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系統識別號 U0026-0908201912302300
論文名稱(中文) 腦脊髓液葡萄糖低下之嬰幼兒其神經發展預後及其帶有SLC2A1變異的比率
論文名稱(英文) Developmental Outcomes and Prevalence of SLC2A1 Variants in Febrile Young Infants with Hypoglycorrhachia
校院名稱 成功大學
系所名稱(中) 臨床醫學研究所碩士在職專班
系所名稱(英) Institute of Clinical Medicine(on the job class)
學年度 107
學期 2
出版年 108
研究生(中文) 余文豪
研究生(英文) Wen-Hao Yu
學號 S97061027
學位類別 碩士
語文別 英文
論文頁數 31頁
口試委員 指導教授-黃朝慶
口試委員-王新台
口試委員-楊燿榮
中文關鍵字 腦脊髓液葡糖低下  嬰兒  腦血管屏障葡萄糖輸送缺陷症候群 
英文關鍵字 hypoglycorrhachia  infant  glucose transporter 1 deficiency syndrome  SLC2A1 
學科別分類
中文摘要 葡萄糖對發展中的腦部是很重要的能量來源,其必須透過血腦屏障上的第一型葡萄糖載體蛋白將其從血中運到腦脊髓液中,提供腦細胞使用。當第一型載體蛋白的功能失調時,便會導致腦脊髓液葡萄糖低下並對大腦產生不良的反應,臨床稱為腦血管屏障葡萄糖輸送缺陷症候群。腦血管屏障葡萄糖輸送缺陷症候群的主要臨床表現有癲癇病變、發展遲緩、小頭、肢體僵直、複雜性動作疾病等。但臨床上常發現一些沒有神經學症狀但在排除中樞神經感染和其他可能因素後,腦脊髓液葡萄糖呈現低下的嬰幼兒。目前這群無臨床症狀但合併腦脊髓液葡萄糖低下的嬰幼兒其後續的神經發展預後仍是未知。因此我們假設這群無臨床症狀但合併腦脊髓液葡萄糖低下的嬰幼兒,未來會有較差的神經發展且其和腦血管屏障葡萄糖輸送缺陷症候群有關聯。
方法:在2006~2016年間,共有1655位年紀小於4個月且沒有神經學症狀的嬰兒,因為發燒接受了腦脊髓液的檢查。排除中樞神經感染及其他可能導致腦脊髓液葡萄糖低下的原因後,找出腦脊髓液葡糖低下病人共30位,並且在腦脊髓液葡萄糖正常的病人中去做年紀及性別的配對找出控制組共50位。這兩組病人在2017年接受神經發展的評估,其接受評估時的平均年紀為5.9 ± 2.4歲 (範圍1~10歲)。
結果:在排除中樞神經感染及其他可能導致腦脊髓液葡萄糖低下的原因後,共有722位病人留下,其中有30位病人 (4.2%) 符合腦脊髓液葡萄糖低下的標準,並有25位回來接受神經發展評估。在這25位腦脊髓液葡萄糖低下的病人中,有4位病人 (16%) 有異常的追蹤結果,其中3位病人 (12%) 有混合型發展遲緩的病史,1位 (4%) 有第一型糖尿病。然而在50位腦脊髓液葡萄糖正常的控制組病人中,只有兩位病人 (4%) 有異常的追蹤結果,且兩位都只有單純語言發展遲緩的病史。兩組在統計結果上顯示,腦脊髓液葡萄糖低下的組別相較於腦脊髓液葡萄糖正常的組別,有較高比率的混合型發展遲緩的病史 (12% vs. 0%, P = 0.034)。然而在腦脊髓液葡萄糖低下的組別中,沒有發現腦血管屏障葡萄糖輸送缺陷症候群致病基因SLC2A1的致病變異。
透過本研究我們發現臨床上沒有神經症狀的嬰幼兒,腦脊髓液葡萄糖低下或許是未來神經發展遲緩的指標而非腦血管屏障葡萄糖輸送缺陷症候群指標。
英文摘要 Glucose is a vital energy source for the developing brain and it is transported from the blood into the cerebrospinal fluid the via the glucose transporter 1 (GLUT1) at the blood brain barrier (BBB). Impaired function of GLUT1 causes hypoglycorrhachia, or low CSF glucose concentration, which has adverse effects on developing brain. Patients with hypoglycorrhachia caused by impaired function of GLUT1, or glucose transporter 1 deficiency syndrome (GLUT1DS), have diverse clinical symptoms, including epileptic encephalopathy, developmental delay, acquired microcephaly, spasticity, and complex movement disorders. The neurodevelopmental outcomes of young infants with hypoglycorrhachia that is comparable to glucose transporter 1 deficiency syndrome (GLUT1DS), i.e. cerebrospinal fluid (CSF) glucose ≤ 40mg/dL and CSF lactate < 2.2 mM without causes of secondary hypoglycorrhachia are unknown. This study hypothesized that developmental outcomes of infants with hypoglycorrhachia were worse than infants without hypoglycorrhachia and this phenomenon was associated with GLUT1DS.
Material and methods: 1655 neurologically asymptomatic infants aged < 4 months had CSF examinations for fever workup from 2006 to 2016. Among the infants with normal CSF cell counts and without isolated pathogens, there were hypoglycorrhachia group who had CSF glucose levels that were comparable to GLUT1DS, and age- and gender-matched non-hypoglycorrhachia group. Both groups were at a mean age of 5.9 ± 2.4 years (ranged 1-10 years) at neurodevelopmental evaluation in 2017. Mutational analysis of solute-carrier-family 2, which facilitated the glucose transporter member 1 (SLC2A1) gene was performed.
Results: Among the 722 infants with normal CSF cell counts and without isolated pathogens, 30 (4.2%) had hypoglycorrhachia that was comparable to GLUT1DS. In the 25 infants with hypoglycorrhachia available for follow-up, 4 (16%) had abnormal outcomes, of which 3 (12%) had the history of mixed-type developmental delay before age 6 and 1 (4%) had type 1 diabetes mellitus. In the non-hypoglycorrhachia control group (n = 50), 2 patients (4%) showed abnormal outcomes, both with the history of pure speech delay. The hypoglycorrhachia group had a higher rate of the history of mixed-type of developmental delay than the control group (12% vs. 0%, P = .034). No SLC2A1 pathogenic variants were observed in the hypoglycorrhachia group.
In conclusion, our study showed that hypoglycorrhachia may be a potential biomarker for neurodevelopmental delay instead of for GLUT1DS in neurologically asymptomatic young infants.
論文目次 中文摘要 1
Abstract 3
Acknowledgement 5
Table Contents 7
Figure Contents 8
Abbreviation Index 9
Introduction 10
Material and methods 11
Results 15
Discussion 17
Conclusion 20
Reference 21
參考文獻 1. Mergenthaler P, Lindauer U, Dienel GA, Meisel A. Sugar for the brain: the role of glucose in physiological and pathological brain function. Trends Neurosci 2013; 36: 587-97.
2. Pascual JM, Wang D,Hinton V, Engelstad K, Saxena CM, Van Heertum RL, et al. Brain glucose supply and the syndrome of infantile neuroglycopenia. Arch Neurol 2007; 64: 507-13.
3. Viola GM. Extreme hypoglycorrhachia: not always bacterial meningitis. Nat Rev Neurol 2010; 6: 637–41.
4. Silver TS, Todd JK. Hypoglycorrhachia in pediatric patients. Pediatrics 1976; 58: 67-71.
5. Chow E, Troy SB. The Differential Diagnosis of Hypoglycorrhachia in Adult Patients. Am J Med Sci 2014; 348: 186-90.
6. Wang D, Pascual JM, Yang H, Engelstad K, Jhung S, Sun RP, et al. Glut‐1 deficiency syndrome: Clinical, genetic, and therapeutic aspects. Ann Neurol 2005; 57: 111-8.
7. Leen WG, Klepper J, Verbeek MM, Leferink M, Hofste T, van Engelen BG, et al. Glucose transporter-1 deficiency syndrome: the expanding clinical and genetic spectrum of a treatable disorder. Brain 2010; 133: 655-70.
8. Pascual JM, Wang D, Lecumberri B, Yang H, Mao X, Yang R, De Vivo DC. GLUT1 deficiency and other glucose transporter diseases. Eur J Endocrinol 2004; 150: 627-33.
9. De DV, Leary L, Wang D. Glucose transporter 1 deficiency syndrome and other glycolytic defects. J Child Neurol 2002; 17: 3S15-23.
10. De Vivo DC, Trifiletti RR, Jacobson RI, Ronen GM, Behmand RA, Harik SI. Defective glucose transport across the blood-brain barrier as a cause of persistent hypoglycorrhachia, seizures, and developmental delay. N Engl J Med 1991; 325: 703–9.
11. Larsen J, Johannesen KM, Ek J, Tang S, Marini C, Blichfeldt S, et al. The role of SLC2A1 mutations in myoclonic astatic epilepsy and absence epilepsy, and the estimated frequency of GLUT1 deficiency syndrome. Epilepsia 2015; 56: e203-8.
12. Mullen SA, Suls A, De Jonghe P, Berkovic SF, Scheffer IE. Absence epilepsies with widely variable onset are a key feature of familial GLUT1 deficiency. Neurology 2010; 75: 432-40.
13. Overweg-Plandsoen W, Groener J, Wang D, Onkenhout W, Brouwer OF, Bakker HD, et al. GLUT-1 deficiency without epilepsy- An exceptional case. J Inherit Metab Dis 2003; 26: 559-563.
14. Joshi C, Greenberg CR, De Vivo D, Wang D, Chan-Lui W, Booth FA. GLUT1 deficiency without epilepsy: Yet another case. J Child Neurol 2008; 23: 832-4.
15. Weber YG, Storch A, Wuttke TV, Brockmann K, Kempfle J, Maljevic S, et al. GLUT1 mutations are a cause of paroxysmal exertion-induced dyskinesias and induce hemolytic anemia by a cation leak. J Clin Invest 2008; 118: 2157-68.
16. Nickels K, Wirrell E. GLUT1-ous maximus epilepticus The expanding phenotype of GLUT-1 variants and epilepsy. Neurology 2010; 75: 390-1.
17. Leen WG, Wevers RA, Kamsteeg E-J, Scheffer H, Verbeek MM, Willemsen MA. Cerebrospinal fluid analysis in the workup of GLUT1 deficiency syndrome: a systematic review. JAMA Neurol 2013; 70: 1440-4.
18. Willemsen MA, Verrips A, Verbeek MM, Voit T, Klepper J. Hypoglycorrhachia: A simple clue, simply missed. Ann Neurol 2001; 49: 685-6.
19. Fujii T, Ito Y, Takahashi S, Shimono K, Natsume J, Yanagihara K, et al. Outcome of ketogenic diets in GLUT1 deficiency syndrome in Japan: A nationwide survey. Brain Dev 2016; 38: 628-37.
20. Klepper J, Scheffer H, Leiendecker B, Gertsen E, Binder S, Leferink M, et al. Seizure control and acceptance of the ketogenic diet in GLUT1 deficiency syndrome: A 2-to 5-year follow-up of 15 children enrolled prospectively. Neuropediatrics 2005; 36: 302-8.
21. Baraff LJ. Management of infants and young children with fever without source. Pediatr Ann 2008; 37: 673.
22. Lieu TA, Baskin MN, Schwartz JS, Fleisher GR. Clinical and cost-effectiveness
of outpatient strategies for management of febrile infants. Pediatrics 1992; 89:1135-44
23. Leen WG, Willemsen MA, Wevers RA, Verbeek MM. Cerebrospinal fluid glucose and lactate: age-specific reference values and implications for clinical practice. PLoS ONE 2012; 7: e42745.
24. Thomson J, Sucharew H, Cruz AT, Nigrovic LE, Freedman SB, Garro AC, et al. Cerebrospinal fluid reference values for young infants undergoing lumbar puncture. Pediatrics 2018; 141: e20173405.
25. Taiwan Biobank.c2012 cited 2018 Feb 01. Available from: https://taiwanview.twbiobank.org.tw/index
26. Chugani HT, Phelps ME, Mazziotta JC. Positron emission tomography study of
human brain functional development. Ann Neurol 1987; 22: 487-97.
27. Rotstein M, Engelstad K, Yang H, Wang D, Levy B, Chung WK, et al. Glut1 deficiency: inheritance pattern determined by haploinsufficiency. Ann Neurol 2010; 68: 955-8.
28. Arsov T, Mullen SA, Rogers S, Phillips AM, Lawrence KM, Damiano JA, et al. Glucose transporter 1 deficiency in the idiopathic generalized epilepsies. Ann Neurol 2012; 72: 807–15.
29. Yang H, Wang D, Engelstad K, Bagay L, Wei Y, Rotstein M, et al. Glut1 deficiency syndrome and erythrocyte glucose uptake assay. Ann Neurol 2011; 70: 996-1005.
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