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1. 11 , , - ,- , ..., ..., .. .. 2. 22 20 . , , . H.Y. Zoghbi et A.L. Beaudet (2010) . 3. 33 1 ACGTAGCTAG 2 ACGTAGCTAG 2 ACGAGCTAG 4. 44 = , . 5. 55 ( ) , . 6. 66 , , . 7. 77 , . de novo ( ) , . 8. 88 , ( - ) ( ) . 9. 99 , , , , . . 10. 1010 . , , , , , . , , , . () , , . 11. 1111 . , . 4 - , , , . 12. 1212 . , . , , . , . 13. 1313 , , -- . . , , . 14. 1414 , , 3 3 ((. Domaine- ):): 1.1. 2.2. 3.3. . . 15. 1515 , , ((ASDASD)).. ASDASD 37 10 00037 10 000 , , . . 13 10 000.13 10 000. 4:14:1 ( ( 1:11:1)) 2,6:10 000 2,6:10 000 8 8:1:1 16. 1616 ASDASD . . , , , , ASDASD:: 1.1. ; ; 2.2. ; ; 3.3. ; ; 4.4. - - 17. 1717 :: 1.1. , , , , , , .. 2.2. , , 25 . 25 . 3.3. , , , , , , , . , . 4.4. 70-90 %, 70-90 %, 0 10%. 0 10%. 18. 1818 , , , , . . 19. 1919 ASDASD.. 15 15q11q11 ASDASD . . , , . . 20. 2020 , (. 1). 21. 2121 1: 1: ASDASD / , ASD ASD, 1 15q dup UBI3A ( ) >40 1,2% 2 16p11 del -1% 3 22q del SHANK3 -1% 4 CNTNAP2 ~ 70% 5 - FMR1 25% ; 6% - 1-2% 22. 2222 1 1 (()):: ASDASD / , ASD ASD, 6 Gobart GOUBIRT, 25% 7 Potocki-Lubski uos 17 11 ~ 90% 8 -- DHSA7 50% 9 C MISP2 , ~ 0,5% 10 SASNAIS 60-80% 11 TSC1, TSC2 20% ~1% 23. 2323 , . , . 24. 2424 K- Methyltetra-hydrofolate reductase MTHFR Vit.B9 Vit.B2 C677T (Ala to Val) A1298C (Asp to Gly) Methionine synthase MTR Vit.B12 A2756G Methionine synthase reductase MTRR A66G - ystathionine-- synthase CBS Vit.B6 Ile to Thr Gly to Ser Cystathionine--lyase CSE / CBL Methionine adenosyltransferase MAT I / III GlycineN- methyltransferase deficiency GNMT S-Adenosyl-homocysteine hydrolase SAHH , , , (.. ) 25. 2525 - . . - - 4- 4- MTHFRMTHFR 677677TT__AA1298C1298C // MTRMTR 27562756 AGAG // MTRRMTRR 6666 AGAG:: CT_AA/AA/GG, CT_AC/AA/GG , C_AA/AA/GG ,CT_AA/AA/GG, CT_AC/AA/GG , C_AA/AA/GG , CT_AC/AA/AA , C_AC/GG/GG, CC_AC/AA/AG,CT_AC/AA/AA , C_AC/GG/GG, CC_AC/AA/AG, CC_AA/AA/AG.CC_AA/AA/AG. AAAA MTR GGMTR GG MTRR.MTRR. 4- 4- MTHFRMTHFR,, MTR,MTR, MTRR MTRR . . . . 26. 2626 , , : (.. ) 27. 2727 : - ; - : , , , , ( ), , -, ; - () , , , , , . 28. 2828 , , ( ) . 29. 2929 :: , , . . 30. 3030 - ( ) , ( ) 31. 3131 2000-2008 . 2000-2008 . 2000. 2001. 2002 . 2003 . 2004. 2005. 2006. 2007. 2008. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. 2 0,99 3 1,53 3 1,45 3 1,38 1 0,44 2 0,90 1 0,41 1 0,39 1 0,36 2. 7 3,49 5 2,55 6 2,90 9 4,16 10 4,40 11 4,75 5 2,07 12 4,72 8 2,9 3. - - 1 0,53 1 0,48 1 0,46 - - - - - - 3 1,18 2 0,72 4. 3 1,49 9 4,59 14 6,78 10 4,63 13 5,72 7 3,56 13 5,38 12 4,72 8 2,9 5. 5 2,49 3 1,53 - - 4 1,85 5 2,20 5 2.97 9 3,72 5 1,96 5 1,8 6. - - - - - - 2 0,92 1 0,44 2 0,90 4 1,64 5 1,96 3 1,09 7. 1 0,49 - - 1 0,48 - - - - - - - - 1 0,39 - - 8. 2 0,99 1 0,53 1 0,48 - - 1 0,44 4 1,79 4 1,64 1 0,39 2 0,72 32. 3232 n=200, % n=4586,% , % 677 MTHFR 40.7 1994/43,48 1926.12/ 42 7.04 416/9,07 412.74/ 9 52.26 2175/47,42 2247.14/ 49 27.39 30.81 66G MTRR AG 43.0 2015/43,93 2248,05/ 49 GG 35.5 1615/35,21 1490,0/ 32,5 AA 21.5 955/20,82 847,95/ 18,5 G 57.0 57.18 AG 334/34,61 341,8/ 35,4 GG 55/5,69 51,0/ 5,3 AA 552/57,20 572,2/ 59,3 G 23.00 C677T MTHFRC677T MTHFR A66G MTRRA66G MTRR ((n=n= 4586)4586) 33. 3333 2008 . : . 34. 3434 35. 3535 36. 3636 --. (.. ) CBL (B6) MAT I/III SAHH - !BHMT GNMT (B6) (B12) (B2) 37. 3838 (.. ) 38. 3939 2 , -, -, NO NAD(P)H- (10 /) !!! (PON 1) !!! + 39. 4141 , . A. Yasko (2010) , . 40. 4242 : : 1.1. , , .. 2.2. -. -. 41. 4343 3.3. . . . . , , . . - - .. . . 42. 4444 , , , , . . , , , , , , . . En Li, Adrian BiraEn Li, Adrian Bira (2010)(2010) 43. 4545 Ehrlich, 2003Ehrlich, 2003;; Dobge et al, 2005Dobge et al, 2005 ,, DNMT3BDNMT3B ICFICF Dnmt 3bDnmt 3b ( ). ( ). , , (, ) (, ) , , . . 44. 4646 , , , , . . 45. 4747 : : 1.1. , , , , . . 2.2. , , FTCD.FTCD. 3.3. , , MTHFR.MTHFR. 46. 4848 4-5.4-5. , , MTR,MTR, - - ((cblG)cblG) , , ( (cblEcblE -- MTRMTR).). 6.6. , , FOLR1FOLR1.. 7.7. , , , , , , MTHFD1MTHFD1 ( , -( , - ).). 47. 4949 , . , , , SNP , . 48. 5050 , 5- , , , (MTR) . 49. 5151 (Amy Yasko, 2010) : . , . . 4- , , , . SNP . . , . . ( CBS) ( 677, 50. 5252 COMT V158M, H62H, 61 . , . , , . . COMT . ADD/ADHD; . COMT . COMT . COMT . 51. 5353 VDR/Taq and VDR/Fok (vitamin D receptor) D, Taq . , Taq . , COMT VDR / Taq . VDR , . 52. 5454 MAO A R297R (monamine oxidase A): . , - . , , , CD . X - , . - , , - ( ) . , , , , - . 53. 5555 ACAT 102 (acetyl coenzyme A acetyltransferase): , . . , , , . , 12, . ACE (angiotensin converting enzyme): Considered for all No longer testing , ACE, . . ACE - . , . , . , , . 54. 5656 MTHFR A1298C, C677T, 3 (methylenetetrahydrofolate reductase): MTHFR . . MTHFR - , . MTR A2756G/MTRR A66G, H595Y, K350A, R415T, S257T, 11 (methionine synthase/ methionine synthase reductase): , . , , . COMT VDR / Taq, MTR MTRR . MTR , B12 . , , A66G MTRR . , , B12 , B12 . 55. 5757 BHMT 1,2,4,8 (betaine homocysteine methyltransferase): , . , ADD / ADHD, . AHCY 1,2,19 (S adenosylhomocysteine hydrolase): AHCY , . CBS C699T, A360A, N212N (cystathionine-beta-synthase): CBS , . , , , , . CBS, SUOX. 56. 5858 SHMT C1420T (serine hydroxymethyltransferase): , . , , , , , . NOS D298E (nitric oxide synthase): NOS . , NOS . NOS CBS , CBS. 57. 5959 SUOX S370S (sulfite oxidase): . , . , , , , (, ), . , , , . FDA , , 5 % . . 58. 02.09.1302.09.13 - , FDA , . , . . , , , . , , . SUOX , . 59. 6161 (-) - , , , . . . 1947. 61 60. 6262 , : - ; - ; - ; - ; - ; - ; - . 61. 6363 () : , , , , . () . 62. 6464 , . Kouzarides T. , , (), . 63. 6565 (Yeijmans B.T. et al., 2007). , , . 64. 6666 ( ) 66 65. 6767 - - 67 66. 6868 , , () (Herst M, Marra M.A.,2009; Feinberg A.P., 2007; Bijornson H.T., 2004) (.: , ). 67. 6969 , , , - (Esteller M., 2007; Jones P.H, Baylin S.B., 2007; Feinberg A.P. et al. 2006). 68. 7070 (HUDS Y.ZOGHBI, ART(HUDS Y.ZOGHBI, ART HUR LHUR L.. BEANDETBEANDET)):: 11.. .. 1.1. ; -.1.1. ; -. 1.2. -1.2. - 1.3. -1.3. - 1.4. .1.4. . 2.2. , -, - :: 2.1. -2.1. - 2.2. 2.2. 2.3. - -, 2.3. - -, . , . , 2.4. .2.4. . 2.52.5. . .. 3.3. , , ciscis-- .. 3.1. -- 3.1. -- 3.2. - 3.2. - 3.3. -- 3.3. -- 69. 7171 ( .. , 2004)( .. , 2004) ( )( ) ( ( )) 1. , 1. , , , ( ( , , ), , ) 1. , 1. , , , ICF, , ATR ICF, , ATR X, , X, , 2. , 2. , de novo de novo ) ) , , , , ; ; ) , ) , 2. , 2. , de novo de novo , , , , , , 70. 7272 , . ( S- -) , .; . 52 . (2S)-2-amino-4- methylsulfanyl-butanoic acid. - C5H11NO2S. 71. 7373 ; ; ; ; 5- -- (-). 72. 7474 74 73. 7575 , . 52 . (2S)-2-amino-4- methylsulfanyl-butanoic acid. - C5H11NO2S. 74. 7676 , 75. 7777 S- 2 N- S- 1 - S- 1. -t , 2 76. 7878 ( ), - MTHFR MTRR , : ; ; ; ; . 77. 7979 78. 8080 (N. Blau et al., 1996) - MIM 10.1 - () 25085 0 10.2 - (CBS) ; ; ; , 21q22.3 23620 0 10.3 - () ; ; 16 21950 0 10.4 ,- , 10.4.1. 10.4.2 ; ; ; ; ; ; 27230 0 79. 8181 (N. Blau et al., 1996) - MIM 10.5 5,10- - (MTHFR) ; , ; ; 136.3 23625 0 10.6 () cblE, cblG ; 23627 0 25094 0 10.7 -- () ; 27740 0 27741 0 80. 8282 , () . 81. 8383 677 MTHFR / 66G MTRR (n=1938) 677 MTHFR / 66G MTRR Hmzg/ Hmzg Hmzg/ Htzg Htzg/ Htzg Htzg/ Hmzg N/ Hmzg N/ Htzg Hmzg/ N Htzg /N (16%) 6 11 36 37 69 99 5 36 3 3 11 13 37 51 1 15 1 1 3 3 Spina bifida 1 2 1 3 7 10 8 19 2 8 ( ) 1 1 / 1 1 4 2 3 7 6 / ( ) 1 3 1 2 1 1 6 6 11 11 1 5 ( ) 1 2 4 3 4 4 1 2 82. 8484 677 MTHFR / 66G MTRR (n=1938) 677 MTHFR / 66G MTRR Hmzg/ Hmzg Hmzg/ Htzg Htzg/ Htzg Htzg/ Hmzg N/ Hmzg N/ Htzg Hmzg/ N Htzg /N (7.8%) 9 10 71 64 71 124 10 44 2 10 11 13 23 4 13 ( ) 2 2 2 1 1 1 2 1 2 2 3 4 8 5 9 17 1 3 ( ) 2 1 1 3 1 2 4 2 7 8 8 3 1 1 3 21 19 13 33 2 11 ( ) 1 1 3 1 1 1 83. 8585 677 MTHFR / 66G MTRR (n=1938) 677 MTHFR / 66G MTRR Hmzg/ Hmzg Hmzg/ Htzg Htzg/ Htzg Htzg/ Hmzg N/ Hmzg N/ Htzg Hmzg/ N Htzg /N 2 1 3 1 1 2 1 1 1 2 2 4 1 1 2 1 1 8 9 10 19 1 7 ( ) 1 - - 1 1 1 3 1 5 10 1 2 84. 8686 677 MTHFR / 66G MTRR (n=1938) 677 MTHFR / 66G MTRR Hmzg/ Hmzg Hmzg/ Htzg Htzg/ Htzg Htzg/ Hmzg N/ Hmzg N/ Htzg Hmzg/ N Htzg /N (8%) 2 5 13 13 46 43 2 22 2 1 5 1 ( ) 1 3 1 1 2 1 1 1 ( ) 1 1 2 2 3 1 1 ( ) 1 1 1 1 1 11 8 8 ( ) 1 9 6 2 2 1 3 ( ) 2 3 4 13 7 4 85. 8787 677 MTHFR / 66G MTRR (n=1938) 677 MTHFR / 66G MTRR Hmzg/ Hmzg Hmzg/ Htzg Htzg/ Htzg Htzg/ Hmzg N/ Hmzg N/ Htzg Hmzg/ N Htzg /N (5%) 2 4 11 11 20 21 4 8 - - 1 2 1 4 5 6 2 - - 1 1 1 1 - - 1 1 - - 1 1 2 2 1 - - 1 1 - - 1 - - 1 - 1 2 1 - - 1 IDD 1 1 - - 1 - - 1 - - 1 86. 8888 677 MTHFR / 66G MTRR (n=1938) 677 MTHFR / 66G MTRR Hmzg/ Hmzg Hmzg/ Htzg Htzg/ Htzg Htzg/ Hmzg N/ Hmzg N/ Htzg Hmzg/ N Htzg /N - 1 - 1 - 1 1 2 1 1 1 3 2 1 2 - 1 - 1 1 2 - - 1 1 1 1 - 1 - 1 2 DHD- 1 1 87. 8989 677 MTHFR / 66G MTRR (n=1938) 677 MTHFR / 66G MTRR Hmzg/ Hmzg Hmzg/ Htzg Htzg/ Htzg Htzg/ Hmzg N/ Hmzg N/ Htzg Hmzg/ N Htzg /N (6%) 2 16 10 29 27 2 14 - 1 5 1 5 14 1 2 - ( ) 6 3 14 6 1 6 - - 2 5 4 4 / 1 3 6 5 3 2 88. 9090 (, (46,, 9 phqh ) ( 677 -, 222 V ). . . 89. 9191 - -.. 677 C/T MTHFR 90. 9292 ? -. . 677 / MTHFR , NO-c 4a/4b ). (MNGIE?). 91. 9393 ? , , ( 21 , 1). MTHFR 677 C/T , MTRR 66 G 92. 9494 ?: ( ). ( 66AG (122) MTRR ). : 46, Y, 14 s+. 93. 9595 - -, , 94. 9696 - . 677677 MTHFR/66A/G MTRRMTHFR/66A/G MTRR. 95. 9797 . . 677677 MTHFR/66GG MTRRMTHFR/66GG MTRR 96. 98 -22, . , 13 -mail: [email protected]