eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Metabolic Diseases

Fructose 1,6-Diphosphatase Deficiency

Author: Robert J Ferry Jr, MD, Chief, Division of Pediatric Endocrinology and Diabetes, Le Bonheur Children's Medical Center, University of Tennessee Health Science Center at Memphis and St Jude Children's Research Hospital; Lieutenant Colonel (Medical Corps), 162nd Area Support Medical Company, Army National Guard
Contributor Information and Disclosures

Updated: Jul 1, 2008

Introduction

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. 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.1 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. 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

History

Focus on symptoms of hypoglycemia induced by foods that contain fructose and by infant formulas. Symptoms of hypoglycemia include hunger, irritability, light-headedness, fatigue, and lethargy. Signs of hypoglycemia include seizures, loss of consciousness, trembling, and sympathetic signs such as tachycardia, hypertension, or miosis.

Physical

Patients may only exhibit hepatomegaly during the metabolic crisis, which promptly resolves with administration of dextrose (ie, cessation of fasting).

Causes

The gene encoding FDPase was reported in 1995,2 and several mutations resulting in loss of function have subsequently been reported in American and Japanese patients.3,4,5

More on Fructose 1,6-Diphosphatase Deficiency

Overview: Fructose 1,6-Diphosphatase Deficiency
Differential Diagnoses & Workup: Fructose 1,6-Diphosphatase Deficiency
Treatment & Medication: Fructose 1,6-Diphosphatase Deficiency
Follow-up: Fructose 1,6-Diphosphatase Deficiency
References
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References

  1. Baker L, Winegrad AI. Fasting hypoglycaemia and metabolic acidosis associated with deficiency of hepatic fructose-1,6-diphosphatase activity. Lancet. Jul 4 1970;2(7662):13-6. [Medline].

  2. 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. Jun 10 1995;27(3):520-5. [Medline].

  3. 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. [Medline].

  4. 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. [Medline].

  5. 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. Sep 15 2000;350 Pt 3:823-8. [Medline]. [Full Text].

  6. 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. Sep 1 2000;746(1):75-82. [Medline].

  7. 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. [Medline].

  8. 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. Oct 2007;30(5):819. [Medline].

  9. 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. [Medline].

  10. 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. [Medline].

  11. 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. Oct 1994;36(4):436-40. [Medline].

  12. 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. [Medline].

  13. Chambers RA, Pratt RT. Idiosyncrasy to fructose. Lancet. Aug 18 1956;271(6938):340. [Medline].

  14. 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. Dec 31 1978;30(24):1973-86. [Medline].

  15. 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. [Medline].

  16. 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. [Medline]. [Full Text].

  17. 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. Apr 2000;58(1):41-55. [Medline].

  18. 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. [Medline].

  19. Hashimoto Y, Watanabe H, Satou M. Anesthetic management of a patient with hereditary fructose-1, 6-diphosphatase deficiency. Anesth Analg. 1978;57:503-506. [Medline].

  20. 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. [Medline].

  21. 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. [Medline].

  22. 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. [Medline].

  23. 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. [Medline].

  24. 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. [Medline].

  25. 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. [Medline].

  26. 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. [Medline].

  27. van den Berghe G. Disorders of gluconeogenesis. J Inherit Metab Dis. 1996;19:470-477. [Medline].

  28. 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. [Medline].

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Further Reading

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Keywords

fructose 1,6-diphosphatase deficiency, FDPase, fructose 1,6-bisphosphatase deficiency, Baker's disease, Baker disease, Baker-Winegrad disease, gluconeogenesis, glycogenolysis, lipolysis, glucose homeostasis, FDPase, hypoglycemia, acidosis, hyperglycemia, type 2 diabetes, lactic acidosis, glyceroluria, metabolic acidosis

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Contributor Information and Disclosures

Author

Robert J Ferry Jr, MD, Chief, Division of Pediatric Endocrinology and Diabetes, Le Bonheur Children's Medical Center, University of Tennessee Health Science Center at Memphis and St Jude Children's Research Hospital; Lieutenant Colonel (Medical Corps), 162nd Area Support Medical Company, Army National Guard
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, Lawson-Wilkins Pediatric Endocrine Society, Society for Pediatric Research, and Texas Pediatric Society
Disclosure: Nutropin Speakers Bureau Honoraria Speaking and teaching

Medical Editor

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
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc
Disclosure: Pfizer Inc Stock Investment from broker recommendation; Avanir Pharma Stock Investment from broker recommendation

Managing Editor

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 and American College of Medical Genetics
Disclosure: Nothing to disclose.

CME Editor

Paul D Petry, DO, FACOP, FAAP, Consulting Staff, Freeman Pediatric Care, Freeman Health System
Paul D Petry, DO, FACOP, FAAP is a member of the following medical societies: American Academy of Osteopathy, American Academy of Pediatrics, American College of Osteopathic Pediatricians, and American Osteopathic Association
Disclosure: Nothing to disclose.

Chief Editor

Bruce Buehler, MD, Professor, Department of Pediatrics, Pathology and Microbiology, Executive Director, Hattie B Munroe Center for Human Genetics and Rehabilitation, University of Nebraska Medical Center
Bruce Buehler, MD is a member of the following medical societies: American Academy for Cerebral Palsy and Developmental Medicine, American Academy of Pediatrics, American Association on Mental Retardation, American College of Medical Genetics, American College of Physician Executives, American Medical Association, and Nebraska Medical Association
Disclosure: Nothing to disclose.

 
 
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