Fructose 1,6-Diphosphatase Deficiency Workup

Updated: Apr 17, 2018
  • Author: Sunil Kumar Sinha, MD; Chief Editor: Maria Descartes, MD  more...
  • Print
Workup

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. [10] 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. [11] This test is presently available only by contacting these investigators.

Next:

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.

Previous