Fructose 1,6-bisphosphatase deficiency: clinical, biochemical and genetic features in French patients.

Fructose-1,6-bisphosphatase (FBPase) deficiency is a very rare autosomal recessive disorder caused by a mutation of the fructose-1,6-bisphosphatase gene(FBP1). Disease is mainly revealed by hypoglycemia and lactic acidosis, both symptoms being characteristic for an enzymatic block in the last steps of the gluconeogenesis. Twelve patients with FBPase deficiency were diagnosed in France in the 2001-2013 period, using a diagnostic system based on a single blood sample which allows simultaneous enzyme activity measurement on mononuclear white blood cells and molecular analysis. Sequencing of exons and intron-exon junctions of FBP1 gene was completed in unsolved cases by a gene dosage assay developed for each exon. For most patients, first metabolic decompensation occurred before two years of age with a similar sequence: the triggering factors were fever, fasting, or decrease of food intake. However, diagnosis was made late at a mean age of 3 years, as mitochondrial defects or glycogen storage diseases were firstly suspected. Enzyme activity in leukocytes was dramatically decreased (<10%). Twelve different mutations were identified in 22 alleles among them seven were novels: one missense mutation c.472C > T, one point deletion c.48del, one point duplication c.865dupA, one deletion-insertion, and two splice mutations (c.427-1del and c.825 + 1G > A). We described the first intragenic deletion in FBP1 (g.97,364,754_97,382,011del) in homozygous state. Our report also confirms that this very rare disease is misdiagnosed, as other energetic defects are firstly suspected.

Transient pseudo-hypertriglyceridemia: a useful biochemical marker of fructose-1,6-bisphosphatase deficiency.

UNLABELLED: Fructose-1,6-bisphosphatase (FBP) deficiency is an autosomal-recessive disorder of gluconeogenesis resulting from mutations within the FBP1 gene. During periods of trivial illness, individuals with FBP deficiency may develop ketotic hypoglycemia, metabolic acidosis, lactic acidemia, and an increased anion gap. Although detection of urinary excretion of glycerol by urine organic acid analysis has been previously described, the presence of transient pseudo-hypertriglyceridemia in serum during metabolic decompensation has not been reported before. This study describes four consanguineous Pakistani families, in which four patients were diagnosed with FBP deficiency. All showed transient pseudo-hypertriglyceridemia during the acute phase of metabolic decompensation, which resolved in a metabolically stable phase. Mutations in the FBP1 gene have been described from various ethnicities, but there is very limited literature available for the Pakistani population. This study also describes one novel mutation in the FBP1 gene which seems to be prevalent in Pakistani-Indian patients. CONCLUSION: As a result of this study, transient pseudo-hypertriglyceridemia should be added to glyceroluria, ketotic hypoglycemia, metabolic acidosis, and lactic acidosis as a useful biochemical marker of FBP deficiency.

Gluconeogenesis defect presenting with resistant hyperglycemia and acidosis mimicking diabetic ketoacidosis.

Fructose-1,6-diphosphatase (FDPase) enzyme deficiency is a rare inherited metabolic disease. Affected patients usually present with metabolic crisis including hypoglycemia, acidosis, ketonuria, and hyperuricemia. A previously healthy 8-month-old male infant presented with fever, vomiting, and hypoactivity. He had tachycardia, tachypnea, and a tendency to sleep. The patient had signs of severe dehydration and shock. Laboratory findings revealed significant lactic acidosis, hyperuricemia, hyperglycemia, elevated liver enzyme level, and hyperlipidemia. The urine analysis had evidence of glycosuria and ketonuria. Hyperuricemia, lactic acidemia, and hyperglycemia persisted despite insulin infusion, adequate hydration, and perfusion. Consequently, peritoneal dialysis was started. About 12 hours after dialysis, his metabolic derangements were normalized, and clinical status was improved dramatically. His metabolic disease workup was compatible with FDPase deficiency. Here, we described a metabolic attack of FDPase deficiency presented with hyperglycemia mimicking diabetic ketoacidosis.

[Severe lactic acidosis requiring continuos haemodiafiltration in a young patient with unrecognized metabolic abnormality. Case report].

BACKGROUND: Lactic acidosis (LA) is the most common form of metabolic acidosis, defined by lactate values greater than 5 mmol/L and pH<7.34. The pathogenesis of LA involves hypoxic causes (type A) and non-hypoxic (type B), often coexisting. Identification and removal of the trigger are mandatory in the therapeutic management of LA. The case: A 38 years-old male patient entered the Emergency Ward for dyspnea, fever, vomiting and hyporexia. An important respiratory distress with hyperventilation due to severe LA was found, together with severe hypoglicemia, without renal impairment. Past medical history unremarkable, except for reported episodic hypoglicemia in the childhood, with fructose "intolerance", without any other data. No evidence of intoxications, septic shock or significant cytolysis. No drugs causing LA. The patient underwent orotracheal intubation, glucose infusion, and continuous haemodiafiltration for 36-hrs. A rapid general improvement was obtained with stabilization of acid-base balance. A diagnosis of fructose-1,6-diphosphatase deficiency was made. It is an autosomical recessive gluconeogenesis abnormality, with recurrent episodes of hypoglicemia and lactic acidosis after fasting, potentially lethal. The therapy is based on avoiding prolonged fasts, glucose infusion, and a specific diet, rich in glucose without fructose intake. CONCLUSIONS: The presence of not-otherwise-explained lactic acidosis in young patients has to place the suspect of an underlying and unknown metabolic derangement; in these cases, the involvement of the nephrologist appears to be pivotal for the differential diagnosis of the abnormalities of the acid-base balance, and for setting the best treatment.

Fructose-1,6-diphosphatase deficiency: a rare cause of prolonged prothrombin time.

A 20-year-old woman presented with severe life-threatening metabolic acidosis and hypoglycemia. In addition, her blood tests revealed elevated hepatic enzymes and a prolonged prothrombin time, with a reduction in factor VII activity. After treatment with a glucose and bicarbonate-containing intravenous infusion, there was a dramatic clinical improvement and normalization of the prothrombin time within 2 days. The patient was found to have fructose-1,6-diphosphatase deficiency, a rare metabolic disorder which has not been described previously as causing coagulation defects.

Biochemical and clinical observations in four patients with fructose-1,6-diphosphatase deficiency.

Three boys and one girl suffering from inherited fructose-1,6-diphosphatase (FDPase) deficiency are reported. All four patients had less than 25% residual hepatic FDPase activity. While in two out of three patients the enzyme deficiency was also expressed in leucocytes, one patient had a normal enzyme activity. Remarkably, three patients had pronounced neonatal hyperbilirubinaemia requiring exchange transfusion.