Citrullinemia type II Citrin neonatal intrahepatic cholestasis caused

瓜胺酸血症第二型 Citrullinemia type II • Citrin 基因變異 • 可表現三種臨床表現： • 新生兒膽汁鬱積症（neonatal intrahepatic cholestasis caused by citrin deficiency，簡稱NICCD） • failure to thrive and dyslipidemia caused by citrin deficiency (FTTDCD) • 第二型瓜胺酸血症（citrullinemia type II，簡稱CTLN 2） • 膽汁鬱積時需使用低糖高中鏈 油飲食，否則造成肝衰竭 • 發生率約1/20000 Journal of Pediatric Gastroenterology and Nutrition 47(2): 187 -192, August 2008.

瓜胺酸血症第二型(Citrullinemia type. II) 可能出現新生兒膽汁鬱積症NICCD Treat with Alfare (lactose-free, MCT-enriched (48%)) 出生時的篩檢指標citrulline可能偏高(左圖)或正常(右圖)

Citrin 基因 (SLC 25 A 13)在台灣有數個好發的突變熱點: 851 del 4, 1638 ins 23, IVS 6+5 G>A 等 Mutation Patients Controls Japan (%) Taiwan (%) China (%) No. alleles analyzed 206 (100) 12 (100) 2744 2784 2016 No. mutations detected 194 (94) 11 (91. 7) 20 20 13 [I] 851 del 4 61 (30) 7 (58. 3) 4 11 10 [II] IVS 11+1 G>A 80 (39) [III] 1638 ins 23 9 (4) [IV] S 225 X 9 (4) 5 [V] IVS 13+1 G>A 18 (9) 1 [VI] 1800 is 1 7 (3) [VII] R 605 X 1 (0. 5) [VIII] E 601 X 5 (2) [IX] E 601 K 1 (0. 5) [X] IVS 6+5 G>A 1 (0. 5) 9 2 (16. 7) 1 8 [XI] R 184 X 1 Others 2 (1) Male: female 45: 58 Heterozygote frequency 2 6: 5 1/69 1/70 1/78 Genetics and Metabolism 2004; 81 Suppl: 20 -6) Molecular

搭配進階突變熱點分析，在不增加偽陽性 的前提下，增加篩檢檢出率 Total 314 (0. 7%) underwent 2 nd tier molecular tests • An incidence of citrin deficiency identified as 1: 23 000 Wang et al. BMC Medical Genetics 2013, 14: 24

有機酸代謝異常疾病 - 新增C 3 與 C 5 OH 指標相關疾病 疾病 監測物質 (新增)丙酸血症 Propionic acidemia C 3 carnitine 甲基丙二酸血症 Methylmalonic acidemia C 3 carnitine 異戊酸血症 Isovaleic acidemia C 5 carnitine 戊二酸血症 I Glutaric acidemia I C 5 DC carnitine (新增)全羧化酶合成酶 缺乏症(HCSD) Multiple Carboxylase Deficiency/ Holocarboxylase Synthetase Deficiency C 3/C 5 OH carnitine 3 -甲基巴豆醯輔酵素羧化酵 素缺乏症 3 -methylcrotonyl-Co. A-carboxylase (3 MCC) deficiency C 5 OH carnitine (新增)3 -羥基-3 -甲基戊二酸 尿症(HMG) 3 -hydroxy-3 -methylglutaric aciduria C 5 OH carnitine

針對甲基丙二酸/丙酸血症的篩檢流程 MMA Lactic Acid Succinic acid

(例)丙酸血症個案表現 • D 1 Hypoglycemia (around 30), IVF and sugar • D 4 Discharge with stable sugar level and appearance • At home: 40~60 ml Q 2~3 H, Normal activity, seizure(-), hypotonia(-), vomit( -) • D 6 Abnormal newborn screen test, and admitted Elevated C 3 carnitine and low free carnitine

3 -羥基-3 -甲基戊二酸尿症 3 -hydroxy-3 -methylglutaric aciduria, HMG • HMG-Co. A Lyase缺乏 • 平日須限制蛋白質攝取，同時補 充特殊營養食品，以維持正常 生長發育 L. -X. Tong et al. / Tzu Chi Medical Journal 26 (2014) 146 e 147

(例)白胺酸代謝異常個案 https: //vita. tw/%E 7%BD%95%E 7%97%85%E 5%85%92%E 5%AE%B 6%E 9%95%B 7%E 6%9 B%BE%E 6%95%8 F%E 5%82%91%E 6%8 A%8 A%E 6%84%9 B%E 5%82%B 3%E 5%87%BA%E 5%8 E%BB-b 97714 cc 4645 https: //www. peoplenews. tw/news/02 d 2253 b-b 3 ec-486 c-8811 -6 d 9885 cccc 3 f

脂肪酸代謝異常疾病 - 新增PCD, 及長鏈脂肪酸代謝異常等疾病 疾病 (新增)原發性肉鹼缺乏症 監測物質 Primary carnitine deficiency (or carnitine transporter deficiency) (PCD) C 0↓ (新增)肉鹼棕櫚醯基轉移酶 Carnitine palmitoyltransferase I (CPT 1 A) deficiency 第一型缺乏症 C 16↓ (新增)肉鹼棕櫚醯基轉移酶 Carnitine palmitoyltransferase II (CPT 2) deficiency 第二型缺乏症 C 16↑ Short-chain acyl-Co. A dehydrogenase (SCAD) deficiency C 4 ↑ 中鏈醯輔酶A脫氫酵素缺乏 Medium-chain acyl-Co. A dehydrogenase (MCAD) deficiency 症 C 6, C 8, C 10, C 12 ↑ (新增)極長鏈醯輔酶A脫氫 酵素缺乏症 Very long-chain acyl-Co. A dehydrogenase (VLCAD) deficiency C 14: 2, C 14: 1, C 16, C 18: 1 ↑ (新增)戊二酸血症第二型 Glutaric aciduria type II (or multiple acyl-Co. A dehydrogenase deficiency) (GA II) C 10 -C 16 acylcarnitines ↑ Long-chain 3 -hydroxyacyl-Co. A dehydrogenase (LCHAD) deficiency C 16 -OH, C 18: 1 -OH ↑

(例)Sudden unexpected death in infancy • Her Apgar score was 6/9, birth weight was 2870 g • At 11 months of age, fever and vomiting and visited a doctor’s office • The morning of the next day, she suddenly lost consciousness, OHCA when arriving the hospital • Reye's-like syndrome suggested by the histology • CPT 2 gene mutation p. F 323 fs/p. V 605 L https: //doi. org/10. 1016/j. ymgmr. 2015. 09. 005

長鏈脂肪酸代謝疾病篩檢容易因複檢產生偽陰性 CPT II Age at sampling Free carnitine C 2 -carnitine C 3 -carnitine C 4 -carnitine C 5 DC-carnitine C 5 OH-carnitine C 6 -carnitine C 8 -carnitine C 10 -carnitine C 12 -carnitine C 14: 1 -carnitine C 16 -carnitine C 18: 1 -carnitine 3 days 1 st screening 19. 9 5. 23 0. 18 0. 09 0. 05 0. 08 0. 05 0. 03 0. 1 0. 38 NA 1. 37 0. 24 7. 1 2. 39 3. 25 9 days 2 nd screening 15. 6 2. 94 0. 12 0. 06 0. 03 0. 06 0. 05 0. 03 0. 1 0. 26 NA 1. 07 0. 28 6. 29 2. 4 3. 73 GA II 19 days 3 rd screening 10. 4 1. 87 0. 09 0. 05 0. 02 0. 07 0. 04 0. 07 0. 33 0. 36 NA 0. 66 0. 26 1. 82 0. 94 1. 96 Age at sampling Cutoffs <70. 0 <7. 0 <6. 0 <1. 5 <0. 6 <0. 3 <0. 8 <0. 5 NA 0. 8 0. 6 <8. 0 <2. 0 <3. 5 Free carnitine C 2 -carnitine C 3 -carnitine C 4 -carnitine C 5 DC-carnitine C 5 OH-carnitine C 6 -carnitine C 8 -carnitine C 10 -carnitine C 12 -carnitine C 14: 1 -carnitine C 16 -carnitine C 18: 1 -carnitine 3 days 1 st screening 38. 60 24. 80 1. 43 0. 55 0. 26 0. 137 0. 15 0. 48 0. 71 1. 30 0. 92 0. 72 1. 20 2. 93 0. 94 1. 53 9 days 2 nd screening 33. 90 14. 20 1. 11 0. 27 0. 31 0. 0571 0. 31 0. 12 0. 10 0. 34 0. 18 0. 20 0. 23 0. 95 0. 46 0. 74 Cutoffs <80. 0 <7. 0 <6. 0 <1. 5 <0. 6 <0. 3 <0. 8 <0. 5 0. 8 0. 6 <8. 0 <2. 0 <3. 5 需要搭配進階突變基因分析，在不增加偽陽性的前提下，增加篩檢檢出率