Documentation of a novel FBP1 gene mutation in the Arabian ethnicity: a case report.

BACKGROUND: Fructose-1,6-bisphosphatase deficiency is a rare autosomal recessive disorder characterized by impaired gluconeogenesis. Fructose-1,6-bisphosphatase 1 (FBP1) mutations demonstrate ethnic patterns. For instance, Turkish populations commonly harbor exon 2 deletions. We present a case report of whole exon 2 deletion in a Syrian Arabian child as the first recording of this mutation among Arabian ethnicity and the first report of FBP1 gene mutation in Syria. CASE PRESENTATION: We present the case of a 2.5-year-old Syrian Arab child with recurrent hypoglycemic episodes, accompanied by nausea and lethargy. The patient's history, physical examination, and laboratory findings raised suspicion of fructose-1,6-bisphosphatase deficiency. Whole exome sequencing was performed, revealing a homozygous deletion of exon 2 in the FBP1 gene, confirming the diagnosis. CONCLUSION: This case highlights a potential novel mutation in the Arab population; this mutation is well described in the Turkish population, which suggests potential shared mutations due to ancestral relationships between the two ethnicities. Further studies are needed to confirm this finding.

Identification of genotype-biochemical phenotype correlations associated with fructose 1,6-bisphosphatase deficiency.

Fructose-1,6-bisphosphatase (FBPase) deficiency, caused by an FBP1 mutation, is an autosomal recessive disorder characterized by hypoglycemic lactic acidosis. Due to the rarity of FBPase deficiency, the mechanism by which the mutations cause enzyme activity loss still remains unclear. Here we identify compound heterozygous missense mutations of FBP1, c.491G>A (p.G164D) and c.581T>C (p.F194S), in an adult patient with hypoglycemic lactic acidosis. The G164D and F194S FBP1 mutants exhibit decreased FBP1 protein expression and a loss of FBPase enzyme activity. The biochemical phenotypes of all previously reported FBP1 missense mutations in addition to G164D and F194S are classified into three functional categories. Type 1 mutations are located at pivotal residues in enzyme activity motifs and have no effects on protein expression. Type 2 mutations structurally cluster around the substrate binding pocket and are associated with decreased protein expression due to protein misfolding. Type 3 mutations are likely nonpathogenic. These findings demonstrate a key role of protein misfolding in mediating the pathogenesis of FBPase deficiency, particularly for Type 2 mutations. This study provides important insights that certain patients with Type 2 mutations may respond to chaperone molecules.

Fructose-1,6-bisphosphatase deficiency causes fatty liver disease and requires long-term hepatic follow-up.

Liver disease, occurring during pediatric or adult age, is often of undetermined cause. Some cases are probably related to undiagnosed inherited metabolic disorders. Hepatic disorders associated with fructose-1,6-bisphosphatase deficiency, a gluconeogenesis defect, are not reported in the literature. These symptoms are mainly described during acute crises, and many reports do not mention them because hypoglycemia and hyperlactatemia are more frequently in the forefront. Herein, the liver manifestations of 18 patients affected with fructose-1,6-bisphosphatase deficiency are described and the corresponding literature is reviewed. Interestingly, all 18 patients had liver abnormalities either during follow-up (hepatomegaly [n = 8/18], elevation of transaminases [n = 6/15], bright liver [n = 7/11]) or during acute crises (hepatomegaly [n = 10/17], elevation of transaminases [n = 13/16], acute liver failure [n = 6/14], bright liver [n = 4/14]). Initial reports described cases of liver steatosis, when liver biopsy was necessary to confirm the diagnosis by an enzymatic study. There is no clear pathophysiological basis for this fatty liver disease but we postulate that endoplasmic reticulum stress and de novo lipogenesis activation could be key factors, as observed in FBP1 knockout mice. Liver steatosis may expose patients to severe long-term liver complications. As hypoglycemia becomes less frequent with age, most adult patients are no longer monitored by hepatologist. Signs of fructose-1,6-bisphosphatase deficiency may be subtle and can be missed in childhood. We suggest that fructose-1,6-bisphosphatase deficiency should be considered as an etiology of hepatic steatosis, and a liver monitoring protocol should be set up for these patients, during lifelong follow-up.

Fructose-1,6-bisphosphatase deficiency with confirmed molecular diagnosis. An important cause of hypoglycemia in children.

OBJECTIVES: To draw attention towards fructose-1,6-bisphosphatase (FBPase) deficiency as an important cause of hypoglycemia and lactic acidosis and to implement preventive strategies. Methods: This observational, cross-sectional study was conducted on 7 Saudi patients with genetically confirmed FBPase deficiency from 2008 to 2018 at Prince Sultan Military Medical City, Riyadh, Saudi Arabia. Results: Participants ranged in age from 1-10 years, and all presented with recurrent hypoglycemia. All but one had associated severe metabolic acidosis, and 3 patients (42.9%) presented with hypoglycemia and severe acidosis since birth. The mean duration from presentation to diagnosis was 39.4 months, as other diagnoses, like glycogen storage diseases and mitochondrial diseases needed to be ruled out. Development was normal apart from speech delay in one patient with a novel variant of the FBP1 gene. All patients have homozygous variants in the FBP1 gene.  Conclusion: Fructose-1,6-bisphosphatase is an important cause of hypoglycemia and acidosis; therefore, it is important to offer early molecular diagnostics in any child presenting with these symptoms. Molecular diagnostics should always be undertaken to confirm the diagnosis and for further preventive strategies.

[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.

International practices in the dietary management of fructose 1-6 biphosphatase deficiency.

BACKGROUND: In fructose 1,6 bisphosphatase (FBPase) deficiency, management aims to prevent hypoglycaemia and lactic acidosis by avoiding prolonged fasting, particularly during febrile illness. Although the need for an emergency regimen to avoid metabolic decompensation is well established at times of illness, there is uncertainty about the need for other dietary management strategies such as sucrose or fructose restriction. We assessed international differences in the dietary management of FBPase deficiency. METHODS: A cross-sectional questionnaire (13 questions) was emailed to all members of the Society for the Study of Inborn Errors of Metabolism (SSIEM) and a wide database of inherited metabolic disorder dietitians. RESULTS: Thirty-six centres reported the dietary prescriptions of 126 patients with FBPase deficiency. Patients' age at questionnaire completion was: 1-10y, 46% (n = 58), 11-16y, 21% (n = 27), and >16y, 33% (n = 41). Diagnostic age was: <1y, 36% (n = 46); 1-10y, 59% (n = 74); 11-16y, 3% (n = 4); and >16y, 2% (n = 2). Seventy-five per cent of centres advocated dietary restrictions. This included restriction of: high sucrose foods only (n = 7 centres, 19%); fruit and sugary foods (n = 4, 11%); fruit, vegetables and sugary foods (n = 13, 36%). Twenty-five per cent of centres (n = 9), advised no dietary restrictions when patients were well. A higher percentage of patients aged >16y rather than ≤16y were prescribed dietary restrictions: patients aged 1-10y, 67% (n = 39/58), 11-16y, 63% (n = 17/27) and >16y, 85% (n = 35/41). Patients classified as having a normal fasting tolerance increased with age from 30% in 1-10y, to 36% in 11-16y, and 58% in >16y, but it was unclear if fasting tolerance was biochemically proven. Twenty centres (56%) routinely prescribed uncooked cornstarch (UCCS) to limit overnight fasting in 47 patients regardless of their actual fasting tolerance (37%). All centres advocated an emergency regimen mainly based on glucose polymer for illness management. CONCLUSIONS: Although all patients were prescribed an emergency regimen for illness, use of sucrose and fructose restricted diets with UCCS supplementation varied widely. Restrictions did not relax with age. International guidelines are necessary to help direct future dietary management of FBPase deficiency.

Fructose-1,6-bisphosphatase deficiency as a cause of recurrent hypoglycemia and metabolic acidosis: Clinical and molecular findings in Malaysian patients.

BACKGROUND: Fructose-1,6-bisphosphatase (FBPase) deficiency is a rare autosomal recessive inborn error of gluconeogenesis. We reported the clinical findings and molecular genetic data in seven Malaysian patients with FBPase deficiency. METHODS: All patients diagnosed with FBPase deficiency from 2010 to 2015 were included in this study. Their clinical and laboratory data were collected retrospectively. RESULTS: All the patients presented with recurrent episodes of hypoglycemia, metabolic acidosis, hyperlactacidemia and hepatomegaly. All of them had the first metabolic decompensation prior to 2 years old. The common triggering factors were vomiting and infection. Biallelic mutations in FBP1 gene (MIM*611570) were identified in all seven patients confirming the diagnosis of FBPase deficiency. In four patients, genetic study was prompted by detection of glycerol or glycerol-3-phosphate in urine organic acids analysis. One patient also had pseudo-hypertriglyceridemia. Seven different mutations were identified in FBP1, among them four mutations were new: three point deletions (c.392delT, c.603delG and c.704delC) and one splice site mutation (c.568-2A > C). All four new mutations were predicted to be damaging by in silico analysis. One patient presented in the neonatal period and succumbed due to sepsis and multi-organ failure. Among six survivors (current age ranged from 4 to 27 years), four have normal growth and cognitive development. One patient had short stature and another had neurological deficit following status epilepticus due to profound hypoglycemia. CONCLUSION: FBPase deficiency needs to be considered in any children with recurrent hypoglycemia and metabolic acidosis. Our study expands the spectrum of FBP1 gene mutations.

Fructose-1,6-diphosphatase deficiency: a treatable neurometabolic disorder.

Fructose-1,6-diphosphatase (FDPase) deficiency is usually considered an inborn error of fructose metabolism, however, strictly speaking it is a defect of gluconeogenesis. The disorder is manifested by the appearance of hypoglycaemia, ketosis and lactic acidosis (neonatally or later during fasting or induced by fructose) and may also be life-threatening. FDPase deficiency can be suspected using simple bedside tests such as glucometer random blood sugar, Benedict's test, Rothera's test and Seliwanoff's test. We report our experience with two cases of FDPase deficiency and review the relevant literature. We also describe the fructosuria in these cases during the crises period, which has not been stressed in the literature.

Novel fructose-1,6-bisphosphatase gene mutation in two siblings.

Fructose-1,6-bisphosphatase (FBPase) deficiency is an autosomal, recessively inherited disease that progresses with severe hypoglycemia, and metabolic attacks result in a defect in gluconeogenesis. If not appropriately treated, and if fructose is not excluded from the diet, the outcome could be fatal. Two Turkish children with FBPase deficiency were diagnosed based on mutation of the FBP1 gene. The first, a 2-year-old girl, was referred to our clinic because of lactic acidosis, uncorrectable hypoglycemia, and increased transaminases. FBPase deficiency was suspected in the patient, who recovered dramatically after a high-dose glucose infusion and adequate bicarbonate replacement. The second patient, a five-and-a-half-year-old male sibling of the patient, was also hospitalized, twice, because of hypoglycemic attacks and metabolic acidosis. Different from previous analyses, a homozygous c.658delT mutation was detected at exon 5 of the FBP1 gene in the two siblings. As a result of this mutation, there was a TGA (stop codon) at exon 6. There was first-degree consanguinity between the parents. These two cases were the first FBP1 gene mutations reported in our country.

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.

Recurrent infantile hypoglycemia due to combined fructose-1,6-diphosphatase deficiency and growth hormone deficiency.

A 14-month-old female infant presented with recurrent episodes of acute gastroenteritis accompanied by severe metabolic acidosis and hypoglycemia. Physical examination showed hepatomegaly. Laboratory evaluation revealed elevated hepatic enzymes, prolonged prothrombin time, hyperuricemia, and extremely elevated lactate and alanine levels. Glucagon injection during hypoglycemia resulted in a further decrease of blood glucose. She was treated with glucose-containing intravenous fluids, with rapid improvement and normalization of her blood pH and glucose levels. Hormonal assessment during two episodes of hypoglycemia indicated growth hormone (GH) deficiency. However, as isolated GH deficiency could not explain all other concomitant features, such as severe lactic acidosis, hepatomegaly, impaired liver function, and hyperuricemia, the possibility of a combined defect was suggested. Further lymphocytic enzymatic investigation revealed fructose-1,6-diphosphatase deficiency and molecular genetic analysis demonstrated frame shift mutation in the FBP1 gene. This enzyme deficiency causes a rare metabolic disorder not previously described in combination with GH 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.

[Fructose 1,6-bisphosphatase deficiency as a cause of recessive serious hypoglycaemia]. / Fruktose-1,6-biphosphatase-mangel som årsag til recidiverende alvorlig hypoglykaemi.

Fructose 1,6-bisphosphatase (FBPase) deficiency is an autosomal recessive disorder of gluconeogenesis. Here we describe a family from Morocco with parental consanguinity with three affected children. All were homozygous for a novel mutation in exon 5: 685 C-->T of the gene coding for the liver isoform of fructose 1,6-bisphosphatase (FBP1). The mutation changed the amino acid codon (Q229X) from a glutamine (CAG) in position 229 to a stop codon (TAG), which caused a shortening of the protein from the normal 338 amino acids to 228. The shortened protein lacks a major part of the active site and is therefore probably without enzymatic activity.

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.

Fructose-1,6-diphosphatase deficiency in Israel.

The clinical and biochemical data on nine patients belonging to six families with fructose-1,6-diphosphatase deficiency are reported. Two of the six families were Jewish, three were Moslem Arabs and one was of Druze origin. All patients had had neonatal hypoglycemia, lactic acidosis and an abnormal fructose or glycerol loading test. At a later age, instances of hypoglycemia occurred in patients both with and without preceding illness. Hypoglycemic attacks were associated with severe hyperuricemia and metabolic acidosis. Therapeutic measures included a restriction in fructose intake and avoidance of prolonged fasting, particularly during febrile episodes.

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.

[Recurrent acidosis with hypoglycemia in an infant: fructose-1,6-diphosphatase deficiency]. / Rezidivierende Azidose mit Hypoglykämie bei einem Säugling: Fruktose-1,6-Diphosphatase-Mangel.

A seven months old infant presented with recurrent episodes of acidosis and hypoglycemia triggered by fasting and febrile infections. The diagnosis of fructose-1,6-diphosphatase deficiency was made by demonstrating the enzyme deficiency in a liver biopsy specimen. Fructose-1,6-diphosphatase is a key enzyme of gluconeogenesis. Fructose-1,6-diphosphatase deficiency results in hypoglycemia and lactic acidosis during episodes of fasting. Diagnosis is made preferably by liver biopsy. Treatment includes elimination of fructose and sucrose from the diet and avoidance of fasting. Acute attacks are treated by intravenous infusion of glucose and bicarbonate if necessary.