFă�EROQDYLL�VH�FăVăWRUHVF�FX�SHUVRDQH�QRUPDOH�úL�KRPR]LJRWH�WRĠL�FRSLLL�YRU�IL�VăQăWRúL��VH�vQUHJLVWUHD]ă�astfel aspectul de

discontinuitate a bolii în VXFFHVLXQHD�JHQHUDĠLLORU�VDu de cazuri izolate; � GDFă�XQ�EROQDY�VH�FăVăWRUHúWH�FX�R�SHUVRDQă�VăQăWRDVă�úL�KHWHUR]LJRWă��ULVFXO�GH�D�DYHD�GHVFHQGHQĠL�EROQDYL��IHWH�úL�EăLHĠL��este

de 50% (pseudo-GRPLQDQĠă���vQ�DFHVW�FD]��WUDQVPLWHUHD�PDPă-ILLFă�HVWH�SRVLELOă� � GRL�SăULQĠL�EROQDYL��KRPR]LJRĠL�SHQWUX�DFHOHDúL�JHQH��QX�YRU�DYHD�FRSLL�VăQăWRúL� � SăULQĠLL�FRSLOXOXL�DIHFWDW�VXQW�PDL�frecvent rude��FRPSDUDWLY�FX�SăULQĠLL�FRSLLORU�VăQăWRúL��GHFL�IUHFYHQĠD�FUHVFXWă�D�

FRQVDQJXLQLWăĠLL�� ÌQ�DIDUD�FULWHULLORU�HQXQĠDWH�PDL�VXV��EROLOH�$5�VH�FDUDFWHUL]HD]ă�SULQ�IDSWXO�Fă�VXQW��vQ�JHQHUDO��DQRPDOLL�SULQ�OLSVă (hipoplazie, KLSRIXQFĠLH��GHILFLW�HQ]LPDWLF�HWF���GHVHRUL�PDL�JUDYH�GHFkW�FHOH�$'��

b). Consanguinitatea în anomaliile recesive. 3UREDELOLWDWHD�FD�GRXă�SHUVRDQH�Vă�ILH�SXUWăWRDUH��N/a��DOH�DFHOHLDúL�PXWDĠLL�FUHúWH�GDFă�SHUVRDQHOH�UHVSHFWLYH�VXQW�

vQUXGLWH�SHQWUX�Fă�ILHFDUH�SRDWH�PRúWHQL�JHQD�PXWDQWă�GH�OD�XQ�VWUăPRú�FRPXQ��DFHDVWă�VLWXDĠLH�HVWH�QXPLWă�FRQVDQJXLQLWDWH�úL se QRWHD]ă�vQ�DUERUHOH�JHQHDORJLF�SULQWU-R�OLQLH�GXEOă�

S-D�REVHUYDW�Fă�IUHFYHQĠD FRQVQJXLQLWăĠLL�SDUHQWDOH�vQ�EROLOH�$5�HVWH�LQYHUV�SURSRUĠLRQDOă�FX�IUHFYHQĠD�JHQHL�UHFHVLYH��cu FkW�ERDOD�HVWH�PDL�UDUă��FX�DWkW�FRQVDQJXLQLWDWHD�OD�SăULQĠL�HVWH�PDL�IUHFYHQWă��$VWIHO�vQ�FD]XO�XQHL�DIHFĠLXQL�FX�R�IUHFYHQĠă�GH�1:10.000 (albinismul) circa ���GLQWUH�SăULQĠLL�FRSLLORU�EROQDYL�YRU�IL�YHUL�SULPDUL��IDĠă�GH����FkW�H[LVWă�vQ�SRSXODĠLD�JHQHUDOă�HXURSHDQă��3URFHQWXO�YD�FUHúWH�OD�����GDFă�DIHFĠLXQHD�HVWH�GH����RUL�PDL�UDUă�������������

3ăULQĠLL�vQUXGLĠL�SRVHGă�XQ�SURFHQWDM�PDL�PDUH�GH�JHQH�LGHQWLFH� FRPSDUDWLY�FX�SRSXODĠLD�JHQHUDOă��$FHVW�SURFHQW�GHSLQGH�GH�JUDGXO�GH�vQUXGLUH��ILLQG�GH�����OD�YHULL�SULPDUL�������OD�YHULL�GH�JUDGXO�,,�ú�D�P�G��WDEHOXO�����

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COEFICIENT DE CONSANGUINITATE (F)

7DWă�–ILLFă��IUate – VRUă��JHPHQL�GL]LJRĠL 1/2 1/4 Unchi – QHSRDWă��GHPL-frate – demi-VRUă 1/4 1/8 Veri de gradul I; demi-unchi – demi-QHSRDWă 1/8 1/16 9ăU�GH�JUDGXO�,�– YDUă�GH�JUDGXO�,,��GHPL-veri primari 1/16 1/32 Veri de gradul II 1/32 1/64 9ăU�JUDGXO�,,�– YDUă gradul III 1/64 1/128 Veri de gradul III 1/128 1/256

&RHILFLHQWXO�GH�vQUXGLUH��U��HVWH�SURSRUĠLD�GH�JHQH�FRPXQH��LGHQWLFH��GLQ�WRWDOXO�JHQHORU�SHUVRDQHORU�FH�DX�XQ�VWUăPRú�FRPXQ� &RHILFLHQWXO�GH�FRQVDQJXLQLWDWH��)��HVWH�SUREDELOLWDWHD�FD�XQ�XUPDú�Vă�ILH KRPR]LJRW�SHQWUX�JHQH�FH�SURYLQ�GH�OD�SăULQĠL��FX�XQ�DQXPLW�JUDG�GH�UXGHQLH��GH�OD�XQ�VWUăPRú�FRPXQ��)� �U����&HL�GRL�FRHILFLHQĠL�VH�FDOFXOHD]ă�SULQ�PHWRGH�VSHFLDOH�

'HRDUHFH�SăULQĠLL�vQUXGLĠL�DX�XQ�QXPăU�PDL�PDUH�GH�JHQH��QRUPDOH�VDX�DQRUPDOH��vQ�FRPXQ��FRQVDQJXLQLWDWHD�FUHúWH�ULVFXO�GH�vQWkOQLUH�D�KHWHUR]LJRĠLORU úL�IDYRUL]HD]ă�DSDULĠLD�VXELHFĠLORU�KRPR]LJRĠL�DIHFWDĠL��$VWIHO��GDFă�vQWU-R�SRSXODĠLH�IUHFYHQĠD�

23 SH�UHDOL]HD]ă�DVSHFWXO�XQXL�FD]�L]RODW�VSRUDGLF�GDU�DU�IL�R�JUHúHDOă�Vă�FRQVLGHUăP�Fă�ERDOD�QX�HVWH�HUHGLWDUă�QXPDL�SHQWUX�Fă�nu sunt alte cazuri în familie.

N/N

N/A

N/a

a/a

16

KHWHUR]LJRĠLORU�SHQWUX�R�DIHFĠLXQH�UHFHVLYă�HVWH�������SUREDELOLWDWHD�XQHL�SHUVRDQH�GH�D�DYHD�XQ�FRSLO�EROQDY�FăVăWRULQGX-se cu o SHUVRDQă�QHvQUXGLWă�HVWH������[������[����� �����������GDFă�V-DU�FăVăWRUL�FX�YDUD�VD�SULPDUă�DWXQFL�ULVFXO�QDúWHULL�XQXL�FRSLO�DIHFWDW�este 1/50 x 1/8 [����� ����������GHFL�GH�FLUFD�úDVH�RUL�PDL�PDUH�

6H�DSUHFLD]ă�Fă�riscul global DO�XQXL�GHVFHQGHQW�DQRUPDO�GLQ�FăVăWRULD�vQWUH�YHUL�SULPDUL�HVWH�WRWXúL�PLF�(3-5%), aproape GXEOX�IDĠă�GH�FHO�DO�SRSXODĠLHL�JHQHUDOH���-�����&RQVHFLQĠHOH�XQXL�LQFHVW��vQFUXFLúDUHD�GLQWUH�UXGH�GH�JUDGXO�,��VXQW�vQVă�PXOW�PDL�dezastruoase: ½ - ¼ din GHVFHQGHQĠL�YRU�IL�DQRUPDOL (retardul mintal fiind pe locul întâi).

F���+HWHUR]LJRĠLL�vQ�DQRPDOLLOH�UHFHVLYH� 8QXO�GLQWUH�FHOH�PDL�LPSRUWDQWH�DVSHFWH�OHJDWH�GH�WUDQVPLWHUHD�$5�vO�FRQVWLWXLH�VWXGLXO�úL�GHSLVWDUHD�KHWHUR]LJRĠLORU��N/a).

(L�VXQW�IHQRWLSLF�VăQăWRúL�úL�DWXQFL�FkQG�VH�FăVăWRUHVF�FX�XQ�DOW�KHWHUR]LJRW�VăQăWRV�DX�XQ�ULVF�GH�����GH�D�DYHD�XQ�FRSLO�EROQDY��3UREOHPD�GHYLQH�ÄDFXWă´�vQ�IDPLOLLOH�vQ�FDUH�H[LVWă�XQ�LQGLYLG�DIHFWDW�GH�R�ERDOă�UHFHVLYă��3UREDELOLWDWHD�FD�R�SHUVRDQă�Vă�PRúWHQHVFă�vQ�DFHVW�FD]�JHQD�DXWRVRPDOă�GHSLQGH�GH�JUDGXO�vQUXGLULL�FX�EROQDYXO�(figura 5.31): cu cât este mai apropiat, cu atât ULVFXO�HVWH�PDL�PDUH��$VWIHO�IUDWHOH�VRUD�XQXL�EROQDY�FX�R�DIHFĠLXQH�UHFHVLYă�DUH�R�SUREDELOLWDWH�GH�����GH�D�IL�KHWHUR]LJRW� aceasta se reduce la 1/��SHQWUX�FRSLOXO�ORU�VăQăWRV��QHSRW�DO�EROQDYXOXL�

Întrucât genele recesive se transmit nemanifeste GLQ�JHQHUDĠLH�vQ�JHQHUDĠLH��SkQă�FH�VH�UHDOL]HD]ă�VWDUHD�KRPR]LJRWă��FD�úL�UkXULOH�VXEWHUDQH�FDUH�DWXQFL�FkQG�DIOXHD]ă�ĠkúQHVF�OD�VXSUDIDĠă���H[LVWă�ULVFXO FD�RULFLQH�Vă�SRVHGH�DVWIHO�GH�JHQH�úL�GHFL�Vă�ILH�KHWHUR]LJRW��$FHVW�ULVF�VH�SRDWH�HVWLPD�SH�ED]D�IUHFYHQĠHL�DIHFĠLXQLL�vQ�SRSXODĠLH��YH]L�FDSLWROXO����úL�VH�SRDWH�FDOFXOD�DSUoximativ GXSă�IRUPXOD��

K� ���¥�IUHFYHQĠD�EROL�� GHFL�IUHFYHQĠD�KHWHUR]LJRĠLORU HVWH�GH�GRXă�RUL�UăGăFLQD�SăWUDWă�D�IUHFYHQĠHL�DIHFĠLXQLL�vQ�SRSXODĠLH��'H�H[HPSOX��GDFă�IHQLOFHWRQXULD�DUH�R�IUHFYHQĠă�GH�����������IUHFYHQĠD�KHWHUR]LJRĠLORU�HVWH�GH�������3UHYDOHQĠD�KHWHUR]LJRĠLORU�SHQWUX�XQHOH�DIHFĠLXQL�AR mai frecvente este de 1/10 pentru KHPRFURPDWR]ă (1:400); 1/25 pentru ILEUR]D�FKLVWLFă�sau PXFRYLVFLGR]ă (1:2.500); 1/30 pentru surdimutitate (1:3.600); 1/35 pentru sindromul adreno-genital �����������6H�REVHUYă�Fă�vQ�SRSXODĠLH�QXPăUXO�KHWHUR]LJRĠLORU�HVWH�IRDUWH�PDUH�FRPSDUDWLY�FX�FHO DO�EROQDYLORU�KRPR]LJRĠL�UHFHVLYL��ÌQ�DFHVWH�FRQGLĠLL�SRVLELOLWDWHD�vQWkOQLULL�D�GRL�KHWHUR]LJRĠL�HVWH�PDUH��DVWIHO��VH�HVWLPHD]ă�Fă�vQ�(XURSD�GH�9HVW�1:625 FXSOXUL�HVWH�DOFăWXLW�GLQ�KHWHUR]LJRĠL�SHQWUX�ILEUR]D�FKLVWLFă��*HQHOH�UHFHVLYH�PRUELGH�VXQW�GHFL�UHODWLY�FRPXQH�úL��SHQWUX�Fă�VXQW�PXOWH�DIHFĠLXQL�UHFHVLYH�HVWH�SUREDELO�Fă�ILHFDUH�GLQWUH�QRL�Vă�SXUWăP�FkWHYD�JHQH�DQRUPDOH�vQ�VWDUH�KHWHUR]LJRWă� ÌQ�DQXPLWH�SRSXODĠLL�IUHFYHQĠD�EROLORU�UHFHVLYH�úL�GHFL�FX�DWkW�PDL�PXOW�D�KHWHUR]LJRĠLORU�HVWH�IRDUWH�PDUe: sicklemia în Africa, beta-talasemia vQ�,WDOLD�úL�*UHFLD��hemocromatoza úL�ILEUR]D�FKLVWLFă�PXFRYLVFLGR]D vQ�(XURSD�GH�9HVW�úL�1RUG, nefroza FRQJHQLWDOă�în Finlanda, boala Tay-Sachs OD�HYUHLL�$VKNHQD]L��RULJLQDUL�GLQ�FHQWUXO�úL�HVWXO�(XURSHL���([SOLFDĠLLle acestui fenomen �DYDQWDMXO�VHOHFWLY�DO�KHWHUR]LJRĠLORU��HIHFWXO�GH�IRQGDWRU��L]RODUHD�HWQLFă�VDX�UHOLJLRDVă�HWF��YRU�IL�GLVFXWDWH�vQ�FDSLWROXl 7.

$úD�FXP�DP�PDL�VSXV��QRĠLXQLOH�GH�GRPLQDQW�úL�UHFHVLY�VXQW�YDODELOH�SHQWUX�IHQRWLS��SHQWUX�FDUDFWHU��úL�UHSUH]LQWă�R�VLPSOLILFDUH�D�UHODĠLLORU�PROHFXODUH��GHRDUHFH�DPEHOH�DOHOH�DOH�JHQHORU�VH�PDQLIHVWă�vQWRWGHDXQD�OD�QLYHO�PROHFXODU��$FHVW�OXcru permite GHSLVWDUHD�KHWHUR]LJRĠLORU��VăQăWRúL�GDU�SXUWăWRUL��SHQWUX�DFHOH�DIHFĠLXQL�OD�FDUH�VH�FXQRDúWH�HIHFWXO�SULPDU DO�JHQHL�úL�OD�FDUH�DFHVWD�SRDWH�IL�HYLGHQĠLDW��1H�YRP�UHIHUL�SH�ODUJ�OD�DFHVW�DVSHFW�LPSRUWDQW�DO�SURILOD[LHL�EROLORU�JHQHWLFH��vQ�FDSLWROXl 18.4) dar DFXP�YRP�UHDPLQWL�H[HPSOXO�VLFNOHPLHL��FDSLWROXO���%����vQ�FDUH�KHWHUR]LJRĠLL�VXQW�LGHQWLILFDĠL��VLPSOX, prin electroforeza KHPRJORELQHL��FDUH�HYLGHQĠLD]ă�+E$�úL�+E6�

G���+HWHUR]LJRĠLL�FRPSXúL� +HWHURJHQLWDWHD�DOHOLFă�HVWH�XQ�IHQRPHQ�IUHFYHQW�vQ�EROLOH�$5��R�JHQă�SRDWH�VXIHUL�PXWDĠLL�DOHOLFH�GLIHULWH��'H�H[HPSOX��vQ�

beta-talasemie s-au identificat numeroase PXWDĠLL�vQ�JHQD�HBB��GHVHRUL�OD�EROQDYL�FHOH�GRXă�DOHOH�DOH�ORFLORU�HBB sunt anormale (a/a��GDU�DX�PXWDĠLL�GLIHULWH��a1/a2��úL�DFHúWLD�VXQW�GH�IDSW�KHWHUR]LJRĠL�FRPSXúL��D��D��� 6H�SDUH�Fă�vQ�FHOH�PDL�PXOWH�GLQ�EROLOH�UHFHVLYH�LQGLYL]LL�DIHFWDĠL�VXQW�vQ�IDSW�PDL�FXUkQG�KHWHUR]LJRĠL�FRPSXúL�GHFkW�KRPR]LJRĠL�DGHYăUDĠL��H[FHSWkQG�HYLGHQW�VLWXDĠLLOH�vQ�FDUH�SăULQĠLL�ORU�VXQW�vQUXGLĠL�úL�DX�PRúWHQLW�DFHHDúL�PXWDĠLH GH�OD�XQ�VWUăPRú�FRPXQ�VDX�FkQG�vQ�DFHD�SRSXODĠLH�SUHGRPLQă�R�DQXPLWă�PXWDĠLH��FD�XUPDUH�D�HIHFWXlui de fondator.

e). Variabilitatea în bolile recesive. %ROLOH�UHFHVLYH�SUH]LQWă�GHVHRUL�R�SHQHWUDQĠă�FRPSOHWă�úL�R�YDULDELOLWDWH�FOLQLFă�UHGXVă��([LVWă�vQVă�úL�H[FHSĠLL��vQ�

KHPRFURPDWR]D��YH]L�FDVHWD������GH�SLOGă�QX�WRĠL�EROQDYLL��a/a��GH]YROWă�ERDOD�LDU IHPHLOH�VXQW�UHODWLY�SURWHMDWH�GDWRULWă�SLHUGHULOU�GH�ILHU�GLQ�FXUVXO�PHQVWUXDĠLHL��'H�DVHPHQHD�vQ�PXFRYLVFLGR]ă EROQDYLL�SRW�DYHD�R�PDUH�YDULDELOLWDWH�D�GLVWULEXĠLHL�úL�VHYHULWăĠLL�PDQLIHVWăULORU�GLJHVWLYH��SXOPRQDUH�HWF��YH]L�FDSLWROXO����(�����H[SOLFDELOă�SULQ�PXWDĠLL�GLIHULWH��VSHFLILFH��DOH�JHQHL�CFTR; KRPR]LJRĠLL�FDUH�DX�PXWDĠLD�)���GHO�SUH]LQWă�LQVXILFLHQĠă�SDQFUHDWLFă�GDU�vQ�DOWH�PXWDĠLL�IXQFĠLD�SDQFUHDWLFă�HVWH�FYDVL-QRUPDOă��IHQRPHQHOH�SXOPRQDUH�UHGXVH�VDX�VH�REVHUYă�R�DEVHQĠă�FRQJHQLWDOă�D�FDQDlelor deferente.

0XWDĠLLOH�QRL�VXQW�UDUH�vQ�EROLOH�$5�úL��GH�UHJXOă��VH�SRDWH�SUHVXSXQH�Fă�DPELL�SăULQĠL�DL�XQXL�FRSLO�DIHFWDW�VXQW�KHWHUR]LJRĠL��7RWXúL����GLQ�FD]XULOH�GH�DWURILH�PXVFXODUă�VSLQDOă (SMA) tip I (boala Werdnig-Hoffman) copilul afectat PRúWHQHúWH�R�DOHOă�GH�OD�XQXO�GLQ�SăULQĠL�FDUH�HVWH�KHWHUR]LJRW�LDU�FHDODOWă�DOHOă�SURYLQH�SULQWU-R�PXWDĠLH�JHUPLQDOă�QRXă�GH�OD�XQ�SăULQWH�QH-SXUWăWRU��vQ�DFHVWH�FD]XUL�ULVFXO�GH�UHFXUHQĠă�HVWH�IRDUWH�PLF�

$úD�FXP�DP�SUHFL]DW�PDL�VXV�KHWHURJHQLWDWHD�DOHOLFă�HVWH�IUHFYHQWă�vQ�EROLOH�$5��GDU�úL�KHWHURJHQLWDWHD�GH�ORFXV�VH�vQWkOQHúWH�LQ�XQHOH�DIHFĠLXQL�$5��0XOWH�GLQ�VXUGLWăĠLOH�FRQJHQLWDOH�VDX�IRUPHOH�GH�FHFLWDWH�UHFHVLYă�VXQW�SURGXVH�GH�PXWDĠLL�în loci DXWRVRPDOL�GLIHULĠL�

9RP�PHQĠLRQD��vQ�VIkUúLW��IHQRPHQXO�GH�GLVRPLH�XQLSDUHQWDOă�SULQ�FDUH�XQ�FRSLO�DIHFWDW�SRDWH�PRúWHQL�DPEHOH�FRSLL�DOH�XQXL�FURPRVRP��FX�DOHOD�PXWDQWă��GH�OD�XQXO�GLQ�SăULQĠL��GDU�DVXSUD�DFHVWXL�IHQRPHQ��UDU�GDU�LQWHUHVDQW��YRP�UHYHQL�PDL�WkU]Lu.

2.5. TRANSMITEREA RE&(6,9Ă�/(*$7Ă�'(�; Dintre bolile RLX cele mai cunoscute sunt KHPRILOLD��GLVWURILD�PXVFXODUă�'XFKHQQH��FHFLWDWHD�SHQWUX�FXORUL��GHILFLHQĠD�vQ�*�3'�ú�D��

2�PXWDĠLH�5/;�VH�PDQLIHVWă�IHQRWLSLF�OD�EăUEDĠLL�KHPL]LJRĠL�XaY �IUHFYHQW��úL�OD�IHPHLOH�KRPR]LJRWH�XaXa (foarte rar); IHPHLOH�VăQăWRDse pot fi XNXN sau XNXa �SXUWăWRDUH�GH�JHQă�PXWDQWă�VDX�FRQGXFWRDUH���&X�FHOH�FLQFL�JHQRWLSXUL�VXQW�SRVLELOH�XUPăWRDUHOH�FRPELQDĠLL��WDEHOXO������GDU�vQ�IXQFĠLH�GH�ERDOă��vQ�SUDFWLFă��VH�vQWkOQHVF�QXPDL�R�SDUWH�GLQWUH�DFHVWHD�

17

Tabel 5.9. Transmiterea reFHVLYă�OHJDWă�GH�;�D�XQXL�FDUDFWHU�SDWRORJLF�

6ăQăWRúL��XNY, XNXN , XNXa��úL�EROQDYL��XaY, XaXa)

&20%,1$ğ,,��GENOTIPICE PARENTALE

*$0(ğ, '(6&(1'(1ğ, Genotipuri Fenotipuri

1. XNY x XaXN (XN + Y) x (Xa + XN) ¼ XaY ; ¼ XNY, ¼ XaXN ;¼ XNXN

8Q�VIHUW�GLQ�FRSLL�YRU�IL�EROQDYL��DFHúWLD�VXQW�ò�EăLHĠL���WRDWH�IHWHOH�YRU�IL�VăQăWRDVH��ò�SXUWăWRDUH�

2. XaY x XNXN (Xa + Y) x (XN + XN) XNY ; XaXN 7RĠL�FRSLL�YRU�IL�VăQăWRúL�GDU�WRDWH�IHWHOH�YRU�IL�SXUWăWRDUH

3. XaY x XaXN (Xa + Y) x (Xa + XN) ¼ XaY ; ¼ XNY, ¼ XaXa ; ¼ XaXN,

ò�EăLHĠL�VXQW�EROQDYL ò�IHWH�VXQW�EROQDYH��ò�IHWH�VXQW�SXUWăWRDUH

4. XNY x XaXa (XN + Y) x (Xa + Xa) XaY ; XaXN 7RĠL�EăLHĠLL�EROQDYL��WRDWH�IHWHOH�SXUWăWRDUH 5. XaY x XaXa (Xa + Y) x (Xa + Xa) XaY ; XaXa 7RĠL�FRSLLL��EăLHĠL�úL�IHWH��EROQDYL 6. XNY x XNXN (XN + Y) x (XN + XN) XNY ; XNXN 7RĠL�FRSLLL�VăQăWRúL

a). Criteriile transmiterii recesive legate de X.În bolile RLX, de obicei, bolnavi sunt QXPDL�EăUEDĠLL, care au primit gena

PXWDQWă�GH�OD�IHPHL�VăQăWRDVH�GDU�SXUWăWRDUH �FRPELQDĠLD����WDEHO�������'HFL��GLQ�SăULQĠL�VăQăWRúL�UH]XOWă�FRSLL�EROQDYL�(1/4) , dar DFHúWLD�YRU�IL�QXPDL�EăLHĠL �������FDUH�DX�SULPLW�JHQD�DQRUPDOă�GH�OD�PDPă��fetele vor IL�VăQăWRDVH �ò�SXUWăWRDUH���ÌQ�DUERUHOH�genealogic (figura 5.33) VH�vQUHJLVWUHD]ă�R�WUDQVPLWHUH�REOLFă��vQ�GLDJRQDOă��úL�GLVFRQWLQXă��GH�OD�XQ�EăUEDW�EROQDY��EXQLF��VWUăEXQLF���SULQ�IHPHL�VăQăWRDVH�GDU�SXUWăWRDUH��OD�XQ�EăLDW�EROQDY��

'DFă�EROQDYLL�DX�FDSDFLWDWH�GH�UHSURGXFHUH��GH�H[HPSOX��vQ�KHPRILOLH��úL�VH�FăVăWRUHVF�FX�R�IHPHLH�VăQăWRDVă�úL�KRPR]LJRWă��FRPELQĠLD����QX�SRW�WUDQVPLWH�ERDOD�EăLHĠLORU��WUDQVPLWHUHD�WDWă�ĺ�ILX�QX�HVWH�GHFL�SRVLELOă��VDX�SULQ�EăLHĠL�OD�JHQHUDĠLLOH�XUPăWRDUH��ÌQ�VFKLPE�WRDWH IHWHOH�YRU�IL�REOLJDWRULX�KHWHUR]LJRWH��SXUWăWRDUH�

ÌQ�FD]XO�XQRU�PXWDĠLL�IUHFYHQWH�úL�SXĠLQ�VHYHUH�DOH�XQRU�JHQH�GH�SH�;��FXP�DU�IL�GHILFLHQĠD�vQ�*�3'��vQ�SRSXODĠLD�$IUR-$PHULFDQă�����GLQ�EăUEDĠL�DX�GHILFLHQĠă�GH�*�3'�LDU�����GLQ�IHPHL�VXQW�KHWHUR]LJRWH� sau daltonismul ����GLQ�EăUEDĠL�úL�������din femei) este posibil ca bolnavii (XaY��Vă�VH�FăVăWRUHDVFă�FX�R�IHPHLH�KHWHUR]LJRWă��FRPELQDĠLD����WDEHO�����24��vQ�GHVFHQGHQĠD�DFHVWXL�FXSOX��SRW�DSăUHD�EăLHĠL�EROQDYL�������GDU�úL�IHWH�EROQDYH��������ÌQ�DUERUHOH genealogic (figura 5.34) VH�REVHUYă�WUDQVPLWHUHD�WDWă�ĺ�ILX�GDU�DOHOD�PXWDQWă�D�EăLHĠLORU�SURYLQH���GH�OD�PDPă��ÌQ�DFHOHDúL�DIHFĠLXQL�VXQW�XQHRUL�SRVLELOH�úL�FRPELQDĠLLOH���úi 5 din WDEHOXO������6H�REVHUYă�IDSXO�Fă�R�IHPHLH�EROQDYă�YD�WUDQVPLWH�ERDOD�OD�WRĠL�EăLHĠLL���VLWXDĠLH�FDUDFWHULVWLFă�WUDQVPLWHULL�5/;��LDU�GLQ�GRL�SăULQĠL�EROQDYL�UH]XOWă�QXPDL�FRSLL�EROQDYL��VLWXDĠLH�VXJHVWLYă�SHQWUX�WUDQVPLWHUHD�UHFHVLYă��vQ�JHQHUDO��

ÌQ�FRQFOX]LH��FULWHULLOH�PDMRUH�SHQWUX�WUDQVPLWHUHD�5/;�VXQW�XUPăWRDUHOH� � bolnavLL�VXQW�DSURDSH�H[FOXVLY�EăUEDĠL��HL�QX�WUDQVPLW�QLFLRGDWă�ERDOD; � IHPHLOH�KHWHUR]LJRWH�VXQW�GHRELFHL�QHDIHFWDWH�úL�SRW�DYHD�EăLHĠL�EROQDYL��LQGLIHUHQW�GH�WLSXO�GH�FăVăWRULH�� � JHQD�PXWDQWă�VH�WUDQVPLWH�GH�OD�EăUEDĠL�DIHFWDĠL�ĺ�OD�IHPHL�VăQăWRDVH�úL�SXUWăWRDre ĺ�úL�GH�OD�DFHVWHD�OD�ò�EăLHĠL��GHFL�

H[LVWă�R�GLVFRQWLQXLWDWH�vQ�VXFFHVLXQHD�JHQHUDĠLLORU��GRL�SăULQĠL�VăQăWRúL��PDPD�KHWHUR]LJRWă��SXWkQG�DYHD�FRSLL�EROQDYL��GDU QXPDL�EăLHĠL

� QX�HVWH�SRVLELOă�QLFLRGDWă�WUDQVPLWHUHD�WDWă�ĺ�ILX �GHRDUHFH�WDWăO�vL�Gă�ILXOXL�FURPRVRPXO<����FkQG�VH�REVHUYă�R�DVWIHO�GH�VLWXDĠLH�YD�WUHEXL�Vă�QH�JkQGLP�OD�R�ERDOă�$'�OLPLWDWă�OD�VH[XO�PDVFXOLQ��GH�H[HPSOX��VFOHUR]D�JORPHUXODUă�IRFDOă��din figura 5.35) E���0XWDĠLL�QRL 0XOWH�EROL�5/;�VXQW�VHYHUH�úL�QX�SHUPLW�VXSUDYLHĠXLUHD�SkQă�OD YkUVWD�UHSURGXFHULL��'LVWURILD�PXVFXODUă�'XFKHQQH��'0'��

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2. XAY x XnXn (XA + Y) x (Xn) XAXn, XnY

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3. XAY x XAXn (XA + Y) x (XA + Xn) XAXA, XAXn

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� Anomaliile de sWUXFWXUă�echilibrate GHúL��vQ�PDUHD�ORU�PDMRULWDWH�QX�PRGLILFă�IHQRWLSXO�SXUWăWRUXOXL�SRW�SURGXFH�WXOEXUăUL�GH�UHSURGXFHUH��ILH�SULQ�EORFDUHD�JDPHWRJHQH]HL�ILH�SULQ�SURGXFHUHD�XQRU�JDPHĠL�DQRUPDOL�

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A. BOLI CROMOSOMICE AUTOSOMALE. Bolile cromosomice SURGXVH�SULQ�DQRPDOLL�QHHFKLOLEUDWH�DOH�DXWRVRPLORU�VXQW�QXPHURDVH��SHVWH�����GH�HQWLWăĠL���([LVWă�QXPDL�WUHL�anomalii FRPSOHWH�úL�RPRJHQH FRPSDWLELOH�FX�VXSUDYLHĠXLUHD��WULVRPLD�����VLQGURPXO�'RZQ���WULVRPLD�����VLQGURPXO�(GZDUGV��úL�trisomia 13 (sindromuO�3DWDX���DOWH�WULVRPLL�DXWRVRPDOH�VXQW�UDUH�úL�VH�JăVHVF�vQ�PR]DLF��$QRPDOLLOH�GH�VWUXFWXUă�QHHFKLOLEUDWH�SURGXF�WULVRPLL�úL�PRQRVRPLL�SDUĠLDOH dintre care vom semnala în special sindromul velo-cardio-facial (del 22q11) considerat al GRLOHD�FD�IUHFYHQĠă�GXSă�VLQGURPXO�'RZQ�� ÌQDLQWH�GH�D�GHVFULH�VXFFLQW�SULQFLSDOHOH�HQWLWăĠL�FOLQLFH��GHWDOLL�SXWHWL�JDVL�SH�LQWHUQHW��YRP�SUHFL]D�FkWHYD�LGHL� � DQRPDOLLOH�IHQRWLSLFH�FDUDFWHULVWLFH�ILHFăUHL�DIHFĠLXQL�VXQW�GHWHUPLQDWH�GH�anomalii de dozaj ale unor gene specifice situate pe

FURPRVRPLL�VHJPHQWHOH�FURPRVRPLFH�LPSOLFDWH��SHQWUX�PRPHQW�VH�FXQRVF�SXĠLQH�GDWH�GHVSUH�DFHVWH�JHQH�GDU�FX�VLJXUDQĠă�HOH�YRU�DSăUHD�vQ�YLLWRUXO�DSURSLDW�VFKLPEkQG�SUREDELO�VXEVWDQĠLDO�PRGXO�GH�DERUGDUH�D�DFHVWRU�DIHFĠLXQL�

� dezechilibrul genetiF��LQGLIHUHQW�GH�WLS��GHWHUPLQă�R�VHULH�GH�„semne comune” �2SLW]���������WXOEXUăUL�GH�FUHúWHUH�SUHQDWDOă�úL�SRVWQDWDOă��GLVPRUILH�IDFLDOă�úL��IUHFYHQW��DQRPDOLL�FRQJHQLWDOH�PDMRUH�PXOWLSOH��GLVSOD]LL��GHUPDWRJOLIH�DQRUPDOH��DOWHUăUL�ale VWUXFWXULL�úL�IXQFĠLHL�61&��UHWDUG�PLQWDO���WXOEXUăUL�DOH�IXQFĠLHL JRQDGDOH��FXQRDúWHUHD�ORU�SRDWH�RULHQWD�XQ�GLDJQRVWLF�VSUH�categoria „boli cromosomice”.

� JUDYLWDWHD�DIHFWăULL�IHQRWLSLFH�GHSLQGH�GH�PDL�PXOĠL�IDFWRUL��PăULPHD�GH]HFKLOLEUXOXL�JHQHWLF��WLSXO�GH�DQRPDOLH�FURPRVRPLFă��FRQĠLQXWXO�JHQLF�úL�FDQWLWDWHD�GH�HXFURPDWLQă���KHWHURFURPDWLQă�D�FURPRVRPXOXL�LPSOLFD��QXPăUXO�FHOXOHORU�DIHFWDWH�(aneuploidii omogene sau în mozaic)(vezi capitolul 6.C.2).

� GHúL�EROLOH�FURPRVRPLFH�VXQW�LQFXUDELOH�LDU�SRVLELOLWăĠLOH�GH�SURILOD[LH�OLPLWDWH��H[LVWă�WRWXúL�PXOWLSOH�DFĠLXQL�FDUH�SRW�DPHOLRUD�vQJULMLUHD�EROQDYLORU�SUHFXP�úL�GHSLVWDUHD�SUHQDWDOă�SUHFRFH�

1. TRISOMIILE AUTOSOMALE

1.1. SINDROMUL DOWN SAU TRISOMIA 21 6LQGURPXO�'RZQ�VDX�WULVRPLD����HVWH�FHD�PDL�IUHFYHQWă�úL�FHD�PDL�ELQH�FXQRVFXWă�ERDOă�FURPRVRPLFă��$�IRVW�GHVFULVă�FOLQLF�GH�

20

-RKQ�/DQJGRQ�'RZQ�vQ������GDU��DELD�vQ�������-HURPH�/HMHXQH�úL�FRODERUDWRULL�DX�VWDELOLW�Fă�DIHFĠLXQHD�HVWH�SURGXVă�GH�WULVRPia 21. ,QFLGHQĠD�WULVRPLHL����D�IRVW�HVWLPDWă�OD�������– 1:800 nou-QăVFXĠL�YLL �SUHYDOHQĠD�JOREDOă�HVWH�– GXSă�%UD\�HW�DO�������– de �����OD���������������IUHFYHQĠD�SURGXúLORU�GH�FRQFHSĠLH�FX�WULVRPLH����HVWH�vQVă�PXOW�PDL�PDUH����OD������GDU�FLUFD�ô�VXQW�HOLPLQDĠL�FD�DYRUWXUL�VSRQWDQH��%RDOD�HVWH�PDL�IUHFYHQWă�OD�FRSLLL�GH�VH[�PDVFXOLQ��UDSRUWXO�VH[HORU�ILLQG�GH���EăLHĠL�OD���IHWH� 6LPSWRPDWRORJLD�FOLQLFă�GLIHUă�vQ�IXQFĠLH�GH�YkUVWD�OD�FDUH�HVWH�H[DPLQDW�SDFLHQWXO��'H�RELFHL�VLQGURPXO�'RZQ�HVWH�diagnosticat clinic („gestalat´��vQ�SHULRDGD�QHRQDWDOă�VDX�OD�VXJDU�GDWRULWă�GLVPRUILLORU�HYRFDWRDUH��FDUH��GHúL�YDULD]ă�OD�GLIHULĠL�SDFLHQĠL��UHDOL]HD]ă�XQ�DVSHFW�IHQRWLSLF�FDUDFWHULVWLF26 (Ä���GDFă�DL�Yă]XW�XQ�FRSLO�FX�VLQGURPXO�'RZQ�L-DL�Yă]XW�SH�WRĠL´). Nou-QăVFXWXO FX�WULVRPLH����DUH�OXQJLPH�úL�JUHXWDWH�PDL�PLFă�GHFkW�SDUDPHWULL�YkUVWHL JHVWDĠLRQDOH��SUH]LQWă�KLSRWRQLH�PXVFXODUă��KLSHUH[WHQVLELOLWDWH�úL�UHIOH[H�FRPSRUWDPHQWDOH��GH�H[HPSOX��UHIOH[XO�0RUR��UHGXVH��&DSXO�HVWH�EUDKLFHIDOLF��FX�RFFLSXW�WXUWLW�úL�IRQWDQHOH�ODUJL��)DĠD�HVWH�URWXQGă��SODWă�úL�SUH]LQWă�R�GLVPRUILH�VXJHVWLYă��epicantus (un repliu în unghiul intern al RFKLXOXL���IDQWHOH�SDOSHEUDOH�REOLFH�vQ�VXV�úL�vQ�DIDUă27��QDVXO�PLF�FX�UăGăFLQD�WXUWLWă�úL�QDULQH�PLFL�úL�DQWHYHUVDWH��JXUD�GHVFKLVă�úL�SURWUX]LH�OLQJXDOă��GDWRULWă�FDYLWăĠLL�RUDOH�PLFL���XUHFKLOH�PDL�MRV�VLWXDWH��PLFL úL�GLVSOD]LFH��*kWXO�HVWH�VFXUW��FX�exces de piele pe FHDIă��PkLQLOH�VXQW�VFXUWH�úL�ODWH��FX�EUDKLGDFWLOLH��FOLQRGDFWLOLH��vQFXUEDUHD��D�GHJHWXOXL�9�úL��IUHFYHQW��XQ�VLQJXU�SOLX�GH�IOHxie SDOPDUă��pliu simian���LQFRQVWDQW�VXQW�SUH]HQWH�XQHOH�PDOIRUPDĠLL�YLVFHUDOH��GHIHFWH�FDUGLDFH��DWUH]LH�GXRGHQDOă��LPSHUIRUDĠLH�DQDOă�� La VXJDU�úL�FRSLO IHQRWLSXO�VLQGURPXOXL�'RZQ�SUH]LQWă�HOHPHQWHOH�GHVFULVH�PDL�VXV��7DOLD�úL�JUHXWDWHD�VH�DIOă�VXE�PHGLD�YkUVWHL��KLSRWRQLD�PXVFXODUă�SHUVLVWă�úL�VH�DVRFLD]ă�FX�KLSHUOD[LWDWH�DUWLFXODUă�úL�KLSRUHIOH[LH�QHUYRDVă��'HYLQ�PDL�HYLGHQWH�FkWHYD�GLVPRUILL�cranio-IDFLDOH��PLFURFHIDOLD�FX�RFFLSXW�WXUWLW��IDQWHOH�SDOSHEUDOH�REOLFH�vQ�VXV�úL�vQ�DIDUă��PDL�DOHV�FkQG�VXJDUXO�SOkQJH�, LULVXO�SHVWULĠ��FX�pete Brushfield, de culoare maronie)��KLSRSOD]LD�HWDMXOXL�PLMORFLX�DO�IHĠHL��IDĠă�SODWă���OLPEă�SURWUX]LRQDWă��úL�PDL�WkU]LX�SOLFDWXUDWă��(figura 10.1). La nivelul membrelor brahidactilia úL�FOLQRGDFWLOLD�DXULFXODUXOXL�VXQW�PDL�SURQXQĠDWH��VH�SRW�REVHUYD��FX�R�OXSă�VDX�SULQ�amprentare) dermatoglifele anormale �SOLX�SDOPDU�WUDQVYHUV�XQLF��H[FHV�GH�EXFOH�FXELWDOH��WULUDGLXV�D[LDO�VLWXDW�GLVWDO��ú�D���LDU�VSDĠLXO�LQWHUGLJLWDO�,�OD�SLFLRU�HVWH�PXOW�PDL�ODUJ��9RP�SUHFL]D�Fă�QLFL�XQXO�GLQ�DFHVWH�VHPQH��OXDWH�VHSDUDW��QX�HVWH�UHOHYDQW��QXPDi în asociere cu celelalte semne permite evocarea diagnosticului de sindromul Down (tabelul 10.1���&RQILUPDUHD�FLWRJHQHWLFă�HVWH�REOLJDWRULH��PDL�ales pentru realizarea unui sfat genetic corect.

Semne )UHFYHQĠă����

+LSRWRQLH�PXVFXODUă 100 Reflex Moro redus 85 Profil facial plat 90 )DQWH�SDOSHEUDOH�REOLFH�vQ�VXV�úL�vQ�DIDUă 80 Urechi mici, rotunde, jos situate 60 ([FHV�GH�SLHOH�SH�FHDIă 80 Pliu simian 45 +LSHUOD[LWDWH�DUWLFXODUă 80 Pelvis displazic 70 Clinodactilie 60 3UH]HQĠD�D���GLQ�FHOH����VHPQH�SOHGHD]ă�SHQWUX�GLDJQRVWLFXO�GH�sindrom Down

$úD�FXP�DP�SUHFL]DW��XQLL�FRSLL�FX�VLQGURP�'RZQ�SRW�SUH]HQWD�GLIHULWH�PDOIRUPDĠLL�YLVFHUDOH� cardio-YDVFXODUH��GLJHVWLYH�úL�UHQDOH��0DOIRUPDĠLLOH�FDUGLDFH�DIHFWHD]ă��DSUR[LPDWLY�����GLQ�QRX-QăVFXĠLL�FX�VLQGURP�'RZn, majoritatea fiind defecte septale (atrio-YHQWULFXODUH��YHQWULFXODUH�VDX�DWULDOH���0DOIRUPDĠLLOH�GLJHVWLYH���-����PDL�IUHFYHQWH�VXQW�DWUH]LLOH�VDX�VWHQR]HOH�GXRGHQDOH�úL�megacolonul. ÌQ�DO�GRLOHD�DQ�GH�YLDĠă�GHYLQH�HYLGHQWă�vQWkU]LHUHD�GH�GH]YROWDUH�SVLho-PRWRULH��WRDWH�DFKL]LĠLLOH�FRSLOăULHL�VH�IDF�FX��-3 ani mai WkU]LX�GHFkW�QRUPDO��PHUVXO�HVWH�PXOW�WLPS�QHVLJXU�LDU�YRUELUHD�UHODWLY�VLPSOă��&RSLLL�VXQW�vQVă�OLQLúWLĠL��DVFXOWăWRUL��DX�R personalitate DWUăJăWRDUH��LXEHVF�DQWXUDMXO��PX]LFD��YHVHOLD��'DU��GLQ�SăFDWH��Vindromul Down VH�DVRFLD]ă�întotdeauna cu un retard mental care YDULD]ă�GH�OD�VHYHU�OD�PRGHUDW��FRHILFLHQWXO�GH�LQWHOLJHQĠă�– QI – DO�SHUVRDQHORU�DIHFWDWH�YDULD]ă�vQWUH����úL�����úL�HVWH�DVRFLDW�FX�WXOEXUăUL�GH�OLPEDM��8Q�EROQDY�FX�VLQGURP�'RZQ SRDWH�DFXPXOD�XQ�QLYHO�PD[LP�GH�FXQRúWLQĠH�FRPSDUDELO�FX�FHO�DO�XQXL�FRSLO�QRUPDO�FX�YkUVWD�vQWUH���úL���DQL�úL�QX�HVWH�FDSDELO�GH�R�YLDĠă�LQGHSHQGHQWă. ÌQ�VLQGURPXO�'RZQ�ULWPXO�GH�FUHúWHUH�HVWH�UHGXV�úL�WDOLD�YD�IL�FX����'6�VXE�PHGLD�QRUPDOă�D�YkUVWHL��WDOLD�PD[LPă�OD�DGXOW�va fi de 140 – ����FP���)UHFYHQW�VH�DVRFLD]ă�REH]LWDWHD�LDU�GH]YROWDUHD�SXEHUWDUă�HVWH�PXOW�vQWkU]LDWă�úL�LQFRPSOHWă��%ăUEDĠLL�VXQW�VWHULOL�LDU�IHPHLOH�DX�R�IHUWLOLWDWH�UHGXVă��UHSURGXFHUHD�HVWH�vQVă�QXPDL�DFFLGHQWDOă��WLQkQG�FRQW�GH handicapul intelectual. 'LDJQRVWLFXO�FOLQLF�GLIHUHQĠLDO�DO�VLQGURPXOXL�'RZQ�VH�LPSXQH�vQ�SXĠLQH�VLWXDĠLL��0DFURJORVLD�úL�PLFURVWRPLD�GLQ�VLQGURPXO�'RZQ�WUHEXLH�GLIHUHQĠLDWH�GH�FHOH�GLQ�KLSRWLURLGLD�FRQJHQLWDOă�VDX�GLQ�VLQGURPXO�%HFNZLWK-Wiedemann; unele elemente ale dismorfiei cranio-IDFLDOH�VH�vQWkOQHVF�úL�vQ�VLQGURDPHOH�6PLWK-Magenis, Zellweger sau triplo-X (pentru detalii vezi OMIM sau 253+$1(7���3ULQ�HIHFWXDUHD�FDULRWLSXOXL�VH�UHDOL]HD]ă�FHUWLILFDUHD�GLDJQRVWLFXOXL�GH�VLQGURP�'RZQ� Analiza citogenetiFă�HVWH�HVHQĠLDOă�SHQWUX�GLDJQRVWLF�úL�REOLJDWRULH�vQ�ILHFDUH�FD]��FKLDU�GDFă�H[DPHQXO�FOLQLF�HVWH�UHOHYDQW��GHRDUHFH�vQ�IXQFĠLH�GH�UH]XOWDWXO��DQDOL]HL�FURPRVRPLFH�VH�FDOFXOHD]ă�ULVFXO�GH�UHFXUHQĠă�úL�VH�DFRUGă�VIDWXO�JHQHWLF��$QDOL]a FURPRVRPLFă�SRDWH�HYLGHQĠLD� � WULVRPLH����OLEHUă�úL�RPRJHQă, în circa 92-95% din cazurile de sindrom Down; ele se produc prin QHGLVMXQFĠLH�PHLRWLFă, cel

26 Diagnosticul este mai dificl la prematuri 27 $FHVWH�FDUDFWHULVWLFL�DX�GXV�OD�GHQXPLUHD�LPSURSULH�úL�SURKLELWă�GH�mongolism. 21

mai frecvent (85-�����PDWHUQă�úL�vQ�VSHFLDO�vQ�PHLR]D�,������28; � WULVRPLH�����OLEHUă�úL�vQ�mozaic cromosomic (de tip 47/46), în circa 2-���GLQ�FD]XUL��UH]XOWă�SULQ�QHGLVMXQFĠLH�PLWRWLFă�

SRVW]LJRWLFă�VDX��IRDUWH�UDU��SULQ�SLHUGHUHD�XQXL�FURPRVRP����vQ�FHOXOH�FH�GHULYă�GLQWU-un zigot trisomic („salvarea” unei trisomii omogene);

� trisomie 21 prin WUDQVORFDĠLH�5REHUWVRQLDQă�QHHFKLOLEUDWă – vQWUH�FURPRVRPXO����úL�XQ�DOW�FURPRVRP�DFURFHQWULF�– poate fi REVHUYDWă�vQ��-���GLQ�FD]XUL��FHO�PDL�IUHFYHQW�VH�vQWkOQHúWH�WUDQVORFDĠLD���T���T�FDUH�vQ�MXPăWDWH�GLQ�FD]XUL�HVWH�PRúWHQLWă�GH�OD�XQXO�GLQWUH�SăULQĠL��FHO�PDL�DGHVHD�GH�OD�PDPă��GDU�IăUă�QLFL�R�OHJăWXUă�FX�YkUVWD�PDWHUQă���WUDQVORFDĠLLOH���T���T�VDX���T���T�VXQW�PXOW�PDL�UDUH�úL�PDMRULWDWHD�VXQW�de novo;

� WULVRPLH����SDUĠLDOă��vQ�PDL�SXĠLQ�GH����GLQ�FD]XUL��UH]XOWă�SULQ�VHJUHJDUHD�PHLRWLFă�D�FURPRVRPLORU�GHULYDWLYL��IRUPDĠL�vQ�urma unor tUDQVORFDĠLL�HFKLOLEUDWH��FH�LPSOLFă�XQ�VHJPHQW�GLQ�FURPRVRPXO������SUH]HQWH�OD�XQXO�GLQWUH�SăULQĠL��

(YROXĠLH�úL�SURJQRVWLF��ÌQ�SULPLL�DQL�GH�YLDĠă PXOĠL�GLQWUH�FRSLLL�FX�VLQGURP�'RZQ�VXQW�FRQIUXQWDĠL�FX�GLIHULWH�SUREOHPH�medicale. Cele mai importante sunt determinate de PDOIRUPDĠLLOH�YLVFHUDOH��vQ�VSHFLDO�FDUGLDFH��úL�GLJHVWLYH. ,QIHFĠLLOH�UHVSLUDWRULL�sunt frecvente (printr-R�LPXQRGHILFLHQĠă�QHVSHFLILFă��LDU�ULVFXO�GH�D�GH]YROWD�leucemie este de 15-20 ori mai mare decât în SRSXODĠLD�JHQHUDOă��'LQ�DFHVWH�PRWLYH��PRUWDOLWDWHD�vQ�SULPLL���DQL�GH�YLDĠă�HVWH��HUD ���PDUH�úL�vQ������QXPDL�MXPăWDWH�GLQWUH�FRSLL�FX�VLQGURP�'RZQ�VXSUDYLHĠXLDX�SkQă�OD�DFHDVWă�YkUVWă��ÌQ�XOWLPLL����GH�DQL��vQ�ĠăULOH�GH]YROWDWH��UDWD�GH�VXSUDYLHĠXLUH�V-a vPEXQăWăĠLW�VHPQLILFDWLY��SULQ WUDWDPHQWXO�FKLUXUJLFDO�DO�FDUGLRSDWLLORU�FRQJHQLWDOH��DQWLELRWHUDSLH��UHGXFHUHD�LQVWLWXĠLRQDOL]ăULL�úL�LQWHJUDUH�VRFLDOă��LDU�VSHUDQĠD�GH�YLDĠă�HVWH�DFXP�GH�FLUFD����GH�DQL��ÌQWUH���úL����GH�DQL�PRUWDOLWDWHD�vQ�VLQGURPXO�'RZQ�HVte DSUR[LPDWLY�DVHPăQăWRDUH�FX�FHD�GLQ�SRSXODĠLD�JHQHUDOă��WRWXúL�PRUELGLWDWHD�HVWH�PDL�FUHVFXWă : un procent de circa 10-15% din SDFLHQĠLL�FX�VLQGURP�'RZQ�SRW�SUH]HQWD�XQD�GLQ�XUPăWRDUHOH�SUREOHPH PHGLFDOH��HSLOHSVLH��WXOEXUăUL�YL]XDOH��FDWDUDFWă��JODXFRP��strabism), surditate, hipotiroidie, instabilitate atlanto-D[LDOă��'XSă����GH�DQL�VH�LQVWDOHD]ă�IUHFYHQW�R�GHPHQĠă�VHQLOă�SUHFRFH úL�PRUWDOLWDWHD�FUHúWH�VHPQLILFDWLY�SULQ�accidente vasculare��ÌQ�ĠăULOH�GH]YROWDWH��UDWD�GH�VXSUDYLHĠXLUH��OD����GH�DQL�HVWH�GH�����LDU�OD�60 de ani esWH�GH�QXPDL������DGLFă�MXPăWDWH�GLQ�DFHHD�D�SRSXODĠLHL�JHQHUDOH� (WLRORJLH�úL�SDWRJHQLH SLQGURPXO�'RZQ�HVWH�SURGXV�GH�WULVRPLD�FURPRVRPXOXL����úL�PDL�H[DFW�GH�WULVRPLD�UHJLXQLL�21q22 �QXPLWă�úL�'6&5�– Down Syndrome Crtitical Region). Prin analiza moleculaUă�D�UDUHORU�FD]XUL�GH�WULVRPLL����SDUĠLDOH�s-D�VWDELOLW�Fă�vQ�UHJLXQHD���T����-22.3 VH�JăVHVF�JHQHOH�FDUH��SULQ�HIHFW�GH�GR]DM��SURGXF�PDMRULWDWHD�VHPQHORU�FOLQLFH�FDUDFWHULVWLFH�VLQGURPXOXL�'RZQ�� 6HFYHQĠLHUHD�UHFHQWă�D�FURPRVRPXOXL����SHUPLWH�vQ�SULQFLSLX�LGHQWLILFDUHD�RULFăUHL�JHQH�GH�SH�FURPRVRP��ÌQ�SUH]HQW�FRQĠLQXWXO�genic al cromosomului 21 este estimat a fi de 329, cu 165 de gene confirmate experimental, 150 de gene prezise pe baza analizei VHFYHQĠHOHRU�H[SULPDWH��WDJ��úL����SUHGLFĠLL�FRPSXWHUL]DWH��2�FDUDFWHULVWLFă�RDUHFXP�QHDúWHSWDWă�HVWH�IDSWXO�Fă�IUDFĠLD�FURPRVRPXOXL����FDUH�HVWH�WUDQVFULVă�vQ�$51�HVWH�GH�IDSW�PDL�PDUH�GHFkW�FHD�FDUH�HVWH�RFXSDWă�GH�VHFYHQĠHOH�FRGDQWH�DOH�JHQHOor. Un mijloc utilizat pentru studiul genelor implicate în producereD�PDQLIHVWăULORU�FOLQLFH�GLQ�VLQGURPXO�'RZQ�HVWH�DFHOD�DO�PRGHOHORU�DQLPDOH��/D�úRDUHFL��JHQHOH�FRUHVSXQ]DWRDUH�FURPRVRPXOXL�XPDQ����VH�DIOD�ORFDOL]DWH�SH�WUHL�FURPRVRPL��6-D�DUăWDW�Fă�trisomia genelor omologe de pe cromosomul 16 (corespunzatoare regiunii ��T���OD�RP��GHWHUPLQă�R�VHULH�GH�FDUDFWHULVWLFL�DVHPăQăWRDUH�FX�FHOH�GLQ�VLQGURPXO�'RZQ��GHILFLWH�DOH�SURFHVHORU�GH�vQYăĠDUH��WXOEXUăUL�DOH�GH]YROWăULL�FUDQLRIDFLDOH�úL�PRGLILFăUL�neuropatologice DVHPăQăWRDUH�FHORU�GLQ�ERDOD�$O]KHLPHU�� La nivelul regiuniL�'6&5�DX�IRVW�FDUWRJUDILDWH�XUPăWRDUHOH�JHQH��+XEHUW�HW�DO��������&DSRQH�HW�DO���������$33�– gena pentru proteina SUHFXUVRU�D�DPLORLGXOXL�EHWD�úL�6���%�– gena pentru o proteina de legare a calciului (corelate cu neuropatia de tip Alzheimer la SDFLHQĠLL�FX sindrom Down), SOD1 – gena pentru superoxid dismutaza 1, ETS2 – oncogena ets-���LPSOLFDWă�vQ�ULVFXO�FUHVFXW�GH�leucemie la bolnavii cu sindrom Down), CBS – gena pentru cistationin-beta-VLQWHWD]ă��LPSOLFDWD�LQ�PHWDEROLVPXO�IRODĠLORU��úL�&5<$��– gena pentru SURWHLQD�DOID�D�FULVWDOLQXOXL��FRUHODWă�FX�IUHFYHQĠD�FUHVFXWă�D�FDWDUDFWHL���&kWHYD�JHQH�FDQGLGDW�SHQWUX�UHWDUGXO�PLQWDO�vQ�VLQGURPXO�'RZQ�VXQW��'<5.�$��FH�FRGLILFă�R�SURWHLQ-NLQD]ă��LPSOLFDWă�vQ�FRQWUROXO�SUROLIHUDULL�QHXUREODúWLORU���6,0���QHFHVDUă�pentUX�VLQFURQL]DUHD�GLYL]LXQLORU�FHOXODUH�vQ�FXUVXO�GH]YROWDULL�FHUHEUDOH���*$57�FH�FRGLILFă�R�IRVIRULER]LO�JOLDFLQDPLG-formil-WUDQVIHUD]D��LPSOLFDWă�vQ�GH]YROWDUHD�SUHQDWDă�D�FHUHEHOXOXL���3&3��– proteina tip 4 a celulelor Purkinje (rol în dezvoltarea cerebelului), DSCAM – 'RZQ�V\QGURPH�FHOO�DGKHVLRQ�PROHFXOH��FRQVLGHUDWă�D�IL�LPSOLFDWă�vQ�FUHúWHUHD�D[RQDOă�SUHFXP�úL�R�JHQă�FDQGLGDW�SHQWUX�GHIHFWHOH�FRQJHQLWDOH�FDUGLDFH��úL�*5,.��– UHFHSWRU�SHQWUX�JOXWDPDW��LPSOLFDW�vQ�IXQFĠLD�FHOXOHORU�SLUDPLGDOH�DOH�cortexuOXL���&X�WRDWH�SURJUHVHOH�UHDOL]DWH��SDWRJHQLD�VLQGURPXOXL�'RZQ�DUH�vQFă�PXOWH�HQLJPH� 3UREOHPD�HVHQĠLDOă�HVWH�vQVă�HOXFLGDUHD�HWLRORJLHL�DFHVWHL�WULVRPLL�IUHFYHQWH��9kUVWD�PDWHUQă este singurul determinant HYLGHQW�DO�QHGLVMXQFĠLHL��YH]L�FDSLWROHOH���&���úL���&��GDU�QXPDL�FLUFD�����GLQ�SDFLHQĠLL�FX�sindrom Down se nasc din femei peste 35 de ani. ùL�WRWXúL��IDSWXO�Fă���-����GLQ�FD]XUL�UH]XOWă�SULQ�QHGLVMXQFĠLH�PDWHUQă������vQ�PHLR]D�,��VXJHUHD]ă�LQWHUYHQĠLD�XQXL�IDFWRU�GH�ULVF�FH�DFĠLRQHD]ă�OD�DFHVW�QLYHO��Yoon et al, 1996). S-DX�HPLV�GLIHULWH�LSRWH]H�GDU�QLFL�XQD�QX�D�IRVW�YDOLGDWă�GH�SUREH�FRQYLQJăWRDUH��(YLGHQĠLHUHD�DVRFLHULL�vQWUH�XQHOH�SROLPRUILVPH�DOH�JHQHORU�FDUH�FRGLILFă�HQ]LPH�LPSOLFDWH�vQ�PHWDEROLVPXO�IRODĠLORU�úL�ULVFXO�SHQWUX�QHGLVMXQFĠLD�FURPRVRPLFă�FH�FRQGXFH�OD�VLQGURPXO�'RZQ�D�IRVW�LQLĠLDO�GHPRQVWUDWă�vQWU-un studiu follow-XS��GH�XUPDULUH���GDU�QX�D�SXWXW�IL�FRQILUPDWă�vQ�DOWH�VWXGLL�XOWHULRDUH� Sfat genetic. 2�SUREOHPă�IUHFYHQWă�vQ�VIDWXO�JHQHWLF�HVWH�GHWHUPLQDUHD�ULVFXOXL�QDúWHULL�XQXL�FRpil cu sindrom Down. Datele actuale DUDWă�Fă�ULVFXO�GHSLQGH�vQ�SULQFLSDO�GH�YkUVWD�PDPHL�GDU�úL�GH�FDULRWLSXO�FHORU�GRL�SăULQĠL��YkUVWD�SDWHUQă�SDUH�Vă�QX�DLEH�Qici o LQIOXHQĠă�DVXSUD�ULVFXOXL� ,QFLGHQĠD�PHGLH�D�VLQGURPXOXL�'RZQ�vQ�SRSXODĠLD�JHQHUDOă�HVWH de 1 la 700 nou-QăVFXĠL��%UD\�HW�DO���������'XSă����GH�DQL�ULVFXO�vQFHSH�Vă�FUHDVFă�GH�OD���OD�����SkQă�OD���OD��������GH�DQL���GH�DFHHD�V-D�DOHV�YkUVWD�GH����GH�DQL�FD�R�LQGLFDĠLH�GH�VFUHHQLQJ�HFRJUDILF�úL�ELRFKLPLF��YH]L�PDL�MRV��SUHFXP�úL�GH�GLDJQRVWLF prenatal (riscul unui fetus cu sindrom Down fiind mai mare decât riscul de avort asociat procedurii – ELRSVLH�GH�YLOR]LWăĠL�FRULDOH�VDX�DPQLRFHQWH]ă���2�SUREOHPă�GHOLFDWă�HVWH�ULVFXO�XQXL�FXSOX�FDUH�DUH�R�UXGă�FX�VLQGURP�'RZQ�úL�FDULRWLS�QHFXQRVFXW��OXkQG vQ�GLVFXĠLH�IUHFYHQĠD�WULVRPLHL�vQ�IXQFĠLH�GH�YkUVWD�IHPHLL�SUHFXP�úL�SRVLELOLWDWHD�XQHL�WUDQVORFDĠLL�FHO�PDL�PDUH�ULVF�FDOFXODW�HVWH�GH���OD������GHFL�DSURDSH�GH�SUHYDOHQĠD�vQ�SRSXODĠLH��úL�HO�

28 2ULJLQHD�PDWHUQă�VDX�SDWHUQă�D�QHGLVMXQFĠLHL�PHLRWLFH�úL�WLSXO ei – QHGLVMXQFĠLH�vQ�PHLR]D�,�VDX�PHLR]D�,,�– au fost stabilite prin tehnici moleculare. 22

este valabil pentru copilul surorii bolnavului. Riscul de rHFXUHQĠă DO�VLQGURPXOXL�'RZQ��GXSă�FH�V-D�QăVFXW�XQ�DVWIHO�GH�FRSLO��HVWH�GHSHQGHQW�GH�WLSXO�GH�WULVRPLH�����ÌQ�

WULVRPLD����OLEHUă�úL�RPRJHQă�ULVFXO�GH�UHFXUHQĠă�HVWH�vQ�PHGLH�����SHQWUX�IHPHLOH�VXE����GH�DQL�HVWH�SXĠLQ�PDL�PDUH��GH�FLUFa 1,4% (probabil daWRULWă�XQRU�PR]DLFXUL�JHUPLQDOH�QHGHSLVWDWH���SHQWUX�IHPHLOH�GH�SHVWH����GH�DQL�ULVFXO�HVWH�DFHODúL�FX�FHO�GHWHUPLQDW�GH�YkUVWD�PDWHUQă��5LVFXO�GH�UHFXUHQĠă�HVWH�QHVHPQLILFDWLY�vQ�WULVRPLLOH�SULQ�PR]DLF����������ÌQ�VFKLPE��vQ�FD]XO�trisomiei 21 prin translRFDĠLH�5REHUWVRQLDQă�QHHFKLOLEUDWă�ULVFXO�HVWH�PRGHUDW�vQ�WUDQVORFDĠLLOH�vQWUH�FURPRVRPL�QHRPRORJL����-����GDFă�PDPD�HVWH�SXUWăWRDUH�úL��-���GDFă�WDWăO�HVWH�SXUWăWRU��úL�WRWDO���������vQ�WUDQVORFDĠLLOH�5REHUWVRQLHQH�vQWUH�FURPRVRPL�21. Depistarea prenataOă�D�VLQGURPXOXL�'RZQ�SRDWH�IL�HIHFWXDWă��OD�RULFH�YkUVWă�GDU�PDL�DOHV�GXSă����GH�DQL��SH�ED]D�XQRU�metode de screening – ELRFKLPLF�úL�HFRJUDILF��XUPDWH�GH�FRQILUPDUHD�FD]XULORU�VXVSHFWH�SULQ�UHDOL]DUHD�FDULRWLSXOXL�� � 3ULPă�PHWRGă�GH�VFUHHQLQJ�HVWH�triplul test ED]DW�SH�GHWHUPLQDUHD�vQ�VkQJHOH�PDWHUQ��WULPHVWUXO�,,�GH�VDUFLQă��D�Į-fetoproteinei

(AFP), gonadotrofinei corionice umane �ȕ-K&*��úL�D�HVWULROXOXL�QHFRQMXJDW��X(����7HVWXO�HVWH�VXJHVWLY�SHQWUX�VLQGURPXO�'RZQ�când sunt depistate: un nivel crescut al Į-IHWRSURWHLQHL��XQ�QLYHO�FUHVFXW�DO�JRQDGRWURILQHL�FRULRQLFH�XPDQH�úL�XQ�QLYHO�VFă]XW�DO�estriolului neconjugat��$FHVW�WHVW�DUH�R�DFXUDWHĠH�GH�����úL�XQ�SURFHQW�GH����UH]XOWDWH�IDOV�SR]LWLYH��'H�FkĠLYD�DQL�VH�IRORVHúWH�FYDGUXSOXO�WHVW��FDUH�DVRFLD]ă�OD�WULSOX�WHVW�úL�GR]DUHD�inhibinei A, D�FăUXL�VHQVLELOLWDWH�HVWH�GH������5RL]HQ�úL�3HWHUVHQ���������GH�DVHPHQHD�D�IRVW�LQWURGXVă�DQDOL]D�XQRU�PDUNHUL�ELRFKLPLFL�GH�WULPHVWUXO�,��vQ�VSHFLDO�SURWHLQD�SODVPDWLFă�$�DVRFLDWă�VDUFLnii – PAPP-A (Pregnancy Associated Plasmatic Protein-A��úL�IUDFĠLD��OLEHUă�D�E-K&*��FDUH�FUHVF�DFXUDWHĠHD�PHWRGHL�OD������reducându-VH�WRWRGDWă�úL�IUHFYHQĠD�UH]XOWDWHORU�IDOV�SR]LWLYH�

� $�GRXD�PHWRGă�GH�VFUHHQLQJ�HVWH�UHSUH]HQWDWă�GH�HFRJUDILD�IHWDOă (la 11-���VăSWăPkQL�GH�VDUFLQă���SULQFLSDlele semne de DODUPă��SHQWUX�SUH]HQĠD�XQXL�IăW�FX�VLQGURP�'RZQ��ILLQG�edemul cefei �WUDQVOXFHQĠD�QXFDOă��vQ�SULPHOH�OXQL�GH�VDUFLQă�úL�scurtarea femurului / humerusului în a doua parte a sarcinii.

&RPELQDUHD�UH]XOWDWHORU�VFUHHQLQJXOXL�HFRJUDILF�úL�ELRFKLPLF�FX�YkUVWD�PDWHUQă�D�GXV�OD�UHDOL]DUHD�XQRU�VFKHPH�GH�SUHGLFĠLH�D�SUREDELOLWăĠLL�XQXL�IHWXV�FX�VLQGURP�'RZQ��&RQILUPDUHD�GLDJQRVWLFXOXL�QHFHVLWă�examenul citogenetic al amniocitelor (efectuat în VăSWăPkQLOH���-���GH�VDUFLQă��VDX�DO�FHOXOHORU�GLQ�YLOR]LWăĠLOH�FRULDOH �HIHFWXDW�vQ�VăSWăPkQLOH��-���GH�VDUFLQă�� ÌQJULMLUHD�FRSLLORU�FX�VLQGURP�'RZQ�ULGLFă�QXPHURDVH�SUREOHPH�FDUH�VXQW�ELQH�VWDQGDUGL]DWH�úL�LPSOLFă�GLYHUúL�VSHFLDOLúWL��LQIRUPDĠLL�OD�DGUHVHOH�,QWHUQHW�PHQĠLRQDWH�vQ�ELEOLRJUDILH���9RP�VXEOLQLD�GRDU�IDSWXO�Fă�HVWH�QHFHVDUă�R�VXVĠLQHUH�SVLKRORJLFă�FRQWLQXă�úL�XQ�VSULMLQ�DGHFYDW�DO�SăULQĠLORU�SHQWUX�D�IDFH�IDĠă�SUREOHPHORU�ULGLFDWH�GH�FUHúWHUHD�XQXL�DVWIHO�GH�FRSLO��'H�DVemenea nu WUHEXLH�LJQRUDWH�SUREOHPHOH�HWLFH�DOH�VIDWXOXL�JHQHWLF�úL�GLDJQRVWLFXOui prenatal în aceste cazuri (vezi capitolul 20).

1.2 SINDROMUL EDWARS SAU TRISOMIA 18.

,QFLGHQĠă��6LQGURPXO�(GZDUGV�VDX�WULVRPLD����DUH�R�LQFLGHQĠă�GH�DSUR[LPDWLY�������-�����GH�QDúWHUL��SUHYDOHQĠD�PHGLH����la 6000 nn), majoritatea cazurilor (80%) fiind GH�VH[�IHPLQLQ��LQFLGHQĠD�OD�FRQFHSĠLH�HVWH�PXOW�PDL�PDUH�GDU�DSUR[LPDWLY�����GLQWUH�HPEULRQLL�FX�WULVRPLH����VXQW�HOLPLQDĠL�SULQ�DYRUW�� Simptomatologie. Nou-QăVFXWXO SUH]LQWă�R�JUHXWDWH�PLFă�SHQWUX�YkUVWD�JHVWDĠLRQDOă��KLSHUWRQLH�����úL�R�GLVPRUILH�FUDnio-IDFLDOă�HYRFDWRDUH��FDS�DOXQJLW��dolicocefalie��FX�RFFLSXW�SURHPLQHQW��IUXQWH�WHúLWă��PLFURUHWURJQDWLVP��XUHFKL�MRV�LPSODQWDWH�úL�hipoplazice ("urechi de faun"). (figura 10.2). 'HJHWHOH�PkLQLL�VXQW�VWUkQV�IOHFWDWH�úL�vQFăOHFDWH într-un mod caracteristic: degetele ��úL���DFRSHUă�GHJHWHOH���úL����8QJKLLOH�VXQW�KLSRSOD]LFH�úL�GHUPDWRJOLIHOH�DQRUPDOH��H[FHV�GH�DUFXUL��SOLX�VLPLDQ���6WHUQXO�este scurt iar piciorul are aspectul de “piolet´��GDWRULWă�SURHPLQHQĠHL�SRVWHULRDUH�D�FDOFDQHXOXL��úL�KDOXFHOH�VFXUW��0DL�H[LVWă�GLYHUVH�WLSXUL�GH�KHUQLL�VDX�RPIDORFHO��)UHFYHQW�VXQW�SUH]HQWH�PDOIRUPDĠLL�FRQJHQLWDOH�JUDYH��FDUGLDFH������GLQWUH�FD]XUL���UHQDOH��FHUHEUDOH��YHUWHEUDOH��6XVSLFLXQHD�FOLQLFă29 HVWH�VXVĠLQXWă�úL�GH�HYLGHQĠLHUHD�DQDPQHVWLFă�D�SROLKLGUDPQLRVXOXL�vQ�cursul sarcinii (la circa 60% din cazuri). 'LDJQRVWLFXO�FOLQLF�GLIHUHQĠLDO�SRDWH�IL�IăFXW�FX�VHFYHQĠD�GH DNLQH]LH�IHWDOă�VDX�VLQGURPXO�3HQD-Shokeir tip I úL�FX�DUWURJULSR]D�GLVWDOă�WLS����DPEHOH�SUH]LQWă�FRQWUDFWXUL�DUWLFXODUH�PXOWLSOH��LQFOXVLY�vQFăOHFări ale degetelor, dar lipsesc PDOIRUPDĠLLOH�FDUGLDFH�úL�GLVPRUILD�IDFLDOă�FDUDFWHULVWLFă�WULVRPLHL�����'H�DVHPHQHD��SUH]HQĠD�PDOIRUPDĠLLORU�YLVFHUDOH�PHQĠLonate SRDWH�GXFH�XQHRUL�OD�FRQIX]LD�FX�DVRFLDĠLD�&+$5*(��YH]L�FDSLWROXO����� $QDOL]D�FLWRJHQHWLFă�VWDELOHúWH�GLDJQRVWLFXO�GHILQLWLY�SULQ�SXQHUHD�vQ�HYLGHQĠă�D�XQHL�WULVRPLL����FRPSOHWH�- RPRJHQă�������VDX�vQ�PR]DLF������VDX�R�WULVRPLH����SDUĠLDOă������

(YROXĠLH�úL�SURJQRVWLF��6SHUDQĠD�GH�YLDĠă�HVWH�IRDUWH�PLFă��DSUR[LPDWLY�����GLQWUH�FRSLL�PXULQG�vQ�SULPHOH���OXQL�GH�YLDĠă�GDWRULWă�PDOIRUPDĠLLORU�YLVFHUDOH�JUDYH��'RDU����VXSUDYLHĠXLHVF�GXSă�YkUVWD�GH���DQ��GDU�SUH]LQWă�R�vQWkU]LHUH�VHYHUă�vQ�GH]Yoltarea psihomotorie. (WLRORJLH�úL�SDWRJHQLH��6LQGURPXO�(GZDUV�HVWH�SURGXV�GH�WULVRPLD�����ÌQ�WULVRPLLOH�FRPSOHWH�FURPRVRPXO�DGLĠLRQDO�UH]XOWă�– în marea majoritate a cazurilor (95%) – prin QHGLVMXQFĠLH�PDWHUQă��IUHFYHQĠD�WULVRPLHL����SULQ�QHGLVMXQFĠLH�FUHúWH�R�GDWă�FX�FUHúWHUHD�YkUVWHL�PDWHUQH��GDU�VSUH�GHRVHELUH�GH�WULVRPLD�����SHVWH�����GLQWUH�HURULOH�GH�GLVWULEXĠLH�VH�SURGXF�în meioza II. Nu s-a ORFDOL]DW�vQFă�R�UHJLXQH�FULWLFă�SH�FURPRVRPXO����FDUH�Vă�ILH�FRUHODWă�FX�IHQRWLSXO�VLQGURPXOXL�(GZDUGV�FODVLF�GDU��IRDUWH�SUobabil DFHDVWD�HVWH�ORFDOL]DWă�SH���T��7ULVRPLLOH�SDUĠLDOH�UH]XOWă�GDWRULWă�XQHL�WUDQVORFDĠLL�VDX�LQYHUVLL��FDUH�GH�RELFHL�HVWH�PRúWHQLWă�GH�OD�XQXO�GLQ�SăULQĠL� 6IDW�JHQHWLF��6H�HVWLPHD]ă�Fă�ULVFXO�GH�UHFXUHQĠă�GXSă�QDúWHUHD�XQXL�FRSLO�FX�WULVRPLH����FRPSOHWă�HVWH�GH��-2%. În WULVRPLLOH�SDUĠLDOH�ULVFXO�GHSLQGH�GH�SUH]HQĠD�VDX�DEVHQĠD��XQHL�WUDQVORFDĠLL�OD�SăULQĠL��'HSLVWDUHD�SUHQDWDOă�D�WULVRPLHL����HVWH�SRVLELOă�vQ�����GLQ�FD]XUL�SH�ED]D�HFRJUDILHL�IHWDOH��vQWkU]LHUH�vQ�FUHúWHUHD�LQWUDXWHULQă��FKLúWL�DL�SOH[XULORU�FRURLGH��PăUirea FLVWHUQHL�PDJQD��SUH]HQĠD�XQHL�PDOIRUPDĠLL�PDMRUH��úL�D�WULSOXOXL test (YDORUL�VFă]XWH�DOH�$)3��K&*�úL�X(�); confirmarea se face vQVă�QXPDL�SULQ�HIHFWXDUHD�DQDOL]HL�FURPRVRPLFH�D�FHOXOHORU�IHWDOH�

1.3 SINDROMUL PATAU SAU TRISOMIA 13.

,QFLGHQĠă��6LQGURPXO�3DWDX��VDX�WULVRPLD����DUH�R�LQFLGHQĠă�GH�DSUR[LPDWLY���������-2������GH�QDúWHUL��:\ONLH�HW�DO�������

29 3HQWUX�XQ�QHRQDWRORJ�IăUă�H[SHULHQĠă�vQ�GLVPRUIRORJLH�HVWH�XWLOă�IRORVLUHD�VFRUXOXL�GH�GLDJQRVWLF�SURSXV�GH�0DULRQ�HW�DO�����8. 23

Simptomatologie. Nou-QăVFXWXO SUH]LQWă�– în cazurile tipice – vQWkU]LHUH�vQ�FUHúWHUH��PLFURFHIDOLH�FX�VXWXUL�ODUJ�GHVFKLVH��DSOD]LH�FXWDQDWă�vQ�UHJLXQHD�YHUWH[XOXL�VDX�RFFLSXWXOXL��IUXQWH�WHúLWă��PLFURIWDOPLH��DQRIWDOPLH��FRORERP�LULDQ���GHVSLFăWXUL�RURIDFLDOH��XUHFKL�PDOIRUPDWH��SXPQXO�VWUkQV�FX�GHJHWHOH�vQFăOHFDWH��SROLGDFWLOLH�SRVWD[LDOă�OD�PkLQL�úL�VDX�SLFLRDUH��$SURDSe FRQVWDQW�VH�vQWkOQHVF�PDOIRUPDĠLL�DOH�61&��DUKLQHQFHIDOLH�VDX�KRORSURVHQFHIDOLH���DOH�FRUGXOXL�������úL�VLVWHPXOXL�XURJHQLWDO� 'LDJQRVWLFXO�FOLQLF�HVWH�VXJHUDW�GH�WULDGD�FDUDFWHULVWLFă��GHVSLFăWXUă�ODELR-SDODWLQă, PLFURIWDOPLH�DQRIWDOPLH�úL�SROLGDFWLOLH�SRVWD[LDOă – REVHUYDWă�OD�DSUR[LPDWLY�����GLQWUH�SDFLHQĠL��$EVHQĠD�ORU�SDUĠLDOă�IDFH�GLDJQRVWLFXO PDL�GLILFLO�GHúL�VXQW�úL�DOWH�semne care pot evoca trisomia 13 (figura 10.3)�GH�H[HPSOX��SURHPLQHQĠD�UăGăFLQLL�úL�YkUIXOXL�QDVXOXL���RULFH�FRSLO�FX�VHPQH�GH�KRORSURVHQFHIDOLH�WUHEXLH�WHVWDW�FLWRJHQHWLF�SHQWUX�WULVRPLH�����([DPLQDUHD�SRVWPRUWHP�HYLGHQĠLD]ă PDOIRUPDĠLL�FDUDFWHULVWLFH��holoprosencefalia30��GLVSOD]LD�FKLVWLFă�UHQDOă�úL�SDQFUHDWLFă�

$QDOL]D�FLWRJHQHWLFă�HVWH�GHFLVLYă�SHQWUX�GLDJQRVWLF� vQ�FLUFD�����GLQ�FD]XUL�WULVRPLD����HVWH�FRPSOHWă��OLEHUă�úL�RPRJHQă��PR]DLFXULOH�VXQW�IRDUWH�UDUH��vQ�VFKLPE�vQ�FLUFD�����GH�FD]XUL�DX�IRVW�LGHQWLILFDWH�WULVRPLL�FRPSOHWH�VDX�SDUĠLDOH�SURGXVH�SULQ�WUDQVORFDĠLL�QHHFKLOLEUDWH��GH�RELFHL�W���T���T��VDX�W���T���T���GLQ�FDUH�MXPăWDWH�VXQW�PRúWHQLWH�GH�OD�XQXO�GLQWUH�SăULQĠL��Necesitatea unor decizii urgente de managemeQW�D�PDOIRUPDĠLLORU�FDUGLDFH�OD�QRX�QăVFXĠL�LPSOLFă�XQ�GLDJQRVWLF�FLWRJHQHWLF�LPHGLDW���vQ�DFHVWH�FD]XUL�VDX�SHQWUX�VWDELOLUHD�GLDJQRVWLFXOXL�SRVWPRUWHP�VH�SRDWH�UHFXUJH�OD�DQDOL]D�),6+�LQWHUID]LFă�FX�VRnde pentru cromosomul 13.

(YROXĠLH�úL�SURJQRVWLF��0DOIRUPDĠLLOH�YLVFHUDOH�PXOWLSOH�úL�VHYHUH GHWHUPLQă�GHFHVXO�D�SHVWH�����GLQ�FD]XUL�vQ�SULPD�OXQă�GH�YLDĠă��'RDU����GLQ�EROQDYL�VXSUDYLHĠXLHVF�SHVWH�XQ�DQ��DYkQG�XQ�UHWDUG�PHQWDO�VHYHU��6XSUDYLHĠXLUHD�HVWH�PDL�PDUH�vQ�WULVRmiile SDUĠLDOH���T� (WLRORJLH�úL�SDtogenie. Sindromul Patau este produs de trisomia 13. În cazurile produse prin QHGLVMXQFĠLH, cromosomul 13 suplimentar este de origine PDWHUQă úL�HURDUHD�GH�GLVMXQFĠLH�V-a produs în meioza I �5RELQVRQ�HW�DO���������ÌQFHUFăULOH�GH�D�LGHQWLILFD�JHQHOH�UăVSXQ]ăWRDUH�GH�VHPQHOH�FDUGLQDOH�DOH�WULVRPLHL����VXQW�vQFă�SXĠLQH�úL�QHFRQFOXGHQWH� Sfat genetic. ÌQ�FD]XO�WULVRPLLORU�OLEHUH��ULVFXO�GH�UHFXUHQĠă�DO�DIHFĠLXQLL�HVWH�IRDUWH�PLF��PDL�PLF�GH�����vQ�WLPS�FH�SHQWUX�WUDQVORFDĠLLOH�5REHUWVRQLHQH�PRúWHQLWH�GH�OD�XQ�SăULQWH�ULVFXO�SRDWH�IL�GH�DSUR[LPDWLY�����SHQWUX�WUDQVORFDĠLL�vQWUH�FURPRVRPL�'�QHRPRORJL�VDX�FKLDU������vQ�WUDQVORFDĠLLOH�vQWUH�FURPRVRPLL�����'LDJQRVWLFXO�SUHQDWDO�GH�WULVRPLH����HVWH�VXJHUDW�GH�LGHQWLILcarea vQWkU]LHULL�GH�FUHúWHUH�úL�SUH]HQĠD�PDOIRUPDĠLLORU�FHUHEUDOH��KRORSURVHQFHIDOLD��úL�YLVFHUDOH�PHQĠLRQDWH��WULSOXO�WHVW�QX�HVWH�HGLILFDWRU�VL�QXPDL�DQDOL]D�FLWRJHQHWLFă�D�FHOXOHORU�IHWDOH�YD�WUDQúD�GLDJQRVWLFXO�

���6,1'52$0(/(�&8�'(/(ğ,,�$872620$/( 6WXGLLOH�FLWRJHQHWLFH�FODVLFH�úL��PDL�DOHV��FHle care folosesc marcajul în benzi al cromosomilor metafazici au dus la LGHQWLILFDUHD�D�QXPHURDVH�GHOHĠLL�FURPRVRPLFH��'DU��vQ�PDMRULWDWHD�FD]XULORU��QXPăUXO�GH�SDFLHQĠL�GHSLVWDĠL�HUD�PLF�úL�DFHVW�lucru a vPSLHGLFDW�GHILQLUHD�XQRU�VLQGURDPH�DVRFLDWH��GHOHĠiilor. Intr-XQ�QXPăU�UHGXV�GH�FD]XUL�D�IRVW��WRWXVL��SRVLELOă�VWDELOLUHD�XQHL�FRUHODĠLL�JHQRWLS�– IHQRWLS�FHHD�FH�D�SHUPLV�GHILQLUHD�FkWRUYD�VLQGURDPH�SURGXVH�GH�GHOHĠLL�FURPRVRPLFH��,QFLGHQĠD�ORU�JOREDOă�HVWH�UHGXVă��FLUFD��������GH�QDúWHUL��&HO�PDL�IUHFYHQW�VXQW�vQWkOQLWH�vQ�SUDFWLFă�VLQGURPXO�FUL�GX�FKDW���Sí��úL�VLQGURPXO�:ROI-+LUVFKKRUQ����Sí���ÌQDLQWH�GH�D�SUH]HQWD�VXFFLQW�FHOH�GRXă�VLQGURDPH�YRP�SUHFL]D�Fă�GHOHĠLLOH�SRW�DSăUHD�de novo sau ca rezultat al XQHL�WUDQVORFDĠLL�QHHFKLOLEUDWH��GH�DFHHD�HVWH�QHFHVDUă�WRWGHDXQD�HIHFWXDUHD�FDULRWLSXOXL�OD�SăULQĠL��SHQWUX�D�GHVFRSHUL�GDFă�XQXO�GLQWUH�HVWH�VDX�QX�SXUWăWRU��VLWXDĠLH�vQ�FDUH�ULVFXO�GH�UHFXUHQĠă�HVWH�FUHVFXW��

2.1. SINDROMUL CRI DU CHAT

Sindromul “cri du chat” este produs printr-R�GHOHĠLH�LPSRUWDQWă�D�EUDĠXOXL�VFXUW�DO�cromosomului 5. Denumirea acestui VLQGURP��GHULYă�GLQ�SDUWLFXODULWDWHD�SOkQVXOXL�FRSLLORU�DIHFWDĠL��DVHPăQăWRU�FX�PLHXQDWXO�GH�SLVLFă��GDWRUDW�XQHL�DQRPDOLL�D�laringelui). ,QFLGHQĠD�EROLL�HVWH�GH�FLUFD���������GH�QDúWHUL��GDU�SUHYDOHQĠD�VLQGURPXOXL�OD�FRSLL�FX�UHWDUG�PHQWDO�VHYHU�HVWH�GH�aproximativ 1%. Simptomatologie. La sugar, semnele clinice sunt: plâns caracteristic, dismorfie cranio-IDFLDOă�FX�PLFURFHIDOLH, facies rotund, hipertelorism, epicantus, urechi jos înserate, uneori cX�WXEHUFXOL�SUHDXULFXODUL��PLFURJQDĠLH�(figura 10.4). Particularitatea plânsului începe Vă�VH�DWHQXH]H�GXSă�YkUVWD�GH���DQL��vQJUHXQkQG�GLDJQRVWLFXO�FOLQLF��PDL�DOHV�SHQWUX�Fă�XQHOH�GLQ�VHPQHOH�PHQĠLRQDWH�VH�PRGLILFă�VDX�VH�DWHQXHD]ă��3DFLHQĠLL�SUH]LQWă�XQ UHWDUG�PHQWDO�VHYHU�úL�DX�GHVHRUL�PDOIRUPDĠLL�FDUGLDFH�úL�JHQLWR-urinare. $QDOL]D�FLWRJHQHWLFă�UHOHYă�GHOHĠLD��S- GDU�PăULPHD�VHJPHQWXOXL�GHOHWDW�YDULD]ă�OD�GLIHULĠL�SDFLHQĠL� (YROXĠLH�úL�SURJQRVWLF��$IHFĠLXQHD�HYROXHD]ă�FX�XQ�UHWDUG�PHQWDO�VHYHU�LDU�VXSUDYLHĠXLUHD�HVWH�YDULDELOă (WLRORJLH�úL�SDWRJHQLH��6LQGURPXO�FUL�GX�FKDW�HVWH�SURGXV�GH�PRQRVRPLD�SDUĠLDOă��S- ILLQG�vQWRWGHDXQD�LPSOLFDWă�EDQGD��S����*HQHOH�LPSOLFDWH�vQ�IHQRWLSXO�VLQGURPXOXL�QX�DX�IRVW�LGHQWLILFDWH��VH�úWLH�GRDU�Fă�PDMRULWDWHD�VHPQHORU fenotipice sunt GHWHUPLQDWH�GH�KDSORLQVXILFLHQĠD�XQRU�JHQH�GLQ�VXEEDQGD��S�����LDU�KLSRSOD]LD�ODULQJLDQă�FH�SURGXFH�SOkQVXO�FDUDFWHULVWLF�DSDre FkQG�GHOHĠLD�LQWHUHVHD]ă�VXEEDQGD��S������0DMRULWDWHD�FD]XULORU�VXQW�sporadice��GRDU�FLUFD�����VXQW�XUPDúLL�XQXL�SăULQWH�SXUWăWRU�DO�XQHL�WUDQVORFDĠLL�HFKLOLEUDWH� 6IDW�JHQHWLF��5LVFXO�HVWH�PLQLP�SHQWUX�GHOHĠLLOH�de novo úL�YDULDELO�DWXQFL�FkQG�XQXO�GLQ�SăULQĠL�DUH�R�WUDQVORFDĠLH��YH]L�capitolul 9.C.3).

2.2. SINDROMUL WOLF-HIRSCHHORN

30 Holoprosencefalia este un defect al liniei mediane, afectând creierul (o singură emisferă cerebrală, ventricul cerebral unic, agenezie de corp calos), VWUXFWXULOH�RFXODUH��PLFURIWDOPLH��DQRIWDOPLH��úL�PXJXUHOH�IURQWDO��PRGLILFăULOH fronto-faciale pot fi severe FX� FLFORSLH� úL� proboscis VDX� KLSRWHORULVP� úL� GHVSLFăWXUă� YHOR-SDODWLQă� PHGLDQă� VDX� PLQRUH� FX� KLSRWHORULVP� úL� LQFLVLY� VXSHULRU�central unic). 24

Sindromul Wolf-Hirschhorn, determinat de monosomia 4p-��HVWH�R�DQRPDOLH�UDUă��FX�R�LQFLGHQĠă�GH�FLUFD����������GH�QDúWHUL�� 6LPSWRPDWRORJLH��%RDOD�HVWH�FDUDFWHUL]DWă�SULQ��KLSRWURILH�VWDWXUR-SRQGHUDOă�PDUFDWă��PLFURFHIDOLH�úL�R�GLVPRUILH�IDFLDOă�FDUDFWHULVWLFă��KLSHUWHORULVPXO��DUFDGHOH�VSUkQFHQDUH�SURHPLQHQWH�úL�UăGăFLQD�QD]DOă�OăUJLWă�GDX�IHĠHL�XQ�DVSHFW�FRPSDUDW�FX�R�“FDVFă�GH�OXSWăWRU�JUHF”) (figura 10.5)��IUHFYHQW�XUHFKLOH�VXQW�DQRUPDOH��MRV�LQVHUDWH��KHOL[�SODW��VLQXV�SUHDXULFXODU��úL�H[LVWă�PDOIRUPDĠLL�FDUGLDFH�JUDYH; UHWDUGXO�PHQWDO�HVWH�FRQVWDQW�úL�VHYHU. $QDOL]D�FLWRJHQHWLFă��'HOHĠLD��S- SRDWH�IL�LGHQWLILFDWă�XQHRUL�SH�FURPRVRPLL�PHWDID]LFL�GDU�VXVSLFLXQHD�FOLQLFă�LPSOLFă�IRORVLUHD�WHKQLFLORU�GH�vQDOWă�UH]ROXĠLH�úL�),6+��5HJLXQHD�FULWLFă��D�FăUHL�GHOHĠLH�SURGXFH�IHQRWLSXO�FDUDFWHULVWLF�HVWH�ORFDOL]DWă�vQ�regiunea 4p16. 6H�UHFRPDQGă�vQWRWGHDXQD�DQDOL]D�FURPRVRPLFă�D�SăULQĠLORU (YROXĠLH�úL�SURJQRVWLF 6SHUDQĠD�GH�YLDĠă�HVWH�OLPLWDWă������GLQ�FD]XUL�PXULQG�vQ�SULPXO�DQ�GH�YLDĠă� Sfat genetic. Numeroase cazuri sunt spoUDGLFH�úL�ULVFXO�GH�UHFXUHQĠă�HVWH�IRDUWH�PLF��GDU�XQHRUL�GHOHĠLD�HVWH�FRQVHFLQĠD�VHJUHJăULL�XQHL�WUDQVORFDĠLL�SDUHQWDOH�úL�ULVFXO�GH�UHFXUHQĠă FUHúWH�

���6,1'52$0(/(�&8�0,&52'(/(ğ,,�ù,�0,&52'83/,&$ğ,,�&5202620,&( Mai multe sindroame dismorfice, care au IRVW�LQLĠLDO�GHILQLWH�FOLQLF��V-DX�GRYHGLW�D�IL�SURGXVH�GH�R�GHOHĠLH�FURPRVRPLFă�PLFă��VXE��0E���GLILFLO�VDX�LPSRVLELO�GH�REVHUYDW�SULQ�WHKQLFLOH�FRQYHQĠLRQDOH��DFHVWH�GHOHĠLL�VXEPLFURVFRSLFH�VDX�PLFURGHOHĠii pot IL�HYLGHQĠLDWH�ILH�SULQ�WHKQLFLOH�GH�DQDOL]ă�FURPRVRPLFă�GH�vQDOWă�UH]ROXĠLH�ILH�SULQ�),6+��IRORVLQG�VRQGH�VSHFLILFH�VHJHPHQWXOXL�respectiv31 (vezi capitolul 2.D.3). Sindrom Tip rearanjament

Localizare Gene identificate

Fenotip

Williams del(7)(q11.23) (ODVWLQ�VLQWD[LQ�LIMK, RFC2, WSCR1

DismoUILH�IDFLDOă�FDUDFWHULVWLFă��VWHQR]ă�DRUWLFă�VXSUDYDOYXODUă��OD[LWDWH�DUWLFXODUă��KLSHUFDOFHPLH��KLSRVWDWXUă��UHWDUG�PHQWDO��SURILO�FRJQLWLY�úL�SVLKLF�SDUWLFXODU

Langer-Giedion (triho-rino-falangian)

del(8)(q23-q24) EIF3S3, RAD21, osteoprotegerina,

Facies SDUWLFXODU��SăU�UDU��QDV�EXOERV��DQRPDOLL�DOH�GHJHWH�exostoze cartilaginoase, retard mental

WAGR del(11)(p13) PAX6, WT1 7XPRUă�:LOPV��$QLULGLH��PDOIRUPDĠLL�*HQLWR-urinare, Retard mental

Beckwith-Wiedemann dup(11)(p15.5) (5% cazuri)1

IGF2, CDKN1C Dismorfie cranio-IDFLDO�PDFURJORVLH��GHIHFWH�DOH�SHUHWHOXL�abdominal, macrosomie, visceromegalie

Prader Willi del(15)(q11-q13) cromosom patern (75% cazuri)1

SNRPN, necdina +LSRWRQLH�QHRQDWDOă��GLVPRUILH�FUDQLR-IDFLDOă�FDUDFWHULVWLFă��obezitate, hipogonadism, UHWDUG�PHQWDO�PRGHUDW��WXOEXUăUL�GH�comportament.

Angelman del(15)(q11-q13) cromosom matern (70% cazuri)1

UBE3A 0LFURFHIDOLH��UHWDUG�PHQWDO�VHYHU��WXOEXUăUL�GH�PHUV�úL�HFKLOLEUX��DEVHQĠD�YRUELULL��WXOEXUăUL�FDUDFWHULVWLFH�GH�comportament.

Rubinstein-Taybi del(16)(p13.3) (20% cazuri)1

CREBBP Dismorfie cranio-IDFLDOă�SDUWLFXODUă��SROLFH�úL�KDOXFH�OăĠLW��PDOIRUPDĠLL�FDUGLR-vasculare, retard mental

Miller-Diecker del(17)(p13.3) LIS1, ABR, 14-3-3-epsilon, CRK, PRP8 MYO1C, SKIP, PITPNA, SCARF1, RILP,SERPINF1

RHWDUG�PLQWDO�VHYHU�úL�WXOEXUăUL�QHXURORJLFH�– secundare OLVHQFHIDOLHL��GLPRUILH�IDFLDOă�FDUDFWHULVWLFă

Smith-Magenis del(17)(p11.2) RAI1, NT5M, SGN3 5HWDUG�PHQWDO�VHYHU��WXOEXUăUL�GH�VRPQ��FRPSRUWDPHQW�DXWRPXWLODQW��GLVPRUILH�IDFLDOă

Alagille del(20)(p11-p12) JAG1 'LVPRUILH�IDFLDOă��VWHQR]ă�DUWHUă�SXOPRQDUă�DQRPDOLL�YHUWHEUDOH��FROHVWD]ă�KHSDWLFă

Velo-cardio-facial /DiGeorge

del(22)(q11.2) (85% cazuri) del(10)(p13) (15% cazuri)

TUPLE1, GSCL +,5$��ú�D

'HVSLFăWXUă�VDX�LQVXILFLHQĠă�YHOR-SDODWLQă����PDOIRUPDĠLL�cardiace cono-WUXQFDOH��GLVPRUILH�IDFLDOă�FDUDFWHULVWLFă��KLSRSOD]LH�WLPXV�úL�SDUDWLURLGH��KLSRFDOFHPLH�

Cat-eye dup(22)(q11) CECR7 Colobom irian si/sau coroidian, despicatura palatina, malformatii cardiace, renale, hernii, atrezie anala.

DMD, CGD, RP, KLSRSOD]LH�VXSUDUHQDOă�

del(X)(q21) DMD, CGD,RP 'LVWURILH�PXVFXODUă�'XFKHQQH��ERDOă�JUDQXORPDWRDVă�FURQLFă��&*'���UHWLQLWă�SLJPHQWDUă��53���LQVXILFLHQĠă�VXSUDUHQDOLDQă

Azoospermie del(Y)(q11.23) AZFa, AZFb, AZFc infertilitate Studiile moleculare au aUăWDW�Fă�SXQFWHOH�GH�UXSWXUă�VXQW�ORFDOL]DWH�vQ�VHFYHQĠH�UHSHWLWLYH�VFXUWH��LGHQWLFH��FDUH�IODQFKHD]ă�

�vQFDGUHD]ă��XQ�DQXPLW�VHJPHQW�FURPRVRPLF��3ULQ�vPSHUHFKHUHD�JUHúLWă�D�DFHVWRU�VHFYHQĠH�GLQ�FURPRVRPLL�RPRORJL�úL�FURVVLQJ�over inegal („recombinare omoloJă�QHDOHOLFă´���YH]L�ILJXUD�������UH]XOWă�GHOHĠLL�VDX�GXSOLFDĠLL�DOH�VHJPHQWXOXL�UHVSHFWLY��ÄDQHXVRPLH�VHJPHQWDUă´���$úD�FXP�DP�DUăWDW�vQ�FDSLWROXO���%������UHFRPELQDUHD�RPRORJă�QHDOHOLFă�VDX�LQHJDOă�HVWH�FRQVHFLQĠD�DUKLWHFWXULL�VSHFLDOH�D�JHQRPXOXL�úL�UHSUH]LQWă�XQ�PHFDQLVP�PDMRU�GH�SURGXFHUH�D�XQRU�ÄEROL�JHQRPLFH´��SULQ�SLHUGHUHD�VDX�GXSOLFDĠLD�XQHL��XQRU�JHQH���YH]L�FDVHWD�������vQ�IXQFĠLH�GH�PăULPHD�VHJHPHQWXOXL�LPSOLFDW�UH]XOWă�EROL�PHQGHOLHQH��VLQGURDPH cu PLFURGHOHĠLL�VDX�PLFURGXSOLFDĠLL��DEHUDĠLL�FUomosomice mari.

)HQRWLSXO�VLQGURDPHORU�FX�PLFURGHOHĠLH�HVWH�GH�RELFHL�GHWHUPLQDW�GH�KDSORLQVXILFLHQĠD�PDL�PXOWRU�JHQH�vQYHFLQDWH��situate în segementul deletat (figura 10.6)��GH�DFHHD�SHQWUX�GHQXPLUHD�DFHVWRU�VLQGURDPH�VH�PDL�XWLOL]HD]ă�WHUPHQXO�GH�VLQGURDme DOH�JHQHORU�FRQWLJXH��6SUH�H[HPSOX�vQ�VLQGURPXO�:LOOLDPV�vQ�VHJPHQWXO�GHOHWDW�GLQ�UHJLXQHD��T������VH�DIOă�JHQD�HODVWLQHL��(/N), gena pentru factorul de replicare 2 (RFC2), gena pentru kinaza tip 1 cu domeniu LIM (LIMK1) – D�FăURU�KDSORLQVXILFLHQĠă�deteUPLQă�PRGLILFăULOH�ĠHVXWXOXL�FRQMXQFWLY��LQFOXVLY�DQRPDOLLOH�YDVFXODUH���WXOEXUăULOH�GH�FRQGXFHUH�QHUYRDVă�úL�SURILOXO�SVLKR-comportamental – FDUDFWHULVWLFH�VLQGURPXOXL�:LOOLDPV��8Q�DOW�H[HPSOX��FH�GHPRQVWUHD]ă�SRDWH�PDL�FODU��LGHHD�GH�IHQRWLS�

31 ([DPHQXO�FOLQLF�HVWH�HVHQĠLDO pentru alegerHD�VRQGHL�GHRDUHFH�WUHEXLH�Vă�RULHQWH]H�GLDJQRVWLFXO�VSUH�XQ�DQXPLW�VLQGURP� 25

„agregat”, eVWH�PLFURGHOHĠLD�;S���FH�DIHFWHD]ă�JHQHOH�'0'��&*'��53�FDUH�ILHFDUH�SURGXFH�SULQ�PXWDĠLH�R�ERDOă�PRQRJHQLFă�GLVWLQFWă�

ÌQ�UHJLXQHD�FURPRVRPLFă�LPSOLFDWă�vQ�VLQGURDPHOH�JHQHORU�FRQWLJXH�V-au identificat trei categorii de gene: � gene dominante��SULQ�DEVHQĠD�JHQHL�VH�SURGXFH�R�KDSORLQVXILFLHQĠă�FH�GHWHUPLQă�XQ�DQXPLW�FDUDFWHU�IHQRWLSLF��GH�H[HPSOX��

DEVHQĠD�JHQHL�GRPLQDQWH�3$;��vQ�PLFURGHOHĠLD���S���SURGXFH�DQLULGLH��SDUWLFXODULWDWH�FOLQLFă�D�VLQGURPXOXL�:$*5� � gene recesive��DSDULĠLD�FDUDFWHUXOXL�IHQRWLSLF�HVWH�SRVLELOă�GRDU�vQ�VLWXDĠLD�vQ�FDUH�DEVHQĠD�JHQHL�VH�DVRFLD]ă�FX�R�PXWDĠLH�

LQDFWLYDWRDUH�D�DOHOHL�ORFDOL]DWă�SH�FURPRVRPXO�QRUPDO��GH�H[HPSOX��DEVHQĠD�JHQHL�UHFHVLYH�:7���VHFXQGDUă�XQHL�PLFURGHOHĠLL���S����GHWHUPLQă�DSDULĠLD�XQHL�WXPRUL�:LOPV�úL�D�XQRU�DQRPDOLL�JHQLWDOH��GRDU�vQ�VLWXDĠLD�vQ�FDUH�SH�FHOăODOW�FURPRVRP����JHQD�:7��D�VXIHULW�R�PXWDĠLH�

� JHQH�FX�DPSUHQWDUH�JHQHWLFă��IHQRWLSXO�HVWH�VHFXQGDU�LQVWDOăULL�XQHL�QXOLVRPLL�IXQFĠLRQDOH�VDX�D�XQHL�GLVRPLL�IXQFĠLRQDOH�D�XQHL�JHQH�FH�SUH]LQWă�DPSUHQWDUH�JHQHWLFă�úL�D�FăUXL�VWDWXV�IXQFĠLRQDO�QRUPDO�HVWH�PRQRDOHOLF��GH�H[HPSOX��vQ�VLQGURDPHOH�Prader-:LOOL�úL�$QJHODPDQ�SULQ�GLVRPLH�XQLSDUHQWDOă���T��-T����IHQRWLSXO�HVWH�FRQVHFLQĠD�XQHL�QXOLVRPLLL�IXQFĠLRQDOH�PDWHUQă��UHVSHFWLY�SDWHUQă��SH�GH�DOWă�SDUWH��vQ�VLQGURPul Beckwith-:LHGHPDQQ��SULQ�GLVRPLH�XQLSDUHQWDOă���S���SDWHUQă��JHQD�,*)��DUH�DFWLYLWDWH�ELDOHOLFă��FHHD�FH�FRQGXFH�OD�FUHúWHUHD�H[DJHUDWă��FDUDFWHULVWLFă�VLQGURPXOXL�

B. SINDROAMELE CU ANOMALII ALE CROMOSOMILOR SEXUALI

Anomaliile cromosomilor sexuali – QXPHULFH�úL�VWUXFWXUDOH��RPRJHQH�VDX�vQ�PR]DLF�– sunt printre cele mai frecvente boli genetice, având R�LQFLGHQĠă�JOREDOă�GH���OD�����QRX-QăVFXĠL�GH�VH[�PDVFXOLQ�úL���OD�����QRX�QăVFXĠL�GH�VH[�IHPLQLQ��5RELQVRQ�HW�DO���������)HQRWLSXULOH�DVRFLDWH�FX�acHVWH�DQRPDOLL�FURPRVRPLFH�VXQW��vQ�JHQHUDO��PDL�SXĠLQ�VHYHUH�FRPSDUDWLY�FX�VLQGURDPHOH�DXWRVRPDOH�GDWRULWă�LQDFWLYăULL�FURPRVRPXOXL�;�úL�QXPăUXOXL�PLF�GH�JHQH�GH�SH�FURPRVRPXO�<��IHQRPHQH�FH�UHGXF�FRQVHFLQĠHOH�GH]HFKLOLEUXOXL�FURPRVRPLF��'H]YROWDUHD�IL]LFă úL�SVLKLFă�VXQW�GH�RELFHL�UHODWLY�SXĠLQ�DIHFWDWH��vQ�VFKLPE�DQRPDOLLOH�FURPRVRPLORU�VH[XDOL�VH�DVRFLD]ă�IUHFYHQW�FX�GLVJHQH]LL�JRQDGLFH�úL�VWHULlitate. De aceea, orice vQWkU]LHUH�vQ�GH]YROWDUHD�SXEHUWDUă��DPHQRUHHD�SULPDUă�VDX�VHFXQGDUă�SUHFRFH��D]RRVSHUPLD�úL�VWHULOLWDWHD�UHSUH]LQWă�LQGLFDĠLL�FOLQLFH�LPSRUWDQWH�pentru studiul cromosomilor.

1. SINDROMUL TURNER

Sindromul Turner este determinat de monosomia X��FRPSOHWă�VDX�SDUĠLDOă��VLQJXUD�PRQRVRPLH�YLDELOă�OD�VSHFLD�XPDQă�� ,QFLGHQĠă��%RDOD�DIHFWHD]ă�DSURximativ 1/2500-1/3000 din nou-QăVFXĠLL�GH�VH[�IHPLQLQ�GDU�VH�HVWLPHD]ă�Fă�DSUR[LPDWLY����GLQ�FRQFHSĠLLOH�UHFXQRVFXWH�FOLQLF�SUH]LQWă�PRQRVRPLH�;��FDUH�HVWH�OHWDOă�vQ�����GLQ�FD]XUL��HPEULRQLL�ILLQG�DYRUWDĠL��6\EHUW����1)(vezi etiopatogenia). SimptomatologLH��(VWH�LPSRUWDQW�GH�VXEOLQLDW�Fă�VLQGURPXO�7XUQHU�WLSLF�SRDWH�IL�LGHQWLILFDW��vQ�FLUFD�����GLQ�FD]XUL��OD�QDúWHUH�VDX�înainte de pubertate, deci la vârste ce permit aplicarea unei terapii hormonale de supleere, destul de eficace. O treime din cazuri pot fi diagnosticate clinic în SHULRDGD�QHRQDWDOă prin XUPăWRDUHOH�VHPQH�HYRFDWRDUH��FRSLO�GH�VH[�IHPLQLQ��FX�WDOLH�úL�JUHXWDWH�PDL�PLFă�SHQWUX�R�YkUVWă�JHVWDĠLRQDOă�QRUPDOă��OLPIHGHP��GXU��QHGXUHURV��WUDQ]LWRULX��SH�IDĠD�GRUVDOă�D�mâinilor úL�SLFLRDUHORU32, gkW�VFXUW��FX�H[FHV�GH�SLHOH�SH�FHDIă�úL�VDX�pterygium coli �SOLX�FXWDQDW�SH�IHĠHOH�ODWHUDOH�DOH�JkWXOXL��úL�GLVWDQĠă�LQWHUPDPHORQDUă�PDUH��figura 10.8). 2�DOWă�WUHLPH�GLQ�FD]XUL�SRW�IL�LGHQWLILFDWH�prepubertar��VXVSLFLXQHD�FOLQLFă�VH�ED]HD]ă�SH�H[LVWHQĠD�unui întârzieri majore de FUHúWHUH��FH�GHYLQH�HYLGHQWă�GXSă��-��DQL�úL�DWLQJH�-��'6�IDĠă�GH�PHGLH�OD����DQL��/D�DFHDVWD�VH�SRDWH�DGăXJD�JkW�VFXUW��SDOPDW��FX�LQVHUĠLD�MRDVă�D�SăUXOXL�SH�FHDIă�úL�WRUDFH�ODW�FX�PDPHORDQH�vQGHSăUWDWH� Postpubertar diagnosticul clinic este sugerat de triada��KLSRVWDWXUă��DPHQRUHH�SULPDUă���FDUDFWHUH�VH[XDOH�VHFXQGDUH�IHPLQLQH�deficitare. � Hipostatura este semnul cardinal al sindromului Turner. ÌQ�DEVHQĠD�WUDWDPHQWXOXL�FX�KRUPRQ�GH�FUHúWHUH��vQăOĠLPHD�SDFLHQWHORU�FX�

sindrom TurQHU�VH�vQFDGUHD]ă�vQ�LQWHUYDOXO�130-150 cm��GHSHQGHQW�GH�WDOLD�SăULQĠLORU��FX�XQ�WUDWDPHQW�FX�67+��LQLĠLDW�vQDLQWH�GH����DQL��VH�FkúWLJă��-���FP�OD�WDOLD�ILQDOă��

� $PHQRUHHD�SULPDUă��DEVHQĠD�FLFOXULORU�PHQVWUXDOH��úL�GHILFLWXO�GH�VH[XDOL]DUH�VXQW�VHFXQGDUH�GLVJHQH]LHL�JRQDGLFH��SURGXVă�SULQ�GHJHQHUHVFHQĠD�RYRFLWHORU��FH�vQFHSH�vQ�YLDĠD�IHWDOă��úL�vQORFXLUHD�RYDUHORU�FX�EDQGHOHWH�ILEURDVH��5DUHRUL��GHJHQHUHVFHQĠD�HVWH�LQFRPSOHWă��PDL�DOHV�OD�SHUVRDQH�FX�PRQRVRPLH�;�vQ�PR]DLF���FHHD�FH��FRQGXFH�OD�R�GH]YROWDUH SXEHUWDUă��DSURDSH�QRUPDOă�úL�OD�DSDULĠLD�GH�FLFOXUL�RYXODWRULL�QHUHJXODWH��WRWXúL��úL�OD�DFHVWH�FD]XUL��PHQRSDX]D�HVWH�SUHFRFH��LDU�SUREDELOLWDtea de a DYHD�R�VDUFLQă�HVWH�LQILPă��'HRDUHFH�RYDUHOH�GLVJHQHWLFH�QX�SURGXF�RYXOH��SDFLHQWHOH�FX�VLQGURP�7XUQHU DX�VWHULOLWDWH�SULPDUă�úL�GHILQLWLYă..

� $EVHQĠD�VHFUHĠLHL�KRUPRQLORU�VH[XDOL�IHPLQLQL �HVWURJHQL�úL�SURJHVWHURQ��LQGXFH�DPHQRUHH�SULPDUă��GH]YROWDUH�LQVXILFLHQWă�D�FDUDFWHUHORU�VH[XDOH�VHFXQGDUH�IHPLQLQH��JODQGH�PDPDUH�SXĠLQ�GH]YROWDWH��SLOR]LWDWH�D[LODUă�DEVHQWă��SLOR]LWDWH�SXELDQă�UHGXVă��úL�FUHúWHUHD�)6+�úL�/+��2UJDQHOH�JHQLWDOH�H[WHUQH�DX�DVSHFW�LQIDQWLO��LDU�XWHUXO�HVWH�KLSRSOD]LF��7HUDSLD�GH�VXSOHHUH�FX�HVWUogeni �vQFHSXWă�SUHSXEHUWDU��FRULMHD]ă�GHILFLWXO�GH�VH[XDOL]DUH�IHQRWLSLFă�

În sindromul TurneU�H[LVWă�R�GLVPRUILH�FUDQLR-IDFLDOă�QHFDUDFWHULVWLFă��PDQLIHVWDWă�SULQ��DVSHFW�PDWXU�DO�IHĠHL��IDFLHV�triunghiular, epicantus, fante palpebrale antimongoloide, palat înalt, anomalii dentare, urechi proeminente. Alte semne ce pot fi identificate la pacientele cu sindrom Turner sunt: diametrul biacromial mai mare decât cel bitrohanterian, torace plat („în scut”) FX�GLVWDQĠă�LQWHUPDPHORQDUă�FUHVFXWă��cubitus valgus �D[XO�DQWHEUDĠXOXL�IDFH�XQ�XQJKL�REWX]�GHVFKLV�vQ�DIDUă�FX�D[XO�humerusului), scurtarea metacarpLDQXOXL�,9��XQJKLL�FRQYH[H�KLSRSOD]LFH��SUH]HQĠD�D�QXPHURúL�QHYL�SLJPHQWDUL��ÌQ���-40% din FD]XUL�SRW�IL�LGHQWLILFDWH�PDOIRUPDĠLL�FRQJHQLWDOH�UHQDOH�VDX�FDUGLDFH��FRDUFWDĠLH�GH�DRUWă��SURODSV�GH�YDOYă�PLWUDOă��ELFXVSidie DRUWLFă���'HUPDWRJOLIHOH�VXQW�DQRUPDOH��WULUDGLXV�D[LDO�vQ�SR]LĠLH�GLVWDOă��W¶�VDX�W´��úL�VXPD�FUHVWHORU�GLJLWDOH��6&'��PDL�PDUH�GHFkW�media la sexul feminin. ,QWHOLJHQĠD�HVWH�QRUPDOă�VDX�OD�OLPLWD�LQIHULRDUă�D�QRUPDOXOXL��FX�R�VFăGHUH�vQ�VSHFLDO�D�SHUFHSĠLHL�VSDĠLDOH�úL�D�FDSDFLWăĠLi de

32 5HSUH]LQWă�SHUVLVWHQĠD�XQXL lLPIHGHP�JHQHUDOL]DW�DSăUXW�vQ�YLDĠD�IHWDOă�úL�YL]LELO�XQHRUL�úL�VXE�IRUPă�GH�hygroma colli cysticum - R�DFXPXODUH�GH�OLFKLG�VHURV�vQ�GLODWDĠLL�OLPIDWLFH�DOH�JkWXOXL 26

abstractizare. Pacientele pot avea deficite auditive prin anomalii ale urechii interne. 'LDJQRVWLFXO�FOLQLF�GLIHUHQĠLDO�VH�IDFH�vQ�FRSLOăULH�FX�VLQGURPXO�1RRQDQ��KLSRVWDWXUă��IDFLHV�FDUDFWHULVWLF��JkW�VFXUW��SDOPDt, GHIRUPDĠLL�WRUDFLFH�VWHUQDOH��PDOIRUPDĠLL�FRQJHQLWDOH�GH�FRUG��vQ�VSHFLDO�VWHQR]ă�SXOPRQDUă��FDUGLRPLRSDWLH�KLSHUWURILFă�VDX�'69���OD�SXEHUWDWH�VH�YRU�OXD�vQ�GLVFXĠLH�DOWH�FDX]H�GH�vQWkU]LHUH�SXEHUWDUă� $QDOL]D�FLWRJHQHWLFă�HVWH�GHFLVLYă�SHQWUX�GLDJQRVWLF�� � Testul cromatinei X este negativ în FD]XULOH�FX�PRQRVRPLH�RPRJHQă�úL�SR]LWLY��GDU�FX�YDORUL�UHGXVH��vQ�FD]XO�PRQRVRPLHL�vQ�

PR]DLF�VDX�vQ�PRQRVRPLLOH�SDUĠLDOH�SULQ�DQRPDOLL�VWUXFWXUDOH��ÌQ�SUH]HQĠD�XQRU�LVRFURPRVRPL�;�GH�EUDĠ�VFXUW��D�XQRU�GHOHĠLL�sau cromosomi inelari X dimensiunea corpusculXOXL�%DUU�HVWH�PDL�PLFă��DSUR[LPDWLY����ȝP��GHFkW�YDORDUHD�QRUPDOă��vQ�WLPS�FH�SUH]HQĠD�XQXL�LVRFURPRVRP�;�GH�EUDĠ�OXQJ�VH�DVRFLD]ă�FX�XQ�FRUSXVFXO�%DUU�PDL�PDUH��DSUR[LPDWLY����ȝP���&RQVLGHUăP�Fă�WHVWXO�FURPDWLQHL�;�HVWH�XQ�WHVW�VFUHHQLQJ�VLPSOX�úL�LHIWLQ.

� Examenul cromosomic HVWH�HVHQĠLDO�SHQWUX�VWDELOLUHD�GLDJQRVWLFXOXL�GH�FHUWLWXGLQH��ÌQ�FLUFD���-60% din cazuri cariotipul HYLGHQĠLD]ă�R�PRQRVRPLH�;�RPRJHQă��vQ�����GLQ�FD]XUL�VH�vQWkOQHVF�GLIHUWLWH�WLSXUL�GH�PR]DLFXUL33, ce includ obligatoriu o linie cu mRQRVRPLH�;�WRWDOă�VDX�SDUĠLDOă��FHO�PDL�IUHFYHQW����;����;;�-����FD]XUL���vQ�UHVWXO�FD]XULORU�VH�JăVHVF�DQRPDOLL�GH�VWUXFWXUă�DOH�FURPRVRPXOXL�;��LVRFURPRVRPL�;�GH�EUDĠ�OXQJ�VDX�GH�EUDĠ�VFXUW��GHOHĠLL�;S�VDX�;T��FURPRVRPL�LQHODUL��

(YROXĠLH�úL�SURJQRVWLF� ÌQ�SHULRDGD�FRSLOăULHL�SUREOHPH�GHRVHELWH�SXQ�FRSLLL�FX�VLQGURP�7XUQHU�FDUH�DX�PDOIRUPDĠLL�FDUGLDFH�VDX�UHQDOH�FH�SRW�IDFH�GLIHULWH�FRPSOLFDĠLL��'HSLVWDUHD�SUHFRFH�D�EROQDYHORU�SHUPLWH�IRORVLUHD�XQHL�WHUDSLL�HILFDFH�cu KRUPRQ�GH�FUHúWHUH�úL��SUHSXEHUWDU��FX�HVWURJHQL��8OWHULRU��SRW�Vă�DSDUă��PDL�IUHFYHQW�GHFkW�vQ�SRSXODĠLD�JHQHUDOă��WLURLGLWH�DXWRLPXQH��+7$��REH]LWDWH�úL�GLDEHW�]DKDUDW�QRQLQVXOLQR-GHSHQGHQW��,QVHUĠLD�VRFLDOă�HVWH�GH�RELFHL�EXQă�LDU�YLDĠD�GH�IDPLOLH�HVWH�SRVLELOă� Etiopatogenie. Studii recHQWH�DX�DUăWDW�Fă�FLUFD����GLQ�VDUFLQLOH�UHFXQRVFXWH�FOLQLF�SUH]LQWă�monosomie X. Cauzele care GHWHUPLQă�OLSVD�IUHFYHQWă�D�XQXL�JRQRVRP�QX�VH�FXQRVF��(OLPLQDUHD�FD�DYRUWXUL�VSRQWDQH�D�SHVWH�����GLQ�HPEULRQLL�FX�PRQRVRPLH�;�VH�GDWRUHD]ă� probabil haploinsufLFLHQĠHL�XQRU�JHQH�LPSRUWDQWH�GH�SH�FURPRVRPXO�;�FDUH�VFDSă�LQDFWLYăULL��1X�VH�FXQRDúWH�vQFă�FDUH�HVWH�H[SOLFDĠLD�IDSWXOXL�Fă�GHúL�OHWDOLWDWHD�LQ�XWHUR�D�PRQRVRPLHL�;�HVWH�PDUH��QRX�QăVFXĠLL�FX�DFHHDúL�DQomalie VXSUDYLHĠXLHVF�PXOĠL�DQL�IăUă�SUREOHPH�YLWDOH GHRVHELWH��,SRWH]D�FRQIRUP�FăUHLD�PDMRULWDWHD�ORU�VXQW�PR]DLFXUL�FURPRVRPLFH�QHGHWHFWDWH�QX�D�IRVW�FRQILUPDWă��VH�SDUH�Fă�QDúWHUHD�FRSLLORU�FX�PRQRVRPLH�;�RPRJHQă�HVWH�FRUHODWă�FX�SUH]HQĠD�XQHL�SODFHQWH�GLSORLGH�� 'LQWUH�FD]XULOH�GH�QRX�QăVFXĠL�FX�PRQRVRPLH�;�RPRJHQă����-����DX�RULJLQH�SDWHUQă��ILLQG�FRQVHFLQĠD�XQHL�QHGLVMXQFĠLL�VDX�vQWkU]LHUL�DQDID]LFH�vQ�PHLR]D�WDWăOXL��FDUH�GXFH�OD�IRUPDUHD�GH�JDPHĠL�OLSVLĠL�GH�JRQRVRP� Patogenia sindromului Turner este în curs de elucidare. Analizele moleculare au iQGLFDW�Fă�DEVHQĠD�EUDĠXOXL�VFXUW�DO�FURPRVRPXOXL�;�GHWHUPLQă�KLSRVWDWXUD��SUREDELO�SULQ�KDSORLQVXILFLHQĠD�JHQHL�6+2;34��ORFDOL]DWă�vQ�UHJLXQHD�SVHXGRDXWRVRPDOă�D�EUDĠXOXL�VFXUW�DO�FURPRVRPXOXL�;��úL�GH�PDOIRUPDĠLLOH�FRQJHQLWDOH��vQ�WLPS�FH�GHOHĠLD�EUDĠXOXL�lung al cromosomului X produce GLVIXQFĠLD�JRQDGLFă� 6IDWXO�JHQHWLF��5LVFXO�GH�UHFXUHQĠă�DO�VLQGURPXOXL�7XUQHU�HVWH�XúRU�FUHVFXW�vQ�UDSRUW�FX�ULVFXO�H[LVWHQW�vQ�SRSXODĠLD�JHQHUDOă��'LDJQRVWLFXO�SUHQDWDO�HVWH�SRVLELO�QXPDL�DWXQFL�FkQG�VH�LGHQWLILFă�VHPQH�HFRJUDILFH�GH�DODUPă��K\JURPD�F\VWLFXP��KLGURSV�IHWDOLV��PDOIRUPDĠLL�FRQJHQLWDOH�FDUGLDFH�VDX�UHQDOH�GDU�GLDJQRVWLFXO�XQXL�IHWXV�7XUQHU�ULGLFă�SUREOHPH�HWLFH�PDMRUH�SULYLQG�FRQWLQXDUea sau întreruperea sarcinii.

2. SINDROMUL KLINEFELTER

Sindromul KlinefeltHU�HVWH�FRQVHFLQĠD�IHQRWLSLFă�D�trisomiei gonosomale XXY VDX�D�DOWRU�SROLVRPLL�;<��XQ�IHQRWLS�DVHPăQăWRU�DX�úL�EăUEDĠLL�;;� ,QFLGHQĠă��6LQGURPXO�.OLQHIHOWHU�DUH�R�LQFLGHQĠă�PDL�PDUH�GH���OD������QRX-QăVFXĠL�GH�VH[�PDVFXOLQ��SUREDELO��������GDU�PXOWH�cazuri QX�VXQW�GLDJQRVWLFDWH�GLQ�FDX]D�PRGLILFăULORU�IHQRWLSLFH�UHGXVH��5HSUH]LQWă�SULQFLSDOD�FDX]ă�GH�KLSRJRQDGLVP�OD�EăUEDW. 6LPSWRPDWRORJLH��'LDJQRVWLFXO�FOLQLF�DO�DFHVWHL�DIHFĠLXQL�HVWH�SRVLELO�GRDU�SRVWSXEHUWDU��ÌQ�FRSLOăULH�VLQGURPXO�.OLQHIHOWHU�poate fi suspectat vQ�SUH]HQĠD�XQHL�staturi înalte��D�DVSHFWXOXL�JUDFLO�úL�D�GLILFXOWăĠLORU�GH�DGDSWDUH�úFRODUă��/D�SXEHUWDWH�WDOLD�FUHúWH��SH�seama membrelor inferioare35�7HVWLFXOLL�UăPkQ�PLFL��VXE���FP�OXQJLPH�[�����FP�OăĠLPH��GHFL�XQ�YROXP���GH��PO���IHUPL��nedureURúL�OD�SDOSDUH�– GDWRULWă�GLVJHQH]LHL�JRQDGLFH��QHGH]YROWDUHD�FHOXOHORU�JHUPLQDOH��KLDOLQL]DUHD�WXELORU�VHPLQLIHUL��úL�GHJHQHUHVFHQĠD�/H\GLJLDQă��GHWHUPLQă�DEVHQĠD�VSHUPDWRJHQH]HL�úL�D�VHFUHĠLHL�GH�WHVWRVWHURQ���1LYHOXO�VFă]XW�DO�WHVWRVWHURQXOXi se asocia]ă�FX�YDORUL�FUHVFXWH�DOH�KRUPRQLORU�JRQDGRWURSL��)6+�úL�/+�� ÌQ�DEVHQĠD�WHVWRVWHURQXOXL��caracterele sexuale secundare sunt slab dezvoltate36��SLOR]LWDWHD�IDFLDOă��D[LODUă�úL�WURQFXODUă�VXQW�DEVHQWH��SLOR]LWDWHD�SXELDQă�HVWH�UHGXVă��FRUSXO�DUH�FRQIRUPDĠLH GH�WLS�IHPLQLQ��YRFHD�HVWH�vQDOWă��LDU�DGLSR]LWDWHD�DUH�R�GLVSR]LĠLH�GH�WLS�JLQRLG��3HQLVXO�VH�GH]YROWă��GH�RELFHL��QRUPDO��ÄGLVRFLDĠLH�SHQR-RUKLWLFă��úL�IXQFĠLD�VH[XDOă�HVWH�QRUPDOă��ÌQ�FLUFD�30% din cazuri apare ginecomastia (dezvoltarea glandelor mamare la un individ de sex masculin)37 (figura 10.9). 6WHULOLWDWHD�GLQ�VLQGURPXO�.OLQHIHOWHU�HVWH�SULPDUă�úL�GHILQLWLYă��SDFLHQĠLL�FX�DFHDVWă�DIHFĠLXQH�UHSUH]HQWkQG�DSUR[LPDWLY�

33 $QDOL]HOH�PROHFXODUH��),6+��3&5��DX�HYLGHQĠLDW�– în unele studii recente – R�IUHFYHQĠă�GH������D�PR]DLFXULORU��GDWHOH�WUHEXLHVF�vQVă�D�IL�FRQILUPDWH� 34 Gena SHOX este una din genele implicate în dezvoltarea organismului. 35 DVSHFW�GHWHUPLQDW�GH�vQFKLGHUHD�WkU]LH�D�FDUWLODMHORU�GH�FUHúWHUH�vQ�DEVHQĠD�WHVWRVWHURQXOXi. 36 $GPLQLVWUDUHD�GH�KRUPRQL�VH[XDOL�PDVFXOLQL��FX�VFRSXO�GH�LQGXFHUH�D�GH]YROWăULL�FDUDFWerelor sexuale secundare masculine, are efecte benefice. 37 *LQHFRPDVWLD�HVWH�FRQVHFLQĠD� VHFUHĠLHL�GH�FăWUH�JODQGHOH� VXSUDUHQDOH� �vQ�SUH]HQĠD�QLYHOXULORU�FUHVFXWH�GH�)6+�úL�/+��D�XQHL�FDQWLWăĠL�FUHVFXWH�GH�DQGURJHQL�DURPDWL]DELOL��WUDQVIRUPDĠL�vQ�ILFDW�vQ�HVWURJHQL��FDUH�SURGXF�VWLPXODUHD�FHOXOHORU�PDPDUH��$SDULĠLD�JLQHFRPDVWLHL�HVWH�DVRFLDWă�FX�XQ�ULVF�FUHVFXW�GH�FDQFHU�PDPDU��SHUVRDQHOH�FX�VLQGURP�.OLQHIHOWHU�UHSUH]HQWkQG�FLUFD����GLQ�Woate FD]XULOH�GH�FDQFHU�PDPDU�OD�EăUEDW� 27

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4. SINDROMUL 47,XYY

7ULVRPLD�;<<�HVWH�UHODWLY�IUHFYHQWă��GDU�GLDJQRVWLFXO�FOLQLF�HVWH�UDUHRUL�VWDELOLW�GDWRULWă�PRGLILFăULORU�IHQRWLSLFH�PLQRUH�Se care le GHWHUPLQă��,QFLGHQĠD�DIHFĠLXQLL�HVWH�GH������� de nou-QăVFXĠL�GH�VH[�PDVFXOLQ� )HQRWLSXO�VH�FDUDFWHUL]HD]ă�SULQ�WDOLH�vQDOWă��GH]YROWDUH�LQWHOHFWXDOă�QRUPDOă��GDU�FRHILFLHQWXO�GH�LQWHOLJHQĠă�HVWH�FX���-15 puncte PDL�PLF�GHFkW�FHO�DO�SHUVRDQHORU�vQUXGLWH��3UH]LQWă�GHVHRUL�vQWkU]LHUH�vQ�GH]YROWDUHD�OLPEDMXOXL��GLILFXOWăĠL�GH�vQYăĠDUH��SULQ�GLILFXOWăĠL�GH�FLWLUH�úL�GHILFLW�GH�DWHQĠLH���SUREOHPH�HGXFDĠLRQDOH��KLSHUDFWLYLWDWH�úL�LPSXOVLYLWDWH��DJUHVLYLWDWHD�úL�FRPSRrtamentul DEHUDQW��GHVFULVH�LQLĠLDO�vQ�OLWHUDWXUă��VXQW�UDUH�� Diagnosticul se pune numai prin analize citogenetice: testul cromatinei Y pozitiv, cu doi corpusculi F, iar cariotipul este ���;<<��7RDWH�FD]XULOH�VXQW�FRQVHFLQĠD�XQHL�QHGLVMXQFĠLL�vQ�PHLR]D�,,�SDWHUQă� 'H�UHJXOă�SHUVRDQHOH�FX�WULVRPLH�;<<�DX�IHUWLOLWDWH�QRUPDOă��GDU�XQHRUL�SRW�IL�GHSLVWDWH�WXOEXUăUL�GH�VSHUPDWRJHQH]ă��FDUH�LQGXF�KLSRIHUWLOLWDWH��'HúL��WHRUHWLF�SRW�IRUPD�JDPHĠL�DQRUPDOL��ULVFXO�XQRU�GHVFHQGHQĠL�;;<�VDX�;;;�QX�HVWH�PDL�PDUH�GHFkW�vn SRSXODĠLD�JHQHUDOă��'LDJQRVWLFXO�SUHQDWDO�HVWH�GH�RELFHL�vQWkPSOăWRU�GDU�HYLGHQĠLHUHD�XQXL�IăW����;<<�SXQH�SUREOHPH�GLILFLOH�SHQWUX�SăVWUDUHD�VDX�vQWUHUXSHUHD�VDUFLQLL�

1. 67(5,/,7$7($�)(0,1,1Ă

Sterilitatea la femei poate avea cauze multiple (tabelul 10.3): GLVJHQH]LH�VDX�GLVIXQFĠLH�RYDULDQă��������REVWUXFĠLH�WXEDUă�������úL�DQRPDOLL�VDX�EROL FH�DIHFWHD]ă�WUDFWXO�UHSURGXFWLY��YDJLQ��FHUYL[��XWHU���������:LOOVRQ�������� CATEGORIE BOLI 0$1,)(67Ă5, 'LVJHQH]LH�RYDULDQă Anomalii cromosomice Anomalii congenitale

Sindrom Turner (45,X) 'LVJHQH]LH�JRQDGLF���;; (233300; 233400)

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'LVIXQFĠLH�RYDULDQă 7XOEXUăUL�vQ�VLQWH]D�KRUPRQLORU sexuali. Ovare displazice. Alte boli endocrine. Boli sistemicH��DIHFĠLXQL�FURQLFH

+LSHUSOD]LD�FRQJHQLWDOă�VXSUDUHQDOă Tip I (201710) Sindromul Stein-Levinthal. 'HILFLHQĠă�KLSRIL]DUă� 'LVIXQFĠLH�FHUHEUDOă��LQIHFĠLL��DXWRLPXQLWDWH

([FHV�GH�DQGURJHQL��GHILFLW�GH�FRUWL]RO�úL�aldosteron. Ovare polichistice, hirsutism. 'HILFLHQĠă�vQ�)6+��/+� 3HUWXUEDUHD�VWLPXOăULL�KLSRIL]DUH�D�RYDUHORU�

Anomalii ale tractului reproductiv Uterine

Uter bicorn, bipartit Multe sindroame plurimalformative

Modificarea anatomiei uterine. Sindromul McKusick/Kaufman (236700):

28

Col uterin, vagin

$VRFLDĠLD�085&6 6HFYHQĠD�5RNLWDQVN\ Aplazie cervix, vagin septat

anomalii cardiace, renale, digitale. Anomalii uterine, renale, ale coloanei cervicale. Anomalii uterine, renale. Anomalii cervix sau vaginale

,QIODPDĠLL�DOH�WUDFWXOXL�UHSURductiv ,QIHFĠLL Endometrioze

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29

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GLIX]DELOă��SUHFXP�IHQLODODQLQD��HD�SRDWH�Vă�ILH�UHGLVWULEXLWă�XúRU�vQ�vQWUHJXO�RUJDQLVP�úL��FD�XUPDUH��PDQLIHVWăULOH�FOLQLFH pot fi DGHVHRUL�VLVWHPLFH��GLPSRWULYă��DWXQFL�FkQG�VXEVWUDWXO�HVWH�R�PDFURPROHFXOă��DFHVWD�YD�UăPkQH�OD�QLYHOXO�ĠHVXWXOXL�UHVSHFWLY�úL�YD�GHWHUPLQD�vQ�VSHFLDO�PDQLIHVWăUL�FOLQLFH�ORFDOL]DWH�

� devierea FăLL�PHWDEROLFH�úL�VLQWH]D�XQRU�SURGXúL�WR[LFL� � deficitul XQXL�SURGXV�GH�UHDFĠLH��ILQDO�VDX�LQWHUPHGLDU��VDX�R�FRPELQDĠLH�ÄGHILFLW�úL�DFXPXODUH³�� � lipsa controlului feed-back GDWRULWă�DEVHQĠHL�SURGXVXOXL�ILQDO� 'HILFLWH�XQRU�HQ]LPH�GLIHULWH�FDUH�LQWHUYLQ�vQVă�vQ�DFHHDúL�FDOH�PHWDEROLFă�SRW�SURGXFH�PDQLIHVWăUL�FOLQLFH�DVHPăQăWRDUH�(de exemplu, mucopolizaharidozele). 3H�GH�DOWă�SDUWH��GHILFLWXO�SDUĠLDO�VDX�GHILFLWXO�FRPSOHW�DO�DFHOHLDúL�HQ]LPH�SRDWH�GHWHUPLQD�boli diferite (vezi exemplul HPRT amintit anterior). 7RDWH�FăLOH�PHWDEROLFH�SRW�IL�DIHFWDWH�SULQ�GHILFLHQĠH�HQ]LPDWLFH��&LWLWRUXO�LQWHUHVDW�YD�JăVL�LQIRUPDĠLL�Hxhaustive în tratatul „The Metabolic and Molecular Bases of Inherited Disease“ (Scriver CR et al., ed. 8, 2001), în care bolile metabolice sunt grupate pe metabolisme; tabelul 11.1 VLQWHWL]HD]ă�SULQFLSDOHOH�FDWHJRULL�GH�EROL�PHWDEROLFH��H[HPSOLILFDWH�FX�FHOH�PDL�IUHFYHQWH�úL�FXQRVFXWH�DIHFĠLXQL��,QIRUPDĠLL�VXSOLPHQWDUH�SUHĠLRDVH�VH�JăVHVF�úL�vQ�FDSLWROXO�„Boli genetice de metabolism“ (Paula Grigorescu-6LGR��GLQ�7UDWDWXO�GH�3HGLDWULH��HG��(��&LRIX��&DUPHQ�&LRIX��������VDX�VH�SRW�REĠLQH�SULQ�DFFHVDUHD�20,0��ÌQ�FHHD�FH�XUPHD]ă�vom prezenta sintetic doar câteva dintre cele mai frecvente enzimopatii. Enzima Gena Localizare

FURPRVRPLFă Boala OMIM

%ROL�DOH�PHWDEROLVPXOXL�FDUERKLGUDĠLORU Galactozo-1-fosfat uridil transferaza GALT 9p13 Galactozemia claVLFă 230400 Fructozo 1,6-bifosfat aldolaza ALDOB 9q13-q32 ,QWROHUDQĠD�HUHGLWDUă�OD�IUXFWR]ă 229600 Fructokinaza KHK 2p23 Fructozuria 229800 Lactaza LCT 2q21 Hipolactazia adultului 223100 Glucokinaza GCK 7p13 Diabetul MODY (maturity

onset diabet of youth) 606321

Glucoza-6-fosfataza G6PC 17q21 Glicogenoza tip Ia (von Gierke) 232200 Alfa-JOLFR]LGD]D�DFLGă GAA 17q25.2 Glicogenoza tip II (Pompe) 232300 Amilo-1,6-glucozidaza AGL 1p21 Glicogenoza tip IIIa (Cori) 232400 Enzima de ramificare a glicogenului GBE1 3p12 Glicogenoza tip IV (Anderson) 232500 )RVIRULOD]D�PXVFXODUă PYGM 11q13 Glicogenoza tip V (McArdle) 232600 Boli ale metabolismului aminoacizilor Fenilalanin hidroxilaza PAH 12q24.1 Fenilcetonuria 261600 Fumarilacetoacetat hidrolaza FAH 15q23-q25 Tirozinemia tip 1 276700 Cistation beta-sintetaza CBS 21q22.3 Homocistinuria 236200 Tirozinaza TYR 11q14-q21 Albinismul oculocutanat 203100 Argininosuccinat sintetaza ASS 9q34 CitrulinemLD�FODVLFă 215700 Boli ale metabolismului lipidic

31

Enzima Gena Localizare FURPRVRPLFă

Boala OMIM

$FLO�&R$�GHKLGURJHQD]D�ODQĠXUL�PHGLL ACADM 1p31 MCAD 607008 $FLO�&R$�GHKLGURJHQD]D�ODQĠXUL�OXQJL ACADL 2q34-q35 LCAD 201460 $FLO�&R$�GHKLGURJHQD]D�ODQĠXUL�VFXUWH ACADS 12q22qter SCAD 201470 %ROL�DOH�PHWDEROLVPXOXL�SXULQLF�úL�SLULPLGLQLF Hipoxantin guanin fosforiboziltransferaza HPRT1 Xq26-q27.2 Sindromul Lesch-Nyhan 300322 Adenozin deaminaza ADA 20q13.11 ,PXQRGHILFLHQĠD�FRPELQDWă�

VHYHUă 102700

Boli ale metabolismului acizilor organici Homogentizic acid oxidaza HGD 3q21-q23 Alcaptonuria 203500 Metilmalonil-CoA mutaza MUT 6p21 $FLGHPLD�PHWLOPDORQLFă 251000 Propionil-CoA carboxilaza PCCA 13q32 $FLGHPLD�SURSLRQLFă 606054 Boli ale metabolLVPXOXL�SRUILULQHORU�úL�KHPXOXL Porfobilinogen deaminaza PBGD 11q23.3 3RUILULD�DFXWă�LQWHUPLWHQWă 176000 Uroporfirinogen decarboxilaza UROD 1p34 Porfiria cutanea tarda 176100 Protoporfirinogen oxidaza PPOX 1q22 Porfiria variegata 176200 UDP-glucuronozil transferaza UGT1A1 2q37 Sindromul Gilbert 143500 Boli ale enzimelor lizozomale Alfa-L-iduronidaza IDUA 4p16.3 Boala Hurler-Scheie 252800 Beta-hexozaminidaza izoenzima A HEXA 15q23-q24 Boala Tay-Sachs 272800 Beta-gluco]LGD]D�DFLGă GBA 1q21 Boala Gaucher tip 1 230800 6ILQJRPLHOLQD]D�DFLGă ASM 11p15.4 Boala Niemann-Pick 257200 Alfa-galactozidaza A GLA Xq22 Boala Fabry 301500 Boli ale enzimelor peroxizomale Catalaza CAT 11p13 Acatalazemia 115500 Fitanoil CoA hidroxilaza PAHX 10p11.2 Boala Refsum 266500 Tulburari în productia de energie Piruvat carboxilaza PC 11q13.4 Sindromul Leigh 266150 Piruvat decarboxilaza PDH Xp22.1 $WD[LD�FX�DFLGR]ă�ODFWLFă�WLS�, 208800 Boli ale enzimelor implicate în sinteza hormonilor 21-hidroxilaza CYP21A2 6p21.3 +LSHUSOD]LD�DGUHQDOLDQă�

FRQJHQLWDOă 201910

Defecte ale enzimelor extracelulare Alfa-1 antitripsina PI 14q32.1 Deficitul de alfa-1 antitripsina 107400 1.1 GALACTOZEMIA

'HILQLĠLH. Galactozemia (OMIM 230400) este o ERDOă�DXWRVRPDO�UHFHVLYă GHWHUPLQDWă�GH�PXWDĠLL�DOH�JHQHL�FDUH�FRGLILFă�galactozo-1-fosfat uridil transferaza (GAL-1-P uridil transferaza).

,QFLGHQĠă��)RUPD�FODVLFă�GH�JDODFWR]HPLH�HVWH�FHD�PDL�IUHFYHQWă�ERDOă�PRQRJHQLFă�FDUH�LQWHUHVHD]ă�PHWDEROLVPXO�FDUERKLGUDĠLORU��DIHFWkQG����������QRX-QăVFXĠL��

0DQLIHVWăULOH�FOLQLFH DSDU�OD�VXJDU��RGDWă�FX�DOLPHQWDĠLD�ODFWDWă��úL�FRQVWDX�vQ�LQFDSDFLWDWHD�GH�KUăQLUH��hepatomegalie cu LQVXILFLHQĠă�KHSDWLFă��WXOEXUăUL�QHXURORJLFH��FDWDUDFWă�úL�vQWkU]LHUHD�GH]YROWăULL�QHXURPRWRULL��3H�WHUPHQ�vQGHOXQJDW�DIHFĠLXQHD�GHWHUPLQă�UHWDUG�vQ�FUHúWHUH��UHWDUG�PLQWDO��FLUR]ă�KHSDWLFă�PDFURQRGXODUă�úL�LQVXILFLHQĠă�RYDULDQă�OD�IHPHL��

*HQHWLFă. Galactozemia se transmite autosomal recesiv. Gena GALT HVWH�DOFăWXLWă�GLQ����H[RQL��GDU�SHVWH�����GLQ�PXWDĠLLOH�FDX]DWRDUH�DOH�DFHVWHL�EROL�OD�FDXFD]LHQL�VXQW�UHSUH]HQWDWH�GH�R�VLQJXUă�PXWDĠLH�SXQFWLIRUPă la nivelul exonului 6, care GHWHUPLQă�VXEVWLWXĠLD�XQHL�glutamine cu arginina (Q188R). IndiYL]LL�KRPR]LJRĠL�SHQWUX�DFHDVWă�PXWDĠLH�DX�R�DFWLYLWDWH�HQ]LPDWLFă�GH�FLUFD������FHHD�FH�DIHFWHD]ă�FDSDFLWDWHD�GH�FRQYHUVLH�D�JDODFWR]HL�vQ�JOXFR]ă��*DODFWR]HPLD�SRDWH�IL�GHWHUPLQDWă��GH�DVHPHnea, GH�PXWDĠLL�DOH�JHQHORU�FDUH�FRGLILFă�JDODFWRNLQD]D�úL�XULGLn difosfat galactozo-4-epimeraza (UDP-galactozo-4-epimeraza). 'HILFLHQĠD�JDODFWRNLQD]HL�DVRFLD]ă�GH]YROWDUHD�FDWDUDFWHL��GDU�QX�GHWHUPLQă�UHWDUGXO�FUHúWHULL��UHWDUG�PLQWDO�VDX�DIHFWDUH�KHSDWLFă���'HILFLHQĠD�8'3-galactozo-4-HSLPHUD]HL�SRDWH�IL�OLPLWDWă�QXPDL�OD�QLYHOXO�HULWURFLWHORU�úL�OHXFRFLWHORU�úL�vQ�DFHVW�FD]�QX�GHWHUPLQă�PDQLIHVWăUL�FOLQLFH��VDX�SRDWH�IL�VLVWHPLFă�úL�GHWHUPLQă�PDQLIHVWăUL�FOLQLFH�VLPLODUH�JDODFWR]HPLHL�FODVLFH� Patogenie. Deficitul enzimatic de galactozo-1-fosfat uridil transferaza duce la acumularea galactozo-1-IRVIDWXOXL�úL�galactiolului (figura 11.3).; primul metabolit este WR[LF�SHQWUX�ILFDW��FUHLHU�úL�ULQLFKL iar cel de al doilea se depune în cristalin

Diagnosticul VH�ED]HD]ă�SH�GDWHOH�FOLQLFH�úL�H[DPHQHOH�GH�ODERUDWRU�FDUH�UHOHYă galactozurie, valori crescute ale JDODFWR]HL�VHULFH�úL�PDL�DOHV�DFWLYLWDWHD�UHGXVă�D�JDODFWR]R-1-fosfat uridil transferazei plasmatice. In prezent este larg utilizat screening-ul neonatal SHQWUX�DFHDVWă�DIHFĠLXQH��UHDOL]DW�SULQ�PăVXUDUHD�DFWLYLWăĠLL�SODVPatice a galactozo-1-fosfat uridil transferazei într-R�SLFăWXUă�XVFDWă�GH�VkQJH��,GHQWLILFDUHD�SUHFRFH�SHUPLWH�LQVWLWXLUHD�SUHFRFH�D�WUDWDPHQWXOXL�GLHWHWLF�FDUH�FRQVWă�vQ�PDUH�vQ�HOLPLQDUHD�DSRUWXOXL�GH�JDODFWR]ă��(VWH�SRVLELO�úL�diagnosticul prenatal.

Tratamentul dietetic SULQ�UHGXFHUHD�DSRUWXOXL�DOLPHQWDU�GH�JDODFWR]ă�SHUPLWH�SUHYHQLUHD�VXEVWDQĠLDOă�D�PRUELGLWăĠLL�DVRFLDWH�HIHFWHORU�DFXWH�LQGXVH�GH�PHWDEROLĠLL�JDODFWR]HL��&X�WRDWH�DFHVWHD��WUDWDPHQWXO�GLHWHWLF�QX�LQIOXHQĠHD]ă�LQVWDODUHD�GLVIXQFĠLHL�FHUHEUDOH�úL�D�LQVXILFLHQĠHL�RYDULHQH�� Prognosticul HVWH�UH]HUYDW�úL�YDULDELO�OD�GLIHULĠL�SDFLHQĠL� 1.2. FENILCETONURIA 'HILQLĠLH��)HQLOFHWRQXULD��20,0���������HVWH�R�ERDOă�DXWRVRPDO�UHFHVLYă�D�PHWDEROLVPXOXL�IHQLODODQLQHL�GHWHUPLQDWă�GH�PXWDĠLL�DOH�genei PAH �ORFDOL]DWă�SH�FURPRVRPXO���T������FDUH�FRGLILFă�IHQLODODQLQ�KLGUR[LOD]D��HQ]LPD�FH�WUDQVIRUPă�IHQLODODQLQD�vQ�WLUR]LQă�

,QFLGHQĠD fenilcetonuriei este de circa 1/15.000 nou-QăVFXWL�vQ�SRSXODĠLD�FDXFD]LDQă��

32

0DQLIHVWăULOH�FOLQLFH VH�LQVWDOHD]ă��GH�RELFHL��GXSă�SULPXO�WULPHVWUX�GH�YLDĠă��QRX-QăVFXWXO�HVWH�LQGHPQ�GLQ�SXQFW�GH�YHGHUH�FOLQLF��FX�H[FHSĠLD�SLJPHQWDĠLHL�FXWDQDWH�UHGXVH��DVRFLDWă�cu SăU�EORQG�úL�RFKL�DOEDúWUL (toate aceste semne fiind GHWHUPLQDWH�GH�GHILFLWXO�GH�WLUR]LQă��XQ�SUHFXUVRU�DO�PHODQLQHL���%RDOD�VH�PDQLIHVWă�SULQ�WXOEXUăUL�QHXURORJLFH, UHWDUG�VRPDWLF�úL�retard mintal��OD�DFHVWH�IHQRPHQH�VH�PDL�SRW�DGăXJD�mirosul particular al urinii �³GH�úRDUHFH³�VDX�ÄGH�KDPEDU³��úL�R GHUPDWLWă�FURQLFă�GHVFXDPDWLYă.

*HQHWLFă. Gena pentru PAH a fost izoODWă�vQ�������LDU�VWXGLLOH�XOWHULRDUH�DX�HYLGHQĠLDW�PDUH�KHWHURJHQLWDWH�DOHOLFă�OD�LQGLYL]LL�EROQDYL��$VWIHO��DX�IRVW�GHVFULVH�SHVWH�����GH�PXWDĠLL��GDU�PDMRULWDWHD�ORU�VXQW�IRDUWH�UDUH��ùDVH�GLQWUH�DFHVWH�PXWDĠLL�VXQW�vQVă�UHVSRQVDELOH�SHQWUX�FLUFD�GRXă�WUHLPL�GLQ�FD]XULOH�GH�IHQLOFHWRQXULH�vQ�SRSXODĠLD�HXURSHDQă��'DWRULWă�PXOWLWXGLQLL�DFHVWRU�PXWDĠLL��FHL�PDL�PXOĠL�GLQWUH�EROQDYL�VXQW�KHWHUR]LJRĠL�FRPSXúL�úL�DFHDVWD�GHWHUPLQă�R�GLYHUVLWDWH�ODUJă�D�QLYHOHORU�UH]LGXDOe ale DFWLYLWăĠLL�HQ]LPDWLFH��

Patogenie���'HILFLWXO�3$+�GHWHUPLQă�LQFDSDFLWDWHD�GH�WUDQVIRUPDUH�D�IHQLODODQLQHL�vQ�WLUR]LQă�úL�DFXPXODUHD�vQ�RUJDQLVP�D�IHQLODODQLQHL�úL�DL�XQRU�PHWDEROLĠL�DL�DFHVWHLD��DFLGXO�IHQLOSLUXYLF��IHQLOODFWLF�HWF��figura 11.4��FDUH�GHWHUPLQă�leziuni ale sistemului nervos central îQ�SULPLL�DQL�GH�FRSLOăULH��([FOXGHUHD�IHQLODODQLQHL�GLQ�DOLPHQWDĠLH�SUHYLQH�DSDULĠLD�DFHVWRU�PDQLIHVWăUL���$SUR[LPDWLY�R�WUHLPH�GLQ�SDFLHQĠLL�FX�KLSHUIHQLODODQLQHPLH�QX�SUH]LQWă�PXWDĠLL�OD�QLYHOXO�3$+��FL�DOH�XQRU�HQ]LPH�LPSOLFDWH�vn metabolismul tetrahidrobiopterinei (BH4), un cofactor al PAH. Aceste enzime sunt: pterin-4-alfa-carbinolamin dehidraza (PCD), dihidropteridin reductaza (DHPR), guanozin trifosfat ciclohidraza (GTP-&+��úL��-piruvoiltetrahidropterin sintetaza (6-PTS) – vezi figura 11.4��,Q�FD]XO�DFHVWRU�SDFLHQĠL��UHVWULFĠLD�DSRUWXOXL�DOLPHQWDU�GH�IHQLODODQLQD�QX�HVWH�HILFLHQWă�vQ�HYLWDUHD�SUREOHPHORU�QHXURORJLFH��GHRDUHFH�%+��HVWH�FRIDFWRU�SHQWUX�DOWH�GRXă�HQ]LPH��WLUR]LQ-KLGUR[LOD]D�úL�WULSWRIDQ-hidroxilaza care intervin în sinteza unoU�QHXURWUDQVPLWăWRUL�PRQRDPLQFL�SUHFXP�'23$��QRUHSLQHIULQD��HSLQHIULQD�úL�VHURWRQLQD��&D�XUPDUH��OD�DFHúWL�SDFLHQĠL�HVWH�QHFHVDUă�VXSOLPHQWDUHD�FX�/-'23$�úL��-hidroxitriptofan.

Diagnosticul GH�FHUWLWXGLQH�VH�VWDELOHúWH�SH�ED]D�XUPăWRDUHORU�FULWHULL��fenilaODQLQD�SODVPDWLFă�PDL�PDUH�GH����PJ�GO� HOLPLQDUH�XULQDUă�FUHVFXWă�GH�DFLG�IHQLO-SLUXYLF�úL�RUWR-hidroxi-IHQLO�DFHWLF��WLUR]LQD�SODVPDWLFă�QRUPDOă��YDORDUH�QRUPDOă�D�tetrahidrobiopterinei��(VWH�LPSRUWDQW�FD�GLDJQRVWLFXO�Vă�VH�SUHFL]H]H�OD�QRX-QăVFXW��vQDLQWHD�DSDULĠLHL�VHPQHORU�FOLQLFH��GHRDUHFH�GLHWD�UHVWULFWLYă�vQ�IHQLODODQLQD�SUHYLQH�LQVWDODUHD�DFHVWRUD�úL�DVLJXUă�R�GH]YROWDUH�VRPDWLFă�úL�QHXUR-SVLKLFă�QRUPDOă��ÌQ�DFHVW�VFRS��vQ�PDMRULWDWHD�ĠăULORU�VH�HIHFWXHD]ă�VFUHHQLQJ-XO�EROLL��vQ�PDWHUQLWăĠL��GXSă�SULPHOH���]LOH�GH�YLDĠă��LQWHUYDO�vQ�FDUH�FRSLOXO�D�SULPLW�IHQLODODQLQD��SULQ�DOLPHQWDĠLD�ODFWDWă���IRORVLQG�testul Güthrie (bazat pe LQKLELĠLD�FUHúWHULL�FRORQLLORU�GH�EDFLO�VXEWLOLV GH�FăWUH�IHQLODODQLQD�GLQ�VkQJH���WHVWXO�SR]LWLY�LPSXQH�HYDOXDUHD�FRPSOHWă a pacientului, pentru precizarea diagnosticului. Diagnosticul GLIHUHQĠLDO WUHEXLH�Vă�H[FOXGă�DOWH�FDX]H�GH�KLSHUIHQLODODQLQHPLH�OD�QRX-QăVFXW�VDX�– în cazul nedorit al unui diagnostic stabilit tardiv – alte cauze de encefalopatie cu spasticitate sau sindrRP�FRQYXOVLY�úL�UHWDUG�PHQWDO�

Tratamentul este dietetic, având ca obiectiv reducerea aportului de fenilalanina la minimum necesar pentru asigurarea GH]YROWăULL�RUJDQLVPXOXL��vQ�DúD�IHO��vQFkW�IHQLODODQLQD�SODVPDWLFă�Vă�VH�PHQĠLQă�OD�YDORUL�între 2-10 mg/dl (preferabil < 6 mg/dl). Momentul LQLĠLHULL�HVWH�FkW�PDL�SUHFRFH��vQ�SULPD�OXQă�GH�YLDĠă��FHO�PDL�WkU]LX�vQ�SULPXO�WULPHVWUX��LDU�durata HVWH�LQGHILQLWă�� Prognosticul. 'DFă�GLDJQRVWLFXO�VH�IDFH�OD�QDúWHUH�úL�WUDWDPHQWXO�GLHWHWLF�HVWH�ELQH�FRQGXV�SURJQRVticul este bun, indivizii DIHFWDĠL�DYkQG�R�YLDĠă�FYDVL-QRUPDOă��)HPHLOH�FX�IHQLOFHWRQXULH�SRW�GD�vQVă�QDúWHUH�XQRU�FRSLL�FX�UHWDUG�PHQWDO�úL�PLFURFHIDOLH��HQFHIDORSDWLD�IHQLOSLUXYLFă��GDFă�SUH]LQWă�YDORUL�vQDOWH�DOH�IHQLODODQLQHL�SODVPDWLFH��'H�DFHHD�VH�UHFRPDQGă�FD�vQDLQWH�úL�vQ�FXUVXO�VDUFLQLL��GLHWD�Vă�ILH�VWULFW�VXSUDYHJKHDWă��vQ�DúD�IHO�vQFkW�IHQLODODQLQD�SODVPDWLFă�Vă�ILH������PJ�GO��SUHIHUDELO�����PJ�GO).

1.3. BOLILE LIZOZOMALE Bolile lizozomale sunt cauzate de deficitul unor enzime (hidrolaze) sau a DOWRU�SURWHLQH�OL]R]RPDOH�IXQFĠLRQDOH��FDUH�GHWHUPLQă�acumularea substratului nemetabolizat în lizozomi, la nivelul sistemului nervos central, viscerelor sau miocardului. $X�IRVW�GHVFULVH�SkQă�vQ�SUH]HQW�SHVWH����GH�EROL�OL]R]RPDOH��FDUH�UHDOL]HD]ă�vPSUHXQă�R�IUHFYHQĠă�GH���������– 1/10.000 nou-QăVFXĠL��ÌQ�IXQFĠLH�GH�VXEVWUDWXO�PHWDEROLF�DFXPXODW��HOH�VH�JUXSHD]ă�vQ�PDL�PXOWH�FDWHJRULL��FHOH�PDL�LPSRUWDQWH�VXQW�VILQJROLSLGR]HOH��PXFRSROL]DKDULGR]HOH�úL�PXFROLSLGR]H� a. Sfingolipidozele constau în acumularea VILQJROLSLGHORU��QHXWUH�úL�JDQJOLR]LGHORU VDX�D�XQRU�SURGXúL�GH�PHWDEROLVP�DL�DFHVWRUD��SUHGRPLQDQW�OD�QLYHOXO�VXEVWDQĠHL�DOEH��leucodistrofiile��VDX�D�VXEVWDQĠHL�FHQXúLL��gangliozidozele) din SNC, mai rar în DOWH�ĠHVXWXUL��'H�DFHHD�PDMRULWDWHD�VILQJROLSLGR]HORU�GHWHUPLQă�VXIHULQĠă�QHXURORJLFă��VHFXQGDUă�DFXPXOăULL�VXEVWUDWXOXL�nemetabolizat. Principalele tipuri de sfingolipidoze sunt: boala Gaucher (prin defict de E-glucozidaza), boala Fabry (prin deficit de D-JDODFWR]LGD]ă���JDQJOLR]LGR]D�*01 (prin deficit de E-JDODFWR]LGD]ă���JDQJOLR]LGR]D�*02 (prin deficit de E-KH[R]DPLQLGD]ă�A) sau boalaTay-Sachs, boala Niemann-Pick �SULQ�GHILFLW�GH�VILQJRPLHOLQD]ă��úL�OHXFRGLVWURILD�PHWDFURPDWLFă (prin deficit de arilsulfataza A).

Boala Gaucher este cea mai frecYHQWă�ERDOă�OL]R]RPDOă�����������QRX-QăVFXĠL���ILLQG�SURGXVă�GH�FăWUH��deficitul de E-JOXFR]LGD]ă���FDX]DW�GH�R�VHULH�GH�PXWDĠLL�OD�QLYHOXO�JHQHL�*%$��ORFDOL]DWă�SH�FURPR]RPXOXL��T����ÌQ�IXQFĠLH�GH�VHYHULWDWHD�deficitului enzimatic, vârsta de debut, prezenĠD�VDX�DEVHQĠD�VXIHULQĠHL�QHXURORJLFH�úL�HYROXĠLH�VH�GHVFULX�WUHL�WLSXUL�GH�ERDOă Gaucher: tipul I �IRUPD�FURQLFă��DGXOWă�VDX�QRQQHXURQRSDWLFă���tipul II �LQIDQWLO��QHXURQRSDWLF�DFXW��úL�tipul III (juvenil, QHXURQRSDWLF�VXEDFXW���%RDOD�VH�PDQLIHVWă�SULQ��sSOHQRPHJDOLH�úL�KHSDWRPHJDOLH�LPSUHVLRQDQWă; osteopatia��WUDGXVă�SH�SODQ�clinic prin dureri (crizele osoase��úL�fracturi PDL�DOHV�OD�QLYHOXO�RDVHORU�PHPEUHORU��FRUSLORU�YHUWHEUHORU�WRUDFLFH�úL�SHOYLVXOXL��simptome secundare de pancitopenie (sindromul anemiF�úL�VLQGURPXO�KHPRUDJLSDU���VXIHULQĠă�QHXURORJLFă��vQ�WLSXO�,,�úL�,,,���7HVWHOH�VSHFLILFH�VXQW��DFWLYLWDWHD�UHGXVă�D�E-JOXFR]LGD]HL�vQ�OHXFRFLWH�úL�SUH]HQĠD�PXWDĠLHL�JHQLFH��DQDOL]D�$'1�39. Boala Gaucher WLSXO�,�EHQHILFLD]ă�GH�WUDWDPHQW�VXEVWLWXWLY�HQ]LPDWLF�FURQLF��FX�HQ]LPă��imingluceraza��REĠLQXWă�SULQ�WHKQRORJLD�$'1-ului recombinant. E��0XFRSROL]DKDULGR]HOH��03=��VXQW�EROL�FX�HYROXĠLH�SURJUHVLYă��FDX]DWH�GH�DFXPXODUHD�LQWUDOL]R]RPDOă�vQ�H[FHV�D�PXFRSROL]DKDULGHORU�DFLGH��FRQVHFXWLYă�GHILFLWXOXL�XQRU�HQzime lizozomale. Mucopolizaharidele acide (glicozaminoglicanii) se

39 3ULPXO� &HQWUX� GH� 'LDJQRVWLF� DO� %ROLORU� /L]R]RPDOH� GLQ� ĠDUă�� vQILLQĠDW� vQ� DQXO� ����� OD� &OXM�� D� LQWURGXV� recent diagnosticul HQ]LPDWLF�úL�GLDJQRVWLFXl molecular pentru boala Gaucher . 33

OHDJă�GH�RELFHL�GH�SURWHLQH��FX�FDUH�IRUPHD]ă�SURWHRJOLFDQLL��FRQVWLWXLHQĠL�PDMRUL�DOH�VXEVWDQĠHL�GH�ED]ă�D�ĠHVXWXOXL�FRQMXQFtiv. În IXQFĠLH�GH�GHIHFWXO�HQ]LPDWLF�VH�GHRVHEHVF�PDL�PXOWH�WLSuri de MPZ, diferite prin defectul enzimatic; cele mai frecvente sunt tipul I (sindromul Hurler); tipul II (sindromul Hunter); tipul III (sindromul Sanfilippo), tipul IV (sindromul Morquio���6LPSWRPHOH�úL�semenele întâlnite în MPZ pot fi cauzate de acumulaUHD�WLVXODUă�GH�JOLFR]DPLQRJOLFDQL��WUăVăWXUL�LQILOWUDWH�DOH�IHĠHL��WHJXPHQWH�vQJURúDWH, opacifierea corneei úL�hepato-spleno-cardiomegalie���GHILFLWXO�IXQFĠLLORU�FHOXODUH�(retardul mintal, GHILFLWXO�GH�FUHúWHUH� GLVSOD]LD�RVRDVă��VDX�GH�LQWHUIHUHQĠD�GLQWUH�JOLFR]DPLQRJOLFDQLL�DFXPXODĠL�úL�FRODJHQ�VDX�ILEURQHFWLQă��RVWHRDUWURSDWLD�FX�DQFKLOR]D�în flexie, herniile).

F��0XFROLSLGR]HOH�VH�SUH]LQWă�VXE���WLSXUL��sialidoza (prin deficit de glicoprotein-VLDOLGD]ă���mucolipidoza tip II (boala ci celule I, secundaUă�GHILFLWXOXL�GH�1-acetil-glucozamino-IRVIRWUDQVIHUD]ă���mucolipidoza III �R�IRUPă�PDL�SXĠLQ�VHYHUă�D�DFHOXLDúL�GHILFLW�HQ]LPDWLF��úL�galactosialidoza.

1.4. BOLILE PERXIZOMALE 3HUR[L]RPLL�VXQW�RUJDQLWH�VXEFHOXODUH�GHOLPLWDWH�GH�R�PHPEUDQă�OLSLGLFă�WULODPLQDUă��SUH]HQĠL�vQ�WRDWH�FHOXOHOH�GDU�DEXQGHQĠL�vQ�ILFDW�úL�ULQLFKL��0DWULFHD�ORU�FRQĠLQH�SHVWH����GH�HQ]LPH�LPSOLFDWH�vQ�UHDFĠLLOH�GH�R[LGDUH�D�DFL]LORU�JUDúL�úL�ELRVLQWH]D�FROHVWHUROXOXL��([LVWă�GRXă�FDWHJRULL�SULQFLSDOH�GH�EROL�SHUR[L]RPDOH��SURGXVH�ILH�GH�WXOEXUăUL�vQ�ELRJHQH]D�SHUR[L]RPLORU��GH�H[HPSOX��VLQGURPXO�=HOOZHJHU��vQ�FDUH�H[LVWă�R�UHGXFHUH�PDUFDWă�D�QXPăUXOXL�GH�SHUR[L]RPL���ILH�SULQ�GHILFLHQĠD�XQHL�DQXPLWH�enzime peroxizomale (de exemplu, adrenoleucodistrofia, acatalazemia, boala Refsum).

6LQGURPXO�=HOOZHJHU�HVWH�R�ERDOă�OHWDOă��WUDQVPLVă�DXWRVRPDO�UHFHVLY�FDUH�vQ�IRUPD�FODVLFă�VH�PDQLIHVWă�SULQ��dismorfie cranio-IDFLDOă (fontanele cu suturi larg deschise, occiput plat, hipertelorism, epicantus, anomalii ale pavilioanelor auriculare); disfuQFĠLH�QHXURORJLFă�JUDYă��KLSRWRQLH��VXUGLWDWH�GH�SHUFHSĠLH�úL�FDWDUDFWă�VDX�FRULRUHWLQRSDWLH��FRQYXOVLL���UHWDUG�SVLKR-motor, KHSDWRVSOHQRPHJDOLH��LFWHU�FROHVWDWLF��LQFRQVWDQW���FKLVWXUL�UHQDOH�úL�UHWDUG�VRPDWLF��(YROXĠLD�HVWH�VHYHUă��FX�GHFHV�vQ�SULPul an de YLDĠă�

$GUHQROHXFRGLVWURILD��HVWH�FDX]DWă�GH�PXWDĠLD�XQHL�JHQH�ORFDOL]DWH�SH�FURPR]RPXO�;��;T������FDUH�GHWHUPLQă�VLQWH]D�unei proteine peroxizomale – ALDP – LPSOLFDWă�vQ�PHWDEROLVPXO�DFL]LORU�JUDúL�VDWXUDĠL�FX�ODQĠ�IRDUWH�OXQJ��%RDOD�VH�WUDQVPLWH�receVLY�OHJDW�GH�;�úL�GHEXWHD]ă�GHRELFHL�GXSă�YkUVWD�GH����DQL��SULQ�VFăGHUHD�SHUIRUPDQĠHORU�úFRODUH��WXOEXUăUL�GH�FRPSRUWDPHQW��FRQYXOVLL�úL�LQVXILFLHQĠă�FRUWLFRVXSUDUHQDOă��VH�SURGXFH�DSRL�SLHUGHUHD�SURJUHVLYă�D�YHGHULL��D�YRUELULL�úL�GHPHQĠă��6XIHULQĠa neurRORJLFă�VHYHUă��FDUDFWHULVWLFă�EROLL��HVWH�H[SUHVLD�XQXL�SURFHV�SURJUHVLY�GH�GHPLHOLQL]DUH�FHUHEUDOă��GHWHUPLQDW�GH�HIHFWXO�FLWRWR[LF�DO�DFL]LORU�JUDúL�VDWXUDĠL��FX�ODQĠ�IRDUWH�OXQJ��'LDJQRVWLFXO�HVWH�FRQILUPDW�SULQ�GHPRQVWUDUHD�YDORULORU�FUHVFXWH�Dle acizilor JUDúL�FX�ODQĠ�IRDUWH�OXQJ�vQ�SODVPă�VDX�ILEUREODúWL�

2. BOLI PRODUSE PRIN ANOMALII ALE PROTEINELOR DE TRANSPORT. 'HSODVDUHD�HILFLHQWă�D�PROHFXOHORU�– VSUH�LQWHULRUXO�FHOXOHORU��vQWUH�GLYHUVHOH�ORU�FRPSDUWLPHQWH��SUHFXP�úL�vQWUH�FHOXOH�– necesită�DGHVHRUL�LQWHUYHQĠLD�XQRU�PDFURPROHFXOH�FDUH�PHGLD]ă WUDQVSRUWXO�ORU��&LUFD�R�WUHLPH�GLQ�WRWDOXO�SURWHLQHORU�FDUH�LQWUă�vQ�VWUXFWXUD�diverselor membrane (ale celulelor sau ale diverselor organite) sunt implicate în procese de transport. La aceste procese SDUWLFLSă�vQVă�úL�XQHOH�SURWHLQH�FLWRSODVPDWLFH�VDX�SURWHLQH�GLQ�VSDĠLXO�H[WUDFHOXODU� 1. 3URWHLQHOH�GH�WUDQVSRUW�WUDQVPHPEUDQDUH�SRW�IL�FODVLILFDWH�vQ�SDWUX�FODVH��SULPHOH�GRXă�ILLQG�LPSOLFDWH�vQ�GLIX]LXQHD�IDFLOLWDWă��

LDU�XOWLPHOH�GRXă�vQ�WUDQVSRUWXO�DFWLY: � Proteinele de transport tip canal UHDOL]HD]ă�SRUL�FDUH�SHUPLW�XQRU�PROHFXOH�PLFL��FH�FRUHVSXQG�FD�GLPHQVLXQH�úL�vQFăUFDUH�

HOHFWULFă��Vă�WUDYHUVH]H�PHPEUDQD�UHVSHFWLYă��$VWIHO��aquaporinele SHUPLW�PROHFXOHORU�GH�DSă�Vă�VWUăEDWă�PHPEUDQD�mult mai rapid decât acestea o pot realiza prin stratul fosfolipidic iar canalele ionice PHGLD]ă�SDVDMXO�LRQLORU�SULQ�PHPEUDQH��&DQDOHOH�LRQLFH�VXQW�FDUDFWHUL]DWH�SULQ�WUHL�SURSULHWăĠL��D��WUDQVSRUWXO�UHDOL]DW�HVWH�H[WUHP�GH�UDSLG��E��VXQW�adeseori înalt selective pentru o DQXPLWă�VSHFLH�GH�LRQL��ILLQG�DVWIHO�FODVLILFDWH�vQ�FDQDOH�GH�VRGLX��SRWDVLX��FORU��FDOFLX�VDX�FDQDOH�FDWLRQLFH���F��PDMRULWDWHD�FDQDOHORU�QX�VXQW�SHUPDQHQW�GHVFKLVH��GHVFKLGHUHD�ORU�ILLQG�UHJODWă�ILH�SULQ�OHJDUHD�tranzitorie a unor liganzi (precum neurotransmitatori sau alte molecule de semnalizare – canale ligand dependente), fie FD�UăVSXQV�OD�VFKLPEDUHD�SRWHQĠLDOXOXL�HOHFWULF�GH-a lungul membranei (canale voltaj dependente). Majoritatea canalelor LRQLFH�VXQW�DOFăWXLWH�GLQ�ROLJRPHUL�DL�XQRU�VXEXQLWăĠL�DOID�LGHQWLFH�VDX�RPRORJH�FDUH�IRUPHD]ă�SRULL��DOăWXUL�GH�VXEXQLWăĠWL�EHWD�úL�XQHRUL�JDPPD�FDUH�VXQW�LPSOLFDWH�vQ�UHJODUHD�IXQFĠLHL�ORU��,Q�JHQRPXO�XPDQ�H[LVWă�FLUFD�����GH�JHQH�FDUH�FRGLILFă�GLYHUVH�VXEXQLWăĠL�DOH�FDQDOHORU�LRQLFH�

� Proteinele de transport tiS�FăUăXú� OHDJă�VSHFLILF�DQXPLWH�PROHFXOHOH�OD�QLYHOXO�XQHL�IHĠH�D�PHPEUDQHL�úL�DSRL�VXIHUă�R�PRGLILFDUH�FRQIRUPDWLRQDOă�FDUH�SHUPLWH�PROHFXOHL�Vă�VWUăEDWă�PHPEUDQD�úL�Vă�ILH�HOLEHUDWă�SH�IDĠD�RSXVă��$VHPHQHD�proteine sunt implicate în transportul glucidelRU��DPLQRDFL]LORU��QXFOHR]LGHORU�HWF��([LVWă�WUHL�IRUPH�GH�WUDQVSRUW�PHGLDW�GH�SURWHLQHOH�FăUăXú��uniport �WUDQVSRUWXO�XQHL�VLQJXUH�PROHFXOH�SULQ�GLIX]LXQH�IDFLOLWDWă���cotransport (transportul a GRXă�VDX�PDL�PXOWH�VSHFLL�GH�PROHFXOH�vQ�DFHHDúL�GLUHFĠLH��Vau antiport �WUDQVSRUWXO�D�GRXă�VDX�PDL�PXOWH�VSHFLL�GH�PROHFXOH�vQ�GLUHFĠLL�RSXVH���(OH�QX�XWLOL]HD]ă�QLFL�R�DOWă�VXUVă�GH�HQHUJLH�vQ�DIDUD�GH�HQHUJLD�FKLPLR-RVPRWLFă��&HOH�PDL�LPSRUWDQWH�SHQWUX�SDWRORJLD�XPDQă�VXQW�SURWHLQHOH�GLQ�IDPLOLD�6/&��solute carrier���ÌQ�JHQRPXO�XPDQ�H[LVWă�����JHQH�FDUH�FRGLILFă�SURWHLQH�FH�DSDUĠLQ�DFHVWHL�IDPLOLL�

� Pompele ionice (precum pompa Na+ í�.+��XWLOL]HD]ă�HQHUJLD�REĠLQXWă�SULQ�KLGUROL]D�$73�SHQWUX�GHSODVDUHD�LRQLORU�împotriva XQRU�JUDGLHQWH�GH�FRQFHQWUDĠLH��(OH�IDF�SDUWH din familia transportorilor ATP-D]LFL��FRGLILFDĠL�vQ�JHQRPXO�uman de 251 de gene.

� Familia transportorilor ABC (ATP-ELQGLQJ�FDVVHWWH��HVWH�DVWIHO�GHQXPLWă�GDWRULWă�SUH]HQĠHL�XQRU�GRPHQLL�GH�OHJDUH�D�ATP, înalt conservate. Au fost identificate circa 50 de gHQH�XPDQH�FDUH�FRGLILFă�DVHPHQHD�SURWHLQH�

2. Proteinele de transport intracitoplasmatice sunt implicate în procese precum transportul oxigenului (hemoglobina), WUDQVSRUWXO�DVRFLDW�PLFURWXEXOLORU��GLQHLQD��GLQDFWLQD��úL�NLQH]LQD��VDX�SURFHVHOH�GH�WUDILF�DOH�Vtructurilor membranare �FODWULQHOH��PLR]LQHOH��SURWHLQHOH�5$%�úL�SURWHLQHOH�61$5(��

3. 3URWHLQHOH�GH�WUDQVSRUW�SODVPDWLFH�DVLJXUă�GHSODVDUHD�D�GLYHUúL�FRPSXúL�vQWUH�FRPSDUWLPHQWHOH�RUJDQLVPXOXL��$VD�VXQW�apolipoproteinele, transtiretina, ceruloplasmina etc.

34

TRDWH�DFHVWH�FDWHJRULL�GH�SURWHLQH�LPSOLFDWH�vQ�WUDQVSRUWXO�XQRU�PROHFXOH�SRW�VXIHUL�PRGLILFăUL�GHWHUPLQDWH�GH�PXWDĠLL��FH�SURduc boli monogenice (vezi tabelul 11.2).

0XWDĠLLOH�LPSOLFDWH�vQ�SURGXFHUHD�XQRU�EROL�DOH�SURWHLQHORU�GH�WUDQVSRUW�SRW�GHWHUPLQD�ILH�SLHUGHUH�GH�IXQFĠLH��ILH�FkWLJ�GH�IXQFĠLH�� � 0XWDĠLLOH�FX�SLHGHUHD�IXQFĠLHL GHWHUPLQă�boli recesive��DúD�FXP�VXQW�ILEUR]D�FKLVWLFă�VDX�VLQGURPXO�%DUWWHU��,Q�FD]XO�SURWHLQHORU�

FDUH�IRUPHD]ă�FRPSOH[H�PXOWLPHULFH��DFHVW�WLS�GH�PXWDĠLL�SRW�DYHD�vQVă�efecte dominant negative. Este interesant de observat Fă�vQ�IXQFĠLH�GH�SUH]HQĠD�VDX�DEVHQĠD�HIHFWHORU�GRPLQDQW�QHJDWLYH��PXWDĠLL�GLIHULWH�OD�QLYHOXO�DFHOHLDúL�JHQH�SRW�GHWHUPLQD�Iie EROL�UHFHVLYH��ILH�EROL�GRPLQDQWH��$úD�HVWH�GH�H[HPSOX�FD]XO�PXWDĠLLORU�JHQHL�&/&1� �FDUH�FRGLILFă�FDQDOXO�GH�FORU�GH�OD�QLYHOXO�PXúFKLORU�VFKHOHWLFL���XQHOH�PXWDĠLL�GHWHUPLQă�IRUPD�UHFHVLYă��WLS�%HFNHU��GH�PLRWRQLH�FRQJHQLWDOă��DOWH�PXWDĠLL�SURGuc IRUPD�GRPLQDQWă��WLS�7KRPVHQ���,Q�SOXV��IRUPHOH�UHFHVLYH�GH�ERDOă�SRW�SUH]HQWD�VLPSWRPH�FDOLWDWLY�QRL�IDĠă�GH�IRUPHOH�GRPLQDQWH��GH�H[HPSOX��SDFLHQĠLL�KHWHUR]LJRĠL�SHQWUX�PXWDĠLL���GRPLQDQW�QHJDWLYH�DOH�JHQHL�.&14���FDQDOXO�GH�SRWDVLX�YROWDM�GHSHQGHQW�WLS����SUH]LQWă�VLQGURP�47-lung cu aritmii cardiace severe (sindromul Romano-Ward), în timp ce PXWDĠLLOH�UHFHVLYH��FDUH�GHWHUPLQă�SLHUGHUHD�FRPSOHWă�D�IXQFĠLHL��YRU�FRQGXFH�OD�KRPR]LJRĠL�OD�DVRFLHUHD�DULWPLLORU�FX��VXUGLWDWHD�FRQJHQLWDOă��VLQGURPXO�-HUYHOO-Lange-Nielsen).

� 0XWDĠLLOH�FX�FkúWLJ�GH�IXQFĠLH care vor produce de obicei boli transmise domLQDQW��8Q�H[HPSOX�vO�FRQVWLWXLH�PXWDĠLLOH�VXEXQLWăĠLORU�EHWD�VDX�JDPPD�DOH�FDQDOXOXL�UHQDO�HSLWHOLDO�GH�VRGLX��6&11�%�VDX�6&11�*��LPSOLFDWH�vQ�SURGXFHUHD�sindromului Liddle (pseudoaldosteronism).

$YkQG�vQ�YHGHUH�QXPăUXO�IRDUWH�PDUH�GH�EROL�JHQHWLFH�FDUH�Sot fi produse prin anomalii ale proteinelor de transport WUHFHUH�ORU�vQ�UHYLVWă�GHSăúHVWH�VFRSXO�DFHVWXL�FDSLWRO��GH�DFHHD�DP�UHDOL]DW�vQ�WDEHOXO������R�VLQWH]ă�D�SULQFLSDOHORU�FDWHJRULL�úL�WLSXUL�PDL�IUHFYHQWH�GH�EROL�úL�QH�YRP�OLPLWD�vQ�FHOH�FH�XUPHD]ă�Goar la prezentarea unui exemplu ilustrativ – ILEUR]D�FKLVWLFă� 2.1.),%52=$�&+,67,&Ă� )LEUR]D�FKLVWLFă�VDX�PXFRYLVFLGR]D��20,0���������HVWH�XQD�GLQWUH�FHOH�PDL�IUHFYHQWH�EROL�JHQHWLFH�FX��WUDQVPLWHUH�DXWRVRPDO�UHFHVLYă�GLQ�SRSXODĠLD�FDXFD]LDQă���SUHYDOHQĠD�VD�ILLQG�HVWLPDWă�OD�DSUR[LPDWLY���������LDU�LQFLGHQĠD�SXUWăWRULORU�VăQăWRúL��1D��– la 1/25. Simptomatologie. 3ULQFLSDOHOH�PDQLIHVWăUL�FOLQLFH�DOH�EROLL�VXQW�GHWHUPLQDWH�GH�DIHFWDUHD�SOăPkQLORU�úL�SDQFUHDVXOXL exocrin. Afectarea acestor organe este rezXOWDWXO�VHFUHĠLLORU�YkVFRDVH�DOH�JODQGHORU�H[RFULQH��FDUH�GHWHUPLQă�REVWUXFĠLD�VWUXFWXULORU�FDQDOLFXODUH��/D�QLYHO�SXOPRQDU�DFHDVWD�GHWHUPLQă�LQIHFĠLL�UHFXUHQWH FX�HYROXĠLH�VSUH�LQVXILFLHQĠD�SXOPRQDUă��LDU�REVWUXFĠLD�canalelor pancreatice are drept conseciQĠă�GHILFLHQĠD�HQ]LPHORU�SDQFUHDWLFH��FX�afectarea digestiei. Un semn major pentru diagnostic este FUHúWHUHD�FRQFHQWUDĠLHL�GH�VRGLX�úL�FORU�vQ�VHFUHĠLLOH�VXGRUDOH (peste 60mEq/L���$OWH�PDQLIHVWăUL�FOLQLFH�FRQVWDX�în ileusul meconial, la 10-25% din nou-QăVFXĠLL�FX�ILEUR]D�FKLVWLFă��úL�DEVHQĠD�FRQJHQLWDOă�ELODWHUDOă�D�YDVHORU�GHIHUHQWH OD�EăLHĠL�în 95% din cazuri. *HQHWLFă��*HQD�UHVSRQVDELOă�GH�SURGXFHUHD�EROLL�D�IRVW�LGHQWLILFDWă�SULQ�FORQDUH�vQ������úL�GHQXPLWă�&)��GH�OD�cystic fibrosis���$QDOL]HOH�IXQFĠLRQDOH�DX�GHPRQVWUDW�Fă�SURWHLQD�FRGLILFDWă�GH�JHQD�&)��GHQXPLWă�&)75��DFĠLRQHD]ă�FD�XQ�FDQDO�GH�FORU�ORFDOL]DW�OD�QLYHOXO�SROXOXL�DSLFDO�DO�FHOXOHORU�HSLWHOLDOH�DIHFWDWH�vQ�FDGUXO�DFHVWHL�EROL��5HFHQW��JHQD�&)�D�IRVW�LQFOXVă�vn familia genelor transportoriORU�$%&��FX�FDVHWă�GH�OHJDUH�D�$73���ILLQG�GHVHPQDWă�FD�$%&&���)UHFYHQĠD�FUHVFXWă�D�KHWHUR]LJRĠLORU�vQ�SRSXODĠLD�JHQHUDOă�D�FRQGXV�OD�HPLWHUHD�LSRWH]HL�Fă�VWDUHD�GH�KHWHUR]LJRW�SUH]LQWă�XQ�DYDQWDM�VHOHFWLY��DFHDVWă�LSRWH]ă�HVWH�VXVĠLQXWă�de descoperirea faSWXOXL�Fă�SURGXVXO�SURWHLF�DO�JHQHL�$%&&��IXQFĠLRQHD]ă�FD�UHFHSWRU�SHQWUX�Salmonella typhimurium úL�HVWH�LPSOLFDW�vQ�LPXQLWDWHD�vPSRWULYD�LQIHFĠLLORU�FX�Pseudomonas aeruginosa, GHFL�KHWHUR]LJRĠLL�VXQW�PDL�UH]LVWHQĠL�OD�DFHVWH�LQIHFĠLL� Gena ABCC7 este locDOL]DWă�SH�FURPRVRPXO��T���úL�FRQĠLQH����GH�H[RQL�FDUH�FRGLILFă�R�SURWHLQă�FDQDO�GH�FORU�WUDQVPHPEUDQDUă�DOFăWXLWă�GLQ�FLQFL�GRPHQLL�IXQFĠLRQDOH��GRXă�GRPHQLL�WUDQVPHPEUDQDUH��06'�– membrane spanning domains), GRXă�GRPHQLL�GH�OHJDUH�D�$73��1%'�– nucleotide binding domains��úL�XQ�GRPHQLX�UHJODWRU��5��FX�PDL�PXOWH�VLWXVXUL�GH�fosforilare (figura 11.5���3ULPD�PXWDĠLH�LGHQWLILFDWă�D�IRVW�R�GHOHĠLH�D�WUHL�QXFOHRWLGH�VROGDWă�FX�DEVHQĠD�DPLQRDFLGXOXL�IHQLODODQLQD�GLQ�SR]LĠLD�����D�SURWHLQHL�� �ŇĶıĹĪįġłŤŦŢŴŵ�ġŮŶŵŢ�ŪH�HVWH�FHD�PDL�IUHFYHQWă�vQ�SRSXODĠLD�FDXFD]LDQă��UHSUH]HQWkQG�FLUFD�����GLQ�WRDWH�PXWDĠLLOH��$X�IRVW�GHVFULVH�vQVă�QXPHURDVH�DOWH�PXWDĠLL��GHúL�GRDU���GLQWUH�HOH�DX�IUHFYHQWH�FDUH�GHSDVHVF��������)UFHYHQĠD�ORU�vQ�GLIHULWH�SRSXODĠLL�HVWH�vQVă�YDULDWă��$VWIHO��PXWDĠLD�:����;�HVWH�SUH]HQWă�OD�����GLQWUH�EROQDYLL�GLQ�FRPXQLWDWHD�HYUHLORU�$VKNHQD]L��vQ�WLPS�FH�PXWDĠLD�����GHO7$�HVWH�vQWLOQLWă�FX�R�IUHFYHQĠă�FUHVFXWă�vQ�%DOFDQL�úL�$VLD�0LFD��,Q�SRSXODĠLLOH�vQ�FDUe IUHFYHQĠD�DOHOHL� �ŇĶıĹġŦŴŵŦġťŦġŢűųŰŹŪŮŢŵŪŷġĸıĦĭġPDL�PXOW�GH�MXPDWDWH�GLQWUH�SDFLHQĠL�VXQW�KRPR]LJRĠL�SHQWUX�DFHDVWă�PXWDĠLH��vQ�WLPS�FH�DOĠL�����VXQW�KHWHUR]LJRĠL�FRPSXúL� S-DX�GHVFULV�SDWUX�FODVH�GH�PXWDĠLL�DOH�JHQHL�$%&&��� � PXWDĠLLOH�GH�FODVD�,�FRQGXF�OD�GHIHFWH�vQ�SURGXFĠLD�SURWHLQHL��DVWIHO�GH�PXWDWLL�VXQW�FHOH�FDUH�GHWHUPLQD�DSDULĠLD�XQRU�FRGRQL�

stop sau a unor specii instabile de ARNm; � PXWDĠLLOH�GH�FODVD�,,��FXP�HVWH��GH�H[HPSOX�� �ŇĶıĹĪġŢŶġ ġ ġ ġ ġ ġ ġ ġ ġ ġde

plicaturare); � PXWDĠLLOH�GH�FODVD�,,,�DSDU�OD�QLYHOXO�GRPHQLLORU�1%'�VDX�5�úL�SURGXF�GHUHJODUL�DOH�DFWLYLWăĠLL�SURWHLQHL�� � PXWDĠLLOH�GH�FODVD�,9�VXQW�ORFDOL]DWH�OD�QLYHOXO�GRPHQLLORU�0%'�úL�DOWHUHD]ă�FDSDFLWDWHD�GH�WUDQVSRUW�D�FORUXOXL�� *UDGXO�FUHVFXW�GH�KHWHURJHQLWDWH�FOLQLFă�REVHUYDW�vQ FDGUXO�EROLL�HVWH�GHWHUPLQDW�GH�KHWHURJHQLWDWHD�DOHOLFă��GDU�úL�GH�LQWHUYHQĠLD�XQRU�gene modificatoare sau a unor factori de mediu. S-D�VWDELOLW�H[LVWHQĠD�XQHL�FRUHODWLL�vQWUH�WLSXO�PXWDĠLLORU�úL�IXQFĠLD�SDQFUHDWLFă��$VWIHO��PXWDĠLLOH�QRQVHQV�FDUH�SURGXF�DOHOH�QXOH�VDX�KRPR]LJR]LWDWHD�SHQWUX�PXWDĠLD� �ŇĶıĹġŵŪů ġ ġ ġ ġ ġġLQVXILFLHQĠD�SDQFUHDWLFă��vQ�WLPS�FH�PXWDĠLLOH�FDUH�SHUPLW�VLQWH]D�XQHL�SURWHLQH�SDUĠLDO�IXQFĠLRQDOH�– ca, de exemplu, R334W – nu DOWHUHD]ă�IXQFĠLD�SDQFUHDWLFă��,Q�VFKLPE��OD�SXUWăWRULL�DFHOHHDúL�PXWDĠLL�H[LVWă�XQ�JUDG�FUHVFXW�GH�YDULDELOLWDWH�D�DOWHUăULL�SXOPRQDUH��3kQă�vQ�SUH]HQW��QX�D�IRVW�LGHQWLILFDWă�QLFL�R�JHQă�PRGLILFDWRDUH�D�IHQRWLSXOXL�SXOPRQDU��vQVă�R�JHQă�PRGLILFDWRDUH��FDUH�LQIOXHQĠHD]ă�DSDULĠLD�LOHXVXOXL�PHFRQLDO�D�IRVW ORFDOL]DWă�SH�FURPRVRPXO���T����,Q�VIkUúLW��OD�SDFLHQĠLL�KRPR]LJRWL�SHQWUX�DOHOH�FDUH�DOWHUHD]ă�GRDU�vQWU-R�PăVXUă�UHGXVă�IXQFĠLD�&)75�VLQJXUXO�VHPQ�DO�EROLL�LO�SRDWH�UHSUH]HQWD�GRDU�DEVHQĠD�FRQJHQLWDOă�ELODWHUDOă�D�vaselor deferente. Recent s-a constatat FD�KHWHUR]LJRĠLL�SHQWUX�PXWDĠLL�&)�SRW�DYHD�R�LQFLGHQĠă�FUHVFXWă�D�SDQFUHDWLWHL�úL�bronsiectaziei.

35

Screening neonatal��)LEUR]D�FKLVWLFă�vQWUXQHúWH�PDMRULWDWHD�FULWHULLORU�QHFHVDUH�SHQWUX�LQWURGXFHUHD�VD�vQ�SURJUDPHOH�GH�screening neonatal. Cu toate acestHD��QX�HVWH�FODU�GDFă�GHWHFWDUHD�SULQ�VFUHHQLQJ�D�SDFLHQĠLORU�vPEXQăWăWHúWH�VHPQLILFDWLY�VXSUDYLHĠXLUHD�ORU��8Q�REVWDFRO�LO�FRQVWLWXLH��KHWHURJHQLWDWHD�JHQHWLFă�D�EROLL��SHVWH����GLQWUH�SDFLHQĠL�ILLQG�KHWHUR]LJRĠL�FRPSXúL�SHQWUX�DOHOH�UDUH�vQ�SRSXODĠLH��7Lpic, screening-XO�HVWH�UHDOL]DW�SHQWUX����SkQă�OD����GLQWUH�FHOH�PDL�IUHFYHQWH�PXWDĠLL�GLQ�UHJLXQHD�JHRJUDILFă�UHVSHFWLYă�

Diagnostic prenatal HVWH�LQGLFDW�vQ�VSHFLDO�vQ�FD]XO�IDPLOLLORU�vQ�FDUH�H[LVWă�EROQDYL�FX�ILEUR]ă�FKLVWLFă�� Tratament. In prezent, FLUFD�����GLQ�SDFLHQĠL�GHSăúHVF�YkUVWD�GH����GH�DQL��8Q�URO�PDMRU�vQ�SUHOXQJLUHD�YLHWLL�vO�DX�WUDWDPHQWXO�LQWHQVLY�DO�EROLL�SXOPRQDUH�úL�VXSOLPHQWDUHD�HQ]LPHORU�SDQFUHDWLFH� 3. BOLI PRIN ANOMALII ALE PROTEINELOR STRUCTURALE Proteinele structurale asigură�IRUPD�úL�RUJDQL]DUHD�FDUDFWHULVWLFă�D�FHOXOHORU�úL�ĠHVXWXULORU�FLWRSODVPHL��6H�SRW�GHRVHEL�WUHL�FDWHJRULL�PDMRUH�GH�SURWHLQH�VWUXFWXUDOH��SURWHLQH�DOH�FLWRVFKHOHWXOXL�FHOXODU��SURWHLQH�DOH�VWUXFWXULL�PHPEUDQDUH�úL�SURWHLQH�VWUXFWXUale extracelulare. � CitRVFKHOHWXO�FHOXODU�HVWH�DOFăWXLW�GLQ�WUHL�WLSXUL�SULQFLSDOH�GH�SURWHLQH�ILODPHQWRDVH��ILODPHQWHOH�GH�DFWLQD��ILODPHQWHOH�

LQWHUPHGLDUH�úL�PLFURWXEXOLL��FDUH�VXQW�PHQĠLQXWH�vPSUHXQă�úL�DWDúDWH�OD�RUJDQLWHOH�FHOXODUH�úL�OD�PHPEUDQD�SODVPDWLFă�SULQWU-o varietate de proteine accesorii. )LODPHQWHOH�GH�DFWLQă�VXQW�DOFăWXLWH�vQ�SULQFLSDO�GLQ�PRQRPHUL�GH�DFWLQă�* �JDPPD��SROLPHUL]DĠL�VXE�IRUPD�XQRU�ILODPHQWH�FX�DVSHFW�GXEOX�KHOLFRLGDO��$FHVWH�ILODPHQWH�VH�DVRFLD]ă�FX�R�VHULH�GH�SURWHLQH�FDUH�DX�URO�vQ�RUJDQL]DUHD�vQ�UHĠHOH�D�ILODPHQWHORU�GH�DFWLQă��SUHFXP�alfa-actinina, filamina, vilina úL�fimbrina��)LODPHQWHOH�GH�DFWLQă�VH�DWDúHD]ă�úL�OD�QLYHOXO�PHPEUDQHL�FHOXODUH�SULQ�LQWHUPHGLXO�XQRU�FRPSOH[H�SURWHLFH��GLIHULWH�vQ�IXQFĠLH�GH�WLSXO�FHOXODU��$VWIHO��OD�QLYHOXO�eritURFLWHORU��UHĠHDXD�ILODPHQWHORU�GH�DFWLQă�HVWH�DWDúDWă�OD�QLYHOXO�proteinelor banda 3 membranare prin intermediul unor FRPSOH[H�SURWHLFH�FDUH�FRQĠLQ�spectrina, ankirina, proteina banda 4.1 úL�aducina. Alte proteine din familia spectrinei sunt distrofina (in celulele musculare striate) sau fodrina. In plachete, filamina este echivalentul proteinei 4.1 eritrocitare iar în celulele epiteliale ezrina DWDúHD]ă�ILODPHQWHOH�GH�DFWLQD�OD�&)75��,Q�VIkUúLW��ILODPHQWHOH�GH�DFWLQă�SRW�IL�DWDúDWH�OD�R�VHULH�GH�structuri VSHFLDOL]DWH�DOH�PHPEUDQHL�SODVPDWLFH�QXPLWH�MRQFĠLXQL��$VWIHO��talina, vinculina úL�alfa-catenina PHGLD]ă�DQFRUDUHD�ILODPHQWHORU�GH�DFWLQă�OD�integrinele GLQ�VWUXFWXUD�MRQFĠLXQLORU�IRFDOH��vQ�WLPS�FH�beta-cateninele PHGLD]ă�LQWHUDFĠLXQHD�ILODPHQWHORU�GH�actina cu caderinele GLQ�VWUXFWXUD�MRQFĠLXQLORU�DGHUHQWH� )LODPHQWHOH�LQWHUPHGLDUH�VXQW�DOFăWXLWH�GLQWU-R�YDULHWDWH�GH�SURWHLQH�FDUH�GLIHUă�vQ�IXQFĠLH�GH�WLSXO�FHOXODU��$X�IRVW�identificate peste 50 asemenea proteine care au fost clasificate în 6 grupuri: tipul I (keratinele acide – localizate în celulele epiteliale), tipul II (keratinele neutre úL�bazice – în celulele epiteliale), tipul III (vimentina – vQ�ILEUREODúWL��HULWURFLWH��desmina – în celulele musculare, SURWHLQD�ILEULODUD�DFLGă�ED]LFă�JOLDOă – în celulele gliale, periferina – în neuronii periferici), tipul IV (proteinele neurofilamentare: NF-L, NF-M, NF-H – în neuroni), tipul V (laminele A, B úL�C în PHPEUDQHOH�QXFOHDUH��úL�WLSXO�9,��nestina – în celulele stem ale SNC). Filamentele intermediare sunt deseori organizate sub IRUPD�XQRU�KHWHURGLPHUL��GH�H[HPSOX�NHUDWLQHOH�WLS�,�úL�,,�VXQW�vQWRWGHDXQD�KHWHURGLPHUL��OD�IHO�FD�úL�QHXURILODPHQWHOH���)LODPHQWHOH�GH�NHUDWLQă�úL�YLPHQWLQD�VXQW�DWDúDWH�OD�PHPEUDQD�QXFOHDUă��DYkQG�VH�SDUH�URO�vQ�SR]LĠLRQDUHD�DFHVWXLD�vQ�FHOXOă��,Q�SOXV��ILODPHQWHOH�LQWHUPHGLDUH�VXQW�DWDúDWH�úL�OD�QLYHOXO�D�GRXă�VWUXFWXUL�VSHFLDOL]DWH�DOH�PHPEUDQHL�SODVPDWLFH��GHVPR]RPLL�úL�KHPLGHVPR]RPLL� 0LFURWXEXOLL�VXQW�DOFăWXLĠL�GLQ�GRXă�WLSXUL�SULQFLSDOH�GH�SURWHLQH��tubulinele alfa úL�beta��(L�VXQW�LPSOLFDĠL�vQ�UHDOL]DUHD�structurilor caracteristice unor tipuri celulare, cum sunt axonii celulelor nervoase, axonema flagelului spermatozoizilor sau EDQGD�PDUJLQDOă�D�SODFKHWHORU��SUHFXP�úL�vQ�IXQFĠLRQDUHD�DSDUDWXOXL�PLWRWLF�HWF��

� Proteinele de VWUXFWXUă�PHPEUDQDUH�VXQW�LPSOLFDWH�vQ�DGH]LXQHD��úL��FRPXQLFDUHD�LQWHUFHOXODUă��([LVWă�FLQFL�FODVH�SULQFLSDOH�GH�SURWHLQH�GH�DGH]LXQH�LQWHUFHOXODUă��&$0V�– cell adhesion molecules): caderinele (precum caderinele E, 3�úL�1), superfamilia imunogobulinelor (N-CAM úL�I-CAM), selectinele (precum selectina P), mucinele úL�integrinele (reprezentate de integrinele DOID�úL�EHWD���'HúL�VXWH�GH�DVHPHQHD�SURWHLQH�LQGLYLGXDOH�VXQW�VXILFLHQWH�SHQWUX�D�DVLJXUD�DGH]LXQHD�LQWHUFHOXODUă��H[LVWă�úL�R�VHULH�GH�DJORPHUăUL�DOH�XQRU�DVHPHQHD�SURWHLQH�FDUH�UHDOL]HD]ă�VWUXFWXUL�VSHFLDOL]DWH�vQ�DGH]LXQHD�LQWHUFHOXODUă��$FHVWHD�VXQW�reprezentate de MRQFĠLXQLOH�DGHUHQWH �FH�FRQĠLQ�caderine E DOăWXUL�GH�cateninele alfa úL�beta), desmozomii �DOFăWXLWH�GLQ�plakoglobina, desmogleina – înrXGLWă�FX�FDGHULQHOH�úL�desmocolina), MRQFĠLXQLOH�VWUkQVH �DOFăWXLWH�GLQ�claudine úL�ocludine��úL�MRQFĠLXQLOH�JDS �DOFăWXLWH�GLQ�conexine,cu în comunicarea intercelulara).

� Proteinele matricei extracelulare au drept reprezentant principal colagenul, cea mai DEXQGHQWă�SURWHLQă�DQLPDOă��6H�FXQRVF�peste 30 de tipuri de colagen care sunt caracterizate prin formarea unor triplu-helixuri. Alte componente proteice majore ale matricei extracelulare sunt elastinele, fibrilinele úL�fibronectina, ultima fiind principala SURWHLQă�GH�DGH]LXQH�D�FRPSRQHQWHORU�ĠHVXWXOXL�FRQMXQFWLY�vQWUH�HOH�SUHFXP�úL�OD�LQWHJULQHOH�PHPEUDQDUH��3ULQWUH�VSHFLDOL]ăULOH�PDWULFHL�H[WUDFHOXODUH�VH�QXPăUă�ODPLQD�ED]DOă�DOFăWXLWD�GLQWU-R�UHĠHD�GH�colagen tip IV, ODPLQLQă, SHUOHFDQ�úL�HQDFWLQă.

MutaĠLLOH�JHQHORU��FH�FRGLILFă�SURWHLQHORU�VWUXFWXUDOH�GHWHUPLQă�EROL�JHQHWLFH�FDUH�SRW�DIHFWD�WRDWH�RUJDQHOH�úL�VLVWHPHOH��Printre clasele cele mai frecvente pot fi amintite colagenozele, keratinopatiile, fibrilinopatiile, distrofiile musculare etc. Intrucât PXOWH�GLQ�SURWHLQHOH�GH�VWUXFWXUă�GHVFULVH�DQWHULRU�IRUPHD]ă�KRPR- VDX�KHWHURSROLPHUL��PXWDĠLLOH�ORU�YRU�DYHD�DGHVHRUL�efecte dominant-negative, ceea ce va conduce la o WUDQVPLWHUH�GRPLQDQWă D�EROLORU��$úD�VXQW�PDMRULWDWHD�EROLORU�SURWHLQHORU�PDWULFHL�extUDFHOXODUH�VDX�DOH�ILODPHQWHORU�LQWHUPHGLDUH��'DWă�ILLQG�DVHPăQDUHD�VWUXFWXUDOă�úL�IXQFĠLRQDOă�D�SURWHLQHORU�GLQ�DQXPLWH�IDPLlii �SUHFXP�FHD�D�FRODJHQLORU��NHUDWLQHORU�HWF����PXWDĠLL�OD�QLYHOXO�XQRU�JHQH�GLIHULWH�SRW�SURGXFH�EROL�JHQHWLFH�LGHQWLFH�FOLQLF.

'H�H[HPSOX��vQ�FD]XO�NHUDWLQRSDWLLORU��NHUDWLQRSDWLD�SDOPRSODQWDUă�HSLGHUPROLWLFă�HVWH�GHWHUPLQDWă�GH�PXWDĠLL�DOH�JHQHORU�.57��úL�.57���GLVWURILD�FRUQHDOD�0HHVPDQQ�HVWH�GHWHUPLQDWă�GH�PXWDĠLL�DOH�JHQHORU�.57��úL�.57����vQ�WLPS�FH�SDFKLRQLFKLD�FRQJHQLWDOă�HVWH�GHWHUPLQDWă�GH�PXWDĠLL�DOH�JHQHORU�.57�$��.57�%��.57���úL�.57���

3H�GH�DOWă�SDUWH��DFHVW�IHQRPHQ�DO�KHWHURJHQLWăĠLL�JHQHWLFH�GH�ORFXV�HVWH�DVRFLDW�FX�IHQRPHQXO�LQYHUV��vQ�FDUH�PXWDĠLLOH�XQHL singure gene pot determina boli genetice diferite.

Astfel, PXWDĠLLOH�JHQHL�SHQWUX�ODPLQD�$�SURGXF��GLVWURILD�PXVFXODUD�(PHU\�'UHLIXVV�FX�WUDQVPLWHUH�$'��20,0����������GLVWURILD�PXVFXODUă�D�FHQWXULORU�WLS��%��20,0����������FDUGLRPLRSDWLD�GLODWDWLYă�tip 1 (cu defect de conducere – OMIM

36

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În tabelul 11.3 am selectat exemplele cele mai reprezentative de boli monogenice produse prin anomali ale unor proteine VWUXFWXUDOH��SHQWUX�D�DYHD�R�LQIRUPDĠLH�SUHOLPLQDUă�SULYLQG�FRPSOH[LWDWHD�DFHVWHL�FDWHJRULL�GH�EROL�úL�LQGLFDĠLLOH�20,0�SHQWUu REĠLQHUHD�XQRU�GDWH�VXSOLPHQWDUH��ÌQ�FHHD�FH�XUPHD]ă�YRP�GHVFULH�FkWHYD�GLQWUH�FHOH�PDL�IUHFYHQWH�EROL�GLQ�DFHDVWă�FDWHJRULH��GLVWURILLOH�PXVFXODUH�'XFKHQQH�úL�%HFNHU��RVWHRJHQHVLV�LPSHUIHFWD��VIHURFLWR]D�HUHGLWDUă��VLQGURPXO�(KOHUV-Danlos; sindromul Marfan a fost descris în capitolul 4 (vezi caseta 4.1). 3.1. DISTROFIA MUSCUL$5Ă�'8&+(11(� 'LVWURILD�PXVFXODUă�'XFKHQQH��20,0���������HVWH�R�ERDOă�WUDQVPLVă�OHJDW�GH�; FX�R�LQFLGHQĠă�GH�FLUFD���OD������QRX-QăVFXĠL�GH�VH[�PDVFXOLQ��*HQD�D�FăUHL�PXWDĠLL�GHWHUPLQă�GLVWURILD�PXVFXODUă�'XFKHQQH�D�IRVW�LGHQWLILFDWă�vQ������ILLQG�XQD�GLQWre primele GHVFRSHULUL�PDMRUH�FDUH�DX�HYLGHQĠLDW�SRWHQĠLDOXO�SH�FDUH�vO�DUH�PHGLFLQD�PROHFXODUă�� Simptomatologie. 3DFLHQĠLL�VH�GH]YROWă�QRUPDO�SkQă�OD�YkUVWD�GH���– ��DQL��FkQG�vQFHS�Vă�DSDUă�VHPQH�GH�hipotrofie �GLVWURILH��PXVFXODUă PDQLIHVWDWă�SUHGRPLQant prin KLSRWRQLH�PXVFXODUă��$FHDVWD�GHEXWHD]ă�OD�QLYHOXO�PXVFXODWXULL�PHPEUHORU�LQIHULRDUH�úL�HYROXHD]ă�DVFHQGHQW��SkQă�FH�DIHFWHD]ă�PXVFXODWXUD�UHVSLUDWRULH�úL�GHWHUPLQă�GHFHVXO�SDFLHQĠLORU�SULQ�LQVXILFLHQĠD�respiratorie în jurul vârstei de 20 de ani. LD�DFHVWH�IHQRPHQH�VH�DVRFLD]ă�úL�retardul mintal moderat, cu o reducere medie a QI de ���SXQFWH��)RUPD�%HFNHU�GH�GLVWURILH�PXVFXODUă�HVWH�GHWHUPLQDWă��GH�DVHPHQHD��GH�PXWDĠLL�DOH�JHQHL�SHQWUX�GLVWURILQă��FLUFD��5% GLQ�PXWDĠLLOH�DFHVWXL�ORFXV���GDU�PDQLIHVWăULOH�FOLQLFH�VXQW�PDL�SXĠLQ�VHYHUH��LDU�VXSUDYLHĠXLUHD�HVWH�PDL�vQGHOXQJDWă��0DMRULWDWHD�IHPHLORU�SXUWăWRDUH�QX�SUH]LQWă�PDQLIHVWăUL�FOLQLFH��GHúL�����GLQ�HOH�DX�QLYHOH�FUHVFXWH�DOH�FUHDWLQNLQD]HL�VHULFH��,QDFWLYDUea SUHIHUHQĠLDOă�D�FURPRVRPXOXL�;�SXUWăWRU�DO�PXWDĠLHL�SDUH�D�FRQWULEXL�OD�DEVHQĠD�PDQLIHVWăULORU�FOLQLFH�OD�IHPHLOH�SXUWăWRDUH��([LVWă�vQVă�úL�FD]XUL��FLUFD����GLQ�IHPHLOH�KHWHUR]LJRWH��FkQG�LQDFWLYDUHD�FURPRVRPXOXL�;�LQWHUHVHD]ă�SUHIHUHQĠLDO�FURPRVRPXO�;�FX�JHQD�'0'�QRUPDOă��FHHD�FH�GHWHUPLQă�KLSRWRQLH�PXVFXODUă�VHPQLILFDWLYă��([LVWă�FKLDU�úL�FD]XUL�UDUH�GH�PDQLIHVWăUL�FOLQLFH�FRPSOHWH�OD�VH[XO�IHPLQLQ�LQ�XQHOH�WUDQVORFDĠLL�;��DXWRVRPDOH�VDX�vQ�VLQGURPXO�7XUQHU�� *HQHWLFă��*HQD�'0'�HVWH�FHD�PDL�PDUH�JHQă�XPDQă��FX�R�OXQJLPH�GH�SHVWH���0E��DGLFă 1,5% din lungimea FURPRVRPXOXL�;��$FHDVWă�OXQJLPH�H[SOLFă�FHO�SXĠLQ�vQ�SDUWH�UDWD�FUHVFXWă�D�PXWDĠLLORU�ORFXV����-4) comparativ cu alte gene. Gena HVWH�DOFăWXLWă�GLQ����GH�H[RQL��FX���SURPRWRUL�FDUH�VXQW�UHVSRQVDELOL�GH�SURGXFHUHD�GH�L]RIRUPH�FX�VSHFLILFLWDWH�WLVXODUă��,]RIRUPD�PDMRUă�HVWH�R�SURWHLQă�YROXPLQRDVă������N'��FDUH�SUHGRPLQă�vQ�PXúFKLL�VFKHOHWLFL��LQ�PLRFDUG�úL�vQ�FUHLHU�úL�vQGHSOLQHúWH�GRXă�IXQFĠLL�PDMRUH��URO�VWUXFWXUDO�vQ�PHQĠLQHUHD�LQWHJULWăĠLL�PHPEUDQHL��SULQ�PHGLHUHD�LQWHUDFĠLXQLL�vQWUH�FLWRVFKHOHWXO�DFWLQLF�úL�PDWULFHD�H[WUDFHOXODUă�– vezi figura 11.6��úL�URO�vQ�IXQFĠLRQDUHD�MRQFĠLXQLORU�VLQDSWLFH�� &HOH�PDL�IUHFYHQWH�PXWDĠLL�OD�SDFLHQĠLL�FX�GLVWURILH�PXVFXODUă�'XFKHQQH�VXQW�GHOHĠLLOH (60%) care în marea lor majoritate sunt localizate în UHJLXQHD���VDX�vQ�]RQD�FHQWUDOă�D�JHQHL��0XWDĠLLOH�SXQFWLIRUPH�UHSUH]LQWă�FLUFD�R�WUHLPH�GLQ�FD]XUL�úL�VXQW�UăVSkQGLWH�SH�vQWUHDJD�OXQJLPH�D�JHQHL��&LUFD�R�WUHLPH�GLQ�FD]XULOH�GH�'0'�VXQW�GHWHUPLQDWH�GH�PXWDĠLL�GH�QRYR, în timp ce restul provin de la mame SXUWăWRDUH�DOH�PXWDĠLHL��'HRDUHFH�ERDOD�HVWH�OHWDOă��EăUEDĠLL�DIHFWDWL�QX�WUDQVPLW�PXWDĠLD��,Q�FD]XO�IRUPHL�%HFNHU�GH�ERDOă��FDSDFLWDWHD�UHSURGXFWLYă�HVWH�GH�FLUFD������LDU�EăUEDWLL�EROQDYL�SRW�WUDQVPLWH�PXWDĠLD�OD�IHWHOH�ORU��&D�XUPare, o SURSRUĠLH�vQVHPQDWă�GLQ�FD]XUL�VXQW�PRúWHQLWH�vQ�IDPLOLH�úL�GRDU�����VXQW�GHWHUPLQDWH�GH�PXWDĠLL�GH�QRYR� Diagnostic prenatal al DMD este posibil. In 60-����GLQ�FD]XUL��GHWHUPLQDWH�GH�GHOHĠLL��GHIHFWXO�SRDWH�IL�SXV�vQ�HYLGHQĠD�prin Southern blot sau prin PCR multiplex (figura 11.7���,Q�IDPLOLLOH�vQ�FDUH�PXWDĠLD�QX�HVWH�FXQRVFXWă�VH�SRW�XWLOL]D�DQDOL]HOH�GH�vQOăQĠXLUH��'H�DVHPHQL��LGHQWLILFDUHD�IHPHLORU�SXUWăWRDUH�SULQWUH�UXGHOH�XQRU�EăLHĠL�DIHFWDĠL�VH�SRDWH�UHDOL]D�FX�VXFFHV�vQ��5% din cazuri, prin dozarea nivelului creatinkinazei serice. Tratament. 6LQJXUXO�WUDWDPHQW�XWLOL]DW�HVWH�FHO�VLPSWRPDWLF��([LVWă�vQVă�QXPHURDVH�VWXGLL�FDUH�vQFHDUFă�Vă�DERUGH]H�GLYHUVH�DOWH�PHWRGH�GH�WUDWDPHQW��SUHFXP�WHUDSLD�JHQLFă��FDUH�YRU�IL�GLVFXWDWH�vQ�FDSLWROXO����

3.2 OSTEOGENEZA IMPERFE&7Ă� 2VWHRJHQH]D�LPSHUIHFWă��20,0��������– ��������UHXQHúWH�XQ�JUXS�GH�EROL�WUDQVPLVH�DXWRVRPDO�GRPLQDQW��SURGXVH�SULQ�PXWDĠLL�DOH�FRODJHQXOXL�WLS�,��FH�GHWHUPLQă�SUHGLVSR]LĠLH�OD�GHIRUPDĠLL�VFKHOHWLFH�úL�IUDFWXUL�RVRDVH�vQ�XUPD�XQRU�WUDXPDWLVPe minime. ,QFLGHQĠD�ORU�FXPXODWă�HVWH�GH�FLUFD���OD�������vQ�SRSXODĠLD�JHQHUDOă�� Simptomatologie. 'LQ�SXQFW�GH�YHGHUH�FOLQLF�VH�GHRVHEHVF�SDWUX�WLSXUL�PDMRUH�GH�ERDOă��7LSXO�,�GH�ERDOă��IRUPD�XúRDUă��VH�FDUDFWHUL]HD]ă�SULQ�DVRFLHUHD�IUDJLOLWăĠLL�RVRDVH�FX�VFOHUH�DOEDVWUH�úL�HYHQWXDO�VXUGLWDWH�SUHVHQLOă��GHIRUPDĠLLOH�VFKHOHWLFH�VXQW�DEVHQWH��7LSXO�,,��VHYHU��HVWH�OHWDO�vQ�SHULRDGD�QHRQDWDOă�úL�DVRFLD]ă�IUDFWXUL�RVRDVH��GHIRUPDĠLL�VFKHOHWLFH�úL�VFOHUH�GH�FXloare vQFKLVă��7LSXO�,,,�DVRFLD]ă�DGHVHRUL�IUDFWXUL�SUH]HQWH�OD�QDúWHUH�FX�GHIRUPDĠLL�RVRDVH�SURJUHVLYH��KLSRVWDWXUă��VFOHUH�DOEDVWUH��WXOEXUăUL�DOH�GHQWLĠLHL�úL�VXUGLWDWH��,Q�WLSXO�,9��VFOHUHOH�DX�DVSHFW�QRUPDO��GHIRUPDĠLLOH�RVRDVH�VXQW�XúRDUH�VDX�PRGHUDWH�GDU�SHUVLVWă�VXVFHSWLELOLWDWHD�OD�IUDFWXUL��VXUGLWDWH�úL�DQRPDOLL�DOH�GHQWLĠLHL�� *HQHWLFă��+HWHURJHQLWDWHD�FOLQLFă�HVWH�H[SOLFDWă�FHO�SXĠLQ�vQ�SDUWH�SULQ�KHWHURJHQLWDWHD�DOHOLFă�úL�GH�ORFXV��IHQRWLSXO�YDULD]ă�vQ�IXQFĠLH�GH�WLSXO�GH�ODQĠ�DO�SURFRODJHQXOXL�,�FDUH�HVWH�DIHFWDW�úL�GH�ORFDOL]DUHD�PXWDĠLHL�OD�QLYHOXO�ILHFăUXL�ORFXV��$X�IRVW�GHVFULVH�SHVWH�����GH�PXWDĠLL�GLIHULWH�FH�DIHFWHD]ă�JHQHOH�SHQWUX�FRODJHQXO�,��&RODJHQXO�WLS�,�HVWH�SULQFLSDOD�SURWHLQă�VWUXFWXUDOă�OD�QLYHOXO�RVXOXL�úL�DOWRU�ĠHVXWXUL�ILEURDVH��0ROHFXOHOH�GH�SURFRODJHQ�WLS�,�VXQW�DOFăWXLWH�GLQ�GRXă ODQĠXUL�DOID��,���FRGLILFDWH�GH�R�JHQă�GH�SH�FURPRVRPXO�����úL�XQ�ODQĠ�DOID��,��FRGLILFDW�GH�R�JHQă�GH�SH�FURPRVRPXO����$VDPEODUHD�DFHVWRU�ODQĠXUL�vQWU-un triplu helix în FXUVXO�PDWXUăULL�SURFRODJHQXOXL�vQFHSH�OD�QLYHOXO�FDSăWXOXL�&-WHUPLQDO�úL�HYROXHD]ă�FăWUH�FDSăWXO�1-WHUPLQDO��&D�XUPDUH��PXWDĠLLOH�vQ�SRUĠLXQHD�&-WHUPLQDOă�DX�HIHFWH�PDL�VHYHUH��'H�DVHPHQHD��PXWDĠLLOH�OD�QLYHOXO�SURFRODJHQXOXL�DOID��,��WLQG�Vă�DLEă�HIHFWH�PDL�VHYHUH�GHFkW�PXWDĠLLOH�OD�QLYHOXO�SURFRODJHQXOXL�DOID��,���GDWRULWă�HIHFWHORU�GRminant negative (vezi figura 11.1). 6H�SRW�GHRVHEL�GRXă�WLSXUL�PDMRUH�GH�PXWDĠLL�LPSOLFDWH�vQ�HWLRORJLD�RVWHRJHQH]HL�LPSHUIHFWă��PXWDĠLL�FH�GHWHUPLQă�UHGXFHUHD�SURGXFĠLHL�GH�FRODJHQ�WLS�,�úL�PXWDĠLL�FDUH�GHWHUPLQă�VLQWH]D�XQRU�PROHFXOH�DQRUPDOH�VWUXFWXUDO��5HGXFHUHD�FDQWLWăĠLL�GH�FRODJHQ�,�VLQWHWL]DWă�HVWH�FRQVHFLQĠD�XQRU�PXWDĠLL�FDUH�DX�XQ�HIHFW�VHYHU�DVXSUD�SURWHLQHL�FRGLILFDWH��6XQW�LPSOLFDWH�vQ�VSHFial PXWDĠLL�FX�DSDULĠLD�XQRU�FRGRQL�VWRS�SUHPDWXUL��PLFL�GHOHĠLL�VDX�LQVHUĠLL�FH�GHWHUPLQă�GHFDODUHD�FDGUXOXL�GH�OHFWXUă�VDX�PXWDĠLL�DOH�VLWXVXULORU�GH�PDWLVDUH��$FHVWH�PXWDĠLL�LQWHUHVHD]ă�GH�UHJXOă�ODQĠXULOH�DOID��,��úL�VXQW�LPSOLFDWH�vQ�SURGXFHUHD�WLSXOXL�,�GH ERDOă��

37

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254800 AR CSTB 21q22.3 Promotor (CCCCGCCCCGCG)n

~2-3 40-80

Boala Huntington 143100 AD HD 4p16.3 Exon 1 (CAG)n ~10-26 36-100 Boala Kennedy – $WURILD�PXVFXODUă�� VSLQDOă�úL�EXOEDUă

313200 XR AR Xq11-q12 Exon 1 (CAG)n 9-35 38-62

Atrofia GHQWDWRUXEUDOă- SDOLGROX\VLDQă

125370 AD DRPLA 12p13.31 Regiunea FRGDQWă

(CAG)n 3-35 49-88

Ataxia spinocerebelara 1

164400 AD ATX1 6p23 Regiunea FRGDQWă

(CAG)n 6-38 39-83

Ataxia VSLQRFHUHEHODU�

183090 AD ATX2 12q24 Regiunea FRGDQWă

(CAG)n 14-31 32-77

Boala Machado- Joseph (SCA3)

109150 AD ATX3 14q32.1 Regiunea FRGDQWă

(CAG)n 12-39 62-86

Ataxia VSLQRFHUHEHODU�

183086 AD CACNA1A

19p13 Regiunea FRGDQWă

(CAG)n ~4-17 21-30

Ataxia VSLQRFHUHEHODU�

164500 AD SCA7 3p12-p21.1 Regiunea FRGDQWă

(CAG)n 7-35 37-200

Ataxia VSLQRFHUHEHODU�

603680 AD SCA8 13q21 Regiunea FRGDQWă

(CTG)n 15-21 100-152

Ataxia spinocerebelara 10

603516 AD SCA10 22q13 Intron 9 (ATTCT)n ~10-22 900-4000

Ataxia VSLQRFHUHEHODU��

604326 AD PPP2R2B 5q31-q33 Regiunea FRGDQWă

(CAG)n ~9-18 55-78

Ataxia VSLQRFHUHEHODU��

607136 AD TBP 6q27 Regiunea FRGDQWă

(CAG)n 25-42 50-55

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43

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� ADNmt este lipsit de introni: exceptând un segment de aproximativ 1000 pb (bucla D – displacement loop��vQ�FDUH�VH�DIOă�DWkW�RULJLQHD�UHSOLFăULL�ODQĠXOXL�JUHX�FkW�úL�SURPRWRULL�WUDQVFULHULL�DPEHORU�FDWHQH��vQWUHDJD�VHFYHQĠă�D�$'1PW�HVWH�FRSLDWă�vQ�PROHFXOH�IXQFĠLRQDOH�GH�$51��

� Genele din ADNmt sunt contigue sau separate prin doar 1-2 pb. � Patru dintre cele 64 de „cuvinte” ale codului genetic al ADNmt au o DOWă�VHPQLILFDĠLH decât cea a codonilor din genomul

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GHVIăúRDUă�IăUă�vQWUHUXpere, parcurgând întreaga lungime a moleculei. � Mitocondriile QX�SRVHGă�VLVWHPH�HILFLHQWH�GH�UHSDUDUH41 D�$'1�úL��FD�DWDUH��HURULOH�LQHUHQWH�UHSOLFăULL��SUHFXP�úL�OH]LXQLOH�

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� $'1�SROLPHUD]D�JDPPD��HQ]LPD�UHSOLFăULL�$'1PW��RSHUHD]ă�FX�R�ILGHOLWDWH�LQIHULRDUă celei a AD1�SROLPHUD]HORU�DOID�úL�GHOWD��DFFHSWkQG�vPSHUHFKHUL�JUHúLWH�VDX�DOXQHFkQG�SHVWH�XQXO�VDX�PDL�PXOWH�QXFOHRWLGH� 8OWLPHOH�WUHL�WUăVăWXUL�VXQW�FHOH�FDUH�IXUQL]HD]ă�H[SOLFDĠLD�IDSWXOXL�Fă�vQ�$'1PW�PXWDĠLLOH�VH�SURGXF�FX�R�IUHFYHQĠă�GH���-20 de ori mai mare decât în ADN nuclear.

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ITGB3 (integrina beta 3)

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ELN (elastin)

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ACE (enzima de conversie a angiotensinei)

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În ultimii ani s-DX�DFXPXODW�SUREH�FRQYLQJăWRDUH�FDUH�GHPRQVWUHD]ă�Fă�'=�WLSXO�,�HVWH�R�ERDOă�DXWRLPXQă��VDX�FHO�SXĠLQ�DUH�R�FRPSRQHQWă�DXWRLPXQă�LPSRUWDQWă��SURGXVă�SULQ�GLVWUXJHUHD��DXWRLPXQă��D�FHOXOHORU�EHWD�DOH�SDQFUHDVXOXL��'LQWUH�DFHVWHD PHQĠLRQăP�

– SUH]HQĠD�XQXL�LQILOWUDW�LQIODPDWRU��LQVXOLWă) în insulele Langerhans ale pancreasului; – SUH]HQĠD�XQRU�anticorpi49 FH�UHDFĠLRQHD]ă�FX�DXWRDQWLJHQHOH�GLQ�FHOXOHOH�LQVXODUH��*$'�����,$-���LQVXOLQă�� – DVRFLHUH�SXWHUQLFă�FX�XQHOH�DOHOH�+/$�GH�FODVă�,, �'5��úL�VDX�'5���'4 – prezente la circa 95% din bolnavii cu DZ

tipul ,�GLQ�SRSXODĠLLOH�HXURSHQH�� 3URFHVHOH�DXWRLPXQH�VXQW�GHFODQúDWH�GH�XQ�IDFWRU�GH�PHGLX��IRDUWH�SUREDELO�R�LQIHFĠLH�YLUDOă50��OD�SHUVRDQH�FX�R�DQXPLWă�susceptibilitate

([LVWă�R�FRPSRQHQWă�JHQHWLFă�FHUWă��GHPRQVWUDWă�GH�DJUHJDUHD�IDPLOLDOă��FRQFRUGDQĠD�GH���-�����OD�JHPHQLL�0=�úL�ULVFXO�crescut la rudele de gradul I ale bolnavilor (tabelul 13.4) Tabelul 13.4 Riscul de DZ al rudelor bolnavilor diabetici. BOLANAV DE DZ (TIPUL I SAU TIPUL II)

RUDE CU RISC RISC (ÎN CAZUL DZ TIPUL I)

RISC (ÎN CAZUL DZ TIPUL II)

Mama Copii 3% 15% 7DWăO Copii 6-9% 15% $PELL�SăULQĠL� Copii 30% 75% Alt membru al familiei )UDĠLL�VDX�VXURULOH�VDOH 6-10% 10%

)UDWH�JHDPăQ�0= )UWDH�JHDPăQ�'=

35-50% 20%

90% 10%

)UDĠLL�VDX�VXURULOH�VDOH�GDFă�VXQW�HLA DR3/DR4

20% -

&RSLL�VăL 10% 33%

&HO�SXĠLQ����GH�JHQH�DX�IRVW�DVRFLDWH�FX�'=�WLSXO�,�GDU�FX�H[FHSĠLD�JHQHORU�+/$�GH�FODVă�,,��'5��úL�VDX�'5���'4-beta51) – care UHDOL]H]D]ă�FLUFD�����GLQ�DJUHJDUHD�IDPLOLDOă�– FHOHODOWH�DVRFLDĠLL�VXQW�VODEH��GH�PHQĠLRQDW�WRWXúL�SROLPRUILVPXO�JHQHL�SHQWUX LQVXOLQă��ORFDOL]DWă�SH�EUDĠXO�VFXUW�DO�FURPRVRPXOXL����

Diabetul zaharat de tipul II DZ de tipul II este produs printr-un dublu defect��VHFUHĠLD�LQDGHFYDWă�GH�LQVXOLQă�GH�FăWUH�FHOXOHOH�EHWD�úL�UH]LVWHQĠD�OD�

DFĠLXQHD�LQVXOLQHL�DWkW�vQ�ĠHVXWXULOH�SHULIHULFH��PXúFKL��DGLSRFLWH��FkW�úL�vQ�FHOXOHOH�EHWD�GHWHUPLQDWă�GH�PRGLILFăUL�DOH�UHFHSWRULORU�GH�LQVXOLQă�VDX�DOH�DOWRU�PROHFXOH�LPSOLFDWH�vQ�IL[DUHD��WUDQVSRWXO�LQWUDFHOXODU�úL�PHWDEROL]DUHD�JOXFR]HL� Factorii de risc pentru DZ de tipul II sunt vârsta, alimHQWDĠLD��REH]LWDWHD��LQDFWLYLWDWHD�IL]LFă SUHFXP�úL�JUHXWDWHD�PLFă�OD�QDúWHUH�ú�D��([LVWă�vQVă�úL�R�YXOQHUDELOLWDWH�JHQHWLFă�PDL�LPSRUWDQWă�GHFkW�vQ�'=�GH�WLSXO�,��GHPRQVWUDWă�PDL�DOHV�GH�FRQFRUGDQĠD���GH�����D�'=�OD�JHPHQLL�0=�úL�ULVFXO�FUHVFXW�GH�UHFXUHQĠă�OD�UXGHOH�GH�JUDGXO�,�DOH�EROQDYXOXL��tabelul 13.4). Studiile genetice în DZ tipul II au relevat câteva elemente importante � ([LVWHQĠD�XQRU�GLIHUHQĠH�HWQLFH�vQ�SUHYDOHQĠD�'=�WLSXO�,,�SUHFXP�úL�D�XQRU�JHQRWLSXUL�GLIHULWH�GH�YXOQHUDELOLWDWH�vQ�SRSXODĠLi

diIHULWH��VHOHFWDWH�FD�UăVSXQV�OD�GLIHULWH�SUHVLXQL�HYROXWLYH��

48 Expunerea in utero la hLSHUJOLFHPLH�FUHúWH�GH�FLUFD���RUL�ULVFXO�FD�QRXO-QăVFXW�Vă�IDFă��OD�DGROHVFHQĠă��XQ�'= 49 AXWRDQWLFRUSLL�DSDU�FX�PXOĠL�DQL�vQDLQWHD�VLPSWRPHORU�FOLQLcH�úL�VXQW�XQ�PDUNHU�XWLO�SHQWUX�LGHQWLILFDUHD�LQGLYL]LORU�FX�ULVF�GH�D�face DZ tipul I 50 In anumite cazuri SRW�LQWHUYHQL�úL�DOĠL�IDFWRUL�GLQ�PHGLX�VDX�VWUXFWXUD�LQGLYLGXOXL��GH�H[���LQWROHUDQĠD�OD�ODSWHOH�GH�YDFă�vQ�FRSLOăULH� 51 De exemplu, haplotipul HLA DRB1*0302-DQA1*0301, în special când este combinat cu haplotipul DRB1*0201-DQA1*0501 creúte de 10-20 de ori susceptibilitatea la dezvoltarea DZ tip 1. 53

Astfel s-a identificat într-R�SRSXODĠLH�GH�PH[LFDQL�GLQ�$PHULFD�R�JHQă�GH�VXVFHSWLELOLWDWH��NIDDM1���ORFDOL]DWă�SH�EUDĠXO�OXQJ�DO�FURPRVRPXOXL���FH�LQWHUDFĠLRQHD]ă�FX�R�JHQă�GH�SH�cromosomul 15; vQ�SRSXODĠLLOH�ILQLFH�GLQ�1RUGXO�(XURSHL�V-au identificat genele NIDDM2 (pe cromosomul 12��úL�NIDDM3 (pe cromosomul 20).

� 8Q�SURFHQW�PLF�GH�FD]XUL�GH�'=�WLSXO�,,�HVWH�SURGXV�SULQ�PXWDĠLL�PRQRJHQLFH��HVWH�YRUED�GH�'=�FX�GHEXW�OD�PDWXULWDWH��02'<�– de la Maturity-Onset Diabetes of Youth��úL�DOWH�IRUPH�SURGXVH�SULQ�GHIHFWH�JHQHWLFH�DOH�IXQFĠLHL�FHOXOHORU�EHWD�VDX�DFĠLXQLL�insulinei;

MODY este responsabil de 2-5% din toate cazurile de DZ tipul II; se transmite autosomal dominant úL�HVWH�SURGXV�SULQ�defecte primDUH�vQ�VLQWH]D�GH�LQVXOLQă��$X�IRVW�GHVFULVH���WLSXUL�GH�PXWDĠLL��vQ�JHQD�SHQWUX�JOXFRNLQD]ă���S����- MODY 2; vQ�JHQHOH�FH�FRGLILFă�IDFWRULL�GH�WUDQVFULSĠLH�KHSDWLFă�FH�VWLPXOHD]ă�FHOXOHOH�EHWD��+1)-�Į��02'<�����+1)-�ȕ��02'<�5), HNF-�Į��02'<�����vQ�JHQD�SHQWUX�IDFWRUXO�GH�WUDQVFULSĠLH�SDQFUHDWLFă�FH�VWLPXOHD]ă�FHOXOHOH�EHWD��,3)-1 (MODY 4). 6WXGLLOH�GH�JHQHWLFă�PROHFXODUă�vQ�02'<�DX�SHUPLV�HOXFLGDUHD�IXQFĠLHL�FHOXOHORU�EHWD�úL�vQĠHOHJHUHD�SDWRJHQLHL�DOWRU�forme de DZ.

� 3UHSRQGHUHQĠD�PDWHUQă�a DZ tipul II s-ar putea explica printr-R�IRUPă�SDUWLFXODUă�de diabet mitocondrial produs de PRGLILFăUL�DOH�$'1PW��PRúWHQLWH�VDX�FkúWLJDWH��FDOLWDWLYH��GHOHĠLL�VDX�PXWDĠLL52��VDX�FDQWLWDWLYH��VFăGHUHD�QLYHOXOXL�SODVPDWLF�DO�ADNmt prin reducerea biogenezei mitocondriilor; maPHOH�FX�QLYHO�VFă]XW�DO�$'1PW�QDVF�IUHFYHQW�FRSLL�FX�JUHXWDWH�PLFă�úL�cu risc crescut de DZ tipul II)

� /D�EROQDYLL�FX�'=�WLSXO�,,�H[LVWă�R�VXVFHSWLELOLWDWH�LQGLYLGXDOă�FODUă�OD�DQXPLWH�FRPSOLFDĠLL��QHIURSDWLH�GLDEHWLFă��QHXURSDWii, retinopatii sau boli cardio-vasculare).

+HWHURJHQLWDWHD�JHQHWLFă�D�'=�WLSXO�,,�FRQWUDVWHD]ă�FX�SDWRJHQLD�DVHPăQăWRDUH�D�'=�WLSXO�,,�vQ�SRSXODĠLL�GLIHULWH��FH�LPSOLFă – DúD�FXP�DP�DUăWDW�– UH]LVWHQĠD�OD�DFĠLXQHD�LQVXOLQHL��vQ�ĠHVXWXULOH�ĠLQWă��úL�VHFUHĠLD�LQDGHFYDWă�GH�LQVXOLQă��5H]LVWHQĠD�OD�LQVXOLQă�SRDWH�IL�SURGXVă�GH�PXWDĠLL�VDX�SROLPRUILVPH�DOH�JHQHORU�SHQWUX�UHFHSWRULL�GH�LQVXOLQă�VDX�SHQWUX�DOWH�PROHFXOH�LPSOLFDWH�vQ�FDOHD�GH�semnalizare (de exemplu IRS-���PROHFXOD�FH�SULPHúWH�VHPQDOXO�GH�OD�UHFHSWRUXO�GH�LQVXOLQă���5HFHQW�D�IRVW�LPSOLFDWă�úL�JHQD�SHQWUX�DPLOLQă��SHSWLG�FRVHFUHWDW�FX�LQVXOLQD�GH�FăWUH�FHOXOHOH�EHWD� 6WXGLLOH�JHQHWLFH�vQ�'=�DX�DGXV�GDWH�SUHĠLRDVH�SHQWUX�vQĠHOHJHUHD�EROLL�úL�LGHQWLILFDUHD�SHUVRDQHORU�FX�ULVF�GDU�QX�DX�HOXFLGDW�WRDWH�DVSHFWHOH�HUHGLWăĠLL�EROLL��(OH�FRQWLQXă�úL�YRU�DGXFH�FX�VLJXUDQĠă�HOHPHQWH�QRL� ���$6708/�%521ù,& $VWPXO�EURQúLF�HVWH�R�ERDOă�SXOPRQDUă�REVWUXFWLYă�UHYHUVLELOă�FDUH�VH�DVRFLD]ă�FX�KLSHUDFWLYLWDWH�EURQúLFă��EURQKRVSDVP��úL�FX�LQIODPDĠLD�FăLORU�DHULHQH��,QFLGHQĠD�DVWPXOXL�YDULD]ă�vQ GLIHULWH�SRSXODĠLL�vQWUH��-10% ) fiind mai frecvent la copii).

(WLRORJLD�DVWPXOXL�EURQúLF�HVWH�PXOWLIDFWRULDOă��factorii de mediu �DOHUJHQL��SROXDQĠL��LQIHFĠLL�YLUDOH��GHFODQúHD]ă�ERDOD�OD�persoane susceptibile. Participarea unor factori genetici care deWHUPLQă�SUHGLVSR]LĠLD�OD�DVWP�úL�DWRSLH��vQ�JHQHUDO��HVWH�VXVĠLQXWă�GH�caracterul familial IUHFYHQW�DO�EROLL��DVWP�VDX�DOHUJLH�VDX�QLYHOXUL�FUHVFXWH�GH�,J(���ULVFXO�FUHVFXW�GH�ERDOă�OD�UXGHOH�SDFLHQWXOXL��GH�2-��RUL�PDL�PDUH�FD�vQ�SRSXODĠLD�JHQHUDOă��úL�LQFLGHQĠD�PDL�PDUH�OD�gemenii MZ comparativ cu gemenii DZ (heritabilitatea bolii a IRVW�HVWLPDWă��vQ�GLIHULWH�SRSXODĠLL��TD�VH�VLWXD�vQWUH�����úL�������'H�PHQĠLRQDW�Fă�atopia �SUHGLVSR]LĠLH�GH�D�GH]YROWD�XQ�UăVSXQV�mediat de IgE) este cel mai puternic factor SUHGLVSR]DQW�vQ�DVWP�LDU�QLYHOXULOH�FUHVFXWH�GH�,J(�VH�FRUHOHD]ă�FX�H[SUHVLD�FOLQLFă�D�DOHUJLHL�úL�DVWPXOXL�

Identificarea genelor de risc – SHQWUX�DVWP�VDX�IHQRWLSXULOH�LQWHUPHGLDUH��QLYHOXO�GH�,J(��KLSHUUHDFWLYLWDWHD�EURQúLFă��atopie) – D�IRVW�úL�HVWH�GLILFLOă�GHRDUHFH�JHQHOH�UHVSRQVDELOH�GH�LQLĠLHUHD�EROLL�SRW�IL�GLIHULWH�GH�JHQHOH�UHVSRQVDELOH�GH�SURJUHVLD�úL�VDX�VHYHULWDWHD�HL��3ULQ�VWXGLL�GH�VFDQDUH�D�JHQRPXOXL�XPDQ��FX�PDUNHUL�$'1�SROLPRUILFL��VDXSULQ�DQDOL]D�JHQHORU�FDQGLGDW�s-au identificat cîteva regiuni cromosomice (5q23-�����S����T����T��FH�FRQĠLQ�JHQH�FH�VXQW�LPSOLFDWH�vQ�SDWRJHQLD�DVWPXOXL��'LQWUH�DFHVWHD�PHQĠLRQăP�genele pentru citokine (în special IL-��úL�,/-���úL�UHFHSWRULL�ORU��adrenoreceptorul 2, glucocorticoid receptorul – toate pe 5q – UHFHSWRUXO�SHQWUX�,J(��SH���T��SUHFXP�úL�XQHOH�JHQH�DOH�FRPSOH[XOXL�+/$�úL�71), pe cromosomul 6p.

(IHFWXO�PHGLFDĠLHL�DQWL-DVWPDWLFH�SRDWH�IL�LQIOXHQĠDW�GH�SROLPRUILVPXO�JHQHORU�SHQWUX�UHFHSWRUXO�DGUHQHUJLF��úL�UHFHSWRUXO�pentru glucocorticoizi sau al genei SHQWUX�OLSR[LJHQD]ă��DQXPLWH�YDULDQWH�DOHOLFH�GHWHUPLQă�XQ�UăVSXQV�UHGXV�OD�PHGLFDĠLH�

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BOALA ALZHEIMER %RDOD�$O]KHLPHU�����GLQ�SHUVRDQHOH�SHVWH����GH�DQL��VH�FDUDFWHUL]HD]ă�SULQ�DWURILH�FRUWLFDOă (pierderea neuronilor) úL�

GHWHULRUDUH�LQWHOHFWXDOă�OHQWă�GDU�SURJUHVLYă��SLHUGHUHD�PHPRULHL��DID]LH��DJQR]LH��GH]RULHQWDUH�WHPSRUR-VSDĠLDOă���SkQă�OD�GHPHQĠă��$FHVWH�IHQRPHQH�VH�DVRFLD]ă�FX�R�GLVIXQFĠLH�D�QHXURWUDQVPLĠăWRULORU �vQ�VSHFLDO�R�GHILFLHQĠă�PDUFDWă�GH�DFHWLOFROLQă���0RGLILFăULOH�DQDWRPRSDWRORJLFH�VSHFLILFH�VXQW�SOăFLOH�VHQLOH�GH�DPLORLG�H[WUD-QHXURQDOH�úL�DJUHJDWHOH�QHXURILEULODUH. 6H�FXQRVF�úL�ED]HOH�PROHFXODUH�DOH�DFHVWRU�PRGLILFăUL��$PLORLGXO�GLQ�SOăFLOH�VHQLOH�VH�IRUPHD]ă�SULQ�FOLYDUHD�XQHL�SURWHLQH�PDL�PDUL��ȕ-amyloid precursor protein VDX��SH�VFXUW�$33��GH�FăWUH�Ȗ-VHFUHWD]ă�vQWU-un peptid mai mic, insolubil, – peptidul amiloid A42 – care se DFXPXOHD]ă�vQ�SOăFL��$JUHJDWHOH�PLRILEULODUH�VXQW�IRUPDWH�SULQ�KLSHUIRVIRULODUHD�SURWHLQHL�PLFURWXEXODUH�tau.

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52 MIDD (de la Maternally Inherited Diabetes and Deafness��HVWH�R�IRUPă�SDULFXODUă�GH�GLDEHW�PLWRFRQGULDO�SUH]HQWă�OD��-3% din SDFLHQĠLL�FX�'=�WLSXO�,,�FDUDFWHUL]DW�SULQ�GHILFLHQĠă�vQ�VHFUHĠLD�GH�LQVXOLQă��VXUGLWDWH��WUDQVPLVLH�PDWHUQă� 54

cromosomul 2153, preseniliQă�� (PSEN1)54 – GH�SH�FURPRVRPXO����úL�SUHVHQLOLQă�� – de pe cromosomul 1. Studiul acestor forme D�SHUPLV�vQĠHOHJHUHD�XQRU�PHFDQLVPH�SDWRJHQLFH�DOH�EROLL�$O]KHLPHU��

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6WXGLXO�DFHVWRU�IRUPH�UDUH��PRQRJHQLFH��GH�ERDOă�3DUNLQVRQ�D�DGXV�GDWH�LQWHUHVDQWH�SHQWUX�GHVFLIUDUHD�HWLRSDWRJHQLHL�formelor adultului; astfel, la circa 5% din aceste cazuri s-DX�LGHQWLILFDW�PXWDĠLL�vQ�JHQD SDUNLQHL��7RWXúL��PHFDQLVPHOH�DFHVWHL�EROL�QX�VXQW�vQFă�HOXFLGDWH��6LQJXUXO�EHQHILFLX�FRQFUHW�HVWH�XWLOL]DUHD�XQHL�WHUDSLL�VXEVWLWXWLYH�FX�OHYR-dopa. 5. PSIHOZELE .

1XPHURDVH�VWXGLL�JHQHWLFH�DX�GHPRQVWUDW�IăUă�HFKLYRF�H[LVWHQĠD�XQHL�FRPSRQHQWH�JHQHWLFH LPSRUWDQWH�vQ�GRXă�GLQWUH�psihozele majore – VFKL]RIUHQLD�úL�ERDOD��SVLKR]D��DIHFWLYă�ELSRODUă�– FX�GHWHUPLQLVP�PXOWLIDFWRULDO�úL��IRDUWH�SUREDELO��KHWHURJHQLWDWH�JHQHWLFă�

SCHIZOFRENIA. 6FKL]RIUHQLD�����GLQ�SRSXODĠLD�JHQHUDOă��VH�FDUDFWHUL]HD]ă��GXSă�'6M-,9��������SULQ��LGHDĠLH�LQFRHUHQWă�úL�GHOLUDQWă��

KDOXFLQDĠLL��GLVRFLHUHD�SHUVRQDOLWăĠLL��L]RODUHD�VRFLDOă�úL�DXWLVP��UHSOLHUH�vQ�VLQH�vQVăúL���FRPSRUWDPHQW�FDWDWRQLF�VDX�GH]Rrganizat. 5LVFXO�HPSLULF�GH�UHFXUHQĠă�OD�UXGHOH�GH�JUDGXO�,�DOH�EROQDYXOXL�HVWH�de circa 9-12% (deci aproape de 10 ori mai mare ca în SRSXODĠLD�JHQHUDOă���FUHúWH�FX�QXPăUXO�EROQDYLORU��úL�VFDGH�OD�UXGHOH�GH�JUDGXO�,,��FLUFD�������.LQH\���������&RQFRUGDQĠD�EROii la gemenii MZ este de 50% iar la gemenii DZ de numai 12% iar heritabilitatHD�D�IRVW�FDOFXODWă�OD�������7RDWH�DFHVWHD�GHPRQVWUHD]ă�H[LVWHQĠD�XQHL�FRPSRQHQWH�JHQHWLFH�LPSRUWDQWH��'DU��vQ�FLXGD�D�QXPHURDVH�VWXGLL�PROHFXODUH�úL�D�LGHQWLILFăULL�XQRU�UHJLXQL�FURPRVRPLFH��SH��S���S�úL���S��vQ�FDUH�DU�SXWHD�IL�ORFDOL]DWH�JHQHOH�VFKL]RIUHQLHL��QX�DX�IRVW�vQFă�LGHQWLILFDWH�úL�FORQDWH�JHQH�specifice.

36,+2=$�$)(&7,9Ă�%,32/$5Ă 3VLKR]D�DIHFWLYă�ELSRODUă�VDX�SVLKR]D�PDQLDFR-GHSUHVLYă�������GLQ�SRSXODĠLD�JHQHUDOă��VH�FDUDFWHUL]HD]ă�SULQ�HSLVRDGH�

DOWHUQDWLYH�GH�DOWHUDUH�D�GLVSR]LĠLHL�úL�QLYHOXOXL�JOREDO�GH�DFWLYLDWH��ILH�vQ�VHQVXO�XQHL�GLVSR]LĠLL�HXIRULFH�úL�D�KLSHUDFWLYLWăĠLL��PDQLH���fie în sensul unei depresii. Riscul empiric al rudelor de gradul I ale bolnavului este de 5-�����FRQFRUGDQĠD�OD�JHPHQLL�0=�HVWH�GH�79% iar heritabilitatea (70%) aUDWă�R�FRPSRQHQWă�JHQHWLFă�SXWHUQLFă��ÌQ�XQHOH�IDPLOLL��vQ�FDUH�ERDOD�VH�WUDQVPLWH�DXWRVRPDO�GRPLQDQW��VWXGLLOH�GH�vQOăQĠXLUH�DX�DUăWDW�FD�ERDOD�VHJUHJă�vPSUHXQă�FX�XQ�PDUNHU�SROLPRUILF�GH�SH�FURPRVRPXO���S��7RWXúL�QX�au IRVW�vQFă�LGHQWLILFDWH�JHQH�VSHFLILce.

6. CANCERUL

&DQFHUXO�HVWH�D�GRXD�FDX]ă�GH�PRUWDOLWDWH�vQ�ĠăULOH�GH]YROWDWH��GXSă�EROLOH�FDUGLR- vasculare. Etiologia bolii canceroase (la FDUH�QH�YRP�UHIHUL�vQ�GHWDOLL�vQ�FDSLWROXO������HVWH�PXOWLIDFWRULDOă�LPSOLFkQG�factori de mediu (fumatul, alimeQWDĠLD��GLIHULĠL�FDQFHULJHQL�FKLPLFL��XQHOH�LQIHFĠLL�YLUDOH�ú�D��FDUH�SURGXF�PXWDĠLL�VRPDWLFH� precum úL�IDFWRUL�JHQHWLFL FDUH�GHWHUPLQă�VXVFHSWLELOLWDWHD�OD�XQHOH�IRUPH�GH�FDQFHU��&HOH�PDL�PXOWH�FD]XUL�GH�FDQFHU���FLUFD������VH�SURGXF�VSRUDGLF��7RWXúL��HVte bine VWDELOLW�Fă�PXOWH�GLQ�IRUPHOH�SULQFLSDOH�GH�FDQFHU��GH�VkQ��FRORQ��SURVWDWă��RYDULDQ���SRW�DYHD�R�DJUHJDUH�IDPLOLDOă�úL�ULVFXl de UHFXUHQĠă�HVWH�GH��-��RUL�PDL�PDUH�OD�UXGHOH�GH�JUDGXO�,�DOH�EROQDYLORU��FRPSDUDWLY�FX�SRSXODĠLD�JHQHUDOă���HO�FUHúWH�FX�QXPăUXO�GH�EROQDYL�GLQ�IDPLOLH�úL�DWXQFL�FkQG�FDQFHUXO�DSDUH�OD�R�YkUVWă�PDL�WkQăUă��ÌQ�PDMRULWDWHD�FDQFHUHORU�V-au identificat gene specifice FDUH��XQHRUL��GH�H[HPSOX�vQ�FDQFHUXO�GH�FRORQ�VDX�GH�VkQ���GHWHUPLQă�úL�IRUPH�HUHGLWDUH��PRQRJHQLFH. De aceea medicul

53 $úD�FXP�DP�PDL�SUHFL]DW�OD�EROQDYLL�FX�WULVRPLH����SUH]HQĠD�XQHL�FRSLL�VXSOLPHQWDUH�D�JHQHL�$33�GXFH�OD�LQVWDOUHD�SUHFRFH�D�boli Alzheimer. 54 Ar putea fi secretaza sau un cofactor al acestei enzime. 55 8ELFXLWLQD�HVWH�R�SURWHLQă�SUH]HQWă�vQ�WRDWH�FHOXOHOH��FX�URO�vQ�UHJODUHD�SURFHVXOXL�GH�GHJUDGDUH�SURWHROLWLFă�D�DOWRU�SURWHLQH�(„marcate” prin fixarea ubicuitinei) într-un proteazom 55

SUDFWLFLDQ�WUHEXLH�Vă�ILH�GHRVHELW�GH�DWHQW�OD�LVWRULFXO�IDPLOLDO�SUHFXP�úL�OD�R�VHULH�GH�VHPQH�FH�SRW�HYRFD�R�IRUPă�IDPLOLDOă�HUHGLWDUă�GH�FDQFHU��$FHVW�OXFUX�HVWH�LPSRUWDQW�SHQWUX�VIDWXO�JHQHWLF��VXSUDYHJKHUHD�SHUVRDQHORU�FX�ULVF�úL�GLDJQRVticul SUHVLPSWRPDWLF��7RDWH�DFHVWH�GDWH�YRU�IL�H[HPSOLILFDWH�SULQ�SUH]HQWDUHD��VXFFLQWă��D�WUHL�IRUPH�GH�FDQFHU��FDUH�vQWU-R�SURSRUĠLH�GH�5-����GLQ�FD]XUL��DX�R�DJUHJDUH�IDPLOLDOă�úL�VDX�VXQW�HUHGLWDUH��$OWH�HOHPHQWH�YRU�IL�GLVFXWDWH�vQ�FDSLWROXO���� Cancerul dH�VkQ�DIHFWHD]ă���-����GLQ�IHPHLOH�FDUH�WUăLHVF�SkQă�OD����GH�DQL��3RDWH�SUH]HQWD�R�DJUHJDUH�IDPLOLDOă�UXGHOH�de gradul I având un risc dublu de a dezvolta un cancer de sân. Au fost identificate mai multe gene ce predispun femeile la DSDULĠLD�XQXL�FDQFHU�Ge sân; cele mai importante sunt %5&$��úL�%5&$���GRXă�JHQH�LPSOLFDWH�vQ�UHSDUDUHD�$'1��gena p53 (ce GHWHUPLQă�VLQGURPXO�/L-Fraumeni), gena PTEN (FH�SURGXFH�VLQGURPXO�&RZGHQ��úL�DOWHOH��7RWXúL��PDL�PXOW�GH�����GLQ�WRDWH�cancerele de sân nu sunt ereditare, fiLQG�SURGXVH�GH�PXWDĠLL�VRPDWLFH�PXOWLSOH� &DQFHUXO�FRORUHFWDO��&&5��DIHFWHD]ă�FLUFD����GLQ�SRSXODĠLH�úL�SUH]LQWă�GHVHRUL�XQ�FDUDFWHU��IDPLOLDO��)RUPHOH�IDPLOLDOH�������UH]XOWă�– cel mai frecvent – SULQ�PXWDĠLL�DOH�JHQHL�VXSUHVRDUH�D�FUHúWHULL�WXPRUDOH�APC (pentru CCR polipozic) sau în genele de reparare a erorilor de împerechere a ADN (pentru CCR nonpolipozic ereditar sau HNPCC). Formele neereditare de FDQFHU�GH�FRORQ�������VXQW�SURGXVH�GH�PXWDĠLL�VRPDWLFH�PXOWLSOH��GHWHUPLQDWH�GH�IDFWRUL�GH�PHGLX��GHVHRUL vQ�DFHOHDúL�JHQH�implicate în formele ereditare. &DQFHUXO�GH�SURVWDWă��HVWH�XQXO�GLQ�FHOH�PDL�IUHFYHQWH�WLSXUL�GH�FDQFHU�GLDJQRVWLFDWH�OD�EăUEDW���,QWHUHYHQĠLD�XQRU�IDFWRUL�JHQHWLFL�HVWH�VXVĠLQXWă�GH�H[LVWHQĠD�XQRU�IRUPH�HUHGLWDUH��PRQRJHQLFH���-10% din WRDWH�FDQFHUHOH�GH�SURVWDWă��SUHFXP�úL�GH�SROLPRUILVPXO�XQRU�JHQH�VLWXDWH�SH�FURPRVRPXO��T�VDX�SLHUGHUHD�KHWHUR]LJR]LWăĠLL�SHQWUX�DOWH�UHJLXQL�JHQRPLFH��3kQă�vQ�SUH]HQt nu au fost identificate gene specifice implicate în patogenia acestei forme comune de cancer. 7. OBEZITATEA Obezitatea (5-����GLQ�SRSXODĠLH��HVWH�R�DQRPDOLH�PHWDEROLFă�PDQLIHVWDWă�SULQ�FUHúWHUHD�PDVHL�ĠHVXWXOXL�DGLSRV�úL�XQ�H[FHV�SRQGHUDO�GH�SHVWH�����vQ�UDSRUW�FX�YDORULOH�QRUPDOH�SHQWUX�YkUVWă�úL�VH[��2EH]LWDWHD�HVWH�PDL�FXUkQG�XQ�VLPStom decât o ERDOă�GDU�UHSUH]LQWă�XQ�IDFWRU�GH�ULVF�PDMRU�SHQWUX�PDL�PXOWH�EROL�FRPXQH��vQ�VSHFLDO�FDUGLR-YDVFXODUH�úL�GLDEHW�]DKDUDW�WLSXO�,,��2EH]LWDWHD�DUH�XQ�GHWHUPLQLVP�PXOWLIDFWRULDO��vQ�FDUH�DOăWXUL�GH�IDFWRUL�H[RJHQL��VXSUDDOLPHQWDĠLH��LQDFWLYLWDWH� sau endogeni �WXOEXUăUL�PHWDEROLFH�VDX�HQGRFULQH��LQWHUYLQ�úL�IDFWRUL�JHQHWLFL�SUHGLVSR]DQĠL��6WXGLLOH�HIHFWXDWH�SH�FRSLL�DGRSWDĠL�DX�DUăWDW�Fă�JUHXWDWHD�FRUSXOXL�DFHVWRUD�VH�FRUHOHD]ă�VHPQLILFDWLY�FX�JUHXWDWHD�FRUSXOXL�SăULQĠLORU�QDWXUDOL�LDU�VWXGLLOH�SH JHPHQL�DX�HYLGHQĠLDW�R�FRQFRUGDQĠă�PDL�PDUH�OD�0=�úL�R�KHULWDELOLWDWH�GH���-80%. 5HFHQW�DX�IRVW�LGHQWLILFDWH�OD�DQLPDOH�úL�RP�FkWHYD�JHQH�FDUH�SULQ�SURGXúLL�ORU�VXQW�LPSOLFDWH�vQ�FRQWUROXO�DSHWLWXOXL�úL�vQ�susceptibilitatea la obezitate. Pe primul plan sH�VLWXHD]ă� gena pentru OHSWLQă, un hormon secretat de adipocite, care se IL[HD]ă�SH�receptori vQ�KLSRWDODPXV�úL�UHJOHD]ă�DSHWLWXO��QLYHOXULOH�FUHVFXWH�GH�OHSWLQă�SURGXF�VDĠLHWDWH�úL�SLHUGHUHD�DSHWLWXOXL��'LQ�SăFDWH��vQ�REH]LWDWHD�XPDQă�QX�DX�IRVW�LGHQWLILFDWH��GHFkW�IRDUWH�UDU��vQ�REH]LWăĠL�H[WUHPH��QXPLWH�úL�PRUELGH��PXWDĠLL�DOH�JHQHORU�SHQWUX�OHSWLQă�úL�QLFL�DOH�JHQHL�SHQWUX�UHFHSWRUXO�OHSWLQHL��3UREDELO�Fă�H[LVWă�PXWDĠLL�DOH�DOWRU�JHQH��vQFă�QHLGHQWLILFDWH��FH�FRGLILFă�diferite molecule (neuropeptidul Y, receptorul pentru melanocortina-���FDUH�LQWHUYLQ��vQ�FRPELQDĠLH�FX�OHSWLQD��vQ�FRQWUROXO�apetitului. 8. ALCOOLISMUL

Alcoolismul cronic (3-����GLQ�SRSXODĠLH��GH��-��RUL�PDL�IUHFYHQW�OD�EăUEDĠL��UHSUH]LQWă�XQ�FRPSOH[�GH�WXOEXUăUL��SVLKLFH��nervoase, orJDQLFH��SURYRFDW�GH�LQJHVWLD�UHSHWDWă��DQL�GH�]LOH��D�XQRU�GR]H�H[FHVLYH�GH�DOFRRO��6H�GHRVHEHVF�GRXă�WLSXUL�PDMRUH�GH�alcoolism: � Tipul I – (2/3 din cazuri) cu debut peste 25 de ani úL�PDUH�GHSHQGHQĠă�SVLKRORJLFă�GH�DOFRRO��SURILO�SVLKRORJLF�introvertit,

băXWRU�VROLWDU� � Tipul II – (1/3 din cazuri) cu debut sub 25 de ani��SUHGRPLQă�OD�EăUEDĠL�úL�WLQGH�Vă�LPSOLFH�LQGLYL]L�H[WURYHUWLĠL, cheflii,

impulsivi/agresivi. $OFRROLVPXO�HVWH�R�ERDOă�FDUH�LPSOLFă��REOLJDWRULX��R�FDX]ă�GH�PHGLX�GDU�HVWH�SRVLELO�Vă�LQWHUYLQă�úL�R�susceptibilitate

JHQHWLFă�OD�DOFRROLVP��6WXGLLOH�IDPLOLDOH�DX�HYLGHQĠLDW�R�DJUHJDUH�IDPLOLDOă�HYLGHQWă��PDL�PDUH�vQ�WLSXO�,,��úL�XQ�ULVF�GH�D�GH]YROWD�DOFRROLVPXO�SHQWUX�LQGLYL]LL�FX�XQ�SăULQWH�DIHFWDW�GH�����RUL�PDL�PDUH�GHFkW�DO�FHORU�IăUă�SăULQĠL�DIHFWDĠL��3HQWUX�D�H[FOXGH�PHGLXO�úL�obiceiurile comune favorizante dintr-o familie, s-DX�HIHFWXDW�VWXGLL�SH�FRSLL�DGRSWDĠL��DFHVWH�VWXGLL�DX�DUăWDW�Fă�XUPDúLL�XQRU�SăULQĠL�DOFRROLFL�FUHVFXĠL�GH�SăULQĠL�QHDOFRROLFL�DX�XQ�ULVF�GH���RUL�PDL�PDUH�GH�D�GHYHQL�DOFRROLFL��ÌQ�VIkUúLW�VWXGLLOH�FRQFRUGDQĠHL�DOFRROLVPXOXL�OD�JHPHQLL�0=�úL�'=�DX�SHUPLV�FDOFXODUHD�XQHL�KHULWDELOLWăĠL�GH�����SHQWUX�WLSXO�,�úL�GH���-80% pentru tipul II, care DUH�HYLGHQW�R�VXVFHSWLELOLWDWH�JHQHWLFă�PDL�PDUH�

%��0$/)250$ğ,,/(�&21*(1,7$/E MULTIFACTORIALE $QRPDOLLOH�FRQJHQLWDOH�VXQW�PRGLILFăUL�PRUIRORJLFH�DOH�XQXL�RUJDQ�VDX�DO�XQHL�UHJLXQL�DQDWRPLFă�SURGXVH�GH�WXOEXUăUL�vQ�GH]YROWDUHD�SUHQDWDOă��HURUL�GH�PRUIRJHQH]ă���SUH]HQWH�OD�QDúWHUH��'LQ�SXQFW�GH�YHGHUH�SDWRJHQLF�VH�FODVLILFă�vQ�PDOIRUPDĠLL��GLVUXSĠLL��GHIRUPDĠLL�úL�GLVSOD]LL�FRQJHQLWDOH��YH]L�FDSLWROXO����%���0DOIRUPDĠLLOH�FRQJHQLWDOH sunt produse printr-un proces primar úL�LQWULQVHF�GH�PRUIRJHQH]ă�DQRUPDOă��3RW�IL�izolate (unice) sau multiple (asociate cu alte anomalii congenitale). 0DOIRUPDĠLLOH�FRQJHQLWDOH�L]RODWH�VXQW�FRQVLGHUDWH�EROL�PXOWLIDFWRULDOH�GHRDUHFH�SRW�DYHD�R�DJUHJDUH�IDPLOLDOă��FRQFRUGDQĠD�OD�JHPHQLL�0=�HVWH�PDL�PDUH�GHFkW�OD�JHPHQLL�'=�LDU�UXGHOH�GH�JUDGXO�,�DOH�EROQDYLORU�DX�XQ�ULVF�GH�UHFXUHQĠă�PDL mare decât în popXODĠLD�JHQHUDOă��&HOH�PDL�IUHFYHQWH�PDOIRUPDĠLL�FRQJHQLWDOH�PXOWLIDFWRULDOH�VXQW�PHQĠLRQDWH�vQ�tabelul 13.5 úL�OD�XQHOH�GLQWUH�DFHVWHD�QH�YRP�UHIHUL�vQ�FRQWLQXDUH��DOWH�SUREOHPH�GHVSUH�PDOIRUPDĠLLOH�FRQJHQLWDOH�VXQW�SUH]HQWDWH�vQ�FDSLWROXO 14. Tabelul 13.���,QFLGHQĠD�OD�QRX-QăVFXĠL��KHULWDELOLWDWHD�úL�ULVFXO�HPSLULF�GH�UHFXUHQĠă�D�XQRU�PDOIRUPDĠLL�FRQJHQLWDOH�L]RODWH��multifactoriale

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ÌQ�DFRUGDUHD�VIDWXOXL�JHQHWLF�WUHEXLH�Vă�ĠLQHP�FRQW�GH�IDSWXO�Fă�vQ�DQXPLWH�PDOIRUPDĠLL�FRQJHQLWDOH�L]RODWH�H[LVWă�úL�IRUPH�rare monogenice (de exemSOX��XQHOH�FD]XUL�GH�KLGURFHIDOLH�SRW�IL�UHFHVLYH�OHJDWH�GH�;��DXWRVRPDO�GRPLQDQWH�VDX�UHFHVLYH��úL�PDL�DOHV�WUHEXLH�Vă�QH�FRQYLQJHP�– SULQ�DQDPQH]ă�úL�HYDOXDUHD�DWHQWă�úL�PLQXĠLRDVă�D�SDFLHQWXOXL�– Fă�DQRPDOLD�HVWH�L]RODWă�úL�QX�VH�DVRFLD]ă�FX�DOWH�DQRPDOii congenitale, uneori minore, într-un sindrom plurimalformativ specific (de exemplu, peste 40% din GHVSLFăWXULOH�SDODWLQH�VXQW�VLQGURPLFH���vQ�DFHDVWă�VLWXDĠLH�HWLRORJLD�HVWH�KHWHURJHQă��FURPRVRPLFă��PRQRJHQLFă��WHUDWRJHQă��úL�ULVFXO�GH�UHFXUHQĠă�HVWH�GLIerit de la un caz la altul.

1. DEFECTELE DE TUB NEURAL Defectele de tub neural (DTN) – DQHQFHIDOLD�úL�VSLQD�ELILGD – DX�R�SDWRJHQLH�FRPXQă56 úL��vQ�FD]XULOH�IDPLOLDOH��VH�SRW�vQWkOQL�ILHFDUH�OD�GLIHULĠL�PHPEUL�DL�IDPLOLHL��,QFLGHQĠD�HVWH�YDULDELOă�����-1% în GLIHULWH�SRSXODĠLL�

ÌQ�DQHQFHIDOLH�VH�SURGXFH�XQ�GHIHFW�GH�vQFKLGHUH�D�SROXOXL�DQWHULRU�DO�WXEXOXL�QHXUDO�úL�HQFHIDOXO��PHQLQJHOH��FDORWD�FUDQLDQă�úL�SLHOHD�FDSXOXL�VXQW�DEVHQWH��VH�DVRFLD]ă�IUHFYHQW�FX�DQRPDOLL�IDFLDOH�úL�DXULFXODUH��VHFXQGDUH��0DOIRUPDĠLD�HVWH�OHWDOă��vQDLQWH�VDX�LPHGLDW�GXSă�QDúWHUH� Meningoencefalocelul se produce printr-R�KHUQLHUH�D�FRQĠLQXWXOXL�FUDQLDQ�GDWRULWă�OLSVHL�GH�GH]YROWDUH��EUHúă��D�XQRU�SRUĠLXQL�GLQ�RDVHOH�FUDQLXOXL��/RFDOL]DUHD�FHD�PDL�IUHFYHQWă�HVWH�RFFLSLWDOă (figura 13.2) sau fronto-QD]DOă (figura 13.3). Când KHUQLHUHD�LQWHUHVHD]ă�QXPDL�PHQLQJHOH�úL�/&5�GHQXPLUHD�HVWH�GH�meningocel��FkQG�KHUQLD]ă�DWkW�PHQLQJHOH�FkW�úL�FUHLHUXO�SRDUWă�denumirea de meningoencefalocel. Tratamentul este chirurgical, precoce. prognosticul depinde de gradul de afectare a encefalului. ÌQ�VSLQD�ELILGD�VH�SURGXFH�XQ�GHIHFW�GH�IX]LXQH�D�DUFXULORU�YHUWHEUDOH��FHO�PDL�IUHFYHQW�vQ�UHJLXQHD�ORPEDUă��([LVWă�JUDGH�variate de severitate, de la spina bifida oculta��vQ�FDUH�GHIHFWXO�LQWHUHVHD]ă�QXPDL�DUFXUile vertebrale, la spina bifida aperta �GHVFKLVă���vQ�FDUH�GHIHFWXO�RVRV�VH�DVRFLD]ă�FX�meningocel (protruzia meningelui) sau meningomielocel (hernierea elementelor QHXUDOH�úL�D�PHQLQJHOXL���ILJXUD��������&kQG�LQWHUHVHD]ă�vQWUHDJD�FRORDQă�YHUWHEUDOă�SRDUWă denumirea de rahischizis. Formele GHVFKLVH�VH�SRW�DVRFLD�IUHFYHQW�FX�KLGURFHIDOLH��SLFLRU�VWUkPE�FRQJHQLWDO��SDUDOL]LH�D�PHPEUHORU�LQIHULRDUH�úL�LQFRQWLQHQĠă�VILQFWHULDQă��3URJQRVWLFXO�HVWH�GHVWXO�GH�VHYHU��GXSă�WUDWDPHQW�FKLUXUJLFDO�����GLQ�FD]XULOH�GH�VSLQD�ELILGD�GHVFKLVă�VXSUDYLHĠXLHVF�FHO�SXĠLQ���DQL��GDU�����GLQWUH�DFHVWHD�YRU�DYHD�XQ�KDQGLFDS�QHXURORJLF�JUDY�úL�GRDU����YRU�IL�IăUă�KDQGLFDS�� 0DMRULWDWHD�FD]XULORU�GH�'71�VXQW�PXOWLIDFWRULDOH�GDU�VXQW�úL�FD]XUL�UDUH�SURGXVH�SULQ�teratogeni (valproat, diabet matern), prin anomalii cromosomiale (trisomia 18) sau prin anomalii monogenice pleiotrope (sindromul Meckel, autosomal recesiv) ÌQ�FD]XULOH�PXOWLIDFWRULDOH��GHWHUPLQDWH�GH�IDFWRUL�JHQHWLFL�úL�GH�PHGLX��V-D�FRQVWDW�Fă�XQ�URO�PDMRU�vO�DUH�GHILFLHQĠa PDWHUQă�GH�DFLG�IROLF��VFăGHUHD�FRQFHQWUDĠLHL�VHULFH�D�DFHVWHL�YLWDPLQH�VXE�XQ�SUDJ�GH�����ȝJ�/�FUHúWH�VHPQLILFDWLY�ULVFXO�GH�D�VH�SURGXFH�OD�IăW�XQ�'71��&RQFRPLWHQW�FX�UHGXFHUHD�QLYHOXOXL�VDQJXLQ�GH�IRODĠL��FUHúWH�QLYHOXO�GH�KRPRFLVWHLQă�úL�VFDGH�FRQFHQWUDĠLD�PHWLRQLQHL��DFHVW�IDSW�D�VXJHUDW�H[LVWHQĠD�XQHL�DQRPDOLL�ELRFKLPLFH�vQ�UHFLFODUHD�WHWUDKLGURIRODĠLORU�úL�PHWLODUHD�KRPRFLVWHLnei în PHWLRQLQă��$VWIHO�V-D�GHVFRSHULW�Fă�DSRUWXO�DOLPHQWDU�UHGXV�GH�DFLG�IROLF�DUH�HIHFWH�PDL�DPSOH�OD�SHUVRDQHOH�KHWHUR]Lgote pentru PXWDĠLD�&���7�D�JHQHL�07+)5��PHWLOHQWHWUDKLGURIRODWUHGXFWD]D��FDUH�vQORFXLHúWH�DODQLQD�GLQ�SR]LĠLD�����FX�R�YDOLQă�úL�GHWHUPLQă�UHGXFHUHD�HILFLHQĠHL�HQ]LPHL��FLUFD��-����GLQ�SRSXODĠLH�HVWH�KRPR]LJRWă�SHQWUX�DFHDVWă�PXWDĠLH� Important este faSWXO�Fă�LQWURGXFHUHD�XQHL�VXSOLPHQWăUL�GH����-����ȝJ�]L�GH�DFLG�IROLF�SHULFRQFHSĠLRQDO��R�OXQă�vQDLQWH�GH�FRQFHSĠLH�úL�GRXă�OXQL�GXSă�DFHHD��VFDGH�LQFLGHQĠD�'71�FX�SHVWH������$FHDVWă�PăVXUă�SUHYHQWLYă�SRDWH�IL�DVRFLDWă��PDL�DOHV�vQ familiile cu risc crescuW�GH�UHFXUHQĠă��GDWRULWă�DOWRU�FDXUL�GH�'71��FX�VFUHHQLQJXO�HFRJUDILF�DO�JUDYLGHORU�úL�GR]DUHD�DOID-

56 2�PDOIRUPDĠLH�vQUXGLWă�FX�'71�HVWH�HQFHIalocelul posterior (occipital) produs printr-o herniere a PHQLQJHOXL��PHQLQJRFHO��úL�uneori a ĠHVXWXOXL�FHUHEUDO��PHQLQJRHQFHIDORFHO��GDWRULWă�OLSVHL�GH�GH]YROWDUH��EUHúă��D�XQRU�SRUĠLXQL�GLQ�RDVHOH�FUDQLXOXL�� 57

IHWRSURWHLQHL��$)3��vQ�VkQJHOH�PDWHUQ�úL�VDX�OLFKLGXO�DPQLRWLF��vQ�VDUFLQLOH�vQ�FDUH�IăWXO�DUH�XQ�'71�VH�JăVHVF�YDORUL�IRDUWH crescute ale AFP).

2. HIDROCEFALIA

Hidrocefalia (0,7‰ nou-QăVFXĠL��UHSUH]LQWă�DFXPXODUHD�H[FHVLYă�GH�OLFKLG�FHIDOR-rahidian vQ�VSDĠLLOH�LQWUDFUDQLHQH��DVRFLDWă�FX�FUHúWHUHD�SUHVLXQLL�LQWUDFUDQLHQH��6H�GDWRUHD]ă�XQRU�WXOEXUăUL�GH�SURGXFHUH�VDX�úL�GH�FLUFXODĠLH�D�OLFKLGXOXL�FHIDOR-rahidian, GHWHUPLQDWH�GH�FDX]H�GLIHULWH��VSLQD�ELILGD��KHPRUDJLL�LQWUDFUDQLHQH��LQIHFĠLL�IHWDOH�VDX�IDFWRUL�JHQHWLFL��� $VSHFWXO�FOLQLF�HVWH�FDUDFWHULVWLF��PăULPH�HQRUPă��XQHRUL�JLJDQWă�D�FUHLHUXOXL��vQ�GLVSURSRUĠLH�HYLGHQWă�FX�GLPHQVLXQLOH�IDFLDOH�úL�FRUSRUDOH��IRQWDQHOHOH�IRDUWH�OăUJLWH�úL�GHKLVFHQĠD�RDVHORU�FUDQLHQH��SULYLUHD�vQ��DSXV�GH�VRDUH���ILJXUD��������FLUFXODĠLH�FRODWHUDOă�OD�QLYHOXO�FDORWHL�FUDQLHQH��DWURILD�QHUYXOXL�RSWLF�FX�FHFLWDWH��UHWDUG�SVLKR-motor important. Tratamentul chirurgical prin efectuarHD�XQXL�úXQW�SHUPDQHQW�vQWUH�FUDQLX�úL�SHULWRQHX�VDX�YHQD�FDYă�VXSHULRDUă�Gă�UH]XOWDWH�EXQH��LQWHOLJHQĠD�úL�FRPSRUWDPHQWXO�QHXURORJLF�ILLQG�QRUPDOH�vQ�����GLQ�FD]XUL� Majoritatea cazurilor de KLGURFHIDOLH�L]RODWă VXQW�GHWHUPLQDWH�PXOWLIDFWRULDO�úL�ULVFXO GH�UHFXUHQĠă�HVWH�PLF��GH��-4%. ([LVWă�vQVă�úL�IRUPH�PRQRJHQLFH�GH�KLGURFHIDOLH�– DXWRVRPDO�GRPLQDWH�VDX�UHFHVLYH��SUHFXP�úL�UHFHVLYH�OHJDWH�GH�;57 – care de RELFHL�VH�DVRFLD]ă�FX�DOWH�DQRPDOLL�FRQJHQLWDOH������GLQ�FD]XUL���ÌQ�DFHVWH�FD]XUL�H[DPHQXO�FOLQLF�DWHQW�úL�DQDQPQH]D�IDPLOLDOă�SRW�contribui decisiv la evitarea unor erori de sfat genetic.

Diagnosticul prenatal este uneori posibil prin ecografie.

3. 0$/)250$ğ,,/(�&21*(1,7$/(�'(�&25' 0DOIRUPDĠLLOH�FRQJHQLWDOH�GH�FRUG��0&&��VXQW�IRDUWH�IUHFYHQWH���-8‰ nou-QăVFXĠL��úL�YDULDWH�FD�WLS�GH�GHIHFW��PDQLIHVWDUH�FOLQLFă�úL�JUDYLWDWH��RULFXP�HOH�UHSUH]LQWă�R�FDX]ă�PDMRUă�GH�PRUELGLWDWH�úL�PRUWDOLWDWH�LQIDQWLOă��0&&�UHSUH]LQWă�XQ�JUXS�KHWHURJHQ�de PDOIRUPDĠLL�SXWkQG�IL�SURGXVH�GH�PXWDĠLL�PRQRJHQLFH, anomalii cromosomice sau expunerea gravidelor la teratogeni (LQIHFĠLD�UXEHROLFă��DOFRROLVPXO��GLDEHWXO�PDWHUQ���0DMRULWDWHD�FD]XULORU�L]RODWH�VXQW�vQVă�GH�RULJLQH�PXOWLIDFWRULDOă��([LVWă�WRWXúL�R�DJUHJDUH�IDPLOLDOă�UHGXVă�LDU�FRSLLL�DIHFWDĠL�QX�DX�H[DFW�DFHODúL�WLS�GH MCC, ci mai curând anomalii care au un mecanism de producere similar.

5LVFXO�GH�UHFXUHQĠă�OD�UXGHOH�GH�JUDGXO�,�YDULD]ă�vQWUH����úL����vQ�IXQFĠLH�GH�WLSXO�GH�0&&��OD�UXGHOH�GH�JUDGXO�,,�ULVFXO�VH�UHGXFH�IRDUWH�PXOW�OD�QLYHOXUL�DSURSLDWH�GH�SRSXODĠLD�JHQHUDOă��0XOWH�0&&�SRW�IL�vQ�SUH]HQW�HYLGHQĠLDWH�SUHQDWDO�SULQ�ecocardiografie.

0DOIRUPDĠLLOH�FRQJHQLWDOH�GH�FRUG�SRW�DSDUH�FD�R�FRPSRQHQWă�FOLQLFă�PDMRUă�vQ�FDGUXO�XQRU�VLQGURDPH�JHQHWLFH (precum tetralogia Fallot în cadrul sindromului velocardiofacial, defectul septal atrial în sindromul Holt-Oram determinat de PXWDĠLL�DOH�JHQHL�7%;��VDX�GHIHFWXO�DWULRYHQWULFXODU�vQ�FDGUXO�VLQGURPXOXL�'RZQ��RUL�FD�boli monogenice �SUHFXP�VWHQR]D�DRUWLFă�VXSUDYDOYXODUă�GHWHUPLQDWă�GH�PXWDĠLL�DOH�JHQHL�SHQWUX�HODVWLQă). Au fost vQVă�LGHQWLILFDWH�úL�PXWDĠLL�DOH�XQRU�JHQH�FDUH�SUHGLSXQ�OD�DSDULĠLD�XQRU�PDOIRUPDĠLL�GH�FRUG�L]RODWH��QRQVLQGURPLFH��SUHFXP�PXWDĠLLOH�-$*��úL�1.;�( �FH�GHWHUPLQă�WHWUDORJLH�)DOORW��VDX�PXWDĠLLOH�CRELD1 (implicate în producerea defectelor septale atriovenWULFXODUH�L]RODWH���'H�DVHPHQL��VWXGLL�GH�vQOăQĠXLUH�DX�HYLGHQĠLDW�SUH]HQĠD�XQXL�ORFXV�PDMRU�GH�VXVFHSWLELOLWDWH�SHQWUX�SHUVLVWHQĠD�FDQDOXOXL�DUWHULDO�OD�QLYHOXO�FURPRVRPXOXL���T���

���'(63,&Ă785,/(�/$%,$/(�ù,�'(63,&Ă785,/(�3$/$7,1( 'HVSLFăWXULOH�ODELDOH (uni- VDX�ELODWHUDOH��FX�VDX�IăUă�GHVSLFăWXUă�SDODWLQă�– DL(P) – VXQW�PDOIRUPDĠLL�FRQJHQLWDOH�IUHFYHQWH��FX�R�LQFLGHQĠă�PHGLH�GH��Å�GH�QRX-QăVFXĠL��'LQ�SXQFW�GH�YHGHUH�SDWRJHQLF�'/�3��– produse (cam în a 35-D�]L�GH�JHVWDĠLH��SULQWU-un defect de fuziune a mugurelui frontal cu mugurii maxilari – VH�GHRVHEHVF�GH�GHVSLFăWXULOH�SDODWLQH��'3��IăUă�GHVSLFăWXUL�ODELDOH��FDUH�UH]XOWă�SULQWU-XQ�GHIHFW�GH�IX]LXQH�D�ODPHORU�SDODWLQH�D�RDVHORU�PD[LODUH��$PEHOH�WLSXUL��'/�3��úL�'3��VH�SUH]LQWă�FD�PDOIRUPDĠLL�L]RODWH�VDX VH�SRW�DVRFLD�FX�DOWH�DQRPDOLL�FRQJHQLWDOH��IRUPHOH�L]RODWH�VXQW�GH�UHJXOă�PXOWLIDFWRULDOH�LDU�FHOH�DVRFLDWH�(circa 2-����GLQ�'/3�úL���-����GLQ�'3��IRUPHD]ă�SHVWH�����GH�VLQGURDPH�PRQRJHQLFH��FURPRVRPLFH�VDX�WHUDWRJHQH��ÌQ�DFHVWH�FRQGLĠLL�HYDOXDUHD�XQXL�FRSLO�FX�'/�3��úL�PDL�DOHV�FX�'3�WUHEXLH�Vă�ILH�FRPSOHWă�úL�PLQXĠLRDVă�SHQWUX�D�LGHQWLILFD�SRVLELOH�DVRFLHUL�FX�DOWH�DQRPDOLL�FRQJHQLWDOH��IDSW�FH�DU�PRGLILFD�SURJQRVWLFXO�úL�VIDWXO�JHQHWLF�� $X�IRVW�LGHQWLILFDWH�R�VHULH�GH�PXWDĠLL�JHQLFH�FDUH�SRW�FUHúWH�ULVFXO�DSDULĠLHL�'/�3���$VWIHO��PXWDĠLLOH�7*)$ (factorul de FUHúWHUH�WXPRUDOă�DOID��DX�IRVW�SULPHOH�DVRFLDWH�FX�FUHúWHUHD�ULVFXOXL�SHQWUX�'/�3���GDU�UH]XOWDWHOH�D�QXPHURDVH�VWXGLL�DX�IRst LQFRQVLVWHQWH��6H�SDUH�FD�DFHVWH�PXWDĠLL�DX�URO�QXPDL�vQ�FD]XULOH�vQ�FDUH�H[LVWă�R�DJUHJDUH�IDPLOLDOă�HYLGHQWă��$OWH�PXWDĠLL�JHQLFH�DVRFLDWH�FX�FUHúWHUHD�ULVFXOXL�SHQWUX�DSDULĠLD�XQRU�GHVSLFăWXUL�ODELRSDODWLQH��LQWHUHVHD]ă�JHQHOH�06;���7*)%���*$%5%��úL�PVRL1.

5LVFXO�GH�UHFXUHQĠă�D�IRUPHORU�L]RODWH�GH�'/�3��VDX�'3�– considerate „prototipuri” de boli multifactoriale – FUHúWH�R�GDWă�FX�VHYHULWDWHD�DIHFWăULL��GH�OD�'/�XQLODWHUDOH������OD�'/�ELODWHUDOH��������úL�GH�OD�'/�OD�'/3�������GH�DVHPHQHD�ULVFXO�GH�UHFXUHQĠă�OD�UXGHOH�GH�JUDGXO�,�FUHúWH�SDUDOHO�FX�QXPăUXO�SHUVRDQHORU�DIHFtate în familie, de la 3-���DWXQFL�FkQG�H[LVWă�XQ�EROQDY��XQ�SăULQWH�VDX�XQ�FRSLO��OD���-����FkQG�H[LVWă�GRL�EROQDYL��XQ�SăULQWH�úL�XQ�FRSLO�VDX�GRL�FRSLL�DIHFWDĠL���ÌQ�WRDWH�DFHVWH�FD]XUL�L]RODWH�ULVFXULOH�VXQW�ÄDFFHSWDELOH´�DYkQG�vQ�YHGHUH�PăULPHD��UH]XOWDWHOH�IRDUWH�EXQH�DOH�FRUHFĠLLORU�FKLUXUJLFDOH�úL�SRVLELOLWăĠLOH�GH�diagnostic prenatal, prin ecografie.

5. ALTE ANOMALII CONGENITALE IZOLATE 6WHQR]D�SLORULFă�KLSHUWURILFă�LQIDQWLOă

SPH a reprezentat pentru Carter (1960) modelul folosit pentru elaborarea coQFHSWXOXL�GH�ERDOă�SROLJHQLFă��PXOWLIDFWRULDOă��,QFLGHQĠD�PHGLH�vQ�SRSXODĠLD�(XURSHDQă�HVWH�������SHQWUX�EăLHĠL�úL��������SHQWUX�IHWH��GHFL�PDOIRUPDĠLD�HVWH de 4-��RUL�PDL�IUHFYHQWă�OD�VH[XO�PDVFXOLQ�GHFkW�OD�FHO�IHPLQLQ��5LVFXO�GH�UHFXUHQĠă�GHSLQGH�GH�VH[ul probandului, fiind mai mare

57 Formele de hidrocefalie legate de X – +6$6�VDX�IRUPD�FODVLFă��VLQGURPXO�0$6$�úL�SDUDSDUH]D�VSDVWLFă�FRPSOLFDWă�GH�WLSXO��(SPG1) – VXQW�GHWHUPLQDWH�GH�PXWDĠLL�GLIHULWH�vQ�JHQD�LICAM GH�SH�;T����FH�FRGLILFă�PROHFXOD�GH�DGH]LXQH�/�� 58

DWXQFL�FkQG�VXQW�DIHFWDWH�SHUVRDQH�GH�VH[�IHPLQLQ��WDEHO���������8QHOH�YDULDQWH�DOHOLFH�DOH�JHQHL�126���FDUH�FRGLILFă�R[LGD]D QLWULFă�QHXURQDOă��SDU�D�FUHúWH�ULVFXO�SHQWUX�DSDULĠLD�KLSHUWURILHL�SLORULFH�L]RODWH�

/X[DĠLD�FRQJHQLWDOă�GH�úROG�

/X[DĠLD�FRQJHQLWDOă�GH�úROG��/&6��UHSUH]LQWă�GHSODVDUHD�FDSXOXL�IHPXUDO�vQ�DIDUD�DFHWDEXOHL��SURGXVă�vQDLQWHD�VDX�vQ�WLPSXO�QDúWHULL��/&6�DUH�R�LQFLGHQĠă�GH��-�������QRX�QăVFXĠL�YLL�SHQWUX�IRUPHOH�WHPSRUDUH��LQVWDELOH���VXEOX[DĠLL��úL�GH��:1000 pentru OX[DĠLLOH�SURSULX-zise. Sex-ratio este de 6F:1M.

/&6�HVWH�GH�IDSW�R�GHIRUPDĠLH�FRQJHQLWDOă�FX�GHWHUPLQLVP�PXOWLIDFWRULDO��IDFWRULL�JHQHWLFL�FRQWUROHD]ă�FRQIRUPDĠLD�DFHWDEXOHL�úL�OD[LWDWHD�DUWLFXODUă��$OĠL�IDFWRUL�GH�ULVF�VXQW�SR]LĠLD�LQWUDXWHULQă�úL�SUH]HQWDĠLD�SHOYLQă��SULPLSDULWDWHD�úL��GHVLJXU��VH[XO�IăWXOXL��VH�FUHGH�Fă�SURGXFĠLD�GH�HVWURQă�GH�FăWUH�RYDUXO�IHWDO�úL�UHOD[LQD�GH�FăWUH�XWHUXO�IHWDO�SURGXF�R�FUHúWHUH�D�OD[LWăĠii articulare). 5LVFXO�GH�UHFXUHQĠă�vQ�IUDWULH�HVWH��vQ�PHGLH��GH��� ILLQG�SXĠLQ�PDL�PDUH�GDFă�SUREDQGXO�HVWH�GH�VH[�PDVFXOLQ�

Piciorul strâmb congenital 3LFLRUXO�VWUkPE�FRQJHQLWDO��36&��HVWH�R�DQRPDOLH�FRQJHQLWDOă�UHODWLY�IUHFYHQWă���-3‰ nou-QăVFXĠL���36&�SRDWH�IL�R�DQRPDOLH�L]RODWă�VDX�R�FRPSRQHQWă�D�PDL�PXOWRU�VLQGURDPH�FX�DIHFWDUH�QHUYRDVă�VDX�D�ĠHVXWXOXL�FRQMXQFWLY��ÌQ�IRUPHOH�L]RODWH�GHWHUPLQLVPXO�HVWH�FHO�PDL�SUREDELO�PXOWLIDFWRULDO�GHRDUHFH�VWXGLLOH�JHQHWLFH�UHOHYă�R�DJUHJDUH�IDPLOLDOă��vQ�XQHOH�FD]XUL�IDmilii se REVHUYă�R�VHJUHJDUH�0HQGHOLDQă��6WXGLLOH�PDL�YHFKL�QX�SUHD�VXQW�YDODELOH�GHRDUHFH�DVWă]L�VH�úWLH�FX�FHUWLWXGLQH�Fă�VXE�GHQXPLUHD�GH�36&�VXQW�LQFOXVH�WUHL�HQWLWăĠL�GLIHULWH��SLFLRUXO�HTXLQRYDUXV��DEGXFĠLD�úL�IOH[LD�SODQWDUă�D�ODEHL�SLFLRUXOXL���SLFLRUXO�FDOFDQHRYDOJXV��IOH[LD�GRUVDOă�D�ODEHL�SLFLRUXOXL��VXSUDIDĠD�SODQWDUă�SULYHúWH�ODWHUDO��úL�PHWDWDUVXV�YDUXV��DGGXFĠLD�úL�LQYHUVLD�ODEHL�SLFLRUXOXL���ÌQ�SUDFWLFD�VIDWXOXL�JHQHWLF�VH�IRORVHVF�vQFă�ULVFXULOH�HPSLULFH�– GH������SHQWUX�SUREDQGXO�GH�VH[�PDVFXOLQ�úL�GH������pentru probandul de sex feminin; pentru un SăULQWH�DIHFWDW�GH�RULFH�VH[��ULVFXO�OD�XUPDúL�HVWH�GH������ C. RETARDUL MENTAL Retardul mental (RM)este definit58 FD�R�LQFDSDFLWDWH�GH�D�GREkQGL�FDSDFLWăĠLOH�FRJQLWLYH��4,�VXE�����úL�DGDSWDWLYH�FRUHVSXQ]ăWRDUH�YkUVWHL��3UHYDOHQĠD�50�HVWH�GH�FLUFD��-3%; DH�IDSW�VXE�GHQXPLUHD�GH�50�VXQW�FXSULQVH�QXPHURDVH�EROL�FX�HWLRORJLH�GLIHULWă�FDUH�SURGXF�RSULUHD�GH]YROWăULL�PHQWDOH�VDX�R�GH]YROWDUH�PHQWDOă�LQFRPSOHWă��vQ�FDUH�HVWH�DIHFWDWă�LQWHOLJHQĠD�vQ�DQVDPEOXO�HL��$Vupra acestui subiect ne vom referi în detalii în FDSLWROXO�����GHRDUHFH�LQWHOLJHQĠD�HVWH�XQ�FDUDFWHU�SROLJHQLF��HVWH�ILUHVF�FD�úL�FHOH�PDL�PXOWH�GLQ�FD]XULOH�GH�50�XúRU��4, ��-70) nespecific Vă�DLEH�XQ�determinism multifactorial; în formele severe de RM (QI sub 50) cauzele specifice (deseori genetice) sunt mult mai frecvente. &RHILFLHQWXO�GH�LQWHOLJHQĠă�DO�XUPDúLORU�HVWH�SUREDELO�vQ�MXUXO�PHGLHL�SDUHQWDOH��'H�DFHHD�GDFă�XQXO�VDX�DPELL�GLQWUH�SăULQĠL�DX�XQ�50�XúRU ULVFXO�XQRU�FRSLL�FX�50�HVWH�PDL�PDUH��5LVFXO�GH�UHFXUHQĠă�GHSLQGH�GH�GLDJQRVWLF�GDU�vQ�50�nespecific �IăUă�R�FDX]ă�LGHQWLILFDWă��HVWH�GH�FLUFD����SHQWUX�UXGHOH�GH�JUDGXO�,��5LVFXO�GH�UHFXUHQĠă�FUHúWH�vQVă�GXSă�QDúWHUHD�D�GRL�Fopii cu 50��������SăULQĠLL�VXQW�FRQVDQJXLQL�������VDX�GDFă�SUREDQGXO�HVWH�GH�VH[�PDVFXOLQ���-5%) (unele cazuri ar putea fi RMLX) .

GENETICA BOLII CANCEROASE &DQFHUXO�HVWH�XQ�WHUPHQ�JHQHULF�SHQWUX�R�JDPă�H[WUHP�GH�ODUJă�GH�EROL�FDUDFWHUL]DWH�SULQ�DOWHUDUHD�SURFHVHORU�GH�FUHúWHUH�úL�SUROLIHUDUH�FHOXODUă�� ,Q�SUH]HQW�FDQFHUXO�HVWH�D�GRXă�FDX]ă�GH�GHFHV�GXSă�EROLOH�FDUGLRYDVFXODUH��FLUFD������GDU��R�GDWă�FX�FUHúWHUHD�GXUDWHL�PHGLL�GH�YLDĠă��VH�HVWLPHD]ă�Fă�SHVWH�MXPDWDWH�GLQ�SRSXODĠLH�DU�SXWHD�IL�GLDJQRVWLFDWă�FX�R�IRUPă�GH�FDQFHU�vQWU-un anumit moment DO�YLHĠLL� 3UROLIHUDUHD�FHOXODUă�QHFRQWURODWă�DUH�FD�UH]XOWDW�IRUPDUHD�XQHL PDVH�FHOXODUH�QXPLWH�WXPRUă sau neoplasm (gr. neo = nou, plasein = a forma). Procesul de formare a unei tumori este denumit WXPRULJHQH]ă. Neoplasmele maligne LQYDGHD]ă�ĠHVXWXULOH�vQYHFLQDWH�úL�DGHVHD�PHWDVWD]HD]ă �GLVHPLQHD]ă��FRORQL]kQG�WHULWRULL�DIODWH�OD�GLVWDQĠă��WUăVăWXUL�FDUH�OH�GLVWLQJ�SH�DFHVWHD�GH�tumorile benigne��7XPRULOH�VXQW�FODVLILFDWH�vQ�IXQFĠLH�GH�ĠHVXWXULOH�GLQ�FDUH�VH�IRUPHD]ă��SULQFLSDOHOH�WLSXUL�ILLQG��carcinoamele (tumori derivate din celulele epiteliale) - FDWHJRULD�FHD�PDL�IUHFYHQWă� sarcoamele �GHULYDWH�GLQ�ĠHVXWXULOH�FRQMXQFWLYH���limfoamele �ĠHVXWXULOH�OLPIDWLFH��úL�leucemiile �FH�DIHFWHD]ă�RUJDQHOH�KHPDWRSRLHWLFH��� &HOXOHOH�FDUH�IRUPHD]ă�R�WXPRUă�DX�RULJLQHD�vQWU-R�VLQJXUă�FHOXOă�SUHFXUVRDUH��FDUH�VH�PXOWLSOLFă�DFWLY�úL�IRUPHD]ă o FORQă��&HOXOHOH�GLQ�FORQD�QHRSOD]LFă�vQ�IRUPDUH�DFXPXOHD]ă�R�VHULH�GH�PRGLILFăUL�JHQHWLFH�úL�HSLJHQHWLFH FDUH�FRQGXF�OD�VFKLPEăUL�vQ�DFWLYLWDWHD�XQRU�JHQH�úL��GDWRULWă�DFHVWRUD��OD�PRGLILFăUL�IHQRWLSLFH��&HOXOHOH�VXQW�VXSXVH�VHOHFĠLHL�úL��vQ�ILQDO��R�SRSXODĠLH�D�FHOXOHORU�FORQDOH�DFXPXOHD]ă�VXILFLHQWH�PRGLILFăUL�IHQRWLSLFH�SHQWUX�FD�DFHO�WHULWRULX�Vă�GHYLQă�XQ�FDQFHU��$FHVWH�WUăVăWXUL�sunt: � DXWRVXILFLHQĠD�IDFWRULORU�GH�FUHúWHUH�� � LQVHQVLELOLWDWHD�OD�VHPQDOHOH�FDUH�EORFKHD]ă�FUHúWHUHD�� � capacitatea de prROLIHUDUH�QHFRQWURODWă�� � sustragerea de sub controlul mecanismelor apoptotice, � capacitatea de invazie, � PHWDVWD]DUH�úL�angiogeneza VXVĠLQXWă� Cauzele FDUH�FRQGXF�OD�DSDULĠLD�FDQFHUHORU�VXQW�QXPHURDVH�úL�YDULDWH�úL�LQFOXG�IDFWRULL�GH�PHGLX��SUHGLVSR]LĠLD�JHQHWLFă�úL�vârsta. $FHúWL�IDFWRUL�GHWHUPLQă�VDX�FRQWULEXLH�OD�WUDQVIRUPDUHD�FHOXOHORU�QRUPDOH�vQ�FHOXOH�FDQFHURDVH�SULQ�SHUWXUEDUHD�XQXL�VSHFWUX�ODUJ�GH�FăL�IL]LRORJLFH��$FHDVWă�FRPSOH[LWDWH�D�PHFDQLVPHORU�IL]LRSDWRORJLFH�HVWH�SULQFLSDOD�SLHGLFă�vQ�GH]YROWarea unor PLMORDFH�WHUDSHXWLFH�VSHFLILFH�úL�HILFLHQWH� )DFWRULL�GH�PHGLX�VXQW�FRQVLGHUDĠL�D�IL�SULQFLSDOD�FDX]ă�vQ�GH]YROWDUHD�FDQFHUHORU��DSUR[LPDWLY�����GLQ�FD]XUL���,QGLIHUHQW�GH�HWLRORJLH�vQVă��WRDWH�FDQFHUHOH�DSDU�FD�XUPDUH�D�XQRU�HYHQLPHQWH�JHQHWLFH úL�HSLJHQHWLFH��0DMRULWDWHD�DFHVWRU�HYHQLPHQWH�VH�SURGXF�vQ�FXUVXO�YLHĠLL�LQGLYLGXOXL��OD�QLYHOXO�FHOXOHORU�VRPDWLFH��ÌQ�DEVHQĠD�UHSDUăULL�ORU��DFHVWH�PXWDĠLL�VRPDWLFH sau

58 American Association of Menral Retardation, 1992. 59

dobândite se vor transmite la celulele fiice, conducând la formarea unei clone. Deoarece apar la nivelul celulelor somatice, DVHPHQHD�PXWDĠLL�QX�SRW�IL�vQVă�WUDQVPLVH�vQ�VXFFHVLXQHD�JHQHUDĠLLORU�GH�RUJDQLVPH��HOH�nu sunt ereditare. 8QHRUL��DQXPLWH�PXWDĠLL�FDUH�SUHGLVSXQ�OD�DSDULĠLD�FDQFHUXOXL�DSDU�OD�QLYHOXO�FHOXOHORU�JHUPLQDOH��$VHPHQea PXWDĠLL�germinale VH�WUDQVPLW�GH�OD�R�JHQHUDĠLH�OD�DOWD�úL�DX�FD�UH]XOWDW�DJUHJDUHD�IDPLOLDOă�D�XQRU�FDQFHUH�VSHFLILFH�� ,QGLIHUHQW�GDFă�XQ�FDQFHU�DSDUH�VSRQWDQ�OD�XQ�VLQJXU�LQGLYLG�VDX�VH�SURGXFH�OD�PDL�PXOWH�SHUVRDQH�GLQWU-o familie, ca un caracter ereditar – FDQFHUXO�HVWH�FRQVLGHUDW�R�ERDOă�JHQHWLFă�GHRDUHFH�LQLĠLHUHD�úL�GH]YROWDUHD�XQHL�WXPRUL�LPSOLFă�SURGXFHUHD�vQ�FDVFDGă�D�XQRU�PXWDĠLL�PXOWLSOH��vQ�GLIHULWH�JHQH�FDUH�FRQWUROHD]ă�SUROLIHUDUHD�FHOXODUă��UHSDUDUHD�$'1��FLFOXO�PLWRWLF�úL�PRartea celuODUă�

A. CLASE DE GENE IMPLICATE ÎN DEZVOLTAREA CANCERULUI

&DQFHUXO�VH�GH]YROWă�FD�XUPDUH�D�PXWDĠLLORU�OD�QLYHOXO�JHQHORU�FDUH�FRQWUROHD]ă�SUROLIHUDUHD�úL�PRDUWHD�FHOXODUă��$FHVWH�JHQH pot fi VHSDUDWH�vQ�GRXă�FDWHJRULL�PDMRUH��oncogenele úL�genele supresoare de tumori. � 2QFRJHQHOH�UHSUH]LQWă�YDULDQWHOH�PXWDQWH��DFWLYDWH��DOH�XQHL�FODVH�GH�JHQH�QRUPDOH�QXPLWH�protooncogene. Activarea acestor

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� *HQHOH�VXSUHVRDUH�GH�WXPRUL�VXQW�JHQH�FDUH�EORFKHD]ă�GH]YROWDUHD�QHRSOD]LLORU�PDOLJQH�SULQ�UHJODUHD�FUHúWHULL�úL�SUROLIHUDULL FHOXODUH��0XWDĠLL�cu SLHUGHUHD�IXQFĠLHL DFHVWRU�JHQH�FRQGXF�OD�SUROLIHUDUH�úL�FUHúWHUH�FHOXODUă�QHFRQWURODWH�úL�OD�apoptoza LQHILFLHQWă��*HQHOH�VXSUHVRDUH�GH�WXPRUL�VH�PDQLIHVWă�FD�JHQH�recesive la nivel celular, pentru convertirea fenotipului fiind QHFHVDUă�SLHUGHUHD�VDX�PXWDĠLD�DPEHORU�DOHOH��LQDFWLYDUHD�DOHOLFă��

1. ONCOGENELE 3ULPHOH�GDWH�GHVSUH�H[LVWHQĠD�RQFRJHQHORU�DX�IRVW�DGXVH�OD�VIkUúLWXO�DQLORU����SULQ�VWXGLXO�XQRU�virusuri FDSDELOH�Vă�LQGXFă�dezvolarea unor tumori la diverse specii animale. Ulterior s-D�GHPRQVWUDW�Fă�R�VLQJXUă�JHQă din structura acestor virusuri poate fi UHVSRQVDELOă�GH�DFHDVWă�WUDQVIRUPDUH��3ULPXO�H[HPSOX�D�IRVW�JHQD�src a virusului sarcomului avian Rous59. Asemenea gene au fost denumite oncogene virale (v-onc���*HQH�vQUXGLWH�FD�VHFYHQĠă�FX�FHOH�DOH�UHWURYLUXVXULORU RQFRJHQH�DX�IRVW�vQVă�LGHQWLILFDWH�úL�vQ�ADN-XO�FHOXOHORU�XPDQH�QRUPDOH��$FHVWH�JHQH�vQGHSOLQHVF�IXQFĠLL�vQ�FRQWUROXO�FUHúWHULL�úL�GLIHUHQĠLHULL�FHOXODUH��LDU�activarea lor QHFRUHVSXQ]DWRDUH��FD�PRPHQW�úL�FD�ORF��SRDWH�FRQGXFH�OD�DSDULĠLD�FDQFHUXOXL��*HQHle celulare normale au fost denumite protooncogene, iar variantele lor activate – oncogene celulare (c-onc). $X�IRVW�LGHQWLILFDWH�úL�YLUXVXUL�RQFRJHQLFH�XPDQH��3ULQWUH�DFHVWHD�VH�QXPDUă�DWkW�YLUXVXUL�$51��SUHFXP�YLUXVXO�+7/9��LPSOLFDW în etiologia leucemiiORU�DGXOWH�FX�FHOXOH�7�VDX�YLUXVXO�KHSDWLWLF�WLS�&�FDUH�GHWHUPLQă�FDQFHUH�KHSDWRFHOXODUH���FkW�úL�YLUXVXUL�FX�genom ADN (cum sunt, de exemplu, virusul Papilloma – HPV – implicat în producerea cancerelor tractului genital, virusul hepatitic tip B – hepatocarcinoame, virusul Epstein-Barr – limfomul Burkitt, virusul HV40 – mezotelioame sau virusul herpetic tip 8 – sarcomul Kaposi). /D�VIkUúLWXO�DQLORU����D�IRVW�GH]YROWDWă�R�PRGDOLWDWH�FRPSOHW�GLIHULWă�GH�LGHQWLILFDUH�D�RQFRJHQHORU��ED]DWă�SH�PHWRGH�GH�transfRUPDUH�FHOXODUă��$VHPHQHD�H[SHULPHQWH�DX�SHUPLV�LQWURGXFHUHD�SULQ�WUDQVIHFĠLH60 a unor fragmente de ADN provenite din celule canceroase umane în culturi de celule non-QHRSOD]LFH��OLQLD�GH�ILEUREODúWL�1,+-�7����3ULPD�JHQă�FDUH�D�LQGXV�WUDQVIRUPDUHD�WXPRUDOă�SULQ�DFHDVWă�WHKQLFă�D�IRVW�R�YDULDQWă�PXWDQWă�D�JHQHL�+5$6��R�SURWRRQFRJHQă�GHMD�FXQRVFXWă�GLQ�VWXGLLOH�UHWURYLUDOH� ÌQ�VIkUúLW��R�DOWă�VXUVă�GH�LGHQWLILFDUH�D�RQFRJHQHORU�D�IRVW�DQDOL]D�SXQFWHORU�GH�UXSWXUă�GLQ�WUDQVORFDĠLLOH�FURPR]RPLFH asociate constant cu anumite forme de cancer. Asemenea exemple sunt gena MYC în limfomul Burkitt61 ori gena ABL în OHXFHPLD�PLHORLGă�FURQLFă� În prezent sunt cunoscute peste 100 oncogene (vezi tabelul 17.1���ÌQ�IXQFĠLH��GH�QLYHOXO�FHOXODU�XQGH�DFĠLRQHD]ă�SURWHLQHOH�codificate de acestea, oncogenele pot fi clasificate în mai multe categorii (figura 17.1): (1) RQFRJHQH�FDUH�FRGLILFă�IDFWRUL�GH�FUHúWHUH (de exemplu PDGFB); (2) RQFRJHQH�FDUH�FRGLILFă�UHFHSWRUL�DL�IDFWRULORU�GH�FUHúWHUH (de exemplu EGFR, RET); (3) RQFRJHQH�FDUH�FRGLILFă FRPSRQHQWH�DOH�FăLORU�GH�VHPQDOL]DUH�LQWUDFHOXODUă (de exemplu familia RAS, gena ABL); (4) RQFRJHQH�FDUH�FRGLILFă�proteine nucleare, în special factori de WUDQVFULSĠLH (de exemplu MYC); (5) RQFRJHQH�FDUH�FRGLILFă�SURWHLQH�LPSOLFDWH�vQ�controlul ciclului celular (de exemplu MDM2). Oncogena Localizarea

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hepatocitar (HGF) MYC 8q24.1 factRU�GH�WUDQVFULSĠLH MYCN 2p24.1 IDFWRU�GH�WUDQVFULSĠLH MYCL1 1p34.3 IDFWRU�GH�WUDQVFULSĠLH PDGFB 22q13.1 VXEXQLWDWHD���D�IDFWRUXOXL�GH�FUHúWHUH��GHULYDW�GLQ�SODFKHWH

59Denumirea oncogenelor identificate prin studiul virusurilor oncogene a foVW�ED]DWă�SH�QXPHOH�DFHVWRUD��'H�H[HPSOX��65&�HVWH�R�RQFRJHQă� D� YLUXVXOXL� VDUFRPXOXL�5RXV� �5RXV� sarcRPD� YLUXV��� 6,6� R� RQFRJHQă� D� YLUXVXOXL� VDUFRPXOXL� VLPLDQ� �Simian sarcoma YLUXV���5$6�HVWH�YLUXVXO�VDUFRPXOXL�úRERODQLORU��rat sDUFRPD�YLUXV��úL�DúD�PDL�GHSDrte. 60TransfecĠLD� UHSUH]LQWă� LQWURGXFHUHD� XQHL� JHQH� vntr-o celulă, permiĠknd celulei transfectate să sintetizeze proteina corespunzătoare. 61Limfomul Burkitt este o forma agresivă de limfom cu origine în celulele tip B. 60

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Uneori protooQFRJHQHOH�SRW�IL�DFWLYDWH�SULQ�PXWDĠLL�FURPR]RPLFH��FHO�PDL�DGHVHD�WUDQVORFDĠLL��$X�IRVW�GHVFULVH�SHVWH����DVHPHQHD�WUDQVORFDĠLL�FX�SRWHQWLDO�DFWLYDWRU�DO�XQRU�RQFRJHQH��vQ�VSHFLDO�vQ�OHXFHPLL�úL�OLPIRDPH��GDU�úL�vQ�XQHOH�sarcoame (vezi tabelul 17.2). ExLVWă�GRXă�PHFDQLVPH�SULQ�FDUH�WUDQVORFDĠLLOH�FURPR]RPLFH�SRW�FRQGXFH�OD�DFWLYDUHD�RQFRJHQHORU��ÌQ�XQHOH�FD]XUL�SXQFWHOH�GH�UXSWXUă�VXQW�ORFDOL]DWH�OD�QLYHOXO�LQWURQLORU�D�GRXă�JHQH��UH]XOWDWXO�UHDUDQMăULL�FURPR]RPLFH�ILLQG�SURGXFHUHD�XQei proteine himerice��FX�SURSULHWăĠL�QRL��PXWDĠLH�FX�FkúWLJ�GH�IXQFĠLH���&HO�PDL�FXQRVFXW�H[HPSOX�HVWH�WUDQVORFDĠLD�vQWUH�FURPRVRPLL���úL����vQWkOQLWă�vQ�OHXFHPLD�PLHORLGă�FURQLFă (vezi caseta 17.1���$OWHURUL�WUDQVORFDĠLD�DFWLYHD]ă�R�RQFRJHQă�SULQ�SODVDUHD�DFHVWHLD�vQ�apropierea unui promotor puternic din structura altei gene. Un asemenea exemplu îl constituie activarea oncogenei MYC în limfomul Burkitt SULQ�SODVDUHD�DFHVWHLD�GLQ�SR]LĠLD�VD�QRUPDOă���T����vQ�SUR[LPLWDWHD�SURPRWRUXOXL�JHQHL�SHQWUX�ODQĠXO�JUHX�DO�imunoglobulinelRU����T�����IRDUWH�DFWLY�vQ�FHOXOHOH�%�FDUH�VLQWHWL]HD]ă�,J� ���$FWLYDUHD�RQFRJHQHORU�SULQ�DPSOLILFDUH�JHQLFă� $PSOLILFDUHD�JHQLFă�HVWH�XQ�IHQRPHQ�FDUH�DUH�FD�UH]XOWDW�SURGXFHUHD�mai multor copii ale unor oncogene normale structural. Fenomenul este respoQVDELO�GH�DFWLYDUHD�XQRU�RQFRJHQH�SUHFXP�FHOH�GLQ�FODVD�0<&�úL�(5%��YH]L�VXEFDSLWROXO����%��� ���$FWLYDUHD�RQFRJHQHORU�SULQ�LQVHUĠLH�YLUDOă� Retrovirusurile oncogene, ca de exemplu HTLV1, îndeplinesc rolul unor vectori, transportând oncogene activate de la un RUJDQLVP�OD�DOWXO��9LUXVXULOH�$'1�DFĠLRQHD]ă�vQVă�SULQ�LQVHUĠLD�vQ�JHQRPXO�JD]Gă�D�XQRU�RQFRJHQH�IăUă�FRUHVSRQGHQW�XPDQ��FD��de SLOGă��JHQD�SHQWUX�DQWLJHQXO�7�DO�YLUXVXOXL�69���– LPSOLFDW�vQ�HWLRORJLD�PH]RWHOLRDPHORU��RUL�DQWLJHQHOH�(��úL�(��DOH�papilomavirusului tip 16 – implicat în producerea cancerelor de col uterin). Caseta 17. 1. /HXFHPLD�PLHORLGă�FURQLFă��/0&� /0&�HVWH�R�ERDOă�FDUDFWHUL]DWă�SULQ�H[SDQVLXQHD�FORQDOă�D�FHOXOHORU�VWHP�KHPDWRSRLHWLFH��WUDQVIRUPDWH�PDOLJQ��FHHD�FH�are drept rezulWDW�R�FUHúWHUH�D�QXPDUXOXL�FHOXOHORU�PLHORLGH��HULWURLGH�úL�DO�SODFKHWHORU�FLUFXODQWH��7UDQVIRUPDUHD�FHOXOHORU�circulante are loc ca rezultat al expresiei oncogenei himerice BCR-ABL. $SUR[LPDWLY�����GLQ�SDFLHQĠLL�FX�/0&�DX�XQ�FURPR]RP�3KLODGHOSKLD��SURGXV SULQ�WUDQVORFDĠLD�W��������LDU�UHVWXO�DX�WUDQVORFDĠLL�FRPSOH[H�VDX�YDULDQWH�DOH�WUDQVORFDĠLHL�SULQFLSDOH��3URWRRQFRJHQD�$%/��$EHOVRQ��FDUH�FRGLILFă�R�WLUR]LQ�NLQD]ă�FLWRSODVPDWLFă�HVWH�ORFDOL]DWă�SH�FURPR]RPXO��T����LDU�JHQD�%&5��breakpoint cluster region���FH�FRGLILFă�R�IRVIRSURWHLQă��HVWH�ORFDOL]DWă�SH�FURPR]RPXO���T����ÌQ�FXUVXO�IRUPDULL�FURPRVRPXOXL�3KLODGHOSKLD�JHQD�$%/�HVWH�UXSWă�OD�QLYHOXO�LQWURQXOXL����LDU JHQD�%&5�FHO�PDL�DGHVHD�OD�QLYHOXO�LQWURQXOXL�����ÌQ�XUPD�WUDQVORFDĠLHL��OD�QLYHOXO�FURPRVRPXOXL����VH�IRUPHD]ă�JHQD�KLPHULFă�BCR-$%/�DOFăWXLWă�GLQ�H[RQLL��-���DL�JHQHL�%&5�úL��-11 ai genei ABL (vezi figura 17.1). )LJXUD�������7UDQVORFDĠLD�W�������FDUH�FRQGXFH�OD�IRUPDUHD�FURPRVRPXOXL�3KLODGHOSKLD�vQ�/0& 3kQă�vQ�SUH]HQW�QX�VH�FXQRVF�SH�GHSOLQ�IXQFĠLLOH�SURWHLQHORU�%&5�úL�$%/��3URWHLQD�$%/�VH�JăVHúWH�vQ�FLWRSODVPă��QXFOHX�úL�OD�QLYHOXO�PHPEUDQHL�FHOXODUH�úL�LQWHUYLQH�vQ�PXOWLSOH�SURFHVH��FRQWUROXO�FLFOXOXL�FHOXODU��VHPQDOL]DUHD�LQWHJULQLFă�úL�GH]YROWDrea QHXUDOă���3URWHLQD�%&5�HVWH�LPSOLFDWă�vQ�UHJODUHD�DFWLYLWăĠLL�SURWHLQHORU�GLQ�IDPLOLD�5$6�úL�D�*73-D]HORU�5$&�úL�5+2��6SUH�GHRVHELUH�GH�SURWHLQD�$%/�QRUPDOă��SURWHLQD�KLPHULFă�DUH�DFWLYLWDWH�WLUR]LQ�NLQD]LFă�FRQVWLWXWLYă�úL�HVWH�ORFDOL]DWă�vQ�SULQFipal în FLWRSODVPă��XQGH�VH�OHDJă�LQWHQV�GH�PLFURILODPHQWHOH�GH�DFWLQă��%&5-$%/�IRVIRULOHD]ă�FkWHYD�VXEVWUDWXUL�FLWRSODVPDWLFH�úL�DFWLYHD]ă��SUREDELO��R�VHULH�GH�FDVFDGH�GH�VHPQDOL]DUH�FDUH�FRQWUROHD]ă�FUHúWHUHD�úL�GLIHUHQĠLHUHD��SUHFXP�úL�DGH]LXQHD�FHOXOelor KHPDWRSRLHWLFH��3UROLIHUDUHD�QHFRQWURODWă�D�FHOXOHORU�VWHP�KHPDWRSRLHWLFH�FRQGXFH�OD�HOLEHUDUHD�vQ�FLUFXODĠLH�D�XQRU�FHOXOH�imature, generând LMC. ,Q�FXUVXO�SURJUHVLHL�/0&�SRW�DSDUH�PRGLILFăUL�FURPRVRPLFH�QRL��SUHFXP�WULVRPLD���VDX�����L���T��RUL�XQ�DO�GRLOHD�FURPR]RP�3KLODGHOSKLD��$SDULĠLD�DFHVWRU�PRGLILFăUL�DUH�FD�UH]XOWDW�GHEXWXO�FUL]HL�EODVWLFH� 61

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Identificarea proteinei de fuziune BCR-ABL a condus la sinteza unui inhibitor specific (Imatinib mesylate – *OHHYHF��FDSDELO�Vă�LQGXFă�PRDUWHD�SULQ�DSRSWR]ă�H[FOXVLY�D�FHOXOHORU�FDUH�H[SULPă�SURWHLQD�DQRUPDOă��,PDWLQLE�PHV\ODWH-XO�HVWH�XQ�PHGLFDPHQW�H[WUHP�GH�HILFLHQW�úL�D�GHYHQLt UDSLG�DJHQWXO�WHUDSHXWLF�GH�HOHFĠLH�SHQWUX�FD]XULOH�QRL�GH�/0&�SHQWUX�FDUH�QX�HVWH�LQGLFDW�WUDQVSODQWXO�PHGXODU�DORJHQLF� 2. GENELE SUPRESOARE DE TUMORI ([SHULPHQWHOH�GH�IX]LXQH�FHOXODUă�DX�HYLGHQĠLDW�IDSWXO�Fă�IHQRWLSXO�WUDQVIRUPDQW�DO�XQHL�Felule tumorale poate fi adesea corectat SULQ�IX]LXQHD�FHOXOHL�PDOLJQH�FX�XQD�QRUPDOă��$FHDWD�DUDWă�Fă�WXPRULJHQH]D�LPSOLFă�QX�QXPDL�DFWLYDUHD�GRPLQDQWă�D�XQRU�RQFRJHQH��GDU�úL�PXWDĠLL�FX�SLHUGHUHD�IXQFĠLHL ale altor gene. Aceste gene au fost denumite gene supresoare de tumori62 (“tumor-suppressor genes”). Deoarece celulele rezultate în urma acestor fuziuni sunt cu certitudine heterozigote, genele supresoare de tumori au efect recesiv la nivel celular. &RQFHSWHOH�úL�PHWRGHOH�GH�FHUFHWDUH�DOH�JHQHORU�VXSUHVRDre de tumori au fost definite prin studiul retinoblastomului, o IRUPă�UDUă�GH�WXPRUă�RFXODUă��YH]L�VXEFDSLWROXO����'�������&LUFD�����GLQ�FD]XULOH�GH�UHWLQREODVWRP�DSDU�FD�WXPRUL�VSRUDGLFH�úi unilaterale, iar 40% în cadrul unei boli ereditare cu transmitere DXWRVRPDO�GRPLQDQWă��QHRSOD]LD�ILLQG�DGHVHRUL�ELODWHUDOă��PXOWLFHQWULFă�úL�FX�GHEXW�PDL�WLPRXULX��3HQWUX�D�H[SOLFD�GLIHUHQĠHOH�vQWUH�FHOH�GRXă�IRUPH�GH�ERDOă��.QXGVRQ�D�SURSXV�vQ����� LSRWH]D�FHORU�GRXă�HYHQLPHQWH�("two hits") necesare pentru transformarea unei celule normale într-R�FHOXOă�WXPRUDOă��,Q�FD]XULOH�GH�UHWLQREODVWRP�HUHGLWDU�SULPD�PXWDĠLH�HVWH�PRúWHQLWă�úL�SUH]HQWă�OD�QDúWHUH�vQ�WRDWH�FHOXOHOH�RUJDQLVPXOXL��$�GRXă�PXWDĠLH�poate DSăUHD�OD�QLYHOXO�XQHLD�VDX�PDL�PXOWRU�FHOXOH�UHWLQLHQH��FHHD�FH�H[SOLFă�IUHFYHQĠD�UHODWLY�FUHVFXWă�D�UHWLQREODWRDPHORU�ELODWHUDOH�vQ�IRUPD�IDPLOLDOă�GH�ERDOă��'H�DVHPHQHD��PRúWHQLUHD�SULPHL�PXWDĠLL�H[SOLFă�GHEXWXO�PDL�WLPSXULX�DO�EROLL� 'HúL�JHQHOH�VXSUHVRDUH�GH�WXPRUL�DX�HIHFWH�UHFHVLY�OD�QLYHO�FHOXODU��SRVLELOLWDWHD�DSDULĠLHL�XQHL�PXWDĠLL�FDUH�Vă�LQDFWLYH]H�D�GRXD�DOHOă�vQ�FHO�SXĠLQ�R�FHOXOă�D�RUJDQLVPXOXL�HVWH�FUHVFXWă�úL��FD�XUPDUH��UHWLQREODVWRPXO�HUHGLWDU��FD�úL�DOWH�EROL�JHQHWLce produse GH�PRúWHQLUHD�XQRU�DVHPHQHD�PXWDĠLL�DOH�JHQHORU�VXSUHVRDUH�GH�WXPRUL��DX�XQ�Podel de transmitere dominant��([LVWD�vQVă�úL�IRUPH�HUHGLWDUH�GH�FDQFHUH�GHWHUPLQDWH�SULQ�WUDQVPLWHUHD�XQRU�PXWDĠLL�JHUPLQDOH�GDU�vQ�FDUH�PRGXO�GH�WUDQVPLWHUH�D�EROLL�HVWH unul recesiv (vezi tabelul 17.4). &DYHQHH�úL�FRODERUDWRULL�VăL��������DX�GHPRQVWUDW YDOLGLWDWHD�LSRWH]HL�OXL�.QXGVRQ�úL�DX�HYLGHQĠLDW�R�VHULH�GH�PHFDQLVPH�UăVSXQ]ăWRDUH�GH�LQDFWLYDUHD�FHOHL�GH-a doua alele a unei gene supresoare de tumori la nivel somatic. Autorii au comparat UH]XOWDWHOH�REWLQXWH�vQ�XUPD�WLSăULL�XQRU�PDUNHUL�SROLPRUILFL�GH�SH�FURPRVRPXO���T��LGHQWLILFDW�D�IL�SXUWăWRUXO�JHQHL�5%�– UHVSRQVDELOă�GH�SURGXFHUHD�UHWLQREODVWRPXOXL�HUHGLWDU��DO�FHOXOHORU�VDQJXLQH�úL�DO�FHOXOHORU�WXPRUDOH��(L�DX�REVHUYDW�XQHOH�Fazuri în care probele din sânge prezentau heterozigozitate pentru asemenea markeri, în timp ce celulele tumorale erau aparent homozigote. &RQFOX]LD�D�IRVW�DFHHD�Fă�IHQRPHQXO�VH�GDWRUHD]ă�XQXLD�GLQWUH�HYHQLPHQWHOH�.QXGVRQ��SLHUGHUHD�XQHL�FRSLL�IXQFĠLRQDOH�D�XQHL�gene supresoare de tumori. Fenomenul a fost denumit pierderea heWHUR]LJR]LWăĠLL (“loss of heterozygosity” - LOH). Studiile citogenetice au permis identificarea mai multor mecanisme de inactivare a celei de-D�GRXă�FRSLL�D�XQHL�JHQH�supresoare de tumori în cancerele ereditare � GHOHĠLL� � UHFRPELQăUL�VRPDWLFH�– prima dovadă�D�H[LVWHQĠHL�DFHVWXL�IHQRPHQ�OD�QLYHOXO�FHOXOHORU�VRPDWLFH� � pierderea unui cromozom; � SLHUGHUHD�XQXL�FURPR]RP�DVRFLDWă�FX�GXSOLFDĠLD�FURPR]RPXOXL�UHVWDQW� 3LHUGHUHD�KHWHUR]LJR]LWăĠLL este mecanismul cel mai frecvent de inactivare a celei de a doua alele în cancerele ereditare SURGXVH�SULQ�PRúWHQLUHD�XQHL�JHQH�VXSUHVRDUH�GH�WXPRUL�PXWDQWH��&kQG�SLHUGHUHD�KHWHUR]LJR]LWăĠLL�QX�HVWH�REVHUYDWă��FHO�GH-al GRLOHD�HYHQLPHQW�PXWDĠLRQDO�HVWH�GH�UHJXOă�R�PXWDĠLH�SXQFWLIRUPă VDX�LQDFWLYDUHD�WUDQVFULSĠLRQDOă�D�FHOHL�Ge-a doua alele printr-un eveniment epigenetic (vezi subcapitolul C.2). ,GHQWLILFDUHD�JHQHORU�VXSUHVRDUH�GH�WXPRUL�D�IRVW�UHDOL]DWă�SULQ�GRXă�FDWHJRULL�GH�VWXGLL� � FORQDUHD�SR]LĠLRQDOă�D�JHQHORU�LPSOLFDWH�vQ�SURGXFHUHD�XQRU�IRUPH�UDUH�GH�FDQFHUH�HUHGLWDUH��vezi subcapitolul 17.C.); � DQDOL]D�IUDJPHQWHORU�FURPR]RPLFH�FDUH�VXIHUă�IUHFYHQW�GHOHĠLL�vQ�FDQFHUHOH�VSRUDGLFH��SULQ�VWXGLL�GH�SLHUGHUH�D�KHWHUR]LJR]LWăĠLL�

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62 3UREDELO�� PDL� FRUHFWă� DU� IL� GHQXPLUHD� ³JHQH� VXSUHVRDUH� D� FUHúWHULL� WXPRUDOH´�� RULFXP�� WHUPHQXO� GH� ³DQWLRQFRJHQH´�� � IRORVLW�LQLĠLDO��HVWH�LPSURSLX 63IniĠial genele caretaker au fost denumite gene ale controlului integrităĠii genomului úL�au fost considerate o categorie separată faĠă de genele supresoare de tumori. 7UăVăWXULle lor comune (prHFXP�FDUDFWHUXO�UHFHVLY�DO�PXWDĠiilor) úL�lipsa unei departajări clare între funcĠiile lor au condus la reunirea acestora într-o singură clasă, cea a genelor supresoare de tumori. 62

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7RDWH�FăLOH�GH�reparare ale leziunilor ADN (vezi capitolul 6��SRW�IL�LPSOLFDWH�vQ�SURGXFHUHD�FDQFHUHORU��GDU�FRQVHFLQĠHOH�VXQW�GLYHUVH��$VWIHO��DOWHUăULle componenetelor implicate în repararea leziunilor ADN prin excizia nucleotidelor (nucleotide excision repair - 1(5��VXQW�vQWkOQLWH�vQ�VSHFLDO�vQ�FDQFHUHOH�FXWDQDWH�GHRDUHFH�DFHDVWă�FDOH�HVWH�UăVSXQ]ăWRDUH�GH�UHSDUDUHD�OH]LXQLORU�LQGXVH�GH�UDGLDĠLLOH�89��0XWDĠLLOH�JHQHORU�FDUH�FRGLILFă�SURWHLQHOH�LPSOLFDWH�vQ�FDOHD�GH�UHSDUDUH�D�HURULORU�GH�împerechere (mismatch repair - 005��GHWHUPLQă�LQVWDELOLWDWHD�PLFURVDWHOLĠLORU��IHQRWLS�vQWkOQLW�vQ�FDQFHUXO�FRORUHFWDO�nonpolipozic ereditar (HNPCC – vezi subcapitolul ���'�������$OWHUăULOH�FRPSRQHQWHOHRU�LPSOLFDWH�vQ�UHSDUDUHD�UXSWXULORU�$'1�DX�GUHSW�FRQVHFLQĠă�FUHúWHUHD�IUHFYHQĠHL�DQRPDOLLORU�FURPR]RPLFH�VWUXFWXUDOH��FDUDFWHULVWLFă�vQ�VSHFLDO�SHQWUX�QHRSOD]LLOH�GLQ�Vfera KHPDWRORJLFă��GDU�úL�SHQWUX�XQHOH�FDQFHUH�VROLGH��,Q�VIkUúLW��DOWHUăULOH�JHQHL�2��0*07�FDUH�SURWHMHD]ă�vPSRWULYD�PXWDĠLLORU�$�– G SUHFHG�DGHVHRUL�XQHOH�PXWDĠLL�SXQFWLIRUPH�GH�DFHVW�WLS�vQWkOQLWH�OD�QLYHOXO�JHQHORU�5$6�vQ�FDQFHUHOH�FRORUHFWDOH�VDX�FX�DOWH�ORFDOL]ăUL�� *HQHOH�D�FăURU�GHUHJODUH�SRDWH�FRQGXFH�OD�LQVWDELOLWDWH�FURPR]RPLFă�FRQWUROHD]ă�SURFHVH�SUHFXP�FRQGHQVDUHD�FURPR]RPLFă��DFWLYLWDWHD�FHQWURPHULORU��&'.���67.����3/.����NLQHWRFRULORU��$3&���RUL�D�SXQFWHORU�GH�FRQWURO�FDUH�SUHYLQ�VHSDUDUHD�SUHPDWXUă�D�FURPDWLGHORU�SkQă�FH�FURPRVRPLL�VXQW�FRUHFW�DOLQLDĠL�OD�QLYHOXO�IXVXOXL�GH�GLYL]LXQH��VHFXULQD��VHSDULQD��MAD2L1, BUB1 – vezi subcapitolul 17.B). Intre genele gatekeeper úL�JHQHOH�caretaker QX�H[LVWă�R�GHOLPLWDUH�SUHFLVă��$VWIHO��JHQHOH�%5&$��úL�%5&$��VXQW�JHQH�gatekeeper prin activitatea lor de FRQWURO�D�WUDQVFULSĠLHL�úL�JHQH�caretaker SULQ�LQWHUYHQĠLD�ORU�vQ�FDOHD�GH�UHSDUDUH�D�UXSWXULORU�$'1�ELFDWHQDUH��'H�DVHPHQL��JHQD�$3&�SDUH�D�IL�LPSOLFDWă�úL�vQ�FRQWUROXO�VWDELOLWăĠLL�JHQRPLFH� 3H�OkQJă�LPSOLFDUHD�ORU�vQ�SURGXFHUHD�XQRU�FDQFHUH�HUHGLWDUH� JHQHOH�VXSUHVRDUH�GH�WXPRUL�VXQW�LQDFWLYDWH�DGHVHD�úL�vQ�cazul cancerelor sporadice. Inactivarea genei TP5364 HVWH��GH�H[HPSOX��FHO�PDL�IUHFYHQW�HYHQLPHQW�PXWDĠLRQDO�vQWkOQLW�vQ�FDQFHUHOH�VSRUDGLFH��FLUFD�����GLQ�DFHVWHD��GDU�FX�IUHFYHQĠH�PDL�PDUL�vQ�DQXPLWH�ORFDOL]ăUL��FDQFHUHOH�PDPDUH��FRORUHFWDOH��YH]LFDOH��pulmonare, cervicale etc.). Alte gene supresoare de tumori care sunt frecvent inactivate în cancerele sporadice sunt APC (in aproximativ 70% dintre cancerele colorectale), NF1 (în cancerele cu origine în celulele nervoase), genele MMR în circa 15% dintre cancerele colorectale, vQ�WLPS�FH�PXWDĠLLOH�%5&$��úL�%5&$��VXQW�vQWkOQLWH�UHODWLY�UDU�vQ�FDQFHUHOH�GH�VkQ�úL�RYDU�VSRUDGLFH� B. ANOMALII CITOGENETICE IN CANCER Anomaliile citogenetice sunt consecLQĠD�LQVWDELOLWăĠLL�JHQRPLFH�- FDUDFWHULVWLFă�WXWXURU�FDQFHUHORU�úL�UHVSRQVDELOă�GH�FUHúWHUHD�QXPăUXOXL�PXWDĠLLORU�FDUH�FRQGXF�OD�GH]YROWDUHD�QHRSOD]LLORU��([LVWă�WUHL�FDWHJRULL�PDMRUH�GH�DQRPDOLL�FURPR]RPLFH�FDUH�SRW�Ii întâlnite în cancer: anomalii numerLFH��DQRPDOLL�VWUXFWXUDOH�úL�DPSOLILFăUL�JHQLFH� 1. ANOMALII CROMOZOMICE NUMERICE $QRPDOLLOH�FURPR]RPLFH�QXPHULFH�LPSOLFă�SLHUGHUHD�VDX�FkúWLJXO�XQRU�FURPR]RPL�vQ�vQWUHJLPH�– aneuploidie65��1XPăUXO�cromozomilor poate fi redus – hipoploidie, crescut – hiperploidie sau aparent normal – pseudodiploidie��$VHPHQHD�PRGLILFăUL�VXQW�vQWkOQLWH�vQ�PDMRULWDWHD�WLSXULORU�WXPRUDOH��,Q�JHQHUDO�QX�H[LVWă�DQRPDOLL�QXPHULFH�VSHFLILFH�SHQWUX�XQ�DQXPLW�WLS�WXPRUDO��GHúL�unele variante pot fi întâlnite mai frecvent în unele forme de cancer. Asemenea exemple sunt pierderea cromozomului 10 în glioblastoame (reflectând adesea inactivarea genei supresoare de tumori PTEN���RUL�DGLĠLD�XQXL�cromozom 7 în carcinoamele renale papilare �UHIOHFWkQG�GXSOLFDĠLD�RQFRJHQHL�0(7��� ([LVWHQĠD DQRPDOLLORU�FURPR]RPLFH�vQ�FHOXOHOH�FDQFHURDVH�D�IRVW�HYLGHQĠLDWă�SHQWUX�SULPD�GDWă�GH�%RYHUL�vQ������FDUH�D�SRVWXODW�WHRULD�DQHXSORLGLHL�FD�ED]D�D�GH]YROWăULL�FDQFHUHORU��/LSVD�XQRU�DQRPDOLL�FURPR]RPLFH�VSHFLILFH�vQ�DQXPLWH�WLSXUL�GH FDQFHUH�úL�HYLGHQĠLHUHD�PXWDĠLLORU�JHQLFH�D�FRQGXV�OD�DEDQGRQDUHD�vQ�PDUH�SDUWH�D�DFHVWHL�WHRULL��2ULFXP��XQHOH�FHUFHWăUL�UHFHQWH�vQFHDUFă�Vă�UHDGXFă�vQ�DFWXDOLWDWH�DFHDVWă�LSRWH]D��&kWHYD�GLQWUH�DUJXPHQWHOH�DGXVH�vQ�IDYRDUHD�DFHVWHL�WHRULL�VXQW�

- H[LVWHQĠD�XQRU�FDUFLQRJHQL�FDSDELOL�Vă�LQGXFă�DQHXSORLGLH�IăUă�D�SURGXFH�PXWDĠLL�JHQLFH��SULQ�DOWHUDUHD�IL]LFă�VDX�FKLPLFă�a elementelor componente ale fusului de diviziune);

- LQFDSDFLWDWHD�FHUFHWăWRULORU�GH�D�GHPRQVWUD�FODU�H[LVWHQĠD�XQRU�PXWDĠLL�FDSDELOH�Vă�FRQGXFă�OD�WUDQVIRUPDUHD�FDQFHURDVă�D�celulelor normale;

- H[LVWHQĠD�REOLJDWRULH�D�DQHXSORLGLHL�vQ�WRDWH�OLQLLOH�FHOXODUH�LPRUWDOL]DWH�SH�FDUH�DX�IRVW�VWXGLDWH�RQFRJHQHOH�VDX�JHQHOH�supresoare de tumori.

&RQIRUP�DFHVWHL�WHRULL��GH]YROWDUHD�FDQFHUXOXL�VH�UHDOL]HD]ă�vQ�GRXă�VWDGLL� - staGLXO�LQLĠLDO�vQ�FDUH�DQHXSORLGLD�HVWH�JHQHUDWă�SULQ�DOWHUDUHD�IL]LFă�VDX�FKLPLFă�D�HOHPHQWHORU��DSDUDWXOXL���PLWRWLF�RUL�SULQ�PXWDĠLD�XQRU�JHQH�FDUH�FRQWUROHD]ă�DFWLYLWDWHD�DFHVWRU�HOHPHQWH��

- VWDGLXO�XOWHULRU�vQ�FDUH�DQHXSORLGLD�VH�SURSDJă�DXWRFDWDOLWLF�GDWRULWă�GH]HFKLOLEUXOXL�LQGXV�vQWUH�SURWHLQHOH�IXVXOXL� GH�GLYL]LXQH��SURWHLQHOH�FHQWURPHUHORU�úL�QXPăUXO�FURPRVRPLORU�

$QHXSORLGLD�SRDWH�H[SOLFD�PDL�ELQH�GHFkW�PXWDĠLLOH�XQRU�JHQH�L]RODWH�PRGLILFăULOH�IHQRWLSLFH�GUDPDWLFH�DOH�FHOXOHORU�canceroase (deRDUHFH�VXQW�LPSOLFDWH�VXWH�VDX�PLL�GH�JHQH��úL�SRDWH�H[SOLFD�GH�DVHPHQL��PDL�ELQH��ODWHQĠD�DFĠLXQLL�XQRU�FDUFLQRJHQL�RUL�GREkQGLUHD�UDSLGă�D�UH]LVWHQĠHL�PXOWLSOH�D�FHOXOHORU�WXPRUDOH�OD�DJHQĠLL�FLWRVWDWLFL� 8QD�GLQWUH�GLUHFĠLLOH�PDMRUH�GH�FHUFHWDUH�vQ�FDQFHU�HVWH�LGHQWLILFDUHD�JHQHORU�FDUH�FRQWUROHD]ă�DSDUDWXO�PLWRWLF��ĠLQWH�vQ�JHQHUDUHD�LQVWDELOLWăĠLL�FURPR]RPLFH� O asemenea gena poate fi TP53��,QDFWLYDUHD�VD�vQ�FXOWXULOH�FHOXODUH�HVWH�DVRFLDWă�FX�DSDULĠLD�DQHXSORLGLHL��DQRPDOLL�DOH�IXVXOXL�GH�GLYL]LXQH�úL FX�EORFDUHD�SURJUHVLHL�SULQ�FLFOXO�FHOXODU�OD�QLYHOXO�SXQFWXOXL�GH�FRQWURO�*��0��3H�GH�DOWă�SDUWH��H[LVWă�vQVă�úL�OLQLL�FHOXODUH�FX�PXWDĠLL�DOH�JHQHL�73���FDUH�VXQW�GLSORLGH��0DL�PXOW��PXWDĠLD�73���HVWH�XQ�HYHQLPHQW�WDUGLY�vQ�HYROXĠLD�PDMRULWăĠLi

64 Rolul central al proteiQHL�73���vQ�VXSUHVLD�WXPRUDOă a condus la desemnarea acesteia ca "molecula anului" de catre revista Science în 1993 (vezi úL�caseta 17.5). 65 Aneuploidia este definită ca fiind orice număr al cromosomilor care nu este un multiplu exact al unui set haploid de cromosomi. 63

cancerelRU��vQ�WLPS�FH�DQHXSORLGLD�DSDUH�SUHFRFH��7RDWH�DFHVWH�UH]XOWDWH�VXJHUHD]ă�Fă�73���SRDWH�H[DFHUED�LQVWDELOLWDWHD�FURPR]RPLFă��GDU�HVWH�SXĠLQ�SUREDELO�Vă�ILH�R�FDX]ă�SULPDUă�D�DFHVWHLD� Teoretic, genele implicate în producerea aneuploidiei pot controla condensarea cromozomilor, coeziunea cromatidelor surori, IXQFĠLD�úL�VWUXFWXUD�NLQHWRFRULORU�úL�FHQWURVRPLORU��RUL�GLQDPLFD�PLFURWXEXOLORU�

8Q�SULP�SXQFW�GH�FRQWURO�HVWH�UHJODUHD�DFWLYLWăĠLL�fusului de diviziune FDUH�SUHvQWkPSLQă�VHSDUDUHD�FURPDWLGHORU�VXURUL�îQDLQWH�GH�DOLQLHUHD�FRUHVSXQ]ăWRDUH�D�FURPR]RPLORU�OD�QLYHOXO�IXVXOXL�PLWRWLF��$VWIHO��UHGXFHUHD�H[SUHVLHL�JHQHL�0$'�/��(cromosomul 4q27) – HYLGHQĠLDWă�vQ�QXPHURDVH�FDQFHUH�PDPDUH�– HVWH�DVRFLDWă�FX�LQVWDELOLWDWH�FURPR]RPLFă�WUDGXVă�SULQ�aneuploidie.

MAD2/��FRGLILFă�R�SURWHLQD�FX�����DPLQRDFL]L�FDUH�VH�DWDúHD]ă�OD�QLYHOXO�FURPRVRPLORU�QHIL[DĠL�SH�ILEUHOH�IXVXOXL�GH�GLYL]LXQH��LQKLEkQG�DFWLYLWDWHD�FRPSOH[XOXL�GH�SURPRYDUH�D�DQDID]HL��0XWDĠLLOH�%8%��úL�%8%5��FDUH�FRQWUROHD]ă�DFWLYLWDWHD�fusului de diviziune LQGXF�DQHXSORLGLH�vQ�XQHOH�FDQFHUH�FRORUHFWDOH��,Q�VIkUúLW��PXWDĠLLOH�VHFXULQHL�úL�VHSDULQHL��GRXă�SURWHLQH�LPSOLFDWH�vQ�SUHYHQLUHD�VHSDUăULL�SUHPDWXUH�D�FURPDWLGHORU�VXURUL�vQ�FXUVXO�PLWR]HL��SRW�FRQGXFH�OD�LQVWDELOLWDWH�FURPRVRPLFă.

2�D�GRXD�FDX]ă�SRWHQĠLDOă�D�DQHXSORLGLHL�LPSOLFă�IXQFĠLD�DQRUPDOă�D�centrosomilor. In multe tipuri de cancere umane, FXP�VXQW�FHOH�GH�VkQ��SOăPkQ��FRORQ�VDX�SURVWDWD�DX�IRVW�HYLGHQĠLDWH�IXVXUL�GH�GLYL]LXQH�PXOWLSRODUH�VDX�XQ�QXPăU�DQRUPDO�GH�FHQWURVRPL��3kQă�vQ�SUH]HQW�DX�IRVW�LGHQWLILFDWH�FkWHYD�JHQH�FDUH�FRQWUROHD]ă�DFWLYLWDWHD�FHQWURVRPLORU�úL�DQXPH�FHOH�FDUH�FRGLILFă�kinazele CDK2, STK15 ori PLK1. 5HFHQW�DX�IRVW�DGXVH�GRYH]L�FDUH�VXVĠLQ�UROXO�SURWHLQHL�$3&�vQ�LQGXFHUHD�LQVWDELOLWăĠLL�FURPRVRPLFH��'RPHQLXO�&-terminal al acHVWHL�SURWHLQH�LQWHUDFĠLRQHD]ă�FX�SURWHLQD�(%��DVRFLDWă�H[WUHPLWăĠLORU�FLWRSODVPDWLFH�DOH�PLFURWXEXOLORU�IXVXOXL�GH�diviziune. Complexul APC-(%��SDUH�D�IL�FUXFLDO�SHQWUX�FDSWDUHD�NLQHWRFRULORU�úL�VWDELOL]DUHD�LQWHUDFĠLXQLORU�PLFURWXEXOL-kinetocori. In pofLGD�DFHVWRU�GDWH��ED]HOH�PROHFXODUH�DOH�LQVWDELOLWăĠLL�FURPRVRPLFH�UăPkQ�QHFXQRVFXWH�vQ�FD]XO�PDMSULWăĠLL�cancerelor umane. Este evident caracterul heterogen al substratului acestui fenotip, cu numeroase gene implicate fiecare într-o PLFă�SDUWH�D�FDQFHUHORr. 2. ANOMALII CROMOZOMICE STRUCTURALE &HD�PDL�IUHFYHQWă�FDWHJRULH�GH�DQRPDOLL�FURPR]RPLFH�VWUXFWXUDOH�vQWkOQLWH�vQ�FDQFHUHOH�XPDQH�HVWH�FHD�D�WUDQVORFDĠLLORU. Pot fi HYLGHQĠLDWH�GRXă�FDWHJRULL�PDMRUH�GH�DQRPDOLL�VWUXFWXUDOH��WLSXO�FRPSOH[�úL�WLSXO�VLPSOu. Tipul complex este observat în special în tumorile solide úL�FRQVWă�vQ�UHDUDQMăUL�FRPSOLFDWH�FH�LQWHUHVHD]ă�PDL�PXOĠL�FURPR]RPL��&DUDFWHUL]DUHD�ORU�HVWH�SRVLELOă�DGHVHRUL�QXPDL�SULQ�PHWRGH�ED]DWH�SH�KLEULGL]DUHD�IOXRUHVFHQWă�LQ�VLWX��),6+��RUL�KLEULGL]Drea JHQRPLFă�FRPSDUDWLYă��&*+���2�FRQVHFLQĠă�IUHFYHQWă�D�XQRU�DVHPHQHD�UHDUDQMăUL�FRPSOH[H�HVWH�DSDULĠLD�cromosomilor marker, vQWkOQLĠL�IUHFYHQW�vQ�WXPRULOH�VROLGH��'H�DVHPHQL��SRW�UH]XOWD�DGHVHRUL�SLHUGHUL�DOH�XQRU�IUDJPHQWH�FURPRVRPLFH�PDUL��WUDGXVH la nLYHO�PROHFXODU�SULQ�SLHUGHUHD�KHWHUR]LJR]LWăĠLL���FkúWLJXUL�GH�PDWHULDO�JHQHWLF�RUL�JHQHUDUHD�XQRU�QRL�SURGXúL�JHQLFL� %D]HOH�PROHFXODUH�DOH�DSDULĠLHL�DQRPDOLLORU�FURPRVRPLFH�GH�VWUXFWXUă�VXQW�vQFă�LQFRPSOHW�vQĠHOHVH��2�LSRWH]ă�DWUDFWLYă�HVWH�vQVă�DSDULĠLD DFHVWRUD�FD�XUPDUH�D�GHFODQúăULL�SUHPDWXUH�D�PLWR]HL��vQDLQWHD�UHSDUăULL�UXSWXULORU�$'1�ELFDWHQDUH�FDUH�SURPRYHD]ă�UHFRPELQDUHD��*HQH�FDQGLGDWH�D�PHGLD�DFHDVWă�IRUPă�GH�LQVWDELOLWDWH�FURPRVRPLFă�VXQW�$70��$75��%5&$���%5&$���73����1%6��.8����.8���úL�DOWH�FRPSRQHQWH�LPSOLFDWH�vQ�UHSDUDUHD�UXSWXULORU�$'1�ELFDWHQDUH�VDX�FDUH�UHJOHD]ă�SXQFWHOH�GH�FRQWURO�DOH�FDOLWăĠLL�DFHVWXL�SURFHV� Tipul simplu GH�DQRPDOLL�FURPRVRPLFH�GH�VWUXFWXUă�HVWH�FDUDFWHUL]DW�SULQ�DSDULĠLD�XQRU�UHDUDQMăUL�FDUH�LPSOLFă�VHJPHQWH�cromozomice adeseori specifice pentru anumite tipuri de neoplazii. Ele apar mai frecvent în OHXFHPLL�úL�OLPIRDPH FD�úL�vQ�XQHOH�tipuri de sarcoame sau forme rare de cancer (tabelul 17.2����'DWRULWă�VSHFLILFLWăĠLL�ORU��LGHQWLILFDUHD�DFHVWRU�IRUPH�GH�DQRPDOLL�cromosoPLFH�SRDWH�IL�XWLOL]DWă�SHQWUX�FODVLILFDUHD�QHRSODVPHORU�úL�SHQWUX�SUHGLFĠLD�UăVSXQVXOXL�ORU�WHUDSHXWLF��$QDOL]HOH�moleculare ale unor asemenea anomalii cromosomice au condus la identificarea unor noi gene, implicate în dezvoltarea cancerelor, în special oQFRJHQH��$FHVWH�UHDUDQMăUL�FRQGXF�vQ�JHQHUDO�OD�DFWLYDUHD�RQFRJHQHORU�SULQ�UHSR]LĠLRQDUHD�ORU�OkQJă�XQ�SURPRWRU�SXWHUQLF�VDX�SULQ�IX]LXQHD�FX�R�DOWă�JHQă�DFWLYă��$VHPHQHD�UHDUDQMăUL�VSHFLILFH�SDU�Vă�ILH�HVHQĠLDOH�SHQWUX�GH]YROWDrea sau progresia cancerelor în care apar. Neoplazia $QRPDOLD�FURPRVRPLFă Genele implicate OHXFHPLD�PLHORLGă�FURQLFă t(2; 22)(q34; q11) BCR-ABL OHXFHPLD�DFXWă�OLPIREODVWLFă t(1;19)(q23; p13.3) E2A-PBX1 OHXFHPLD�DFXWă�SURPLHORFLWDUă t(15; 17)(q22; q12) PML-RARA limfomul Burkitt t(8; 14)(q24; q32) MYC sarcomul Ewing t(11; 22)(q24; q12) EWS-FLI1 liposarcomul mixoid t(12; 16)(q13; p11) FUS-CHOP rabdomiosarcomul alveolar t(2; 13)(q35; q14) PAX3-FKHR 6SUH�GHRVHELUH�GH�WLSXO�FRPSOH[��WLSXO�VLPSOX�GH�UHDUDQMăUL�FURPRVRPLFH�QX�SDUH�Vă�ILH�UH]XOWDWXO�XQHL�LQVWDELOLWăĠL�JHQHWLFH caUH�Vă�SURPRYH]H�DSDULĠLD�ORU�FX�R�IUHFYHQĠă�PDL�FUHVFXWă�GHFkW�vQ�FHOXOHOH�QRUPDOH��'H�IDSW��PXOWH�GLQWUH�DFHVWH�DQRPDOLL�VWUXFWXUDle UHSUH]LQWă�DEHUDĠLL�DOH�XQRU�SURFHVH�QRUPDOH�GH�UHFRPELQDUH��SUHFXP�FHOH�SURPRYDWH�GH�SURWLQHOH�5$*�FDUH�LQWHUYLQ�vQ�UHDUDQMăUL�JHQHORU�FH�FRGLILFă�LPXQRJOREXOLQHOH�VDX�UHFHSWRULL�7&5� ���$03/,),&Ă5,/(�*(1,&( $PSOLILFăULOH�JHQLFH�VXQW�HYLGHQĠLDWH�FLWRJHQHWLF�VXE�IRUPD�regiunilor colorate omogen (homogeneously stained regions - HSR) ori a cromosomilor minusculi (double minutes – DMIN) (figura 17.�����$PSOLFRQLL�UH]XOWDĠL�FRQĠLQ�����- 10 megabaze ADN. 5H]XOWDWXO�vO�UHSUH]LQWă�DSDULĠLD�D�]HFL�VDX�VXWH�GH�FRSLL�DOH�XQHL�VLQJXUH�JHQH, în general protooncogene sau gene implicate în UH]LVWHQĠD�OD�DJHQĠL�DQWLWXPRUDOL��$PSOLILFDUHD�JHQLFă�HVWH�XQ�IHQRPHQ�vQWkOQLW�vQ�QXPHURDVH�WLSXUL�GH�FDQFHUH��FRORUHFDWDOH��GH�VkQ��FDQFHUHOH�FDSXOXL�úL�JkWXOXL�VDX�vQ�QHXUREODVWRDPH��)HQRPHQXO�HVWH�DVRFLDW�vQ�VSHFLDO�ID]HORU�DYDQVDWH�GH�ERDOă�úL�LPSOLFă�XQ�prognostic nefavorabil. Câteva exemple sunt amplificarea N-MYC în 30% din neuroblastoamele avansate, ori amplificarea ERBB2 (HER2/neu) în cancerele mamare avansate.

64

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Acest mecanism de inactivare este frecvent în mod particular în cazul unor gene precum: APC, BRCA1, CDH1, LBK1, MLH1, P16 ori VHL, dar nu în formele familiale de boala ci în cele sporadice. Lista genelor hipermetilate în cancer include, de DVHPHQHD��R�VHULH�GH�JHQH�FDUH�QX�DX�DFWLYLWDWH�SH�GHSOLQ�GRFXPHQWDWă�GH�VXSUHVLH�D�FUHúWHULL�WXPRUDOH��GH�H[HPSOX��SLHUGHUHD expresiei genei O6-0*07�FDUH�SURWHMHD]ă�vPSRWULYD�PXWDĠLLORU�*-A). &XP�KLSHUPHWLODUHD�VH�SRDWH�DFFHQWXD�R�GDWă�FX�SUROLIHUDUHD�FHOXODUă��DFHDVWD�SRDWH�FRQGXFH�OD�JUDGH�GLIHULWH�GH�LQDFWLYDUH�D H[SUHVLHL�JHQLFH��VSUH�GHRVHELUH�GH�LQDFWLYDUHD�SURGXVă�GH�PXWDĠLLOH�JHQLFH��3H�GH�DOWă�SDUWH��KLSHUPHWLODUHD�SRDWH�IL�SRWHQĠial rHYHUVLELOă�úL�DFHVWXL�IDSW�L�VH�DWULEXLVHPQLILFDĠLL�SDUWLFXODUH�vQ�FD]XO�XQRU�JHQH��'H�H[HPSOX��vQ�XQHOH�IRUPH�GH�FDQFHU�LQDFtivarea SULQ�KLSHUPHWLODUHD�SURPRWRUXOXL�JHQHL�&'+���FDUH�FRGLILFă�FDGHULQD�(�– R�SURWHLQă�LPSOLFDWă�vQ�DGH]LXQHD�FHOXODUă��HVWH�XQ HYHQLPHQW�SUHFRFH�FDUH�DU�IDYRUL]D�LQYD]LD�WXPRUDOă��3H�GH�DOWD�SDUWH��IRUPDUHD�XQRU�DJUHJDWH�FHOXODUH�FDUH�Vă�SHUPLWă�VXSUDYLHĠXLUHD�FHOXOHORU�PHWDVWD]DWH�SRDWH�QHFHVLWD�UHH[SULPDUHD�FDGHULQHL�(��REĠLQXWă�SULQ�UHGXFHUHD�UHJLRQDOă�D�PHWLOăULL�promotorului VăX� 0RGLILFDUHD�HSLJHQHWLFă�D�H[SUHVLHL�JHQLFH�vQ�FDQFHUHOH�XPDQH�HVWH�vQWkOQLWă��GH�DVHPHQHD��vQ�FD]XO�XQRU�gene amprentate��$FHVWH�JHQH�VXQW�H[SULPDWH�vQ�PRG�QRUPDO�PRQRDOHOLF�úL�FX�VSHFLILFLWDWH�SDUHQWDOă��ILH�QXPDL�GH�SH�FURPRVRPLL�paterni – de exemplu IGF2, fie numai de pe cromosomii materni – GH�H[HPSOX�+�����LDU�WXOEXUăULOH�PHWLOăULL�XQRU�UHJLXQL�ERJDWH�vQ�GLQXFOHRWLGH�&S*�GLQ�VWUXFWXUD�ORU�SRW�FRQGXFH�OD�H[SULPDUHD�DEHUDQWă��ELDOHOLFă��$FHVW�IHQRPHQ�GHQXPLW�pierderea DPSUHQWăULL (“loss of imprinting” - LOI) este întâlnit frecvent în cazul genei IGF2 în unele cancere, cum sunt tumorile Wilms ori WXPRULOH�FRORUHFWDOH��,Q�FDQFHUHOH�FRORUHFWDOH�/2,�SHQWUX�JHQD�,*)��HVWH�DVRFLDWă�vQ�PRG�SDUWLFXODU�FX�LQDFWLYDUHD�SULQ�KLSHUPHWLODUH�D�JHQHL�0/+��úL��FD�XUPDUH��FX�LQVWDELOLWDWHD�PLFURVDWHOLĠLORU��0,1�� 'HúL�KLSHUPHWLODUHD�SURPRWRUXOXL�HVWH�FODU�LPSOLFDWă�vQ�LQDFWLYDUHD�JHQHORU�VXSUHVRDUH�GH�WXPRUL��H[LVWă�úL�DOWH�PHFDQLVPH�SULQ�FDUH�PHWLODUHD�DQRUPDOă�SRDWH�IL�LPSOLFDWă�vQ�WXPRULJHQH]D��$VWIHO��PRGHOHOH�H[SHULPHQWDOH�DX�DUăWDW�Fă�VWDWXVXO�KHWHUR]LJRW�SHQWUX�JHQD�'107���UăVSXQ]ăWRDUH�GH�PHQĠLQHUHD�PHWLOăULL�$'1��VH�DVRFLD]ă�FX�FUHúWHUH�D�IUHFYHQĠHL�PXWDĠLLORU�somatice. ���087$ğ,,�$/(�$'1�0,72&21'5,$/ *HQRPXO�PLWRFRQGULDO�HVWH�PDL�YXOQHUDELO�OD�DOWHUăULOH�R[LGDWLYH�úL�VXIHUă�R�UDWă�PDL�vQDOWă�D�PXWDĠLLORU�GHFkW�JHQRPXO�QXFOHDU��7XPRULOH�SUH]LQWă�DGHVHRUL�PXWDĠLL�DOH�$'1PW��$VHPHQHD�DOWHUăUL�DX�IRVW�LGHQWLILFDWH�vQ�FDQFHUHOH�GH�YH]LFă�XULQDUă��VkQ��FROon, FDS�úL�JkW��ULQLFKL��ILFDW��VWRPDF��vQ�OHXFHPLL�úL�OLmfoame. 5DWD�FUHVFXWă�D�PXWDĠLLORU�OD�QLYHOXO�JHQRPXOXL�PLWRFRQGULDO�SRDWH�IL�H[SOLFDWă�SULQ�WUHL�IDFWRUL�

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Cu toate acestea, QHFHVLWDWHD�H[SDQVLXQLL�FORQDOH�úL�D�LQVWDELOLWăĠLL�JHQHWLFH�LPSXQH�R�DQXPLWă�UHJXODULWDWH�D�PRGLILFăULORU�vQWkOQLWH��0XWDĠLLle JHQHWLFH�vQWkOQLWH�vQ�HWDSD�LQLĠLDOă��GH�LQGXFĠWLH��SRW�IL�vQ�PRG�SDUWLFXODU�PXOW�PDL�VSHFLILFH�GHFât cele ulterioare, din cadrul progresiei tumorale. 8QHRUL�UHODĠLD�FDX]DOă�GLQWUH�R�DQXPLWă�PRGLILFDUH�JHQHWLFă�úL�WLSXO�SDUWLFXODU�GH�FDQFHU�vQ�FDUH�DSDUH�DFHDVWD�HVWH�XQD�ORJLFă��'H�H[HPSOX��WUDQVORFDĠLLOH�RQFRJHQHL�0<&�OD�QLYHOXO�XQXL�ORFXV�,J�HVWH�ORJLF�Vă�LQGXFă�SHUWXUEăUL�DOH�FHOXOHORU�FDUH�H[SULPă�LPXQRJOREXOLQHOH�OD�XQ�QLYHO�IRDUWH�FUHVFXW��$OWHRUL�vQVă��QX�H[LVWă�QLFL�R�DVHPHQHD�FRQH[LXQH�DSDUHQWă��'H�H[HPSOX��FDX]HOH�care FRQGXF�OD�GH]YROWDUHD�XQRU�IRUPH�SDUWLFXODUH�GH�FDQFHU�FD�XUPDUH�D�PXWDĠLLORU�XQRU�JHQH�FH�FRGLILFă�SURWHLQH�HVHQĠLDOH�SHQWUX�DFWLYLWDWHD�WXWXURU�FHOXOHORU��SUHFXP�UHWLQREODVWRDPHOH�vQ�FD]XO�PXWDĠLHL�5%��VXQW�vQFă�REVFXUH��2�SRVLELOă�H[SOLFDĠLH�VH�JăVHúWH�vQ�ipoteza genelor gatekeeper �.LQ]OHU�úL�9RJHOVWHLQ���������FRQIRUP�FăUHLD�fiecare tip celular este caracterizat printr-R�JHQă�SDUWLFXODUă�UăVSXQ]ăWRDUH�GH�FRQWUROXO�SUROLIHUăULL�úL�GH�PHQĠLQHUHD�KRPHRVWD]LH�WLVXODUH��0XWDĠLD�DFHVWHL�JHQH�gatekeeper conduce OD�XQ�GH]HFKLOLEUX�vQWUH�UDWD�GLYL]LXQLORU�úL�D�PRUĠLL�FHOXODUH��vQ�WLPS�FH�PXWDĠLLOH�DOWRU�JHQH�QX�DX�QLFL�XQ�HIHFW�SH�WHUPHQ�OXQJ�GDFă�gena gatekeeper HVWH�LQWHJUD�IXQFĠLRQDO� Genele supresoare de tumori identificate prin studiul cancerelor ereditare sunt astfel de gene gatekeeper SHQWUX�ĠHVXWXULOH�respective: NF1 pentru celulele Schwann, VHL pentru celulele renale, APC pentru celulele epiteliale intestinale etc. Motivul pentru care gene larg exprimate sunt gatekeeper QXPDL�SHQWUX�XQ�DQXPLW�WLS�FHOXODU�UH]LGă�SUREDELO�vQ�GLIHUHQĠHOH�FDUH�H[LVWă�vQWUH�UHĠHOHOH�FRPSOH[H�GH�VHPQDOL]DUH�DOH�YDULDWHORU�WLSXUL�FHOXODUH��GLIHUHQĠH�FDUH�IDF�FD�R�DQXPLWă�JHQă�Vă�DLEă�XQ�URO�GRPLQDQW�într-XQ�DQXPLW�WLS�FHOXODU��3HQWUX�FDQFHUHOH�FDUH�QX�DX�HFKLYDOHQW�PHQGHOLDQ�HVWH�SRVLELOă�úL�H[LVWHQĠD�PDL�PXOWRU�JHQH�gatekeeper. 3ULPD�IRUPă�GH�FDQFHU�SHQWUX�FDUH�D�IRVW�SRVWXODWă�VHFYHQĠD�HYHQLPHQWHORU�JHQHWLFH�UăVSXQ]ăWRDUH�GH�HYROXĠLD�PXOWLVWDGLDOă�D�IRVW�FDQFHUXO�FRORUHFWDO��PRGHOXO�)HDURQ�úL�9RJHOVWHLQ�������– figura 17.6). $FHVWHD�QX�VXQW�VLQJXUHOH�PRGLILFăUL�genetice întâlnite în cancerele colorectDOH��GDU�VXQW�FHOH�PDL�IUHFYHQW�DVRFLDWH�FX�XQ�DQXPLW�VWDGLX�HYROXWLY��0RGHOH�DVHPăQăWRDUH�DX�IRVW�FRQVWUXLWH�úL�SHQWUX�DOWH�IRUPH�GH�FDQFHU� '��35(',632=,ğ,$�*(1(7,&Ă�Ì1�&$1&(5 3ULQFLSDOD�WUăVăWXUă�FDUH�SHUPLWH�UHFXQRDúWHUHD�FOLQLFă�D�H[LVWHQĠHL�XQHL�SUHGLVSR]LĠLL�JHQHWLFH�HVWH�LVWRULFXO�IDPLOLDO�SR]LWLY��&DQFHUXO�HVWH�vQVă�R�DIHFĠLXQH�IUHFYHQWă�úL��FD�XUPDUH��vQ�XQHOH�IDPLOLL�VH�SRW�vQUHJLVWUD�FkWHYD�FD]XUL��DSDUHQWD�DJUHJDUH�IDPLOLDOă�ILLQG�vQWkPSOăWRDUH��3UHGLVSR]LĠLD�JHQHWLFă�SRDWH�vPEUăFD�XQ�VSHFWUX ODUJ��GH�OD�H[LVWHQĠD�XQRU�IRUPH�UDUH�GH�FDQFHUH�HUHGLWDUH�SkQă�OD�FDQFHUH�FX�SUHGLVSR]LĠLH�JHQHWLFă��GDU�IăUă�LVWRULF�IDPLOLDO�VXJHVWLY�(tabelul 17.3). ,Q�PRG�SDUDGR[DO�FHD�PDL�ODUJă�FDWHJRULH�GH�FDQFHUH�FX�SUHGLVSR]LĠLH�JHQHWLFă�vQ�FHHD�FH�SULYHúWH�LQFLGHQĠD�JOREDOă�HVWH�FHD�IăUă�DJUHJDUH�IDPLOLDOă�HYLGHQWă��'H�H[HPSOX��vQ�FD]XO�FDQFHUHORU�GH�VkQ�úL�RYDU��IRUPHOH�HUHGLWDUH�DVRFLDWH�PXWDĠLLORU�JHQHORU�%5CA1 úL�%5&$���FDUH�LQGXF�XQ�ULVF�GH���-����SkQă�OD�YkUVWD�GH����GH�DQL��UHSUH]LQWă�VXE����GLQ�WRWDO��ÌQ VFKLPE��R�DOHOă�FDUH�DU�LQGXFH�XQ�ULVF�UHODWLY�HJDO�FX���IDĠă�GH�SRSXODĠLD�JHQHUDOă�úL�FDUH�DU�DYHD�R�IUHFYHQĠD�GH�FLUFD�����vQ�SRSXODĠLH�DU�SXWHD�IL�UăVSXQ]ăWRDUH�GH�SkQă�OD�����GLQ�LQFLGHQĠD�DFHVWRU�FDQFHUH� 1. CANCERELE EREDITARE Se cunosc aproximatiY����GH�DIHFĠLXQL�FX�WUDQVPLWHUH�PHQGHOLDQă�FDUH�VH�DVRFLD]ă�XQ�ULVF�IRDUWH�FUHVFXW�SHQWUX�GH]YROWDUHD�XQRU�forme specifice de cancer (tabelul 17.4���6WXGLXO�DFHVWRU�EROL�D�SHUPLV�LGHQWLILFDUHD�XQRU�JHQH�FDUH�VXQW�LPSOLFDWH�úL�vQ�IRUPHOH�sporadice de canceU��0DMRULWDWHD�DFHVWRU�EROL�VXQW�WUDQVPLWH�GRPLQDQW��GDU�H[LVWă�úL�VLQGURDPH�FX�WUDQVPLWHUH�UHFHVLYă��6H�FXQRVF�GRDU�GRXă�EROL�GHWHUPLQDWH�GH�PRúWHQLUHD�XQHL�PXWDĠLL�JHUPLQDOH�OD�QLYHOXO�XQRU�RQFRJHQH��FHOHODOWH�ILLQG�DVRFLDWH�PXWDĠLLORU unor gene supresoare de tumori. ,Q�SUH]HQW�WHVWDUHD�JHQHWLFă�SHQWUX�LGHQWLILFDUHD�SHUVRDQHORU�FX�ULVF�GLQ�FDGUXO�DFHVWRU�IDPLOLL�HVWH�SDUWH�D�managementului standard pentru unele dintre aceste sindroame (neoplaziile endocrine multiple tip 2, boala von Hippel-Lindau, retinREODVWRPXO�IDPLOLDO�VDX�SROLSR]D��DGHQRPDWRDVă�IDPLOLDOD��YH]L�VXEFDSLWROXO�'��������3HQWUX�DOWH�VLQGURDPH��FXP�VXQW�FDQFHUHOH�GH�VkQ�úL�RYDU�HUHGLWDUH��YH]L�VXEFDSLWROXO�'�������FDQFHUXO�FRORUHFWDO�QRQSROLSR]LF�HUHGLWDU�RUL�VLQGURPXO�3HXW]-Jeghers testareD�JHQHWLFă�HVWH�SUREDELO�EHQHILFă��ÌQ�VIkUúLW��vQ�DOWH�VLQGURDPH��FD�GH�H[HPSOX�VLQGURPXO�/L-Fraumeni ori melanomul HUHGLWDU�WHVWDUHD�JHQHWLFă�ILH�QX�HVWH�GLVSRQLELOă��ILH�QX�HVWH�GH�QDWXUă�Vă�PRGLILFH�PDQDJHPHQWXO�PHGLFDO� 'RXD�WUăVăWXUL�LPSRUWDQWH�DOH�FDQFHUHORU�GLQ�FDGUXO�DFHVWRU�VLQGURDPH�VXQW�VSHFLILFLWDWHD�WLVXODUă�úL�H[SUHVLD�YDULDELOă��7RDWH�FDQFHUHOH�HUHGLWDUH�SDU�Vă�SUH]LQWH�XQ�JUDG�FUHVFXW�GH�VSHFLILFLWDWH�WLVXODUă��GHúL�QX�H[LVWă�QLFL�R�H[SOLFDĠLH�IL]LRORJLFă�ELQH�IXQGDPHQWDWă�SHQWUX�DFHDVWD��YH]L�úL�VXEFDSLWROXO����&���'H�DVHPHQHD��SDUH�Vă�H[LVWH�R�YDULDELOLWDWH�VXEVWDQĠLDOă�vQ�FHHD�FH�SULYHúWH�YkUVWD�GH�GHEXW�úL�WLSXO�VSHFLILF�GH�FDQFHU�FH�SUHGRPLQă�vQ�FDGUXO�XQRU�IDPLOLL��$FHVWH�YDULDĠLL�SRW�IL�GDWRUDWH�XQRU�PXWDĠLL�diferite în cadrul aceleeaúL�JHQH��GH�H[HPSOX�vQ�ERDOD�YRQ�+LSSHO-/LQGDX��SROLSR]D�DGHQRPDWRDVă�IDPLOLDOă��0(1����GDU�úL�LQWHUYHQĠLHL�XQRU�JHQH�PRGLILFDWRDUH�RUL�D�XQRU�IDFWRUL�GH�PHGLX��8Q�LQWHUHV�SDUWLFXODU�vO�DX�JHQHOH�PRGLILFDWRDUH�FDUH�UHGXF SHQHWUDQĠD�PXWDĠLLORU�JHQHORU�FDX]DWRDUH��DWkW�SHQWUX�DSUHFLHUHD�FRUHFWă�D�ULVFXOXL��FkW�úL�SHQWUX�GH]YROWDUHD�SRVLELOă�D�XQRU�QRL�PHWRGH�GH�SUHYHQĠLH�úL�WUDWDPHQW�

1.1 NEOPLAZIILE ENDOCRINE MULTIPLE TIP 2 (MEN2) 0(1���20,0���������HVWH�R�ERDOă�JHQHWLFă�WUDQVPLVă�DXWRVRPDO�GRPLQDQW��FDUH�SUH]LQWă�GRXă�YDULDQWH�FOLQLFH��Varianta A este FHD�PDL�IUHFYHQWă�úL�HVWH�FDUDFWHUL]DWă�SULQWU-R�LQFLGHQĠă�FUHVFXWă�D�FDUFLQRDPHORU�PHGXODUH�GH�WLURLGă��FX�RULJLQHD�vQ�FHOXOHOH�SDUDIROLFXODUH�&�FDUH�SURGXF�FDOFLWRQLQD���DVRFLDWH�DGHVHRUL�FX�IHRFURPRFLWRDPH�úL�Vau adenoame paratiroidiene benigne.

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([LVWă�FkWHYD�VHWXUL�GH�FULWHULL�SHQWUX�GLDJQRVWLFXO�FOLQLF�DO�+13&&��SULQWUH�FHOH�PDL�XWLOL]DWH�ILLQG�FULWHULLOH�Amsterdam II (1999): a) trei rude cu cancere asociate H13&&��FRORUHFWDOH��HQGRPHWULDOH��GH�LQWHVWLQ�VXEĠLUH��XUHWHU�VDX�SHOYLV�UHQDO���E��XQD�GLQ�SHUVRDQH�WUHEXLH�Vă�ILH�UXGD�GH�JUDGXO�,�FX�FHOHODOWH�GRXă��F��DIHFWDUHD�WUHEXLH�Vă�LQFOXGă�FHO�SXĠLQ�GRXă JHQHUDĠLL��G��FHO�SXĠLQ�XQXO�GLQ�SDFLHQĠL�WUHEXLH�Vă�ILH�GLDJQRVWLFDW�vQDLQWH�GH����GH�DQL��H��SROLSR]D�DGHQRPDWRDVă�IDPLOLDOă�WUHEXLH�H[FOXVă�� 'HRDUHFH�����GLQWUH�FDQFHUHOH�GH�FRORQ�GH]YROWDWH�vQ�FDGUXO�+13&&�SUH]LQWă�LQVWDELOLWDWHD�PLFURVDWHOLĠLORU��WHVWDUHD�DFHVWXL�IHQRWLS�WUHEXLH�HIHFWXDWă�vQDLQWHD�WHVWHORU�JHQHWLFH�SHQWUX�LGHQWLILFDUHD�XQRU�PXWDĠLL�DOH�JHQHORU�005�OD�WRĠL�SDFLHQĠLL�FDUH�întrunesc criteriile clinice de diagnostic.

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