新生兒先天代謝異常疾病篩檢作業手冊

------------------------------------------------------------------- 1 I ---------------------------- I- 1 ---------------------------- I- 3 ---------------------------- I- 4 ---------------------------- I- 5 ---------------------------- I- 7 II ---------------------------- II- 1 ---------------------------- II- 1 () ---------------------------- II- 1 () ---------------------------- II- 3 () ---------------------------- II- 4 () ---------------------------- II- 5 () ---------------------------- II- 6 ---------------------------- II- 7 ---------------------------- II- 7 i

() ---------------------------- II- 8 () ---------------------------- II- 9 () ---------------------------- II-10 ---------------------------- II-11 ---------------------------- II-11 () ---------------------------- II-12 () ---------------------------- II-13 () ---------------------------- II-15 () ---------------------------- II-16 () ---------------------------- II-17 () ---------------------------- II-18 () ---------------------------- II-18 () 1 ---------------------------- II-19 2 ---------------------------- II-21 ii

3 ---------------------------- II-23 酶 () ---------------------------- II-24 () ---------------------------- II-24 () 1 ---------------------------- II-24 2 ---------------------------- II-26 3 ---------------------------- II-28 III -- ---------------------------- III- 1 ---------------------------- III- 7 ---------------------------- III-16 IV ---------------------------- IV- 1 ---------------------------- IV- 5 ---------------------------- IV- 7 ---------------------------- IV- 9 ---------------------------- IV-10 ---------------------------- IV-12 iii

V ---------------------------- V- 1 ---------------------------- V- 2 ---------------------------- V- 3 ---------------------------- V- 4 G6PD ---------------------------- V- 7 ---------------------------- V- 13 ---------------------------- V-14 ---------------------------- V-48 ---------------------------- V-49 ---------------------------- V-49 ---------------------------- V-68 iv

6.7 96.5 2,459,921 56 834 酶 33,571 10 17 1

( )

() () () () () () () I-1

() () () I-2

( ) ( ) I-3

(PhenylketonuriaPKU) (Homocystinuria) (Ga1actosemia) (Congenital hypothyroidism) 酶 (G1ucose-6-phosphate dehydrogenase deficiencyg6pd deficiency ) I-4

GCI I-5

PKU HCU GAL TSH G6PD (mg/dl) (mg/dl) (mg/dl) (mu/l) (U/gHb) * 40 40 2.6 4 2 16 40 6.0 30 40 4 2 8 10 40 4 2 8 10 40 2 3.9 1 1.9 8 15.9 10 30 4 2 8 10 4 2 8 10 2.6 2 1 8 10 6.0 * 92.7.8 I-6

I-7

() () () () () ()

() () () () () () () 1 ( ) ( FORM BH-1) 2 II-1

3 ( ) ( ) 4 ( FORM SAMP) ( ) ( (1) (2) (3) (4) (5) (6) (7) (8) (9) ) ( ) 5 (discharge routine) 6 ( ) 7 ( FORM C-1) 8 ( 4 ) ( l 10 /) 9 10 4 2 11 12 13 II-2

() (0.20.3 c.c.) 1 ( 24 ) 2 3 (39-44) 3 10 ( ) 4 5 (Lancet) 2.4mm 1.5 2.3mm ( ) 1.52.3mm 2.4mm 6 ( ) II-3

7 75% 8 9 10 ( ) ( Heparin) 3 4 11 ( ) 12 ( ) 13 ( ) 14 ( ) ( ) 15 (25 ) ( FORM SAMP) ( ) () 1 - ( FORM REP-1) II-4

2 ( ) 3 (1) ( ) (2) ( ) (3) (4) 4 ( ) () 1 2 ( ) ) 3 ( FORM M-1M-2 M-3) (1) (2) (3) () ( ) II-5

II-6

() () () () () () () () ( ) () ( ) () ( ) II-7

II-8

II-9

II-10

() () () 1 2 3 () () 1 2 3 II-11

() - (FORM REP-1) ( ) 1 (1) (Form C-12) ( ) (2) (3) (FORM N-1.1) (4) (5) (6) ( ) II-12

2 (1) (FORM N-1) (2) (FORM N-1) 3 () (1) () (2) () (3) (4) (FORM N-1 FORM N-1.1) (5) ( II-3 4 ) (6) ( (7) (8) (FORM N-1 FORM N-1.1) (FORM N-1 FORM N-1.1) (9) (FORM N-1 FORM N-1.1) II-13

() 1 (1) (2) (3) (FORM N-1.1) 2 (1) (FORM N-1) (2) (FORM N-1) 3 () (1) () (2) () (3) (4) (FORM N-1 FORM II-14

N-1.1) (5) ( II-3 4 ) (6) ( (7) (8) (FORM N-1 FORM N-1.1) (FORM N-1 FORM N-1.1) (9) (FORM N-1 FORM N-1.1) () 1 (1) (2) - (FORM REP-1) (3) (FORM BH-4) (FORM RH-4RH-5RH-6RH-7 RH-8) II-15

(4) 2 () (1) (FORM N-2) () (2) (3) (FORM N-2) () () ( ) II-16

II-17

() 1 2 () 1 (1) (2) ( ) (3) ( ) (4) II-18

(5) (6) (7) 2 (1) (2) (3) () 1 (1) (FORM RH-2) (FORM RH-3) (FORM RH-5RH-6RH-7 RH-8) (FORM RH-2) (FORM RH-3) (FORM RH-3) II-19

(2) (3) (4) (FORM RH-2) (5) (FORM RH-2) (6) (FORM RH-2) (FORM RH-2) (FORM RH-5 RH-6RH-7 RH-8) (7) ( ) II-20

(8) (9) 2 (1) (FORM RH-5RH-6 RH-7 RH-8) (FORM N-3 1,500 ) (2) (3) (4) (5) ( ) (FORM RH-5RH-6RH-7 RH-8) (FORM RH-2) ( ) (6) (7) II-21

3 ( ) II-22

II-23

G6PD () 1 2 () 1 2 (1) (2) (FAX) 3 4 () 1 II-24

(1) (FORM RH-3) (FORM RH-2) (FORM RH-3) (FORM RH-2) (FORM RH-3) (2) (3) G6PD (FORM C-2.2) (4) G6PD (FORM C-2.3) (FORM RH-2) II-25

(5) (FORM RH-2) (6)G6PD (FORM RH-4) (7) (FORM C-5.2) (8) (FORM C-5.2) (9) G6PD (FORM N-10) 2 (1) G6PD (FORM RH-4) (FORM N-3 ) G6PD ( ) (2) (FORM C-5.3) (3) (8)(9) II-26

(4) G6PD (FORM RH-4) (5) G6PD (FORM C-11) (6) G6PD (FORM RH-4) (FORM N-3) (7) (FORM C-6) (8) G6PD (FORM RH-4) (9) (FORM C-6) G6PD (FORM N-11) G6PD (FORM RH-4) (10) (10), G6PD (FORM RH-4) (FORM RH-2) ( ) 3G6PD ( ) II-27

II-28

-- 100 ( (G) (E) (E) (G) G E (Mendelian inheritance) () (autosomal dominant) (Huntington s chorea) () (autosomal recessive) (cystic fibrosis)() (hemophilia) (multifactorial inheritance) ( ) ( ) III-1

(genetic heterogeneity) McKusick 1992 1/50 1/100 1/200 60 (Down syndrome)3-4 (Turner syndrome)150 (triploidy) (tetraploidy) (stillbirth) (neonatal death) 6-7 1 ( 0.21)3 ( 0.12) (2/1,000) (0.5/1,000) (0.8/1,000) (0.4/1,000) 0.7 0.25 0.05 III-2

Tay-Sachs ) ( ) 10 2-1914 -1954-1966 -1967 83.5 62.5 58.0 50.0 2.0 12.0 8.5 8.9 2.5 2.9 14.5 25.5 31.0 38.2 Madras 1976 95 5 III-3

10 20 1 1/4 (1) (2) (3) (congenital hypothyroidism) (hemoglobino pathesis) (α-antitrypsin deficiency) (Duchenne III-4

muscular dystrophy) 1960 Guthrie 1962 (bacterial inhibition assay) (phenylketonuria) (maple syrup urine disease) (histidinemia) (galactosemia) (homocystinuria) 1970 Dussault 1974 (radioimmunoassay) 1:4,000-1:5,000 1:13,000 1:50,000 1:170,000 1:200,000 III-5

III-6

(thyroxinet4) (congenital hypothyroidism) 1/3,000 () 1 (athyreosis) 2 (thyroid hypoplasia) 3 (ectopic thyroid) () () 1/50,0001/150,000 III-7

() (transient congenital hypothyroidism) 1 2 3 4 (L-thyroxine) (thyroid stimuiating hormonetsh) 10 mu/l blood 10 mu/l () () () ()thyroid sonogram 99m Tc thyroid scan( ) III-8

1934 Dr. Folling (phenylpyruvic acid) 1937 (phenylketonuriapku) (phenylalanine Phe) (hydroxylation) (tyrosinetyr) 酶酶 (phenylalanine hydroxylase PAH) 酶 (Gtp cyclohydrolase I GTPCHI) 酶 (6-pyruvoyl tetrahydropterin synthaseptps) 酶 (dihydropteridine reductasedhpr) 酶 (pterin-4α-carbinolamine dehydratasepcd) 酶 (PAH) PKU 98 99% PKU 70 80% 酶 (tetrahydrobiopterinbh4) ( ) 酶 PKU 20% 30% III-9

PKU 95 85 53-45 BH4 PKU () PKU 4-8 mg/dl (maternal PKU) () ( 酶酶酶 ) BH4(1-5 mg/kg/day) 4mg/dL L-dopa (5-15 mg/kg/day) 5-hydroxy tryptophan (4-10 mg/kg/day)carbidopa(1-2 mg/kg/day) () 酶 BH4 folinic acid PKU 2 mg/dl blood ( 48 ) PKU III-10

() () () (GC/Mass) () (HPLC) (neopterinn) 酶 (biopterinb) B%=[B/(B+N)] 100% () DHPR ()BH4 (BH4 loading test) BH4 (7.5 mg/kg) 4-6 2 mg/dl BH4 (responsive) BH4 (nonresponsive) PKU () PKUB% ( )BH4 DHPR ()GTPCHI PKUB% N BH4 DHPR ()PTPS SR PKUB%5%BH4 DHPR ()DHPR PKUB%80%BH4 DHPR ()PCD PKU 7- (7-biopterin) III-11

(homocystinuria) 酶 (cystathionine-β-synthase) (homocysteine) (cystinecys) (methioninemet) (homocystinehcy ) (Mix disulfide) B6(VitB6) (betain) B6 B6 B12 (folic acid) B6 1000 mg/day 1 mg/dl blood 酶 III-12

(galactosemia) (galactose) (glucose) 酶酶 (galactokinase) -1- 苷酶 (galactose-1-phosphate uridyltransferase) 苷 -4- 酶 (UDP galactose-4-epimerase) -1- 苷酶 -1- 苷酶酶苷 -4- 酶 AL 110-1- (galactose-1-phosphate) galactitol (galactose-1-phosphate uridyl- transferase ) ( ) ( Uridine) III-13

-1-8 mg/dl blood -1- -1- 酶 -1- 苷酶 III-14

-- 酶 -- 酶 (glucose-6-phosphate dehydrogenase G6PD) (X-link) G6PD 酶苷肽 (Glutathione, G-SH) G6PD G-SH G6PD 2% G6PD G6PD ( ) ( ) G6PD 萘 ( ) G6PD G6PD 20% (Heterozygote) G6PD ( ) 80% G6PD III-15

" "(genetic counseling) 1947 (Reed) " " " " III-16

" (clinical geneticist) (PhD medical geneticist) (clinical cytogeneticist) (clinical biochemical geneticist) (genetic counselor) ( " ") ( ) III-17

() () () () -- III-18

III-19

( ) ( ) " "(forme fruste) " "(forme tardive) " " " " " " ( ) III-20

" " " III-21

III-22

( ) ( ) III-23

1992;91(3):S183-6 : 1987 : 199l 1982;23:31-5 : 1985;26:542-7 : 1970;11:163-5 Bergsma D:Birth Defects and Compendium, 2nd ed. New York:Alan R Liss, 1979:1-1122 Emery AEH, Rimoin DL:Principles and Practice of Medical Genetics, 2nd ed.edinburgh:churchill Livingstone,1990:1-2035. III-24

Fuhrmann W, VogeI F:Genetic Counseling, 3rd ed New York:Springer-Verlag, 1983:1-374. HarPer PS:Practical Genetic Counselling, 3rd ed. London:Wright, 1988:1-489. Murphy EA, Chase GA:Principles of Genetic Counselng. Chicago: Year Book Medical Publishers, 1975:1-476. III-25

60 B () () () ( () 12 25 B IV-1

() () 2 () 15 2 IV-2

4 4 6 7 67? 25 ()PKU 24 ()G6PD IV-3

35 G6PD () () 1 2 () G6PD () () IV-4

() () () () () ( ) ( ) ( III ) ()G6PD IV-5

() PKUHCUGALCHT () PKUHCUGALCHT () PKUHCUGALCHT G6PD 24 IV-6

G6PD G6PD ( III ) G6PD G6PD () G6PD () G6PD G6PD G6PD G6PD G6PD ()G6PD () IV-7

G6PD G6PD G6PD G6PD () ()G6PD G6PD IV-8

G6PD G6PD () () ( ) IV-9

() () ( ) IV-10

( (04)223-4804) IV-11

IV-12

G6PD () ()

() (02)321-0151 269268 (02)397-9154 100 () (04)223-4804 (04)225-1144 103 () (02)396-1637 (02)393-4697 24 6 () (07)322-1449 (07)322-1476 976 2 V-1

() 6702 6716 ( ) 2129 ( ) 1407 (02)3123456 671567162714 (02)381-0373 10016 1 () ( ) (02)8596-2050 713 (02)8596-2050 401~403 (02)8596-2065 (02)8596-2067 146 4 () (02)753-0707 (02)760-9461 (02)760-9462 48-133 V-2

() ( RH-01 ) (02)3123456 67085134 (02)381-0373 10016 1 () ( RH-02 ) (02)8712121 3467 (02)873-9019 201 V-3

() 1 ( RH-01 ) (02)3123456 67085134 (02)381-0373 10016 1 2 ( RH-02 ) (02)8712121 3467 (02)873-9019 201 V-4

() 1 ( RH-06 ) (04)374-1379 (04)359-1498 160 () 1 ( RH-07 ) (07)311-4995 (07)311-0947 100 2 ( RH-15 ) (06)235-3535 52862324 (06)238-0519 138 V-5

() 1 ( RH-10 ) (038)227-547 (038)225-985 44 V-6

G6PD () 1 ( RH-01 ) (02)3123456 5134 (02)381-0373 10016 1 2 ( RH-02 ) (02)8712121 3467 (02)873-9019 201 3 ( RH-03 ) (039)543-131 1270, 1271 (039)576-301 82 V-7

4 ( RH-18 ) (02)431-3131 2628 (02)431-3159 222 ( ) () 1 ( RH-04 ) (03)369-9721 2237 (03)369-7307 1492 2 ( RH-05 ) (035)326-151 2351 (035)321-450 25 V-8

() 1 ( RH-06 ) (04)374-1379 (04)359-1498 160 2 ( RH-12 ) (04)723-8595 5971 (04)726-5984 135 3 ( RH-19 ) (04)206-2121 2410 (04)205-2245 75 ( ) V-9

() 1 ( RH-07 ) (07)311-4995 (07)311-0947 100 2 ( RH-08 ) (06)220-0055 3010 (06)229-3601 125 3 ( RH-13 ) (05)633-7333 2275 (05)633-6333 74 V-10

4 ( RH-14 ) (05)276-5041 2111 (05)276-1011 539 5 ( RH-09 ) (08)736-3026 249 (08)737-1973 60 ( ) () 1 ( RH-10 ) (038)227-547 (038)225-985 44 V-11

2 ( RH-11 ) (089)310-150 460 ( ) (089)382-436 303 1 () 1 ( RH-16 ) (0823)339-44 2281 (0823)339-41 2 () 1 811 ( RH-17 ) (06)921-1116 311 (06)737-1973 90172 V-12

FAX 192 (02 )257-7155 (02 )257-0524 141 (039)367-855 (039)362-317 55 (03 )337-8854 (03 )332-1073 1 (035)518-164 (035)512-743 6 (037)336-729 (037)329-020 353 (045)266-154 (045)276-645 2 162 (04)724-5827 (04 )723-1309 1 (049)231-624 (049)229-041 8 (055)335-134 (055)322-074 3 (05 )223-1840 (05 )224-6405 72 (06 )635-2633 (06 )632-1251 117 (07 )733-4875 (07 )747-7420 271 (08 )737-2507 (08 )736-2596 336 (089)321-144 (089)329-171 123 (038)223-943 (038)227-022 115 (06 )927-2162 (06 )926-1557 266 (02 )426-1133 (02 )427-6154 197 (04 )223-9885 (04 )224-1456 418 (06 )267-9751 (06 )269-8029 111 (035)256-504 (035)245-049 184 5 (05 )222-7645 (05 )224-7939 2 (0823)307-51 (0823)339-41 164 (0836)25-115 (0836)223-90 V-13

FORM SAMP - FORM REP-1 FORM BH-1 FORM BH-2 FORM BH-3 FORM BH-4 FORM RH-2 FORM RH-3 G6PD FORM RH-4 FORM RH-5 FORM RH-6 FORM RH-7 FORM RH-8 FORM C-1 G6PD FORM C-2.2 G6PD FORM C-2.3 G6PD FORM C-5.2 V-14

G6PD FORM C-5.3 G6PD FORM C-6 G6PD G6PD FORM C-11 FORM C-12 FORM N-1 FORM N-1.1 FORM N-2 FORM N-3 G6PD FORM N-10 G6PD FORM N-11 V-15

4 3 2 1 5 6 7 ( ) ( ) ; ; ; XXXXXXXXXXXXX XXXXX XXXX XXXXXXXXXXXXXXXXXXXXXXXXXXX 1 2 3 4 x x FORM SAMP V-16

00 10 20 01 11 21 02 12 22 03 13 23 04 14 24 05 15 25 06 16 07 17 08 18 09 19 99 V-17

1 (Phenylketonuria) 2 (Homocystinuria) 3 (Galactosemia) 4 (Hypothyroidism) Phenylalanine Methionine Galactose Thyrotropin (TSH) 酶 (G6PD Deficiency) G6PD dehydrogenase XXXXXX XXXXXXXX 1. 2. 3. 4. 5. (XX)XXX-XXXX (XX)XXX-XXXX XXX FORM REP-1 V-18

V-19

( ) ( ) - ( ) - --------------------------------------------------------------------------------------------------- ( ) ( ) FORM BH-2 V-20

( ) - ( ) - FORM BH-3 V-21

( ) ( ) - ( ) - FORM BH-4 V-22

XXXX ------------------------------------------------------------------------------------------------------------------------------------------ ( ) / / / / / / ------------------------------------------------------------------------------------------------------------------------------------------ ( ) ( ) EXT ----------------------------------------------------------------------------------------------------------------------------------------- : : ( ) ( ) ( ) ---------------------------------------------------------------------------------------------------------------------------------------- 1 2 xxxxxx 3 4 ( ) FORM RH-2 V-23

/ XXXX () (RH- ) ** FAX( ) - TEL( ) - FORM RH-3 V-24

G6PD I II (1) (2) (3) (4) (5) (6) (7) (8) ( ) III IV U/gHb ----------------- U/gHb U/gHb; U/gHb; U/gHb; U/gHb. VI (I) (Hemizygote) (Homozygote). (Heterozygote) (1) 10016 (02) 312-3456 ext 6716 (2) (02) 704-4075 (3) 48-133 (02)760-9461 --------------------------------------------------------------------------------------------------------------------------------------- : FORM RH-4 V-25

/ / G P A gm cm cm ( ) TSH (mu/l blood) gm cm cm (Bilirubin mg/dl, at days of age) V-26

T4 (µg/dl) TSH (mu/l) T3 (ng/dl) Free T4 (µg/dl) AMIA () ATA () TBII (%) (thyroid sonogram) (thyroid scan) ( ) - FAX( ) - ---------------------------------------------------------------------------------------------------------------------- () FORM RH-5 V-27

/ / G P A gm cm cm ( ) Phe(mg/dL) gm cm cm (Bilirubin mg/dl, at days of age) 1 Ferric chloride test negative positive trace 2,4-Dinitrophenylhydrazine test negative positive trace V-28

2BH4 (1) Phe (Ref.Range ) Tyr (Ref.Range ) (2) Biopterin (B)* Neopterin (N) B B+N % * mmol / mol Creatinine (3) (GC/MS) (4) DHPR (Ref.Range ) 3BH4 non-response response partial-response 4 ( ) - FAX( ) - ---------------------------------------------------------------------------------------------------------------------- () FORM RH-6 V-29

/ / G P A gm cm cm ( ) Met (mg/dl) gm cm cm (Bilirubin mg/dl, at days of age) V-30

Met (umol/l) Hcy (umol/l) Cys (umol/l) Met (umol/l) Hcy (umol/l) Cys (umol/l) CNP Test SNP Test Vit.B6 dosage mg/kg/day non-responseresponsepartial-response ( ) - FAX( ) - ---------------------------------------------------------------------------------------------------------------------- () FORM RH-7 V-31

/ / G P A gm cm cm ( ) galactose(mg/dl) gm cm cm (Bilirubin mg/dl, at days of age) 1 galactose (Ref. Range ) galactose-1-phosphate (Ref. Range ) galactosegalactose-1-phosphate (Ref. range ) V-32

2 (1) galactose-1-phosphate uridyl trasferase (negative) (positive) (trace) (2) galactose-1-phosphate uridyl trasferase Relative intensity = (Ref.Range ) (3) UDP galactose-4-epimerase (negative) (positive) (trace) 3 galactose-1-phosphate uridyl trasferase mu/ghb (Ref. Range ) mu/ghb (Ref. Range ) mu/ghb (Ref. Range ) 4 Benedict s test negative positive trace 5 6 7 ( ) - FAX( ) - ---------------------------------------------------------------------------------------------------------------------- () FORM RH-8 V-33

酶萘萘 V-34

(G6PD ) 酶, 萘 ( ) 萘 ( ) 酶 ** ** FORM C-2.2 V-35

(G6PD ) 酶,, 萘 ( ) 萘 ( ) 酶 ** ** FORM C-2.3 V-36

( G6PD ) : 酶萘 ( ) 萘 ( ) 酶, ** FORM C-5.2 V-37

(G6PD ) 酶 ** FORM C-5.3 V-38

(G-6-PD deficiency) () () Primaquine Pamaquine (Plasmoquinum) Pentaquine Salicylazosulfapyridine (Azulfidine) Sulfanilamide Sulfacetamide (Sulamyd) Sulfapyridine Sulfamethoxazole (Gontanol) Thiazolesulfone Acetanilid Aminopyrine (Pyramidon) Antipyrine Nitrofurantoin (Furadantin) Nitrofurazone (Furacin) Furazolidone (Firoxone) Methylene blue Naphthalene (Moth Balls) Nalidixic acid (Negacide) Phenylhydrazine Toluidine blue Trinitrotoluene FORM C-6 V-39

(G6PD ) 酶 ** ** FORM C-11 V-40

( ) () ** FORM C-12 V-41

( ) - ( ) - ------------------------------------------------------------------------------------------------- ( ) FORM N-1 V-42

( ) ------------------------------------------------------------------------------------------------- ( ) FORM N-1.1 V-43

( ) -------------------------------------------------------------------------------------------- FORM N-2 V-44

( ) 1 2 1 4 1 4 1 4 1. (1) (2) (3) (4) 2. (1) (2) (4) 1. 1. FORM N-3 V-45

(G6PD ) 酶 -------------------------------------------------------------------------------------------- FORM N-10 V-46

(G6PD ) 酶 (G6PD) G6PD -------------------------------------------------------------------------------------------- FORM N-11 V-47

() FORM M-1 FORM M-2 FORM M-3 () FORM M-4 FORM M-5 XX FORM M-6 FORM M-7 FORM M-8 V-48

FORM S-1 FORM S-2 FORM S-3 ( ) FORM S-4 FORM S-5 FORM S-6 G6PD FORM HY-1 FORM HY-2 V-49

(xxxxxx) xx/xx/xx xx ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- (g) ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------ xxxxxxxxx xx/xx/xx xxxxxxxx xxxxxxxxxx x (xxxx)xxxxxxx xx/xx/xx xx/xx/xx xxxx xxxxxxxxxx xx xx/xx/xx ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- xxxxx xxxxx xxxxx FORM M-1 V-50

xx/xx/xx xx -------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- ---------------------------------------------------------------------------------- ----------------------------------------------------------------- -------------------------------------------------------------------------- 7 7-15 16-30 30 77-15 7 7-15 16-30 30 ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------ (xxxxxx) xxxx xxxx xxxx xxxx xxxx xxxx xxxx xxxx xxxx xxxx xxxx xxxx xxxx xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% =========================================================================================================================================================================== xxxxx xxxx xxxxx xxxxx xxxxx xxxxx xxxxx xxxxx xxxxx xxxxx xxxxx xxxxx xxxxx xxxxx xxxxx xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- xxxxx xxxx xxxxx xxxxx xxxxx xxxxx xxxxx xxxxx xxxxx xxxxx xxxxx xxxxx xxxxx xxxxx xxxxx xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- xxxxx xxxx xxxxx xxxxx xxxxx xxxxx xxxxx xxxxx xxxxx xxxxx xxxxx xxxxx xxxxx xxxxx xxxxx xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- xxxxx xxxx xxxxx xxxxx xxxxx xxxxx xxxxx xxxxx xxxxx xxxxx xxxxx xxxxx xxxxx xxxxx xxxxx xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% ======================================================================================================================================================================================== xxxxx xxxx xxxxx xxxxx xxxxx xxxxx xxxxx xxxxx xxxxx xxxxx xxxxx xxxxx xxxxx xxxxx xxxxx xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------ FORM M-2 V-51

(xxxxxx) xx/xx/xx xx ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- (g) ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------ xxxxxxxxx xx/xx/xx xxxxxxxx xxxxxxxxxx xxxxxxxx x (xxxx)xxxxxxx xx/xx/xx xx/xx/xx xxxx xxxxxxxxxx xx xx/xx/xx ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- FORM M-3 V-52

() xx/xx/xx xx -------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- ---------------------------------------------------------------------------------- ----------------------------------------------------------------- -------------------------------------------------------------------------- 7 7-15 16-30 30 77-15 7 7-15 16-30 30 -------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- xxxxx xxxx xxxxx xxxxx xxxxx xxxxx xxxxx xxxxx xxxxx xxxxx xxxxx xxxxx xxxxx xxxxx xxxxx xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- xxxxx xxxx xxxxx xxxxx xxxxx xxxxx xxxxx xxxxx xxxxx xxxxx xxxxx xxxxx xxxxx xxxxx xxxxx xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- xxxxx xxxx xxxxx xxxxx xxxxx xxxxx xxxxx xxxxx xxxxx xxxxx xxxxx xxxxx xxxxx xxxxx xxxxx xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- xxxxx xxxx xxxxx xxxxx xxxxx xxxxx xxxxx xxxxx xxxxx xxxxx xxxxx xxxxx xxxxx xxxxx xxxxx xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% ====================================================================================================================================================================================== xxxxx xxxx xxxxx xxxxx xxxxx xxxxx xxxxx xxxxx xxxxx xxxxx xxxxx xxxxx xxxxx xxxxx xxxxx xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- * FORM M-4 V-54

xx/xx/xx xx xxxxxxx xxx xxxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxxx * xxx xxxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxxx (%) xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x * * (%) = ( / ) 100 FORM M-5 V-55

xx/xx/xx PKU xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx (%) xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x PKU xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx (%) xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x HCU xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx (%) xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x HCU xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx (%) xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x GAL xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx (%) xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x GAL xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx (%) xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x TSH xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx (%) xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x TSH xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx (%) xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x G6PD xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx (%) xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxxx (%) xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxxx (%) xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x * FORM M-7 (%) = ( / ) 100 (%) = ( / ) 100 (%) = ( / ) 100 (%) = ( / ) 100 V-57

G6PD CHT PKU HCU GAL Form M-8 V-58

() xx/xx/xx xx -------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- ---------------------------------------------------------------------------------- ----------------------------------------------------------------- -------------------------------------------------------------------------- 7 7-15 16-30 30 77-15 7 7-15 16-30 30 -------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- xxxxxx xxxxx xxxxxx xxxxxx xxxxxx xxxxxx xxxxxx xxxxxx xxxxxx xxxxxx xxxxxx xxxxxx xxxxxx xxxxxx xxxxxxx xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- xxxxxx xxxxx xxxxxx xxxxxx xxxxxx xxxxxx xxxxxx xxxxxx xxxxxx xxxxxx xxxxxx xxxxxx xxxxxx xxxxxx xxxxxxx xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- xxxxxx xxxxx xxxxxx xxxxxx xxxxxx xxxxxx xxxxxx xxxxxx xxxxxx xxxxxx xxxxxx xxxxxx xxxxxx xxxxxx xxxxxxx xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- xxxxxx xxxxx xxxxxx xxxxxx xxxxxx xxxxxx xxxxxx xxxxxx xxxxxx xxxxxx xxxxxx xxxxxx xxxxxx xxxxxx xxxxxxx xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% ====================================================================================================================================================================================== xxxxxx xxxxx xxxxxx xxxxxx xxxxxx xxxxxx xxxxxx xxxxxx xxxxxx xxxxxx xxxxxx xxxxxx xxxxxx xxxxxx xxxxxxx xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% xx.xx% ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- * FORM S-1 V-60

PKU CHT HCU GAL G6PD FORM S-2 PKU CHT HCU GAL G6PD FORM S-3 V-61

(G6PD) G6PD : FORM S-4 (PKU) PKU FORM S-4 V-62

(HCU) HCU FORM S-4 (CHT) CHT FORM S-4 V-63

(GAL) GAL FORM S-4 FORM S-5 V-64

FORM S-6 V-65

G6PD (%) (%) RH-01 RH-02 RH-03 RH-04 RH-05 RH-06 RH-07 RH-08 RH-09 RH-10 RH-11 RH-12 RH-13 RH-14 RH-16 RH-17 RH-18 RH-19 Form HY-1 V-66

FORM HY-2 V-67

15 ( ) () 1 10016 1 (02)312-3456 1407 () 1 2 16490311 4 10 12F (02)325-7566 27 () 1 2 17166783 48-133 (02)760-9461 V-68

XX XX V-69

73 1 74 7 79 86.3