Background

Glucose homeostasis is essential for life. Because most of an organism's life is spent in a fasting state (ie, between meals), no fewer than 3 major mechanisms have evolved to maintain glucose homeostasis during a fast.^[1]These mechanisms are gluconeogenesis, glycogenolysis, and lipolysis.

In the immediate postprandial period, glycogenolysis represents the major homeostatic process to maintain euglycemia. In neonates, gluconeogenesis is particularly important for maintaining euglycemia. Fructose 1,6-diphosphatase (FDPase) (also termed fructose 1,6-bisphosphatase) is a focal enzyme in gluconeogenesis via its conversion of fructose 1,6-diphosphate (FDP) to fructose 6-phosphate (F-6-P), which permits endogenous glucose production from gluconeogenic amino acids (eg, alanine and glycine), glycerol, or lactate.

Deficiency of hepatic FDPase was first confirmed in 1970 by Baker and Winegrad.^[2]They reported the dramatic clinical picture of acidosis in response to D-fructose challenge.

Of broader clinical interest, excess hepatic FDPase action contributes to hyperglycemia in patients with type 2 diabetes.^[3]The development of specific FDPase inhibitors has opened a novel avenue for treating patients with type 2 diabetes.

Pathophysiology

FDPase catalyzes the conversion of FDP to F-6-P, which is a central step in gluconeogenesis. When challenged with D-fructose, patients lacking FDPase accumulate intrahepatocellular FDP, which inhibits gluconeogenesis and, if intracellular phosphate stores are depleted, inhibits glycogenolysis. The inability to convert lactic acid or glycerol into glucose leads to hypoglycemia, lactic acidosis, and glyceroluria.

Frequency

International

Incidence is approximately 1 in 20,000 live births worldwide.

Mortality/Morbidity

Patients develop severe hypoglycemia with metabolic acidosis upon ingestion of fructose. Fatal hepatic or renal injury following ingestion of fructose has been reported in these patients.

Early diagnosis of this disorder allows clinicians to advise patients regarding the avoidance of prolonged fasting and to initiate administration of intravenous dextrose promptly during illnesses associated with inadequate dextrose absorption (eg, vomiting or severe diarrhea).

Sex

Males and females appear to be affected in equal numbers.

Age

Patients with FDPase deficiency typically present in the newborn period with symptoms or signs related to hypoglycemia and metabolic acidosis following ingestion of fructose.

Clinical Presentation

Uluseker C, Simoni G, Marchetti L, Dauriz M, Matone A, Priami C. A closed-loop multi-level model of glucose homeostasis. PLoS One. 2018. 13 (2):e0190627. [QxMD MEDLINE Link]. [Full Text].
Baker L, Winegrad AI. Fasting hypoglycaemia and metabolic acidosis associated with deficiency of hepatic fructose-1,6-diphosphatase activity. Lancet. 1970 Jul 4. 2(7662):13-6. [QxMD MEDLINE Link].
Kaur R, Dahiya L, Kumar M. Fructose-1,6-bisphosphatase inhibitors: A new valid approach for management of type 2 diabetes mellitus. Eur J Med Chem. 2017 Dec 1. 141:473-505. [QxMD MEDLINE Link].
Paksu MS, Kalkan G, Asilioglu N, Paksu S, Dinler G. Gluconeogenesis defect presenting with resistant hyperglycemia and acidosis mimicking diabetic ketoacidosis. Pediatr Emerg Care. 2011 Dec. 27(12):1180-1. [QxMD MEDLINE Link].
Paksu MŞ, Kalkan G, Asilioglu N, Paksu S, Dinler G. Gluconeogenesis defect presenting with resistant hyperglycemia and acidosis mimicking diabetic ketoacidosis. Pediatr Emerg Care. 2011 Dec. 27 (12):1180-1. [QxMD MEDLINE Link].
el-Maghrabi MR, Lange AJ, Jiang W, et al. Human fructose-1,6-bisphosphatase gene (FBP1): exon-intron organization, localization to chromosome bands 9q22.2-q22.3, and mutation screening in subjects with fructose-1,6-bisphosphatase deficiency. Genomics. 1995 Jun 10. 27(3):520-5. [QxMD MEDLINE Link].
Herzog B, Morris AA, Saunders C, Eschrich K. Mutation spectrum in patients with fructose-1,6-bisphosphatase deficiency. J Inherit Metab Dis. 2001. 24:87-88. [QxMD MEDLINE Link].
Kikawa Y, Inuzuka M, Jin BY, et al. Identification of genetic mutations in Japanese patients with fructose-1,6-bisphosphatase deficiency. Am J Hum Genet. 1997. 61:852-861. [QxMD MEDLINE Link].
Santamaria R, Esposito G, Vitagliano L, et al. Functional and molecular modelling studies of two hereditary fructose intolerance-causing mutations at arginine 303 in human liver aldolase. Biochem J. 2000 Sep 15. 350 Pt 3:823-8. [QxMD MEDLINE Link]. [Full Text].
Iga M, Kimura M, Ohura T, et al. Rapid, simplified and sensitive method for screening fructose-1,6- diphosphatase deficiency by analyzing urinary metabolites in urease/direct preparations and gas chromatography-mass spectrometry in the selected-ion monitoring mode. J Chromatogr B Biomed Sci Appl. 2000 Sep 1. 746(1):75-82. [QxMD MEDLINE Link].
Kikawa Y, Shin YS, Inuzuka M, et al. Diagnosis of fructose-1,6-bisphosphatase deficiency using cultured lymphocyte fraction: a secure and noninvasive alternative to liver biopsy. J Inherit Metab Dis. 2002. 25:41-46. [QxMD MEDLINE Link].
Krishnamurthy V, Eschrich K, Boney A, Sullivan J, McDonald M, Kishnani PS, et al. Three successful pregnancies through dietary management of fructose-1,6-bisphosphatase deficiency. J Inherit Metab Dis. 2007 Oct. 30(5):819. [QxMD MEDLINE Link].
Asberg C, Hjalmarson O, Alm J, Martinsson T, Waldenström J, Hellerud C. Fructose 1,6-bisphosphatase deficiency: enzyme and mutation analysis performed on calcitriol-stimulated monocytes with a note on long-term prognosis. J Inherit Metab Dis. 2010 Feb 12. [QxMD MEDLINE Link].
Beatty ME, Zhang YH, McCabe ER, Steiner RD. Fructose-1,6-diphosphatase deficiency and glyceroluria: one possible etiology for GIS. Mol Genet Metab. 2000. 69:338-340. [QxMD MEDLINE Link].
Besley GT, Walter JH, Lewis MA, et al. Fructose-1,6-bisphosphatase deficiency: severe phenotype with normal leukocyte enzyme activity. J Inherit Metab Dis. 1994. 17:333-335. [QxMD MEDLINE Link].
Boesiger P, Buchli R, Meier D, et al. Changes of liver metabolite concentrations in adults with disorders of fructose metabolism after intravenous fructose by 31P magnetic resonance spectroscopy. Pediatr Res. 1994 Oct. 36(4):436-40. [QxMD MEDLINE Link].
Buhrdel P, Bohme HJ, Didt L. Biochemical and clinical observations in four patients with fructose-1,6-diphosphatase deficiency. Eur J Pediatr. 1990. 149:574-576. [QxMD MEDLINE Link].
Chambers RA, Pratt RT. Idiosyncrasy to fructose. Lancet. 1956 Aug 18. 271(6938):340. [QxMD MEDLINE Link].
De Pra M, Laudanna E. [Baker-Winegrad disease (hepatomegaly, hypoglycemia during fasting, hyperlactacidemic metabolic acidosis, hepatic fructose-1-6-diphosphatase deficiency). Presentation of the 1st Italian case and pathogenetic hypothesis]. Minerva Pediatr. 1978 Dec 31. 30(24):1973-86. [QxMD MEDLINE Link].
Elpeleg ON, Barash V, Hurvitz H, Branski D. Fructose-1,6-diphosphatase deficiency: a 20-year follow-up. Erratum in: Am J Dis Child 1989 Nov;143(11):1345. Am J Dis Child. 1989. 143:140-142. [QxMD MEDLINE Link].
Erion MD, van Poelje PD, Dang Q, et al. MB06322 (CS-917): A potent and selective inhibitor of fructose 1,6-bisphosphatase for controlling gluconeogenesis in type 2 diabetes. Proc Natl Acad Sci USA. 2005. 102:7970-7975. [QxMD MEDLINE Link]. [Full Text].
Fu X, Iga M, Kimura M, Yamaguchi S. Simplified screening for organic acidemia using GC/MS and dried urine filter paper: a study on neonatal mass screening. Early Hum Dev. 2000 Apr. 58(1):41-55. [QxMD MEDLINE Link].
Hasegawa Y, Kikawa Y, Miyamaoto J, et al. Intravenous glycerol therapy should not be used in patients with unrecognized fructose-1,6-bisphosphatase deficiency. Pediatr Int. 2003. 45:5-9. [QxMD MEDLINE Link].
Hashimoto Y, Watanabe H, Satou M. Anesthetic management of a patient with hereditary fructose-1, 6-diphosphatase deficiency. Anesth Analg. 1978. 57:503-506. [QxMD MEDLINE Link].
Heng S, Harris KM, Kantrowitz ER. Designing inhibitors against fructose 1,6-bisphosphatase: exploring natural products for novel inhibitor scaffolds. Eur J Med Chem. 2010 Apr. 45(4):1478-84. [QxMD MEDLINE Link].
Kinugasa A, Kusunoki T, Iwashima A. Deficiency of glucose-6-phosphate dehydrogenase found in a case of hepatic fructose-1,6-diphosphatase deficiency. Pediatr Res. 1979. 13:1361-1364. [QxMD MEDLINE Link].
Krywawych S, Katz G, Lawson AM, et al. Glycerol-3-phosphate excretion in fructose-1,6-diphosphatase deficiencY. J Inherit Metab Dis. 1986. 9:388-392. [QxMD MEDLINE Link].
Lund AM, Leonard JV. False positive fructose loading: a pitfall in the diagnosis of fructose-1,6-bisphosphatase deficiency. J Inherit Metab Dis. 2000. 23:634-635. [QxMD MEDLINE Link].
Morris AA, Deshphande S, Ward-Platt MP, et al. Impaired ketogenesis in fructose-1,6-bisphosphatase deficiency: a pitfall in the investigation of hypoglycaemia. J Inherit Metab Dis. 1995. 18:28-32. [QxMD MEDLINE Link].
Nagai T, Yokoyama T, Hasegawa T, et al. Fructose and glucagon loading in siblings with fructose-1,6-diphosphatase deficiency in fed state. J Inherit Metab Dis. 1992. 15:720-722. [QxMD MEDLINE Link].
Nakai A, Shigematsu Y, Liu YY, et al. Urinary sugar phosphates and related organic acids in fructose-1,6-diphosphatase deficiency. J Inherit Metab Dis. 1993. 16:408-414. [QxMD MEDLINE Link].
Nitzan O, Saliba WR, Goldstein LH, Elias MS. Fructose-1,6-diphosphatase deficiency: a rare cause of prolonged prothrombin time. Ann Hematol. 2004. 83:302-303. [QxMD MEDLINE Link].
van den Berghe G. Disorders of gluconeogenesis. J Inherit Metab Dis. 1996. 19:470-477. [QxMD MEDLINE Link].
van Poelje PD, Potter SC, Chandramouli VC, et al. Inhibition of fructose 1,6-bisphosphatase reduces excessive endogenous glucose production and attenuates hyperglycemia in zucker diabetic Fatty rats. Diabetes. 2006. 55:1747-1754. [QxMD MEDLINE Link].
Kamate M, Jambagi M, Gowda P, Sonoli S. Fructose-1,6-diphosphatase deficiency: a treatable neurometabolic disorder. BMJ Case Rep. 2014 Sep 22. 2014:[QxMD MEDLINE Link].

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Author

Sunil Kumar Sinha, MD Clinical Assistant Professor, Division of Pediatric Endocrinology, University of Arizona College of Medicine

Sunil Kumar Sinha, MD is a member of the following medical societies: American Academy of Pediatrics, American Association of Clinical Endocrinology, Endocrine Society, Pediatric Endocrine Society

Disclosure: Nothing to disclose.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Chief Editor

Maria Descartes, MD Medical Geneticist, Miami Cancer Institute, Baptist Health South Florida

Maria Descartes, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics and Genomics, American Medical Association, American Society of Human Genetics, International Skeletal Dysplasia Society, Society for Inherited Metabolic Disorders, Southeastern Regional Genetics Group

Disclosure: Nothing to disclose.

Additional Contributors

Michael Fasullo, PhD Senior Scientist, Ordway Research Institute; Associate Professor, State University of New York at Albany; Adjunct Associate Professor, Center for Immunology and Microbial Disease, Albany Medical College

Michael Fasullo, PhD is a member of the following medical societies: Radiation Research Society, American Society for Biochemistry and Molecular Biology, Genetics Society of America, Environmental Mutagenesis and Genomics Society

Disclosure: Nothing to disclose.

David Flannery, MD, FAAP, FACMG Vice Chair of Education, Chief, Section of Medical Genetics, Professor, Department of Pediatrics, Medical College of Georgia

David Flannery, MD, FAAP, FACMG is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics and Genomics

Disclosure: Nothing to disclose.

Acknowledgements

Robert J Ferry Jr, MD Le Bonheur Chair of Excellence in Endocrinology, Professor and Chief, Division of Pediatric Endocrinology and Metabolism, Department of Pediatrics, University of Tennessee Health Science Center

Robert J Ferry Jr, MD is a member of the following medical societies: American Academy of Pediatrics, American Diabetes Association, American Medical Association, Endocrine Society, Pediatric Endocrine Society, Society for Pediatric Research, and Texas Pediatric Society

Disclosure: Eli Lilly & Co Grant/research funds Investigator; MacroGenics, Inc Grant/research funds Investigator; Ipsen, SA (formerly Tercica, Inc) Grant/research funds Investigator; NovoNordisk SA Grant/research funds Investigator; Diamyd Grant/research funds Investigator; Bristol-Myers-Squibb Grant/research funds Other; Amylin Other; Pfizer Grant/research funds Other; Takeda Grant/research funds Other