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Fructose 1,6-Diphosphatase Deficiency Workup

  • Author: Sunil Sinha, MD; Chief Editor: Maria Descartes, MD  more...
 
Updated: Nov 03, 2015
 

Laboratory Studies

Determine serum levels of lactate, glucose, glycerol, and insulin during hypoglycemia. Considerations are as follows:

  • 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.[7] 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.[8] This test is presently available only by contacting these investigators.

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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.

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Contributor Information and Disclosures
Author

Sunil Sinha, MD Assistant Professor, Division of Pediatric Endocrinology and Metabolism, Department of Pediatrics, University of Tennessee Health Science Center

Sunil Sinha, MD is a member of the following medical societies: American Academy of Pediatrics, American Association of Clinical Endocrinologists, 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.

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.

Chief Editor

Maria Descartes, MD Professor, Department of Human Genetics and Department of Pediatrics, University of Alabama at Birmingham School of Medicine

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, Society for Inherited Metabolic Disorders, International Skeletal Dysplasia Society, 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.

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

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