Fructose-1,6-diphosphatase is an enzyme involved in the process of gluconeogenesis - the conversion of non-carbohydrate (lactic acid, certain amino acids, and glycerol) molecules into glucose. Thus, the deficiency of this enzyme results in hypoglycemia [1] [2] [3]. The stores of glycogen in these patients are limited, thus contributing to hypoglycemia [1]. Fructose-1,6-diphosphatase deficiency is present from birth (given the autosomal recessive mode of inheritance) and the clinical presentation may be evident in very early life, but symptoms become most prominent in periods of excessive fasting, heavy exercise, and infections that diminish appetite [1] [2] [4] [5]. Ingestion of fruits that are high in fructose is also a mechanism that may induce hypoglycemia, whereas pregnancy is a state during which a high demand for glucose due to embryogenesis and fetal development can unmask the condition [2] [4] [5] [6]. Signs and symptoms of fructose-1,6-disphosphatase deficiency stem from hypoglycemia, severe lactic acidosis and ketosis, with lethargy, irritability, hypotonia, and altered consciousness, ranging from milder somnolence to coma being the most prominent symptoms [1] [2]. Hyperventilation is often reported [2]. Regardless of the onset of symptoms, lactic acidosis and ketosis may be life-threatening [1] [2]. For this reason, an early diagnosis can be life-saving.

• Hematochezia

  Haug Browse recently published Learning/CME Learning/CME View all learning/CME CME Partial Oral versus Intravenous Antibiotic Treatment of Endocarditis Case 4-2019: An 18-Year-Old Man with Abdominal Pain and Hematochezia Bridging the Gap Challenge Yourself [nejm.org]

• Tachycardia

  Neonatal hyperbilirubinemia 0003265 Neonatal hypoglycemia Low blood sugar in newborn 0001998 Pallor 0000980 Respiratory distress Breathing difficulties Difficulty breathing [ more ] 0002098 Reye syndrome-like episodes 0006582 Seizures Seizure 0001250 Tachycardia [rarediseases.info.nih.gov]

  These signs and symptoms include hunger, irritability, light-headedness, fatigue, lethargy, seizures, loss of consciousness, trembling, and even tachycardia, and hypertension. [cags.org.ae]

• Skeletal Dysplasia

  Dysplasia Society, Southeastern Regional Genetics Group Disclosure: Nothing to disclose. [emedicine.com]

• Irritability

  Signs and symptoms of fructose-1,6-disphosphatase deficiency stem from hypoglycemia, severe lactic acidosis and ketosis, with lethargy, irritability, hypotonia, and altered consciousness, ranging from milder somnolence to coma being the most prominent [symptoma.com]

  Irritable 0000737 Ketosis High levels of ketone bodies 0001946 Muscular hypotonia Low or weak muscle tone 0001252 Neonatal hyperbilirubinemia 0003265 Neonatal hypoglycemia Low blood sugar in newborn 0001998 Pallor 0000980 Respiratory distress Breathing [rarediseases.info.nih.gov]

  These signs and symptoms include hunger, irritability, light-headedness, fatigue, lethargy, seizures, loss of consciousness, trembling, and even tachycardia, and hypertension. [cags.org.ae]

Because of the rare occurrence of fructose-1,6-diphosphatase deficiency in clinical practice (approximately 1-9 per 100,000 newborns), the diagnosis may be difficult to attain, particularly because of the variable onset of symptoms [1] [4]. Therefore, the physician must obtain a detailed patient history and perform a meticulous physical examination in patients with suspected hypoglycemia that is induced under circumstances of fasting and high demand for glucose. Additional findings that may be encountered in the biochemical workup are excessive levels of lactate, uric acid, and increased levels of ketones and glycerol in urine [2]. Several non-invasive tests have been described as highly useful tools to make a more solid diagnosis. In addition to the detection of ketonuria and glycerol in urine, a positive Seliwanoff's test, which evaluates the presence of fructose in urine, strongly points to fructose-1,6-diphosphatase deficiency, as fructose is not converted to glucose and thus is excreted in urine [2]. This test is usually performed after the patient is given a loading dose of fructose [2]. Gas chromatography-mass spectrometry (GC/MS) can be further performed as a more specific method, but a definitive diagnosis is made by a combination of enzyme assays and genetic studies that confirm reduced activity fructose-1,6-diphosphatase [1] [2] [3] [6].

• Ketonuria

  They presented with ketonuria, elevated plasma transaminase activity and severe metabolic acidosis during hypoglycaemic crises, which resembled Reye syndrome. Intravenous fructose tolerance tests provoked severe hypoglycaemia and metabolic acidosis. [ncbi.nlm.nih.gov]

  Steiner, Robert D. 2000-04-01 00:00:00 Fructose-1,6-diphosphatase (FDPase) deficiency is characterized by episodes of lactic acidemia, hypoglycemia, and ketonuria. Liver biopsy and subsequent enzyme analysis most reliably make the diagnosis. [deepdyve.com]

  In addition to the detection of ketonuria and glycerol in urine, a positive Seliwanoff's test, which evaluates the presence of fructose in urine, strongly points to fructose-1,6-diphosphatase deficiency, as fructose is not converted to glucose and thus [symptoma.com]

  99% 4. medium chain β-ketothiolase deficiency，中鎖β‐ケトチオラーゼ欠損症 70 99% 5. short chain acyl-CoA dehydrogenase deficiency，短鎖アシル‐CoA脱水素酵素欠損症 70 99% 6. medium- / short- chain 3-hydroxyacyl-CoA dehydrogenase deficiency，中鎖／短鎖3‐ヒドロキシアシル‐CoA脱水素酵素欠損症 70 99% 7. ketonuria [jc-metabolomics.com]

• Fasting Hypoglycemia

  Deficiency of fructose-1,6-bisphosphatase is associated with fasting hypoglycemia and metabolic acidosis because of impaired gluconeogenesis. We have cloned and characterized the human liver fructose-1,6-bisphosphatase gene (FBP1). [experts.umn.edu]

  • A girl aged 3 years and 11 months, with recurrent episodes of unexplained metabolic acidosis, hepatomegaly, and fasting hypoglycemia unresponsive to glucagon, showed profound falls in blood glucose levels in response to oral fructose and glycerol challenge [jamanetwork.com]

  Baker L, and Winegrad Al (1970): Fasting hypoglycemia and metabolic acidosis associated with deficiency of hepaticfructose-1, 6-bisphosphatase activity. Lancet II. 13-16 4. [jmscr.igmpublication.org]

1. Sugita G, Tsuyoshi H, Nishijima K, Yoshida Y. Fructose-1,6-Bisphosphatase Deficiency: A Case of a Successful Pregnancy by Closely Monitoring Metabolic Control. JIMD Rep. 2014;14:115-118.
2. Kamate M, Jambagi M, Gowda P, Sonoli S. Fructose-1,6-diphosphatase deficiency: a treatable neurometabolic disorder. BMJ Case Rep. 2014;2014:bcr2013201553.
3. Kato S, Nakajima Y, Awaya R, et al. Pitfall in the Diagnosis of Fructose-1,6-Bisphosphatase Deficiency: Difficulty in Detecting Glycerol-3-Phosphate with Solvent Extraction in Urinary GC/MS Analysis. Tohoku J Exp Med. 2015;237(3):235-239.
4. Douillard C, Mention K, Dobbelaere D, Wemeau J-L, Saudubray J-M, Vantyghem M-C. Hypoglycaemia related to inherited metabolic diseases in adults. Orphanet J Rare Dis. 2012;7:26.
5. Krishnamurthy V, Eschrich K, Boney A, et al. Three successful pregnancies through dietary management of fructose-1,6-bisphosphatase deficiency. J Inherit Metab Dis. 2007;30:819.
6. Kamate M, Patil V, Chetal V, Darak P, Hattiholi V. Glutaric aciduria type I: A treatable neurometabolic disorder. Ann Indian Acad Neurol. 2012;15(1):31-34.