A novel variant in the FBP1 gene causes fructose-1,6-bisphosphatase deficiency through increased ubiquitination.

Fructose-1,6-bisphosphatase (FBPase) deficiency is an autosomal recessive disorder characterized by impaired gluconeogenesis caused by mutations in the fructose-1,6-bisphosphatase 1 (FBP1) gene. The molecular mechanisms underlying FBPase deficiency caused by FBP1 mutations require investigation. Herein, we report the case of a Chinese boy with FBPase deficiency who presented with hypoglycemia, ketonuria, metabolic acidosis, and repeated episodes of generalized seizures that progressed to epileptic encephalopathy. Whole-exome sequencing revealed compound heterozygous variants, c.761 A > G (H254R) and c.962C > T (S321F), in FBP1. The variants, especially the novel H254R, reduced protein stability and enzymatic activity in patient-derived leukocytes and transfected HepG2 and U251 cells. Mutant FBP1 undergoes enhanced ubiquitination and proteasomal degradation. NEDD4-2 was identified as an E3 ligase for FBP1 ubiquitination in transfected cells and the liver and brain of Nedd4-2 knockout mice. The H254R mutant FBP1 interacted with NEDD4-2 at significantly higher levels than the wild-type control. Our study identified a novel H254R variant of FBP1 underlying FBPase deficiency and elucidated the molecular mechanism underlying the enhanced NEDD4-2-mediated ubiquitination and proteasomal degradation of mutant FBP1.

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.

Genetic Analysis of Tyrosinemia Type 1 and Fructose-1, 6 Bisphosphatase Deficiency Affected in Pakistani Cohorts.

Background: Inborn errors of metabolism are inherited disorders that present in early childhood and are usually caused by monogenic recessive mutations in specific enzymes that metabolize dietary components. Distinct mutations are present in specific populations.Objective: To determine which genomic variants are present in Pakistani cohorts with hepatorenal tyrosinemia type 1 (HT1) and fructose 1,6-bisphosphatase deficiency (FBPD).Materials and Methods: We sequenced the fumaryl acetoacetate hydrolase encoding gene (FAH) including flanking regions in four unrelated HT1 cohorts and the fructose 1,6-bisphosphatase gene (FBP1) in eight FBPD cohorts.Results: We mapped two recessive mutations in FAH gene for HT1; c.1062 + 5G > A(IVS12 + 5G > A) in three families and c.974C > T(pT325M) in one. We identified three mutations in FBP1 gene; c.841G > A(p.E281K) in five FBPD families, c.472C > T(p.R158W) in two families and c.778G > A(p.G260R) in one.Conclusion: Knowledge of common variants for HTI and FBDP in our study population can be used in the future to build a diagnostic algorithm.

Exon 2 deletion represents a common mutation in Turkish patients with fructose-1,6-bisphosphatase deficiency.

Fructose-1,6-bisphosphatase (FBPase) deficiency is an autosomal recessive inborn error of gluconeogenesis. We aimed to investigate clinical and biochemical findings and molecular genetic data in ten Turkish patients with fructose-1,6-bisphosphatase deficiency. Ten Turkish patients who were diagnosed with fructose-1,6-biphosphatase deficiency in a single center from 2013 to 2019 were included in this study. Their clinical and laboratory data were collected retrospectively. All patients were hospitalised in intensive care unit mostly after catabolic stress conditions such as infections, starvation and rarely fructose consumption. Prognosis was good after correct diagnosis and treatment. Molecular analyses of FBP1 gene revealed a homozygous exon 2 deletion in eight patients, a novel homozygous c.910_911dupTT mutation in one patient and a homozygous IVS5 + 1G > A splicing mutation in one patient. Exon 2 deletion (previously termed exon 1) was found to be the most common mutation in Turkish fructose-1,6-biphosphatase deficiency patients.

[Genetic analysis of a child with fructose-1, 6 bisphosphatase deficiency].

OBJECTIVE: To analyze the genetic variant of a child with fructose-1, 6 bisphosphatase deficiency. METHODS: Potential variant of the FBP1 gene was detected by next generation sequencing and verified by Sanger sequencing. RESULTS: A compound heterozygous variant, c.826-2T>C and c.490G>A (p.Gly164Ser), was detected in the FBP1 gene. Among them, the c.490G>A(p.Gly164Ser) variant was derived from his mother and known to be pathogenic. The c.826-2T>C variant was derived from his father and was not reported previously. CONCLUSION: The compound heterozygous variant of c.826-2T>C and c.490G>A(p.Gly164Ser) of the FBP1 gene probably underlie the disease in this patient. Genetic testing can facilitate diagnosis and genetic counseling and prenatal diagnosis.

Clinical and molecular characterization of Indian patients with fructose-1, 6-bisphosphatase deficiency: Identification of a frequent variant (E281K).

Fructose-1, 6-bisphosphatase deficiency is an autosomal recessive disorder of gluconeogenesis caused by genetic defect in the FBP1 gene. It is characterized by episodic, often life-threatening metabolic acidosis, liver dysfunction, and hyperlactatemia. Without a high index of suspicion, it may remain undiagnosed with devastating consequences. Accurate diagnosis can be achieved either by enzyme assay or gene studies. Enzyme assay requires a liver biopsy and is tedious, invasive, expensive, and not easily available. Therefore, genetic testing is the most appropriate method to confirm the diagnosis. Molecular studies were performed on 18 suspected cases presenting with episodic symptoms. Seven different pathogenic variants were identified. Two common variants were noted in two subpopulations from the Indian subcontinent; p.Glu281Lys (E281K) occurred most frequently (in 10 patients) followed by p.Arg158Trp (R158W, in 4 patients). Molecular analysis confirmed the diagnosis and helped in managing these patients by providing appropriate genetic counseling. In conclusion, genetic studies identified two common variants in the Indian subcontinent, thus simplifying the diagnostic algorithm in this treatable disorder.

Loss of fructose-1,6-bisphosphatase induces glycolysis and promotes apoptosis resistance of cancer stem-like cells: an important role in hexavalent chromium-induced carcinogenesis.

Hexavalent chromium (Cr(VI)) compounds are confirmed human carcinogens for lung cancer. Our previous studies has demonstrated that chronic exposure of human bronchial epithelial BEAS-2B cells to low dose of Cr(VI) causes malignant cell transformation. The acquisition of cancer stem cell-like properties is involved in the initiation of cancers. The present study has observed that a small population of cancer stem-like cells (BEAS-2B-Cr-CSC) exists in the Cr(VI)-transformed cells (BEAS-2B-Cr). Those BEAS-2B-Cr-CSC exhibit extremely reduced capability of generating reactive oxygen species (ROS) and apoptosis resistance. BEAS-2B-Cr-CSC are metabolic inactive as evidenced by reductions in oxygen consumption, glucose uptake, ATP production, and lactate production. Most importantly, BEAS-2B-Cr-CSC are more tumorigenic with high levels of cell self-renewal genes, Notch1 and p21. Further study has found that fructose-1,6-bisphosphatase (FBP1), an rate-limiting enzyme driving glyconeogenesis, was lost in BEAS-2B-Cr-CSC. Forced expression of FBP1 in BEAS-2B-Cr-CSC restored ROS generation, resulting in increased apoptosis, leading to inhibition of tumorigenesis. In summary, the present study suggests that loss of FBP1 is a critical event in tumorigenesis of Cr(VI)-transformed cells.

Clinical and Molecular Characterization of Patients with Fructose 1,6-Bisphosphatase Deficiency.

Fructose-1,6-bisphosphatase (FBPase) deficiency is a rare, autosomal recessive inherited disease caused by the mutation of the FBP1 gene, the incidence is estimated to be between 1/350,000 and 1/900,000. The symptoms of affected individuals are non-specific and are easily confused with other metabolic disorders. The present study describes the clinical features of four Chinese pediatric patients who presented with hypoglycemia, hyperlactacidemia, metabolic acidosis, and hyperuricemia. Targeted-next generation sequencing using the Agilent SureSelect XT Inherited Disease Panel was used to screen for causal variants in the genome, and the clinically-relevant variants were subsequently verified using Sanger sequencing. Here, DNA sequencing identified six variations of the FBP1 gene (NM_000507.3) in the four patients. In Case 1, we found a compound heterozygous mutations of c.704delC (p.Pro235GlnfsX42) (novel) and c.960_961insG (p.Ser321Valfs) (known pathogenic). In Case 2, we found a compound heterozygous mutations of c.825 + 1G>A and c.960_961insG (both were known pathogenically). In Case 3, a homozygous missense mutation of c.355G>A (p.Asp119Asn) (reported in ClinVar database without functional study) was found. Case 4 had a compound heterozygous mutations c.720_729del (p.Tyr241GlyfsX33) (novel) and c.490G>A (p.Gly164Ser) (known pathogenically). Further in vitro studies in the COS-7cell line demonstrated that the mutation of ASP119ASN had no impact on protein expression, but decreased the enzyme activity, and with which the clinical significance of Asp119Asn can be determined to be likely pathogenic. This report not only expands upon the known spectrum of variation of the FBP1 gene, but also deepens our understanding of the clinical features of FBPase deficiency.

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.

Pitfall in the Diagnosis of Fructose-1,6-Bisphosphatase Deficiency: Difficulty in Detecting Glycerol-3-Phosphate with Solvent Extraction in Urinary GC/MS Analysis.

Fructose-1,6-bisphosphatase (FBPase), an enzyme involved in gluconeogenesis, catalyzes the hydrolysis of fructose-1,6-bisphosphate to fructose-6-phosphate and inorganic phosphate. FBPase deficiency is an autosomal recessive inherited disorder, characterized by episodic attacks of hypoglycemia, ketosis, and lactic acidosis during fasting. In general, urinary organic acid analysis using gas chromatography-mass spectrometry (GC/MS) is very useful for the diagnosis of FBPase deficiency, because the appearance of glycerol or glycerol-3-phosphate in the urine is characteristic of this disease. Here, we report a case of FBPase deficiency in a girl with a history of several severe lactic acidosis events, both as a neonate and after the age of 12 months. The patient was identified as a compound heterozygote with two mutations in the FBPase 1 gene: c.841G>A (p.Glu281Lys) and c.960_961insG (p.Ser321fs). The c.841G>A is a newly identified pathogenic mutation. An abnormal level of glycerol-3-phosphate was not detected in the conventional urinary organic acid analysis using GC/MS after solvent extraction. This method, which is a widely used diagnostic standard, could not detect increased levels of glycerol or glycerol-3-phosphate in the patient's urine, which was sampled during the episode. However, glycerol and glycerol-3-phosphate were detected in the same sample, when it was analyzed using GC/MS with the urease pretreatment non-extraction method. Patients with FBPase deficiency have good glycemic control after correct treatment. Therefore, accurate and early diagnosis is essential for a good prognosis. Accordingly, when a patient presents with hypoglycemia and lactic acidosis, it is important to select the appropriate method of urinalysis for organic acids by GC/MS.

An interesting newborn case of fructose 1-6 diphosphatase deficiency triggered after thyme juice ingestion.

Herbs have been used for centuries to prevent and control many diseases. The biggest challenge and problem is lack of information about the effect of herbs and its side effects. Thyme (thymus vulgaris) is a small shrubby plant with a strong, spicy taste, and odor. Thyme has carminative, diaphoretic, expectorant, sedative, antibacterial and antifungal properties. It also has antispasmodic effects; tea made by infusing the herb in water or thyme juice ready-to-use is traditionally frequently used for infantile colic in our country. A fourteen-day-old male newborn was admitted to the emergency department with severe respiratory distress. There was a history of 50 mL of thyme juice (added table sugar) ingestion given for his infantile colic two hours before admission. He had hypoglycemia, hyperuricemia, and lactic acidosis. Further investigation confirmed fructose 1-6 diphosphatase deficiency in the patient. We thought that lactic acidosis may have been triggered by fructose added to the thyme water to sweeten its taste. However, phenolic compounds of thyme juice may also cause acidosis.

[Genetic diagnosis of fructose-1, 6-bisphosphatase deficiency: a case report].

OBJECTIVE: To report the first case of fructose-1,6-bisphosphatase (FBPase) deficiency diagnosed by genetic sequencing in China, and to improve the cognition of this rare disease. METHODS: The clinical and laboratory characteristics of FBPase deficiency were reviewed, and the findings of direct sequencing of genomic DNA described, and published literature on FBPase deficiency reviewed. RESULTS: A 23-month-old boy was repeatedly admitted for 5 times with recurrent onset of lethargy and drowsiness every time after diarrhea and vomiting for 2-3 days during the last 7 months after being weaned, and he had convulsion this time. On admission, his physical examination showed tachypnea, and mild hepatomegaly, and he had normal physical and mental development. His paternal-grandparents had cousinship, and his parents were collateral relatives in the fifth generation. The laboratory findings revealed severe hypoglycemia, lacticacidemia, metabolic acidosis, ketonemia and hyperuricacidemia. After intravenous infusion of glucose, bicarbonate and antibiotics, there was a dramatic clinical improvement in a short time. Urine organic acids analyses ever showed an elevation of gluconeogenetic substrates including lactic acid, ketone and glycerol. The molecular analysis of liver fructose-1, 6-bisphosphatase (FBP1) gene showed a homozygous mutation with one G residue insertion at base 961 in exon 7(c.960/961insG), resulting in a reading frame shift mutation of 320th amino acid and premature termination at 333th amino acid. This mutation had been reported to be the most common mutation among patients with FBPase deficiency. Frequent feeding by avoiding taking in too much sweet food, restriction of food with high protein and fat, and the use of uncooked starch had been taken after our patient was discharged from the hospital. There had been no attack in the last 9 months. CONCLUSION: Clinicians must consider the diagnosis of FBPase deficiency when confronted with the patient who has episodes of severe hypoglycemia and lacticacidemia, especially accompanied by metabolic acidosis and ketonemia, which are typically triggered by infection and fasting. Early diagnosis, urgent treatment of hypoglycemia and appropriate diet control can prevent death, improve growth and quality of life of these children.

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.

An extremely rare case of hypoglycemia with a novel mutation and review of the literature: fructose-1,6 bisphosphatase deficiency in an adult man.

Hypoglycemia is an uncommon clinical problem among non-diabetic patients. It requires systematic evaluation to determine the etiology. It may be related to critical illness, hepatic insufficiency, renal insufficiency, cardiac insufficiency, drugs, alcohol, cortisol insufficiency, growth hormone insufficiency, insulinoma, gastric bypass surgery, and paraneoplastic (insulin-like growth factor-2-related) immune-mediated or inherited metabolic disorders. We aimed to summarize the literature and present a case who suffered from hypoglycemia throughout his life and was diagnosed with fructose-1, 6 bisphosphatase deficiency in adulthood to attract attention to the rare causes of hypoglycemia in adulthood.

Novel compound heterozygous mutations of the FBP1 gene in a patient with hypoglycemia and lactic acidosis: A case report.

BACKGROUND: Fructose-1,6-bisphosphatase (FBPase) deficiency, caused by an FBP1 mutation, is an autosomal recessively inherited metabolic disorder characterized by impaired gluconeogenesis. Due to the rarity of FBPase deficiency, the mechanism by which the mutations cause enzyme activity loss still remains unclear. METHODS: We report a pediatric patient with typical FBPase deficiency who presented with hypoglycemia, hyperlactatemia, metabolic acidosis, and hyperuricemia. Whole-exome sequencing was used to search for pathogenic genes, Sanger sequencing was used for verification, and molecular dynamic simulation was used to evaluate how the novel mutation affects FBPase activity and structural stability. RESULTS: Direct and allele-specific sequence analysis of the FBP1 gene (NM_000507) revealed that the proband had a compound heterozygote for the c. 490 (exon 4) G>A (p. G164S) and c. 861 (exon 7) C>A (p. Y287X, 52), which he inherited from his carrier parents. His father and mother had heterozygous G164S and Y287X mutations, respectively, without any symptoms of hypoglycemia. CONCLUSION: Our results broaden the known mutational spectrum and possible clinical phenotype of FBP1.

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.

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: outcomes of patients in a single center in Turkey and identification of novel splice site and indel mutations in FBP1.

OBJECTIVES: Fructose 1,6 bisphosphatase (FBPase) deficiency is a rare autosomal recessively inherited metabolic disease. It is encoded by FBP1, and the enzyme catalyzes the hydrolysis of fructose-1,6-bisphosphate to fructose 6-phosphate. Patients with recurrent episodes of metabolic acidosis, hypoglycemia, hypertriglyceridemia, and hyperketonemia are present. METHODS: In this study, we describe the clinical, biochemical, and molecular genetic features of six unrelated Turkish patients from six different families who were genetically diagnosed with FBPase deficiency in our clinic between 2008 and 2020. Their clinical and laboratory data were collected retrospectively. Next-generation sequencing (NGS) was performed for the molecular genetic analysis. RESULTS: All patients were hospitalized with recurrent hypoglycemia and metabolic acidosis episodes. Three out of six patients were presented in the neonatal period. The mean age at diagnosis was 26 months. NGS revealed a known homozygous gross deletion including exon 2 in three patients (50%), a known homozygous c.910_911dupTT pathogenic variant in one patient (16%), a novel homozygous c.651_653delCAGinsTAA likely pathogenic variant, and another novel homozygous c.705+5G>A splice site variant. Leukocyte FBPase analysis detected no enzyme activity in the patient with homozygous c.705+5G>A splice site variant. CONCLUSIONS: We identified two novel mutations in this study. One of them is a splice site mutation which is five bases downstream of the exon, and the other one is an indel mutation. Both of the splice site and indel mutations are exceedingly rare in FBP1, and to the best of our knowledge, there are second splice site and indel variants reported in the literature. Exon 2 deletion is the most common mutation consistent with the previous reports in Turkish patients. FBPase is a frequent cause of hypoglycemia and metabolic acidosis, and the widespread use of molecular genetic analysis would contribute to the enlightenment of advanced genetic factors and possible genotype/phenotype correlation.

Fructose-1,6-bisphosphatase deficiency.

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