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3 RNA ATP BH4 PAH PAA PPA PLA T3,T4 PheTyr Phe 8PKU

4 PKUMSUD OTC, CPS PDH,MELAS MCAD () Smith-Lemli-Opitz, XP,MRI (CK, MR MR 1st 1st GC/MS GC/MS ( ) 2nd 2nd 3rd 3rd 4th 4th

5 I, III I, III FDPase FDPase CDG CDG 24 (+) (-) etc - etc (+) (-) etc HHH (+) (-) OTC CPS I NAGS (+) (-) NH3 / () (+) GH TSH/FT st 1st GC/MS GC/MS ( ) 2nd 2nd 3rd 3rd 4th 4th

6 (+) (-) 24 (-) (+) 2nd 1st 3rd GC/MS ( ) 4th (+) (-) etc HHH - etc etc OTC (+) (-) CPS I NAGS 1st 3rd 2nd GC/MS ( ) 4th

7 CTLN2) NICCD) - CTLN2 Na cm 7cm 1st 1st GC/MS GC/MS ( ) 2nd 2nd 3rd 3rd 4th 4th NH3 / () (+) GH TSH/FT4 0.3 I, III I, III FDPase FDPase CDG CDG

8 1 7 AEEGMRI B -2.5SDA Hb 9.5g/dlPlt 6.8 Gaucher / 290/kg 8 1st 2nd 3rd GC/MS ( ) 4th Copper transporting ATPase(ATP7B) Fabry TSH, 17OHP µ

9 Fabry Fabry / MPS QOL 6.

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11 References 1. Miyahara H, Korematsu S, Nagakura T and Izumi T. Efficasious difference of spirometry between a fluticasone MDI and a DPI for pediatric asthma. Pediatr Int 2008;50: Group (from 90 MDI-S 80 to 70 DPI) Group (from 100 DPI 80 to 60 MDI-S) Total (Group ) %FEV 1.0 (%) Pre MDI-S DPI Pre DPI MDI-S ;4: p< p= p=0.014 Pre MDI-S DPI PEAK study Guilbert TW et al. N Engl J Med 2006;354: fluticasone 1 PAC study Bisgaard H et al. N Engl J Med 2006;354: double-blind, control study 32budesonide 3 IFWIN study Murray CS et al. Lancet 2006;368: , randomised, double-blind, control study fluticasone 5

12 2. RS11 (Stein RT et al. Lancet 1999;354: ) 24%11% (Harju TH et al. Thorax 2006;61: ) IL8 RSVIL8 (Friedland JS. Res Virol 1996;147: ) IL8 (Thanawonqnuwech R et al. Vet Immunol Immunopathol 2001;79: ) IL8 IL8 (Norzila MZ et al. Am J Respir Crit Care Med 2000;161: ) IgE IgEIL8 (Gounni AS et al. FASB J 2001;15: ) IL8polymorphism (Puthothu B et al. Clin Mol Allergy 2006;4:2) IL8 (Kikuchi I et al. Am J Respir Cell Mol Biol 2006;34: ) IL4 2 T (Th2) IL5 3. IgE B IL8 IgE References ;66: ;44: LF/HF HF PER (msec 2 /Hz) LF/HF p< (msec 2 /Hz) HF (L/min) PER 350 p<0.01 p<

13 % (114) 62% (189) % 2-4 IgE IL4 2 T (Th2) B IL5 Bao B et al. Am J Physiol Endocrinol Metab 2003;285:E Th1 Kitamura H et al. Nat Immunol 2006;7:971-7 Li H et al. J Biol Chem 2007;282: MHC class Metz CH et al. Nutrition 2007;23: Th2Th1 T Infection Naïve helper T cell Th1 (TB, bacteria) 1 B cell IgG 5. Allergen (mite, food) Th2 B cell IgE Reference Korematsu S, Miyahara H, Nagakura T, Suenobu S and Izumi T. The theophylline-associated seizures and their clinical characterizations. Pediatr Int 2008;50:95-95.

14 Table 1. The list of pediatric patients with TAS Patient No Age (year) Sex Family history FC Epilepsy Severity of Asthma Clinical findings on first sz Serum The concentration (g/ml M a Intermittent N.E M Intermittent F + - Intermittent M + - Moderate N.E. + 1 b 5. 4 M - + Intermittent F - - Intermittent M Moderate F ++ - Intermittent Fever (38) FC: febrile convulsion, sz: seizure, N.E.: not examined a: Epilepsy, treated with antiepileptic drugs, b: Benign childhood epilepsy with centrotemporal spikes Table 2. The neurological findings and outcomes in eleven patients with TAS outcome Patient Seizure EEG SPECT MRI No type medication seizure other neurological findings 1. GTS Lt. hemisphere Lt. T hypo. U.R. - - TIQ 89, VIQ 85, PIQ 96 slow wave 2. Rt. unilateral sz. Lt. hemisphere low volt. act. N.O. Lt. T T2-high CBZ - cessation 3. GTS Diffuse slow Lt. T hypo. U.R GTCS Diffuse slow N.O. U.R. 5. CPS with 2nd T spikes N.O. U.R. - - generalization CPS with 2nd CBZ Rt. hemisphere Rt. F hypo. U.R. - generalization cessation slow wave 7. Lt. hemisphere GTCS slow wave N.O. N.O. - - Lt. unilateral 8. dominant sz. Rt. F,C,P spikes N.O. Rt. venous - - angioma Rt: right, Lt: left, sz: seizure, epi: epilepsy, GTS: general tonic sz, GTCS: general tonic clonic sz, CPS: complex partial sz, volt: voltage, act: activity, hypo: hypoperfusion, HHE: hemiconvulsion hemiplegia and epilepsy, CBZ: carbamazepin, F: frontal, T: temporal, P: parietal, O: occipital, FC: febrile convulsion, N.O.: not obtained, U.R.: unremarkable CBZ - HHE, TIQ 53, VIQ 64, PIQ 58 Hyperkinetics, DQ65 6. TIQ 112, VIQ 111, PIQ 110 TAS Yarnell PR et al. Neurology 1975;25:819 / Mori H et al. J Neurol Neurosurg Psychiatry 1992;55:466 Dunn DW et al. Neuropediatrics 1991;22:24 Tchekalarova J et al. Brain Res Bull 2000;52:13 TAS Magnussen I et al. Acta Neurol Scand 1977;55:131 Bowton DL et al. Am Respir Crit Care Med 1994;150:1002 Bartel PR et al. Am J Clin Nutr 1994;60:93 pyridoxal Bonfiglio MF et al. Pharmacotherapy 1996;16:1166 adenosinebenzodiazepine Gulati K. Pharmacol Biochem Behav 2004;82:241 free radical T References 1. Korematsu S, Tanaka Y, Hosoi S et al. C8/119S mutation of major mite allergen Derf-2 leads to degenerate secondary structure and molecular polymerization and induces potent and exclusive Th1 cell differentiation. J Immunol 2000;165: Korematsu S, Tanaka Y, Nagakura T, Minato N and Izumi T. Human T cells modurate the mite allergen-specific Th2-skewed immunity. Clin Exp Allergy 2007;37: T 2Derf2Th2 Th1 IL-4 IFN- (pg/ml) Th2Th1 IgE (Korematsu S et al. J Immunol 2000;165:2895)

15 IgE SS C8/119S Derf2 IL IFN- SS Th1 C8/119S (Korematsu S et al. J Immunol 2000;165:2895) C8/119STh1 IgE Derf2 C8/119S B Th2 DC M IL6 B Th1 DC M TNF Infection (TB, bacteria) Naïve helper T cell Allergen (mite, food) Th1 Th2 (Shirakawa T et al. Science 1997;275:77) B cell B cell IgG IgE Th1Treg Th2 in vitro BCGTh1T Th Derf22BCG Derf2Th2BCGTh1 T Derf2Th2BCGTh1T Th2IL4

16 Derf2 (cpm: x 1,000) (g/ml) BCG (cpm: x 1,000) (%) (cpm: x 1,000) (M) Derf2 BCG BCG Derf2 A Derf2Th2 B Derf2Th2 A BCGTh1 C BCGTh1 D BCGTh1 A T B T C T D T T IL10 (IL4: pg/ml) n.d. n.d. n.d. n.d. n.d. n.d. n.d (IFN: pg/ml) Derf2Th2T (IL4: pg/ml) Derf2 (IFN: pg/ml) (IL4: pg/ml) (g/ml) (M) 0 (IFN: pg/ml) Th2 TT5% Th2 T Th2 Th2 Th2 T Th2 * Th2 Th2 T T T Th2 Th2 T T T T T T T T T T * Tanaka Y et al. Nature 1995;375:155 carry over

17 1 4(100cm) = ICP growth model

18 LH Orchid meter

19

20

21 Growth potential () Target height 75cm 50cm 10kg 5kg 1 2

22 6 3

23 SD 119 P:2 PH:1-2 Testis:7-8ml g

24 Arm span 2 septo-optic-dysplaisia Karyotype Prenatal* Postnatal 45,X 134 (64%) 162 (47%) 45,X/46,XX 45 (22%) 59 (17%) 45,X/46,X,I (Xq); 45,X/46,X,I (Xq)/47,X,I(Xq),I(Xq) 9 (4%) 41 (12%) etc 45,X/46,X,del(X); 46,X,del(X) 15 (7%) 27 (8%) 45,X/46,XX/47,XXX; 45,X/47,XXX; 5 (2%) 16 (5%) 45,X/46,XX/47,XXX/48,XXXX 45,X/46,X,r(X) 1 (<1%) 20 (6%) 45,X/46,XY 10 (3%) Others with Y material 11 (3%) Critical regions for TS phenotypes on the X chromosome Phenotype Stature, skeletal anomalies Stature, gonadal failure, minor physical features Viability Gonadal failure X Gene (candidate) p q SHOX (ZFX) (USP9X) (RPS4X) (DIAPH2) =

25 Medical conditions common in TS Organ/System Feature Frequency (%) Heart Congenital cardiac 30 problems Skeleton Bone age retardation 85 Reduced bone mineral 5085 density Kidneys Renal abnormalities 30 Endocrine Glucose intolerance 30 Thyroid dysfunction 1030 Ears Middle ear infection 60 Hearing defects 30 Psychosocial problems Emotional immaturity and learning problems Up to 40% (Hypophyseal dysplasia) Hypophyseal dysplasia Prader-Willi IGF-1C TSHfT3fT4

26 L-dopa

27

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