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

Fructose 1,6-Diphosphatase Deficiency: Differential Diagnoses & Workup

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

Differential Diagnoses

Acidosis, Metabolic
Fructose 1-Phosphate Aldolase Deficiency (Fructose Intolerance)
Growth Failure
Hypoglycemia
Lactose Intolerance
Sudden Infant Death Syndrome

Other Problems to Be Considered

Hepatic aldolase B deficiency
Reye syndrome

Workup

Laboratory Studies

  • Determine serum levels of lactate, glucose, glycerol, and insulin during hypoglycemia.
    • Hypoglycemia is defined by the author as a blood glucose concentration below 60 mg/dL as determined in a hospital laboratory.
    • Portable glucometers are notoriously inaccurate and imprecise in the hypoglycemic range. However, their convenience and wide distribution often place them as the first diagnostic tool in the evaluation of patients with hypoglycemia.
    • To improve the chance of obtaining a diagnostic sample during the metabolic crisis, the practitioner should obtain 10 mL of whole blood in a red top tube during the crisis (seizure, loss of consciousness) or when hypoglycemia is suspected.
    • The laboratory should process the blood immediately to separate the serum by centrifugation and to store it at -70°C for subsequent analysis of metabolic intermediates.
    • The next voided urine specimen (obtained as close to the crisis as possible) is equally valuable.
  • The most specific, minimally invasive, diagnostic test for fructose 1,6-diphosphatase (FDPase) deficiency is D-fructose challenge; however, this provocative test is dangerous and should be avoided during an acute crisis. In patients with FDPase deficiency, blood glucose levels fall below 60 mg/dL in response to D-fructose challenge, and the serum lactate levels rise (typically >2 standard deviations above the mean).
  • Direct enzymatic assay of hepatic FDPase activity from hepatic specimens remains the most specific diagnostic test for this disorder. The assay is performed by a handful of reference laboratories (eg, Chen at Duke University).
  • A prolonged fast can induce lactic acidosis with hypoglycemia in patients with FDPase deficiency as a result of impaired gluconeogenesis.
  • Elevated urinary excretion of glycerol-3-phosphate appears to be specific to the disorder. The presence of glyceroluria at or shortly after the time of the metabolic crisis is a useful adjunct to confirm intact lipolytic pathways. However, hyperglyceroluria is not specific because it also can occur in patients with glycerol kinase deficiency.
  • A controlled fasting study or D-fructose challenge under the supervision of a pediatric endocrinologist in the hospital setting permits recapitulation of the presentation to confirm the diagnosis. Less dangerous diagnostic techniques are available at few medical centers. However, simple peripheral blood specimens can be mailed to these centers for diagnosis while supportive care is provided to the patient.
  • Glycerol challenge results in glyceroluria in patients with FDPase deficiency, although this result also occurs with disorders of glycerol metabolism (eg, glycerol kinase deficiency).
  • In Japan, Iga et al reported a breakthrough for the screening of FDPase deficiency based on routine urine specimens.6 Their work suggests that this method can rapidly determine FDPase deficiency in these patients either during a metabolic crisis or during the stable clinical condition. The technique combines modifications of the Matsumoto and Kuhara method of urinalysis with gas chromatography and mass spectrometry in the selected-ion monitoring mode. This landmark paper delineates the possibility of identifying many asymptomatic patients who may be undiagnosed, as well as patients misclassified with sudden infant death syndrome or Reye syndrome.
  • Kikawa et al reported a minimally invasive diagnostic test using cultured lymphocytes.7 This test is presently available only by contacting these investigators.

Procedures

  • Assessment of hepatic FDPase isoenzyme activity is the definitive diagnostic procedure.
  • Needle biopsy of the liver may be performed under local anesthesia. Most investigators prefer an open biopsy specimen to guarantee a sample of hepatic tissue sufficient to complete multiple enzymatic analyses.

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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