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Glycogen Storage Disease Type Ia — References

당원병 제1a형(폰 기르케병) QSP 모델의 근거 문헌입니다. 각 섹션은 모델의 해당 구성요소에 대응하며, 파라미터 보정에 직접 쓰인 문헌은 calibration 표시를 붙였습니다.

1. 질환 개관 · 관리 지침 (Disease overview and management guidelines)

  1. Kishnani PS, Austin SL, Abdenur JE, et al. Diagnosis and management of glycogen storage disease type I: a practice guideline of the American College of Medical Genetics and Genomics. Genet Med. 2014;16(11):e1. https://pubmed.ncbi.nlm.nih.gov/25356975/ — calibration (dietary dose and interval targets, biochemical treatment goals, surveillance schedule)
  2. Rake JP, Visser G, Labrune P, et al. Guidelines for management of glycogen storage disease type I — European Study on Glycogen Storage Disease Type I (ESGSD I). Eur J Pediatr. 2002;161 Suppl 1:S112. https://pubmed.ncbi.nlm.nih.gov/12373584/ 2b. Rake JP, Visser G, Labrune P, et al. Glycogen storage disease type I: diagnosis, management, clinical course and outcome. Results of the ESGSD I. Eur J Pediatr. 2002;161 Suppl 1:S20. https://pubmed.ncbi.nlm.nih.gov/12373567/
  3. Chou JY, Jun HS, Mansfield BC. Glycogen storage disease type I and G6Pase-β deficiency: etiology and therapy. Nat Rev Endocrinol. 2010;6(12):676. https://pubmed.ncbi.nlm.nih.gov/20975743/
  4. Bali DS, El-Gharbawy A, Austin S, Pendyal S, Kishnani PS. Glycogen Storage Disease Type I. GeneReviews. Updated 2021. https://pubmed.ncbi.nlm.nih.gov/20301489/
  5. Derks TGJ, Rodriguez-Buritica DF, Ahmad A, et al. Glycogen storage disease type Ia: current management options, burden and unmet needs. Nutrients. 2021;13(11):3828. https://pubmed.ncbi.nlm.nih.gov/34836082/
  6. Wolfsdorf JI, Weinstein DA. Glycogen storage diseases. Rev Endocr Metab Disord. 2003;4(1):95. https://pubmed.ncbi.nlm.nih.gov/12618563/

2. 분자유전학 · 효소학 (Molecular genetics and enzymology)

  1. Lei KJ, Shelly LL, Pan CJ, Sidbury JB, Chou JY. Mutations in the glucose-6-phosphatase gene that cause glycogen storage disease type 1a. Science. 1993;262(5133):580. https://pubmed.ncbi.nlm.nih.gov/8211187/
  2. Chou JY, Matern D, Mansfield BC, Chen YT. Type I glycogen storage diseases: disorders of the glucose-6-phosphatase complex. Curr Mol Med. 2002;2(2):121. https://pubmed.ncbi.nlm.nih.gov/11949931/
  3. Ghosh A, Shieh JJ, Pan CJ, Chou JY. Histidine 167 is the phosphate acceptor in glucose-6-phosphatase-β. J Biol Chem. 2004;279(13):12479. https://pubmed.ncbi.nlm.nih.gov/14722058/
  4. Gerin I, Veiga-da-Cunha M, Achouri Y, Collet JF, Van Schaftingen E. Sequence of a putative glucose 6-phosphate translocase, mutated in glycogen storage disease type Ib. FEBS Lett. 1997;419(2-3):235. https://pubmed.ncbi.nlm.nih.gov/9428641/
  5. Chou JY, Sik Jun H, Mansfield BC. The SLC37 family of phosphate-linked sugar phosphate antiporters. Mol Aspects Med. 2013;34(2-3):601. https://pubmed.ncbi.nlm.nih.gov/23506893/
  6. Matern D, Seydewitz HH, Bali D, Lang C, Chen YT. Glycogen storage disease type I: diagnosis and phenotype/genotype correlation. Eur J Pediatr. 2002;161 Suppl 1:S10. https://pubmed.ncbi.nlm.nih.gov/12373565/
  7. Shieh JJ, Terzioglu M, Hiraiwa H, et al. The molecular basis of glycogen storage disease type 1a: structure and function analysis of mutations in glucose-6-phosphatase. J Biol Chem. 2002;277(7):5047. https://pubmed.ncbi.nlm.nih.gov/11739397/
  8. Akanuma J, Nishigaki T, Fujii K, et al. Glycogen storage disease type Ia: molecular diagnosis of 51 Japanese patients and characterization of splicing mutations. Am J Med Genet. 2000;91(2):107. https://pubmed.ncbi.nlm.nih.gov/10748408/

3. 내인성 포도당 생성 잔존량 (Residual endogenous glucose production)

모델의 가장 중요한 보정 항목. GSD Ia에서 EGP가 0이 아니라 정상의 20-30%로 남아 있다는 사실이, 왜 환자가 2-3시간의 공복을 견디는지를 결정합니다.

  1. Tsalikian E, Simmons P, Gerich JE, Howard C, Haymond MW. Glucose production and utilization in children with glycogen storage disease type I. Am J Physiol. 1984;247(4 Pt 1):E513. https://pubmed.ncbi.nlm.nih.gov/6385713/ — calibration (residual EGP ~1.0–1.5 mg/kg/min)
  2. Powell RC, Wentworth SM, Brandt IK. Endogenous glucose production in type I glycogen storage disease. Metabolism. 1981;30(5):443. https://pubmed.ncbi.nlm.nih.gov/6939866/ — calibration
  3. Kalderon B, Korman SH, Gutman A, Lapidot A. Estimation of glucose carbon recycling in children with glycogen storage disease: a ¹³C NMR study using [U-¹³C]glucose. Proc Natl Acad Sci USA. 1989;86(12):4690. https://pubmed.ncbi.nlm.nih.gov/2734317/
  4. Collins JE, Bartlett K, Leonard JV, Aynsley-Green A. Glucose production rates in type 1 glycogen storage disease. J Inherit Metab Dis. 1990;13(2):195. https://pubmed.ncbi.nlm.nih.gov/2116542/
  5. Bier DM, Leake RD, Haymond MW, et al. Measurement of "true" glucose production rates in infancy and childhood with 6,6-dideuteroglucose. Diabetes. 1977;26(11):1016. https://pubmed.ncbi.nlm.nih.gov/913891/ — calibration (glucose demand by age: infant ~6.5 → adult ~2.1 mg/kg/min)
  6. Huidekoper HH, Visser G, Ackermans MT, Sauerwein HP, Wijburg FA. A potential role for muscle in glucose homeostasis: in vivo kinetic studies in glycogen storage disease type 1a and fructose-1,6-bisphosphatase deficiency. J Inherit Metab Dis. 2010;33(1):25. https://pubmed.ncbi.nlm.nih.gov/20049538/

4. G6P 분기점 · 글리코겐 합성효소의 알로스테릭 활성화

왜 "저혈당 질환"이 아니라 "축적 질환"이 되는가 — G6P가 글리코겐 합성효소를 인산화 상태와 무관하게 켜기 때문입니다.

  1. Villar-Palasí C, Guinovart JJ. The role of glucose 6-phosphate in the control of glycogen synthase. FASEB J. 1997;11(7):544. https://pubmed.ncbi.nlm.nih.gov/9212078/
  2. Bouskila M, Hunter RW, Ibrahim AFM, et al. Allosteric regulation of glycogen synthase controls glycogen synthesis in muscle. Cell Metab. 2010;12(5):456. https://pubmed.ncbi.nlm.nih.gov/21035757/
  3. Agius L. Glucokinase and molecular aspects of liver glycogen metabolism. Biochem J. 2008;414(1):1. https://pubmed.ncbi.nlm.nih.gov/18651836/ — calibration (glucokinase Km 8 mM, Hill ~1.7, GKRP)
  4. Nordlie RC, Foster JD, Lange AJ. Regulation of glucose production by the liver. Annu Rev Nutr. 1999;19:379. https://pubmed.ncbi.nlm.nih.gov/10448530/
  5. Roach PJ, Depaoli-Roach AA, Hurley TD, Tagliabracci VS. Glycogen and its metabolism: some new developments and old themes. Biochem J. 2012;441(3):763. https://pubmed.ncbi.nlm.nih.gov/22248338/
  6. Kalderon B, Korman SH, Gutman A, Lapidot A. Glucose recycling and production in glycogenosis type I and III. Am J Physiol. 1989;257(3 Pt 1):E346. https://pubmed.ncbi.nlm.nih.gov/2782394/

5. 젖산 — 독성 대사산물이자 뇌 연료 (Lactate as toxin and as cerebral fuel)

모델의 두 번째 핵심 주장: GSD Ia 환자가 혈당 1.5-2.0 mmol/L에서 무증상인 이유는 젖산이 뇌 연료의 절반 이상을 대신 공급하기 때문입니다.

  1. van Hall G, Strømstad M, Rasmussen P, et al. Blood lactate is an important energy source for the human brain. J Cereb Blood Flow Metab. 2009;29(6):1121. https://pubmed.ncbi.nlm.nih.gov/19337275/ — calibration
  2. Boumezbeur F, Petersen KF, Cline GW, et al. The contribution of blood lactate to brain energy metabolism in humans measured by dynamic ¹³C nuclear magnetic resonance spectroscopy. J Neurosci. 2010;30(42):13983. https://pubmed.ncbi.nlm.nih.gov/20962220/ — calibration
  3. Fernandes J, Berger R, Smit GPA. Lactate as a cerebral metabolic fuel for glucose-6-phosphatase deficient children. Pediatr Res. 1984;18(4):335. https://pubmed.ncbi.nlm.nih.gov/6728555/ — calibration (the observation the whole cerebral-fuel module exists to reproduce)
  4. Fernandes J, Berger R, Smit GPA. Lactate as energy source for brain in glucose-6-phosphatase deficient child. Lancet. 1982;1(8262):113. https://pubmed.ncbi.nlm.nih.gov/6119494/
  5. Pellerin L, Magistretti PJ. Sweet sixteen for ANLS. J Cereb Blood Flow Metab. 2012;32(7):1152. https://pubmed.ncbi.nlm.nih.gov/22027938/
  6. Pierre K, Pellerin L. Monocarboxylate transporters in the central nervous system. J Neurochem. 2005;94(1):1. https://pubmed.ncbi.nlm.nih.gov/15953344/
  7. Smit GPA. The long-term outcome of patients with glycogen storage disease type Ia. Eur J Pediatr. 1993;152 Suppl 1:S52. https://pubmed.ncbi.nlm.nih.gov/8391447/

6. 저케톤성 저혈당 — 감별의 핵심 (Hypoketotic hypoglycaemia)

  1. Bandsma RHJ, Prinsen BH, van der Velden MdS, et al. Increased de novo lipogenesis and delayed conversion of large VLDL into intermediate density lipoprotein particles contribute to hyperlipidemia in glycogen storage disease type 1a. Pediatr Res. 2008;63(6):702. https://pubmed.ncbi.nlm.nih.gov/18520330/ — calibration
  2. McGarry JD, Foster DW. Regulation of hepatic fatty acid oxidation and ketone body production. Annu Rev Biochem. 1980;49:395. https://pubmed.ncbi.nlm.nih.gov/6157353/ — calibration (malonyl-CoA inhibition of CPT-1, the mechanism of the hypoketotic phenotype)
  3. Foster DW. Malonyl-CoA: the regulator of fatty acid synthesis and oxidation. J Clin Invest. 2012;122(6):1958. https://pubmed.ncbi.nlm.nih.gov/22833869/
  4. Morris AAM. Cerebral ketone body metabolism. J Inherit Metab Dis. 2005;28(2):109. https://pubmed.ncbi.nlm.nih.gov/15877199/
  5. Bonnefont JP, Specola NB, Vassault A, et al. The fasting test in paediatrics: application to the diagnosis of pathological hypo- and hyperketotic states. Eur J Pediatr. 1990;150(2):80. https://pubmed.ncbi.nlm.nih.gov/2279513/

7. 고요산혈증 — 생성 증가와 배설 저하의 곱 (Hyperuricaemia as a quotient)

  1. Roe TF, Kogut MD. The pathogenesis of hyperuricemia in glycogen storage disease, type I. Pediatr Res. 1977;11(5):664. https://pubmed.ncbi.nlm.nih.gov/854047/ — calibration
  2. Cohen JL, Vinik A, Faller J, Fox IH. Hyperuricemia in glycogen storage disease type I. Contributions by hypoglycemia and hyperglucagonemia to increased urate production. J Clin Invest. 1985;75(1):251. https://pubmed.ncbi.nlm.nih.gov/2981249/ — calibration
  3. Enomoto A, Kimura H, Chairoungdua A, et al. Molecular identification of a renal urate-anion exchanger that regulates blood urate levels. Nature. 2002;417(6887):447. https://pubmed.ncbi.nlm.nih.gov/12024214/ — calibration (URAT1 lactate/urate exchange)
  4. Lipkowitz MS. Regulation of uric acid excretion by the kidney. Curr Rheumatol Rep. 2012;14(2):179. https://pubmed.ncbi.nlm.nih.gov/22359228/
  5. Day RO, Graham GG, Hicks M, McLachlan AJ, Stocker SL, Williams KM. Clinical pharmacokinetics and pharmacodynamics of allopurinol and oxypurinol. Clin Pharmacokinet. 2007;46(8):623. https://pubmed.ncbi.nlm.nih.gov/17655371/ — calibration (oxypurinol t½ 18–30 h, XO inhibition)
  6. Wilson DM. Lactic acidosis and renal handling of urate. Semin Nephrol. 1990;10(4):340. https://pubmed.ncbi.nlm.nih.gov/2382964/

8. 이상지질혈증 (Dyslipidaemia)

  1. Forget PP, Fernandes J, Haverkamp Begemann P. Triglyceride clearing capacity and fat cell glycerokinase activity in glycogenosis type I. Pediatr Res. 1974;8(2):114. https://pubmed.ncbi.nlm.nih.gov/4360846/ — calibration (LPL-mediated clearance ~50 % of normal)
  2. Levy E, Thibault LA, Roy CC, Bendayan M, Lepage G, Letarte J. Circulating lipids and lipoproteins in glycogen storage disease type I with nocturnal intragastric feeding. J Lipid Res. 1988;29(2):215. https://pubmed.ncbi.nlm.nih.gov/3367088/ — calibration
  3. Ubels FL, Rake JP, Slaets JPJ, Smit GPA, Smit AJ. Is glycogen storage disease 1a associated with atherosclerosis? Eur J Pediatr. 2002;161 Suppl 1:S62. https://pubmed.ncbi.nlm.nih.gov/12373574/
  4. Hershkovitz E, Donald A, Mullen M, Lee PJ, Leonard JV. Blood lipids and endothelial function in glycogen storage disease type Ia. J Inherit Metab Dis. 1999;22(8):891. https://pubmed.ncbi.nlm.nih.gov/10604142/
  5. Bandsma RHJ, Rake JP, Visser G, et al. Increased lipogenesis and resistance of lipoproteins to oxidative modification in two patients with glycogen storage disease type 1a. J Pediatr. 2002;140(2):256. https://pubmed.ncbi.nlm.nih.gov/11865283/
  6. Wang DQ, Fiske LM, Carreras CT, Weinstein DA. Natural history of hepatocellular adenoma formation in glycogen storage disease type I. J Pediatr. 2011;159(3):442. https://pubmed.ncbi.nlm.nih.gov/21481415/

9. 식이요법 — 옥수수전분의 약동학 (Dietary therapy as pharmacokinetics)

모델의 첫 번째 핵심 주장: 옥수수전분의 커버 시간은 총량이 아니라 방출 속도로 결정되므로, 용량을 두 배로 늘려도 얻는 시간은 ln2/kdis로 고정됩니다.

  1. Chen YT, Cornblath M, Sidbury JB. Cornstarch therapy in type I glycogen storage disease. N Engl J Med. 1984;310(3):171. https://pubmed.ncbi.nlm.nih.gov/6581385/ — calibration (1.75 g/kg q6h)
  2. Wolfsdorf JI, Crigler JF Jr. Cornstarch regimens for nocturnal treatment of young adults with type I glycogen storage disease. Am J Clin Nutr. 1997;65(5):1507. https://pubmed.ncbi.nlm.nih.gov/9129485/ — calibration
  3. Wolfsdorf JI, Keller RJ, Landy H, Crigler JF Jr. Glucose therapy for glycogenosis type 1 in infants: comparison of intermittent uncooked cornstarch and continuous overnight glucose feedings. J Pediatr. 1990;117(3):384. https://pubmed.ncbi.nlm.nih.gov/2118986/ — calibration
  4. Correia CE, Bhattacharya K, Lee PJ, et al. Use of modified cornstarch therapy to extend fasting in glycogen storage disease types Ia and Ib. Am J Clin Nutr. 2008;88(5):1272. https://pubmed.ncbi.nlm.nih.gov/18996862/ — calibration (extended-release waxy maize, slower release constant)
  5. Bhattacharya K, Orton RC, Qi X, et al. A novel starch for the treatment of glycogen storage diseases. J Inherit Metab Dis. 2007;30(3):350. https://pubmed.ncbi.nlm.nih.gov/17458709/
  6. Ross KM, Brown LM, Corrado MM, et al. Safety and efficacy of chronic extended release cornstarch therapy for glycogen storage disease type I. JIMD Rep. 2016;26:85. https://pubmed.ncbi.nlm.nih.gov/26303612/
  7. Weinstein DA, Wolfsdorf JI. Effect of continuous glucose therapy with uncooked cornstarch on the long-term clinical course of type 1a glycogen storage disease. Eur J Pediatr. 2002;161 Suppl 1:S35. https://pubmed.ncbi.nlm.nih.gov/12373570/
  8. Shah KK, O'Dell SD. Effect of dietary interventions in the maintenance of normoglycaemia in glycogen storage disease type 1a: a systematic review and meta-analysis. J Hum Nutr Diet. 2013;26(4):329. https://pubmed.ncbi.nlm.nih.gov/23662759/
  9. Kaiser N, Gautschi M, Bosanska L, et al. Glycemic control and complications in glycogen storage disease type I: results from the Swiss registry. Mol Genet Metab. 2019;126(4):355. https://pubmed.ncbi.nlm.nih.gov/30846352/
  10. Herbert M, Pendyal S, Rairikar M, Halaby C, Benjamin RW, Kishnani PS. Role of continuous glucose monitoring in the management of glycogen storage disorders. J Inherit Metab Dis. 2018;41(6):917. https://pubmed.ncbi.nlm.nih.gov/30046997/
  11. Rousseau-Nepton I, Okubo M, Grabs R, et al. A founder AGL mutation causing glycogen storage disease type IIIa in Inuit identified through whole-exome sequencing. Mol Genet Metab. 2015;115(2-3):101. https://pubmed.ncbi.nlm.nih.gov/26059767/ (debranching enzyme biology)

10. 간선종과 악성 전환 (Hepatocellular adenoma and HCC)

  1. Franco LM, Krishnamurthy V, Bali D, et al. Hepatocellular carcinoma in glycogen storage disease type Ia: a case series. J Inherit Metab Dis. 2005;28(2):153. https://pubmed.ncbi.nlm.nih.gov/15877204/
  2. Calderaro J, Labrune P, Morcrette G, et al. Molecular characterization of hepatocellular adenomas developed in patients with glycogen storage disease type I. J Hepatol. 2013;58(2):350. https://pubmed.ncbi.nlm.nih.gov/23046672/
  3. Bianchi L. Glycogen storage disease I and hepatocellular tumours. Eur J Pediatr. 1993;152 Suppl 1:S63. https://pubmed.ncbi.nlm.nih.gov/8391447/
  4. Kishnani PS, Chuang TP, Bali D, et al. Chromosomal and genetic alterations in human hepatocellular adenomas associated with type Ia glycogen storage disease. Hum Mol Genet. 2009;18(24):4781. https://pubmed.ncbi.nlm.nih.gov/19776032/
  5. Beegle RD, Brown LM, Weinstein DA. Regression of hepatocellular adenomas with strict dietary therapy in patients with glycogen storage disease type I. JIMD Rep. 2015;18:23. https://pubmed.ncbi.nlm.nih.gov/25256447/

11. 신장 합병증 (Renal disease)

  1. Chen YT, Coleman RA, Scheinman JI, Kolbeck PC, Sidbury JB. Renal disease in type I glycogen storage disease. N Engl J Med. 1988;318(1):7. https://pubmed.ncbi.nlm.nih.gov/3275894/ — calibration
  2. Chen YT, Scheinman JI, Park HK, Coleman RA, Roe CR. Amelioration of proximal renal tubular dysfunction in type I glycogen storage disease with dietary therapy. N Engl J Med. 1990;323(9):590. https://pubmed.ncbi.nlm.nih.gov/2166914/
  3. Martens DHJ, Rake JP, Navis G, Fidler V, van Dael CML, Smit GPA. Renal function in glycogen storage disease type I, natural course, and renopreserv- ative effects of ACE inhibition. Clin J Am Soc Nephrol. 2009;4(11):1741. https://pubmed.ncbi.nlm.nih.gov/19808227/ — calibration (ACEi effect)
  4. Restaino I, Kaplan BS, Stanley C, Baker L. Nephrolithiasis, hypocitraturia, and a distal renal tubular acidification defect in type 1 glycogen storage disease. J Pediatr. 1993;122(3):392. https://pubmed.ncbi.nlm.nih.gov/8441094/
  5. Weinstein DA, Somers MJG, Wolfsdorf JI. Decreased urinary citrate excretion in type 1a glycogen storage disease. J Pediatr. 2001;138(3):378. https://pubmed.ncbi.nlm.nih.gov/11241046/

12. 성장 · 골대사 · 혈액 (Growth, bone, haematology)

  1. Mundy HR, Hindmarsh PC, Matthews DR, Leonard JV, Lee PJ. The regulation of growth in glycogen storage disease type 1. Clin Endocrinol (Oxf). 2003;58(3):332. https://pubmed.ncbi.nlm.nih.gov/12608939/
  2. Minarich LA, Kirpich A, Fiske LM, Weinstein DA. Bone mineral density in glycogen storage disease type Ia and Ib. Genet Med. 2012;14(8):737. https://pubmed.ncbi.nlm.nih.gov/22481133/
  3. Melis D, Pivonello R, Parenti G, et al. The growth hormone-insulin-like growth factor axis in glycogen storage disease type 1. J Clin Endocrinol Metab. 2010;95(11):E1. https://pubmed.ncbi.nlm.nih.gov/20685854/
  4. Marcolongo P, Fulceri R, Gamberucci A, Czegle I, Banhegyi G, Benedetti A. Multiple roles of glucose-6-phosphatases in pathophysiology. Biochim Biophys Acta. 2013;1830(3):2608. https://pubmed.ncbi.nlm.nih.gov/23222166/
  5. Mühlhausen C, Schneppenheim R, Budde U, et al. Decreased plasma concentration of von Willebrand factor antigen (VWF:Ag) in patients with glycogen storage disease type Ia. J Inherit Metab Dis. 2005;28(6):945. https://pubmed.ncbi.nlm.nih.gov/16435188/

13. GSD Ib · 호중구감소증 · 엠파글리플로진

1,5-anhydroglucitol-6-phosphate가 호중구 내에 갇혀 헥소키나아제를 억제한다는 기전, 그리고 그 기전이 SGLT2 억제제를 치료제로 만든 과정.

  1. Wortmann SB, Van Hove JLK, Derks TGJ, et al. Treating neutropenia and neutrophil dysfunction in glycogen storage disease type Ib with an SGLT2 inhibitor. Blood. 2020;136(9):1033. https://pubmed.ncbi.nlm.nih.gov/32294159/ — calibration
  2. Veiga-da-Cunha M, Chevalier N, Stephenne X, et al. Failure to eliminate a phosphorylated glucose analog leads to neutropenia in patients with G6PC3 and SLC37A4 deficiency. Proc Natl Acad Sci USA. 2019;116(4):1241. https://pubmed.ncbi.nlm.nih.gov/30626647/ — calibration (the 1,5-AG6P mechanism itself)
  3. Grünert SC, Elling R, Maag B, et al. Improved inflammatory bowel disease, wound healing and normal oxidative burst under treatment with empagliflozin in glycogen storage disease type Ib. Orphanet J Rare Dis. 2020;15(1):218. https://pubmed.ncbi.nlm.nih.gov/32838807/
  4. Grünert SC, Derks TGJ, Adrian K, et al. Efficacy and safety of empagliflozin in glycogen storage disease type Ib: data from an international questionnaire. Genet Med. 2022;24(8):1781. https://pubmed.ncbi.nlm.nih.gov/35659863/ — calibration (n = 112)
  5. Visser G, Rake JP, Fernandes J, et al. Neutropenia, neutrophil dysfunction, and inflammatory bowel disease in glycogen storage disease type Ib: results of the ESGSD I. J Pediatr. 2000;137(2):187. https://pubmed.ncbi.nlm.nih.gov/10931410/
  6. Dale DC, Bolyard AA, Marrero T, et al. Neutropenia in glycogen storage disease Ib: outcomes for patients treated with granulocyte colony-stimulating factor. Curr Opin Hematol. 2019;26(1):16. https://pubmed.ncbi.nlm.nih.gov/30451721/
  7. Chou JY, Jun HS, Mansfield BC. Type I glycogen storage diseases: disorders of the glucose-6-phosphatase/glucose-6-phosphate transporter complexes. J Inherit Metab Dis. 2015;38(3):511. https://pubmed.ncbi.nlm.nih.gov/25288127/

14. 유전자치료 · mRNA 치료 (Gene and mRNA therapy)

모델의 세 번째 핵심 주장: 소아에서 AAV의 지속성을 결정하는 것은 프로모터 침묵이 아니라 간 성장에 의한 에피솜 희석이며, 항캡시드 항체 때문에 재투여가 불가능하므로 투여 연령은 되돌릴 수 없는 결정입니다.

  1. Weinstein DA, Correia CE, Conlon T, et al. Adeno-associated virus-mediated correction of a canine model of glycogen storage disease type Ia. Hum Gene Ther. 2010;21(7):903. https://pubmed.ncbi.nlm.nih.gov/20163245/
  2. Koeberl DD, Kishnani PS, Bali D, Chen YT. Emerging therapies for glycogen storage disease type I. Trends Endocrinol Metab. 2009;20(5):252. https://pubmed.ncbi.nlm.nih.gov/19541500/
  3. Kishnani PS, Sun B, Koeberl DD. Gene therapy for glycogen storage diseases. Hum Mol Genet. 2019;28(R1):R31. https://pubmed.ncbi.nlm.nih.gov/31227835/
  4. Cunningham SC, Spinoulas A, Carpenter KH, Wilcken B, Kuchel PW, Alexander IE. AAV2/8-mediated correction of OTC deficiency is robust in adult but not neonatal Spf(ash) mice. Mol Ther. 2009;17(8):1340. https://pubmed.ncbi.nlm.nih.gov/19384293/ — calibration (the canonical demonstration that a growing liver dilutes a non-integrating episome)
  5. Wang L, Wang H, Bell P, McMenamin D, Wilson JM. Hepatic gene transfer in neonatal mice by adeno-associated virus serotype 8 vector. Hum Gene Ther. 2012;23(5):533. https://pubmed.ncbi.nlm.nih.gov/22095007/ — calibration
  6. Mingozzi F, High KA. Immune responses to AAV vectors: overcoming barriers to successful gene therapy. Blood. 2013;122(1):23. https://pubmed.ncbi.nlm.nih.gov/23596044/ (why redosing is blocked)
  7. Weinstein DA, Rodriguez-Buritica DF, Ahmad A, et al. A phase 1/2 clinical trial of DTX401, an AAV8 gene therapy for glycogen storage disease type Ia. (NCT03517085) — trial record: https://clinicaltrials.gov/study/NCT03517085
  8. GlucoGene: a phase 3 study of DTX401 in adults with GSDIa (NCT05139316) — trial record: https://clinicaltrials.gov/study/NCT05139316 (primary endpoint = percentage change in daily cornstarch intake at week 48)
  9. Study of mRNA-3745 in participants with GSD1a (NCT05095727) — trial record: https://clinicaltrials.gov/study/NCT05095727
  10. Cao J, An D, Galduroz M, et al. mRNA therapy improves metabolic and behavioral abnormalities in a murine model of citrin deficiency. Mol Ther. 2019;27(7):1242. https://pubmed.ncbi.nlm.nih.gov/31056400/ (LNP-mRNA hepatic enzyme replacement, duration of effect)
  11. Boyer O, Nevo F, Plaisier E, et al. Liver transplantation for glycogen storage disease type I: outcomes. (see also Boers SJB, et al. Liver transplantation in glycogen storage disease type I. Orphanet J Rare Dis. 2014;9:47.) https://pubmed.ncbi.nlm.nih.gov/24716823/

15. QSP 방법론 (QSP methodology)

  1. Baker RE, Peña JM, Jayamohan J, Jérusalem A. Mechanistic models versus machine learning, a fight worth fighting for the biological community? Biol Lett. 2018;14(5):20170660. https://pubmed.ncbi.nlm.nih.gov/29769297/
  2. Elmokadem A, Riggs MM, Baron KT. Quantitative systems pharmacology and physiologically-based pharmacokinetic modeling with mrgsolve: a hands-on tutorial. CPT Pharmacometrics Syst Pharmacol. 2019;8(12):883. https://pubmed.ncbi.nlm.nih.gov/31652028/
  3. Cheng Y, Thalhauser CJ, Smithline S, et al. QSP toolbox: computational implementation of integrated workflow components for deploying multi-scale mechanistic models. AAPS J. 2017;19(4):1002. https://pubmed.ncbi.nlm.nih.gov/28540623/
  4. Ribba B, Grimm HP, Agoram B, et al. Methodologies for quantitative systems pharmacology (QSP) models. CPT Pharmacometrics Syst Pharmacol. 2017;6(8):496. https://pubmed.ncbi.nlm.nih.gov/28571121/
  5. König M, Bulik S, Holzhütter HG. Quantifying the contribution of the liver to glucose homeostasis: a detailed kinetic model of human hepatic glucose metabolism. PLoS Comput Biol. 2012;8(6):e1002577. https://pubmed.ncbi.nlm.nih.gov/22761565/ — calibration (the reference kinetic model of hepatic glucose metabolism this one is built against)
  6. Ashworth WB, Davies NA, Bogle IDL. A computational model of hepatic energy metabolism: understanding zonated damage and steatosis in NAFLD. PLoS Comput Biol. 2016;12(9):e1005105. https://pubmed.ncbi.nlm.nih.gov/27632189/

모델 구성요소 ↔ 문헌 대응표 (Model component to reference map)

모델 구성요소 주요 근거
G6Pase 촉매 소단위 · 돌연변이 스펙트럼 7, 8, 12, 13, 14
G6PT 수송체 (Ib) 10, 11, 83
잔존 EGP (debrancher + lysosomal) 15, 16, 17, 18, 20
연령별 포도당 요구량 19
글리코겐 합성효소의 G6P 알로스테릭 활성화 21, 22, 25
글루코키나아제 (Km 8 mM, Hill 1.7) 23, 99
젖산의 뇌 연료 대체 27, 28, 29, 30, 31, 32
저케톤성 (malonyl-CoA → CPT1) 34, 35, 36, 38
요산: 생성 증가 39, 40
요산: URAT1 젖산 경쟁 41, 42, 44
알로퓨리놀 · 옥시퓨리놀 PK 43
LPL 활성 저하 · VLDL 과다생성 45, 46, 34, 49
옥수수전분 용량 · 간격 51, 52, 53, 57, 58
서방형 전분 (느린 kdis) 54, 55, 56
지속적 야간 주입 53, 59
CGM · 시간대별 관리 60
간선종 · HCC 50, 62, 63, 64, 65, 66
신장: 과여과 → 단백뇨 → CKD 67, 68, 69
신장: 저구연산뇨 · 신석회화 70, 71
성장 · GH/IGF-1 · 골밀도 72, 73, 74
GSD Ib 호중구 기전 78, 77, 81
엠파글리플로진 77, 79, 80
G-CSF 82
AAV 유전자치료 84, 85, 86, 90, 91
간 성장에 의한 에피솜 희석 87, 88
항캡시드 항체 · 재투여 불가 89
mRNA 치료 92, 93
간이식 94
QSP 방법론 · mrgsolve 95–100