Fructose-1,6-Bisphosphatase Deficiency

Metabolic Disorder MONDO:0009251 Pathograph 17 Show in embeddings browser hereditary disease metabolic disorder Inborn Error of Carbohydrate Metabolism

Fructose-1,6-bisphosphatase (FBPase) deficiency is a rare autosomal recessive inborn error of gluconeogenesis caused by biallelic pathogenic variants in FBP1. FBPase catalyzes the hydrolysis of fructose-1,6-bisphosphate to fructose-6-phosphate, the penultimate committed step of hepatic gluconeogenesis. Loss of this step leaves the liver unable to generate glucose from lactate, glycerol, and gluconeogenic amino acids once glycogen stores are exhausted, so patients are well between episodes but decompensate acutely when a catabolic stress — fever, fasting, vomiting, intercurrent infection, or a large fructose load — raises gluconeogenic demand. The resulting crisis is a stereotyped combination of ketotic hypoglycemia and lactic acidosis with hyperventilation, apnea, seizures, and lethargy or coma. Hepatomegaly, transaminase elevation, and hepatic steatosis are also characteristic, and are increasingly recognized as persisting between crises rather than being confined to them. Management is preventive — avoidance of fasting, restriction of fructose, sucrose, glycerol, and sorbitol, and aggressive intravenous glucose during acute illness — and prognosis with treatment is generally good.

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1
Inheritance
7
Pathophys.
13
Phenotypes
1
Hypotheses
1
Gaps
17
Pathograph
1
Genes
4
Medical Actions
2
Differentials
1
References
🏷

Classifications

ICIMD (Inherited Metabolic Disorders)
gluconeogenesis
👪

Inheritance

1
Autosomal recessive HP:0000007
FBP1 deficiency is inherited in an autosomal recessive manner; affected individuals carry biallelic pathogenic FBP1 variants.
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:31804789 SUPPORT Other
"FBP1 deficiency is inherited in an autosomal recessive manner."
GeneReviews states the mode of inheritance directly. Evidence source is OTHER because GeneReviews is a synthesizing clinical review rather than a primary cohort report.
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Mechanistic Hypotheses

1
ER stress and de novo lipogenesis as the basis of FBP1-deficiency fatty liver
fbp1_steatosis_er_stress_dnl EMERGING
Evidence balance 1 support
The steatosis of FBP1 deficiency has no established pathophysiological explanation. The leading proposal, extrapolated from Fbp1 knockout mice, is that the gluconeogenic block drives endoplasmic reticulum stress and activation of de novo lipogenesis in hepatocytes. This has not been demonstrated in human liver tissue.
Pathograph links
Gluconeogenic Substrate Accumulation and Energy Deficit -> Hepatic Steatosis and Liver Injury INDIRECT UNKNOWN INTERMEDIATES Chronic carbon accumulation behind the block is associated with fatty liver, but the connecting steps are not established. Endoplasmic reticulum stress and de novo lipogenesis activation have been postulated on the basis of Fbp1 knockout mice; this edge is deliberately typed as having unknown intermediates.
Show evidence (1 reference)
PMID:34687058 SUPPORT INDIRECT Human Clinical
"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."
States both the absence of an established mechanism and the specific mouse-derived hypothesis. Graded INDIRECT because the mechanism is offered as a postulate extrapolated from Fbp1 knockout mice and has not been demonstrated in human liver tissue.
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Discussions and Knowledge Gaps

1
Does the endoplasmic reticulum stress and de novo lipogenesis mechanism observed in Fbp1 knockout mice actually account for the fatty liver seen in human FBP1 deficiency?
HUMAN MODEL MISMATCH OPEN fbp1_steatosis_mechanism_model_translation
Attached to
pathophysiology#Hepatic Steatosis and Liver Injury
Human evidence establishes that steatosis is present and clinically important (all 18 patients in the French series had liver abnormalities), but the proposed mechanism rests entirely on an Fbp1 knockout mouse and is stated by the authors as a postulate. Mice tolerate the gluconeogenic block differently from humans and the human hepatic lipid phenotype has not been mechanistically characterized, so the translational validity of the ER-stress/DNL chain is the open question rather than the existence of the phenotype.
Proposed experiments
ER stress and de novo lipogenesis profiling in human FBP1-deficient liver
fbp1_human_liver_er_stress_dnl
Characterize endoplasmic reticulum stress markers and de novo lipogenesis flux in liver biopsy or explant tissue from individuals with FBP1 deficiency, against age-matched non-steatotic control liver.
Decision criterion
Elevated ER-stress markers and increased lipogenic flux in human FBP1-deficient liver would support the mouse-derived mechanism; their absence would refute it and require an alternative explanation for the steatosis.
Cross-species hepatic lipidomic and transcriptomic comparison
fbp1_mouse_human_liver_omics_comparison
Compare hepatic lipidomic and transcriptomic signatures between FBP1-deficient human liver and Fbp1 knockout mouse liver to establish which features of the mouse phenotype are conserved in humans.
Decision criterion
Concordant lipid species and lipogenic transcriptional programs across species would justify using the mouse as a mechanistic model; divergence would bound its translational use.
Longitudinal association of steatosis severity with metabolic control
fbp1_steatosis_metabolic_control_cohort
Determine whether steatosis severity tracks with metabolic control (fasting avoidance, fructose and sucrose restriction, crisis frequency) in a longitudinal patient cohort with serial hepatic imaging.
Decision criterion
If steatosis severity is independent of metabolic control, the fatty liver is a constitutive consequence of the enzyme defect rather than of accumulated decompensations.
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Pathophysiology

7
FBP1 Fructose-1,6-Bisphosphatase Deficiency
Biallelic loss-of-function FBP1 variants deplete cytosolic fructose-1,6-bisphosphatase activity in the liver. The enzyme hydrolyzes fructose-1,6-bisphosphate to fructose-6-phosphate, the irreversible step that commits carbon to glucose synthesis rather than back to glycolysis, so its loss is an enzymatic block in the last steps of gluconeogenesis. Residual activity in patient leukocytes is typically under 10% of normal.
Hepatocyte CL:0000182 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Hepatocyte (CL:0000182). CL:0000182 is a cell type from the Cell Ontology.
FBP1 hgnc:3606 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves FBP1 (hgnc:3606). hgnc:3606 is a gene from the HUGO Gene Nomenclature Committee.
gluconeogenesis GO:0006094 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased gluconeogenesis (GO:0006094). GO:0006094 is a biological process from the Gene Ontology. ↓ DECREASED
fructose 1,6-bisphosphate 1-phosphatase activity GO:0042132 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased fructose 1,6-bisphosphate 1-phosphatase activity (GO:0042132). GO:0042132 is a molecular function from the Gene Ontology. ↓ DECREASED
cytosol GO:0005829 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves cytosol (GO:0005829). GO:0005829 is a cellular component from the Gene Ontology.
Downstream
Impaired Hepatic Gluconeogenesis Loss of the fructose-1,6-bisphosphatase step directly interrupts flux through hepatic gluconeogenesis.
Show evidence (2 references)
PMID:25601412 SUPPORT Human Clinical
"Disease is mainly revealed by hypoglycemia and lactic acidosis, both symptoms being characteristic for an enzymatic block in the last steps of the gluconeogenesis."
Identifies the proximal lesion as an enzymatic block in the terminal steps of gluconeogenesis, the trigger node of this pathograph.
PMID:25601412 SUPPORT Human Clinical
"Enzyme activity in leukocytes was dramatically decreased (<10%)."
Quantifies the residual enzyme activity in the French diagnostic cohort, supporting the DECREASED modifier on fructose 1,6-bisphosphate 1-phosphatase activity.
Impaired Hepatic Gluconeogenesis
With the fructose-1,6-bisphosphatase step blocked, the hepatocyte cannot convert lactate, glycerol, and gluconeogenic amino acids into glucose. Glycogenolysis still works, so glucose homeostasis is maintained in the fed and early-fasted state; the defect becomes clinically apparent only once glycogen stores run down and the liver must switch to de novo glucose production. Neonates are especially vulnerable because glycogen stores are small.
Hepatocyte CL:0000182 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Hepatocyte (CL:0000182). CL:0000182 is a cell type from the Cell Ontology.
gluconeogenesis GO:0006094 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased gluconeogenesis (GO:0006094). GO:0006094 is a biological process from the Gene Ontology. ↓ DECREASED glucose homeostasis GO:0042593 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal glucose homeostasis (GO:0042593). GO:0042593 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Gluconeogenic Substrate Accumulation and Energy Deficit Carbon entering gluconeogenesis stalls proximal to the block, so lactate, glycerol, and glycerol-3-phosphate accumulate while glucose output falls.
Fasting Hypoglycemia Once hepatic glycogen is exhausted, the blocked gluconeogenic pathway cannot sustain blood glucose.
Show evidence (1 reference)
PMID:31804789 SUPPORT Other
"Acute crises are most common in early childhood; nearly half of affected children have hypoglycemia in the neonatal period (especially the first four days) resulting from deficient glycogen stores."
Attributes neonatal hypoglycemia specifically to exhaustion of glycogen stores in the setting of a gluconeogenic block, supporting the glycogen-dependent buffering described in this node. Evidence source is OTHER because GeneReviews is a synthesizing review.
Gluconeogenic Substrate Accumulation and Energy Deficit
Substrates that would normally be consumed by gluconeogenesis build up behind the block. Lactate accumulates and drives a high-anion-gap lactic acidosis; glycerol and glycerol-3-phosphate spill into urine (and can produce spurious pseudo-hypertriglyceridemia on glycerol-blanked triglyceride assays); urate rises. A catabolic stress — fever, fasting, reduced intake, vomiting, infection, or a large fructose load — sharply increases demand for hepatic glucose output and converts the compensated state into a crisis.
ER stress and de novo lipogenesis as the basis of FBP1-deficiency fatty liver
Hepatocyte CL:0000182 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Hepatocyte (CL:0000182). CL:0000182 is a cell type from the Cell Ontology.
generation of precursor metabolites and energy GO:0006091 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased generation of precursor metabolites and energy (GO:0006091). GO:0006091 is a biological process from the Gene Ontology. ↓ DECREASED fructose metabolic process GO:0006000 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal fructose metabolic process (GO:0006000). GO:0006000 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Acute Metabolic Decompensation Accumulating lactate plus failure of glucose output produces the acute decompensated state.
Hepatic Steatosis and Liver Injury Chronic carbon accumulation behind the block is associated with fatty liver, but the connecting steps are not established. Endoplasmic reticulum stress and de novo lipogenesis activation have been postulated on the basis of Fbp1 knockout mice; this edge is deliberately typed as having unknown intermediates. ER stress and de novo lipogenesis as the basis of FBP1-deficiency fatty liver
Show evidence (2 references)
PMID:29203193 SUPPORT Human Clinical
"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."
Documents accumulation of gluconeogenic substrates proximal to the block, including the glycerol-driven pseudo-hypertriglyceridemia artifact.
PMID:31804789 SUPPORT Other
"Common factors known to trigger episodes include fever, fasting, decreased oral intake, vomiting, infections, and ingestion of large amounts of fructose."
Identifies the catabolic and fructose-load stressors that amplify the block into an acute crisis. Evidence source is OTHER because GeneReviews is a synthesizing review.
Fasting Hypoglycemia
Blood glucose falls when fasting outlasts hepatic glycogen. Because lipolysis and ketogenesis remain intact, the hypoglycemia is ketotic — a key discriminator from fatty-acid oxidation defects, which give hypoketotic hypoglycemia. Between episodes children are asymptomatic and normoglycemic.
glucose homeostasis GO:0042593 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal glucose homeostasis (GO:0042593). GO:0042593 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Acute Metabolic Decompensation Hypoglycemia is one of the two defining biochemical components of the decompensated crisis.
Show evidence (2 references)
PMID:31804789 SUPPORT Other
"Fructose-1,6-bisphosphatase 1 (FBP1) deficiency is characterized by episodic acute crises of lactic acidosis and ketotic hypoglycemia, manifesting as respiratory distress or hyperventilation, apneic spells, seizures, and/or lethargy/coma."
Establishes ketotic hypoglycemia as the defining episodic metabolic abnormality. Evidence source is OTHER because GeneReviews is a synthesizing review.
PMID:31804789 SUPPORT Other
"In between acute episodes, children are asymptomatic."
Supports the episodic rather than continuous character of the hypoglycemia. Evidence source is OTHER because GeneReviews is a synthesizing review.
Acute Metabolic Decompensation
The central effector is a stereotyped crisis of ketotic hypoglycemia plus high-anion-gap lactic acidosis, usually with hepatomegaly and transaminase elevation. Unlike the urea-cycle and organic-acidemia conformers of this module, hyperammonemia is not a feature; the acid load is lactate and ketoacid. First decompensation is almost always before two years of age.
glucose homeostasis GO:0042593 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal glucose homeostasis (GO:0042593). GO:0042593 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Acute Metabolic Encephalopathy and Multiorgan Crisis Neuroglycopenia and acidosis produce the neurologic and systemic manifestations of the crisis.
Show evidence (2 references)
PMID:29203193 SUPPORT Human Clinical
"All the patients presented with recurrent episodes of hypoglycemia, metabolic acidosis, hyperlactacidemia and hepatomegaly."
Defines the composite decompensation phenotype in a molecularly confirmed patient series.
PMID:29203193 SUPPORT Human Clinical
"All of them had the first metabolic decompensation prior to 2 years old. The common triggering factors were vomiting and infection."
Supports the early-childhood timing and the catabolic triggers of the decompensated state.
Hepatic Steatosis and Liver Injury
Liver involvement is near-universal and is not confined to crises. In a French series every one of 18 patients had liver abnormalities — hepatomegaly (8/18), transaminase elevation (6/15), or a bright (steatotic) liver on ultrasound (7/11) — during routine follow-up as well as during acute episodes (hepatomegaly 10/17, transaminase elevation 13/16, bright liver 4/14), and acute liver failure occurred in 6/14 during crises. This reframes FBP1 deficiency as a chronic hepatic disorder warranting long-term liver surveillance, not only an episodic hypoglycemic one.
Hepatocyte CL:0000182 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Hepatocyte (CL:0000182). CL:0000182 is a cell type from the Cell Ontology.
Show evidence (1 reference)
PMID:34687058 SUPPORT Human Clinical
"Interestingly, all 18 patients had liver abnormalities either during follow-up"
Establishes that liver abnormalities were universal in the 18-patient multicenter series and occurred on routine follow-up, not only during crises. The per-finding counts quoted in the node description come from the bracketed figures in the same sentence.
Acute Metabolic Encephalopathy and Multiorgan Crisis
Neuroglycopenia combined with lactic acidosis produces hyperventilation, apneic spells, seizures, and lethargy or coma. Most treated children have normal growth and psychomotor development, but profound or prolonged hypoglycemia can leave permanent neurological deficit, and untreated continued catabolism progresses to multiorgan failure involving liver, brain, and later heart, with high mortality.
Show evidence (2 references)
PMID:31804789 SUPPORT Other
"In untreated individuals, clinical manifestations worsen progressively as continued catabolism leads to multiorgan failure (especially liver, brain, and later heart)."
Supports progression from decompensation to multiorgan crisis when untreated. Evidence source is OTHER because GeneReviews is a synthesizing review.
PMID:29203193 SUPPORT Human Clinical
"One patient had short stature and another had neurological deficit following status epilepticus due to profound hypoglycemia."
Documents permanent neurological injury attributable to profound hypoglycemia in a molecularly confirmed patient.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Fructose-1,6-Bisphosphatase Deficiency Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

13
Digestive 3
Hepatomegaly FREQUENT HP:0002240 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hepatomegaly (HP:0002240). HP:0002240 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29203193 SUPPORT Human Clinical
"All the patients presented with recurrent episodes of hypoglycemia, metabolic acidosis, hyperlactacidemia and hepatomegaly."
Hepatomegaly was present in all seven patients of the Malaysian series; the larger French series found it in a majority but not all, so the band is set to FREQUENT rather than VERY_FREQUENT.
Hepatic Steatosis FREQUENT HP:0001397 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hepatic steatosis (HP:0001397). HP:0001397 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34687058 SUPPORT Human Clinical
"Initial reports described cases of liver steatosis, when liver biopsy was necessary to confirm the diagnosis by an enzymatic study."
Documents hepatic steatosis on biopsy in the disorder; the bright-liver counts reported in the same series (7/11 on follow-up, 4/14 during crises) support the FREQUENT band.
Acute Hepatic Failure FREQUENT HP:0006554 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Acute hepatic failure (HP:0006554). HP:0006554 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34687058 SUPPORT Human Clinical
"acute liver failure [n = 6/14] ... bright liver [n = 4/14]"
Directly reports acute liver failure in 6 of 14 patients assessed during acute crises.
Metabolism 5
Hypoglycemia VERY_FREQUENT Ketotic hypoglycemia HP:0012734 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ketotic hypoglycemia (HP:0012734). HP:0012734 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:31804789 SUPPORT Other
"Fructose-1,6-bisphosphatase 1 (FBP1) deficiency is characterized by episodic acute crises of lactic acidosis and ketotic hypoglycemia, manifesting as respiratory distress or hyperventilation, apneic spells, seizures, and/or lethargy/coma."
Names ketotic hypoglycemia as a defining feature of the disorder. Evidence source is OTHER because GeneReviews is a synthesizing review.
PMID:29203193 SUPPORT Human Clinical
"All the patients presented with recurrent episodes of hypoglycemia, metabolic acidosis, hyperlactacidemia and hepatomegaly."
All seven molecularly confirmed patients had recurrent hypoglycemia, supporting the VERY_FREQUENT band.
Lactic Acidosis VERY_FREQUENT HP:0003128 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Lactic acidosis (HP:0003128). HP:0003128 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29203193 SUPPORT Human Clinical
"All the patients presented with recurrent episodes of hypoglycemia, metabolic acidosis, hyperlactacidemia and hepatomegaly."
Hyperlactacidemia with metabolic acidosis was present in all patients in the series, supporting the VERY_FREQUENT band.
Metabolic Acidosis VERY_FREQUENT HP:0001942 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Metabolic acidosis (HP:0001942). HP:0001942 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28420223 SUPPORT Human Clinical
"The present study describes the clinical features of four Chinese pediatric patients who presented with hypoglycemia, hyperlactacidemia, metabolic acidosis, and hyperuricemia."
Metabolic acidosis was present in all four molecularly characterized patients.
Elevated Hepatic Transaminases FREQUENT Elevated circulating hepatic transaminase concentration HP:0002910 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Elevated circulating hepatic transaminase concentration (HP:0002910). HP:0002910 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34687058 SUPPORT Human Clinical
"Interestingly, all 18 patients had liver abnormalities either during follow-up"
Establishes universal liver involvement in the series; transaminase elevation is one of the three enumerated abnormalities, with the counts given parenthetically in the same sentence.
Hyperuricemia FREQUENT HP:0002149 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hyperuricemia (HP:0002149). HP:0002149 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28420223 SUPPORT Human Clinical
"The present study describes the clinical features of four Chinese pediatric patients who presented with hypoglycemia, hyperlactacidemia, metabolic acidosis, and hyperuricemia."
Hyperuricemia was part of the presenting biochemical picture in all four patients.
Nervous System 3
Seizure HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39036704 SUPPORT Human Clinical
"By comparing to phenotypes of HFI patients, FBP1D patients were more likely to present hypoglycemia, metabolic acidosis, and seizures (all p-value < 0.05)."
Seizures were significantly enriched in FBP1 deficiency relative to hereditary fructose intolerance across 122 collected patients.
Lethargy HP:0001254 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Lethargy (HP:0001254). HP:0001254 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31804789 SUPPORT Other
"Fructose-1,6-bisphosphatase 1 (FBP1) deficiency is characterized by episodic acute crises of lactic acidosis and ketotic hypoglycemia, manifesting as respiratory distress or hyperventilation, apneic spells, seizures, and/or lethargy/coma."
Lists lethargy and coma among the crisis manifestations. Evidence source is OTHER because GeneReviews is a synthesizing review.
Intellectual Disability OCCASIONAL HP:0001249 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intellectual disability (HP:0001249). HP:0001249 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31804789 SUPPORT Other
"While the majority of affected children have normal growth and psychomotor development, a few have intellectual disability, presumably due to early and prolonged hypoglycemia."
"A few" against a majority-normal background supports the OCCASIONAL band. Evidence source is OTHER because GeneReviews is a synthesizing review.
Respiratory 2
Hyperventilation FREQUENT HP:0002883 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hyperventilation (HP:0002883). HP:0002883 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31804789 SUPPORT Other
"Fructose-1,6-bisphosphatase 1 (FBP1) deficiency is characterized by episodic acute crises of lactic acidosis and ketotic hypoglycemia, manifesting as respiratory distress or hyperventilation, apneic spells, seizures, and/or lethargy/coma."
Lists hyperventilation among the manifestations of the acute crisis. Evidence source is OTHER because GeneReviews is a synthesizing review.
Apnea HP:0002104 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Apnea (HP:0002104). HP:0002104 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31804789 SUPPORT Other
"Fructose-1,6-bisphosphatase 1 (FBP1) deficiency is characterized by episodic acute crises of lactic acidosis and ketotic hypoglycemia, manifesting as respiratory distress or hyperventilation, apneic spells, seizures, and/or lethargy/coma."
Lists apneic spells among the crisis manifestations. Frequency is omitted because no source quantifies it. Evidence source is OTHER because GeneReviews is a synthesizing review.
🧬

Genetic Associations

1
FBP1 (Causal biallelic variant)
Gene: FBP1 hgnc:3606 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is FBP1 (hgnc:3606). hgnc:3606 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (3 references)
PMID:29203193 SUPPORT Human Clinical
"Biallelic mutations in FBP1 gene (MIM*611570) were identified in all seven patients confirming the diagnosis of FBPase deficiency."
Directly supports FBP1 as the causal gene with biallelic inheritance in a molecularly confirmed series.
PMID:25601412 SUPPORT Human Clinical
"We described the first intragenic deletion in FBP1 (g.97,364,754_97,382,011del) in homozygous state."
Supports copy-number variation as part of the FBP1 mutational spectrum, which matters because exon-level deletions are missed by sequencing alone.
PMID:39036704 SUPPORT Human Clinical
"In the Chinese population, c.490G>A and c.355G>A had significantly higher AFs than in the non-Finland European population"
Supports population-specific FBP1 variant hotspots.
💊

Medical Actions

4
Acute intravenous glucose and bicarbonate
Action: Supportive CareNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. NCIT:C15747
Agent: glucose CHEBI:17234 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses glucose (CHEBI:17234). CHEBI:17234 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Acute crises are treated with intravenous glucose, transitioning to feeds as tolerated, with sodium bicarbonate added if acidemia requires correction.
Mechanism Target:
BYPASSES Fasting Hypoglycemia — Exogenous glucose supplies the glucose that the blocked gluconeogenic pathway cannot produce.
Show evidence (1 reference)
PMID:31804789 SUPPORT Other
"Acute inpatient treatment includes intravenous glucose with transition to feeds as tolerated; sodium bicarbonate may be required for treatment of acidemia."
Specifies intravenous glucose as the acute treatment that substitutes for absent endogenous glucose production. Evidence source is OTHER because GeneReviews is a synthesizing review.
Show evidence (1 reference)
PMID:31804789 SUPPORT Other
"Acute inpatient treatment includes intravenous glucose with transition to feeds as tolerated; sodium bicarbonate may be required for treatment of acidemia."
Directly supports the acute inpatient regimen. Evidence source is OTHER because GeneReviews is a synthesizing review.
Fasting avoidance with frequent feeds and uncooked cornstarch
Action: Dietary InterventionNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Dietary Intervention (NCIT:C15447). NCIT:C15447 is a clinical intervention from the NCI Thesaurus. NCIT:C15447
Platform: Behavioral / lifestyle
Long-term prevention of hypoglycemia rests on avoiding fasting, frequent meals, and uncooked cornstarch overnight to provide slow-release glucose across the overnight fast.
Mechanism Target:
BYPASSES Fasting Hypoglycemia — Continuous exogenous carbohydrate supply keeps the fast from ever outlasting glycogen stores, so the gluconeogenic block is never unmasked.
Show evidence (1 reference)
PMID:31804789 SUPPORT Other
"Long-term management includes prevention of hypoglycemia with avoidance of fasting, frequent meals, (including use of uncooked cornstarch overnight), and restriction of foods or medicines that contain fructose, sucrose, glycerol, and/or sorbitol"
Directly supports fasting avoidance and cornstarch as the preventive strategy against hypoglycemia. Evidence source is OTHER because GeneReviews is a synthesizing review.
Show evidence (1 reference)
PMID:31804789 SUPPORT Other
"Long-term management includes prevention of hypoglycemia with avoidance of fasting, frequent meals, (including use of uncooked cornstarch overnight), and restriction of foods or medicines that contain fructose, sucrose, glycerol, and/or sorbitol"
Directly supports the long-term dietary management plan. Evidence source is OTHER because GeneReviews is a synthesizing review.
Restriction of fructose, sucrose, glycerol, and sorbitol
Action: Dietary InterventionNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Dietary Intervention (NCIT:C15447). NCIT:C15447 is a clinical intervention from the NCI Thesaurus. NCIT:C15447
Platform: Behavioral / lifestyle
Foods and medicines containing fructose, sucrose, glycerol, or sorbitol are restricted because each feeds carbon into the pathway proximal to the enzymatic block. Antipyretics must be checked for these excipients.
Mechanism Target:
INHIBITS Gluconeogenic Substrate Accumulation and Energy Deficit — Limiting intake of substrates that must traverse the blocked step reduces further accumulation behind it.
Show evidence (1 reference)
PMID:31804789 SUPPORT Other
"treatment with antipyretics for fever that do not contain fructose, sucrose, glycerol, and/or sorbitol"
Shows the restriction extends to medication excipients, supporting substrate restriction as the mechanism-targeted intervention. Evidence source is OTHER because GeneReviews is a synthesizing review.
Show evidence (1 reference)
PMID:31804789 SUPPORT Other
"Management of acute crisis includes increasing frequency of carbohydrate feedings; intake of glucose polymers; restriction of fructose, sucrose, glycerol, and sorbitol"
Directly supports substrate restriction as a core management measure. Evidence source is OTHER because GeneReviews is a synthesizing review.
Genetic counseling
Action: Genetic CounselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic Counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. NCIT:C15240
Platform: Behavioral / lifestyle
Autosomal recessive recurrence counseling, carrier testing for at-risk relatives, and prenatal or preimplantation testing once the familial variants are known. Presymptomatic molecular testing of at-risk sibs allows preventive measures before a first crisis.
Show evidence (1 reference)
PMID:31804789 SUPPORT Other
"Offer molecular genetic testing for the familial FBP1 pathogenic variants to apparently asymptomatic older and younger at-risk sibs of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of measures to prevent acute crises and prompt..."
Supports cascade testing of at-risk relatives as an actionable preventive measure. Evidence source is OTHER because GeneReviews is a synthesizing review.
🌍

Environmental Factors

2
Fasting and catabolic stress
Fever, fasting, decreased oral intake, vomiting, and intercurrent infection raise demand for hepatic gluconeogenesis and precipitate acute crises. These are the dominant triggers in every reported series.
Show evidence (2 references)
PMID:31804789 SUPPORT Other
"Common factors known to trigger episodes include fever, fasting, decreased oral intake, vomiting, infections, and ingestion of large amounts of fructose."
Enumerates the catabolic triggers. Evidence source is OTHER because GeneReviews is a synthesizing review.
PMID:25601412 SUPPORT Human Clinical
"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."
Independently confirms the trigger profile in the French cohort.
Mechanism Target:
TRIGGERS Acute Metabolic Decompensation — Fasting, fever, reduced intake, vomiting, and infection directly precipitate acute metabolic decompensation when glycogen is exhausted and gluconeogenic demand rises.
Show evidence (1 reference)
PMID:31804789 SUPPORT Other
"Common factors known to trigger episodes include fever, fasting, decreased oral intake, vomiting, infections, and ingestion of large amounts of fructose."
Directly supports the link from fasting and catabolic stress to acute metabolic decompensation. Evidence source is OTHER because GeneReviews is a synthesizing review.
Large fructose load
Ingestion of a large amount of fructose precipitates crises. Small amounts (up to about 2 g/kg/day) are generally tolerated, but a single high dose (>1 g/kg) is harmful, especially in young children — which is also why diagnostic fructose challenge testing is contraindicated.
Show evidence (1 reference)
PMID:31804789 SUPPORT Other
"Although small amounts of fructose (≤2 g/kg/day) are generally well tolerated, single ingestion of a high dose of fructose (>1g/kg) is harmful, especially in younger children."
Quantifies the fructose exposure threshold that triggers harm. Evidence source is OTHER because GeneReviews is a synthesizing review.
Mechanism Target:
TRIGGERS Acute Metabolic Decompensation — A large fructose load directly precipitates acute metabolic decompensation in FBPase deficiency.
Show evidence (1 reference)
PMID:31804789 SUPPORT Other
"Although small amounts of fructose (≤2 g/kg/day) are generally well tolerated, single ingestion of a high dose of fructose (>1g/kg) is harmful, especially in younger children."
Directly supports the link from a large fructose load to acute metabolic decompensation. Evidence source is OTHER because GeneReviews is a synthesizing review.
🔬

Biochemical Markers

5
Lactate (INCREASED)
Context: Elevated blood lactate is a core laboratory hallmark of the acute crisis and reports accumulation of gluconeogenic substrate behind the FBPase block.
Pathograph Readouts
Readout Of Gluconeogenic Substrate Accumulation and Energy Deficit Positive Diagnostic
Rising lactate reports accumulation of gluconeogenic carbon proximal to the fructose-1,6-bisphosphatase step.
Show evidence (1 reference)
PMID:25601412 SUPPORT Human Clinical
"Disease is mainly revealed by hypoglycemia and lactic acidosis, both symptoms being characteristic for an enzymatic block in the last steps of the gluconeogenesis."
Explicitly interprets lactic acidosis as characteristic of the terminal gluconeogenic block.
Show evidence (1 reference)
PMID:29203193 SUPPORT Human Clinical
"All the patients presented with recurrent episodes of hypoglycemia, metabolic acidosis, hyperlactacidemia and hepatomegaly."
Hyperlactacidemia in all patients supports elevated lactate as a core biochemical finding.
Glucose (DECREASED)
Context: Low blood glucose during fasting or catabolic stress, with preserved ketone production.
Pathograph Readouts
Readout Of Fasting Hypoglycemia Negative Diagnostic
Falling glucose during fasting reports failure of hepatic glucose output once glycogen is exhausted.
Show evidence (1 reference)
PMID:31804789 SUPPORT Other
"Acute crises are most common in early childhood; nearly half of affected children have hypoglycemia in the neonatal period (especially the first four days) resulting from deficient glycogen stores."
Ties measured hypoglycemia to glycogen exhaustion unmasking the gluconeogenic block. Evidence source is OTHER because GeneReviews is a synthesizing review.
Show evidence (1 reference)
PMID:31804789 SUPPORT Other
"Fructose-1,6-bisphosphatase 1 (FBP1) deficiency is characterized by episodic acute crises of lactic acidosis and ketotic hypoglycemia, manifesting as respiratory distress or hyperventilation, apneic spells, seizures, and/or lethargy/coma."
Establishes hypoglycemia as a defining biochemical abnormality. Evidence source is OTHER because GeneReviews is a synthesizing review.
Urinary glycerol and glycerol-3-phosphate (INCREASED)
Context: Glycerol and glycerol-3-phosphate on urine organic acid analysis are a practical diagnostic clue and can trigger molecular testing; the same glycerol elevation can produce spurious pseudo-hypertriglyceridemia.
Pathograph Readouts
Readout Of Gluconeogenic Substrate Accumulation and Energy Deficit Positive Diagnostic
Urinary glycerol species report accumulation of a gluconeogenic substrate that cannot be consumed once the FBPase step is blocked.
Show evidence (1 reference)
PMID:39036704 SUPPORT Human Clinical
"The genotype-phenotype association analyses showed that patients carrying homozygous c.841G>A were more likely to present increased urinary glycerol"
Independently confirms increased urinary glycerol as an FBP1-deficiency biochemical phenotype and links it to genotype.
Show evidence (1 reference)
PMID:29203193 SUPPORT Human Clinical
"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."
Documents both the urinary finding and the pseudo-hypertriglyceridemia artifact in molecularly confirmed patients.
Uric acid (INCREASED)
Context: Hyperuricemia is part of the presenting biochemical profile during metabolic crises.
Show evidence (1 reference)
PMID:28420223 SUPPORT Human Clinical
"The present study describes the clinical features of four Chinese pediatric patients who presented with hypoglycemia, hyperlactacidemia, metabolic acidosis, and hyperuricemia."
Hyperuricemia was documented in all four molecularly characterized patients.
Fructose-1,6-bisphosphatase enzyme activity (DECREASED)
Context: Enzyme activity measured in liver or mononuclear white blood cells is dramatically reduced and is diagnostic; a single blood sample can support simultaneous enzyme assay and molecular analysis.
Pathograph Readouts
Readout Of FBP1 Fructose-1,6-Bisphosphatase Deficiency Negative Diagnostic
Leukocyte or hepatic FBPase activity below about 10% of normal reports the primary enzymatic lesion.
Show evidence (1 reference)
PMID:31804789 SUPPORT Other
"The diagnosis of FBP1 deficiency is established in a proband with suggestive clinical and metabolic findings and biallelic pathogenic variants in FBP1 identified by molecular genetic testing and/or deficient FBP1 activity in liver or mononuclear white blood cells."
Establishes deficient FBP1 activity in liver or leukocytes as a diagnostic readout of the lesion. Evidence source is OTHER because GeneReviews is a synthesizing review.
Show evidence (1 reference)
PMID:25601412 SUPPORT Human Clinical
"Enzyme activity in leukocytes was dramatically decreased (<10%)."
Directly supports reduced enzyme activity as the biochemical readout of the molecular lesion.
🔬

Diagnosis

3
Molecular genetic testing of FBP1
Identification of biallelic pathogenic FBP1 variants establishes the diagnosis. Testing should cover copy-number variation, since whole-exon and intragenic deletions are part of the spectrum and are missed by sequencing alone.
molecular genetic testing NCIT:C19770 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:31804789 SUPPORT Other
"The diagnosis of FBP1 deficiency is established in a proband with suggestive clinical and metabolic findings and biallelic pathogenic variants in FBP1 identified by molecular genetic testing and/or deficient FBP1 activity in liver or mononuclear white blood cells."
Directly states the diagnostic criteria. Evidence source is OTHER because GeneReviews is a synthesizing review.
PMID:39036704 SUPPORT Human Clinical
"Genetic sequencing could effectively help to diagnose FBP1D."
Supports sequencing as the practical diagnostic route given nonspecific clinical manifestations.
Enzyme activity assay in leukocytes or liver
Measurement of fructose-1,6-bisphosphatase activity in mononuclear white blood cells or liver confirms the enzymatic lesion. A leukocyte assay avoids liver biopsy and can be run on the same blood sample used for molecular analysis. NCIT has no clinical-action term for an enzyme activity assay, so the generic Diagnostic Procedure term is used with a specific preferred_term.
enzyme activity assay NCIT:C18020 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:25601412 SUPPORT Human Clinical
"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."
Directly supports the combined single-sample leukocyte enzyme plus molecular diagnostic strategy.
Urine organic acid analysis
Detection of glycerol or glycerol-3-phosphate on urine organic acid analysis is a practical trigger for targeted FBP1 testing in a child with recurrent hypoglycemia and acidosis.
urine organic acid analysis NCIT:C18020 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:29203193 SUPPORT Human Clinical
"In four patients, genetic study was prompted by detection of glycerol or glycerol-3-phosphate in urine organic acids analysis."
Directly supports urine organic acid analysis as the finding that prompted molecular diagnosis in over half the series.
📊

Prevalence

2
Chinese population
Point Prevalence 0.076 per 100,000 <1 in 1,000,000
Estimated at 1/1,310,034 from curated FBP1 variant allele frequencies in a Chinese cohort plus ChinaMAP and gnomAD, using carrier-frequency, permutation-combination, and Bayesian methods.
Show evidence (1 reference)
PMID:39036704 SUPPORT Human Clinical
"The estimated Chinese FBP1D prevalence was 1/1,310,034."
Reports the population point-prevalence estimate used for the normalized rate.
Worldwide
Birth Prevalence 0.11–0.29 per 100,000 1–9 per 1,000,000 (births)
Frequently quoted incidence range of 1/350,000 to 1/900,000; recorded as a range because the two bounds derive from different case ascertainment rather than a single population denominator.
Show evidence (1 reference)
PMID:28420223 SUPPORT Human Clinical
"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."
States the commonly cited incidence range for the disorder.
🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Fructose-1,6-Bisphosphatase Deficiency:

Hereditary Fructose Intolerance
Overlapping Features Also a defect of fructose metabolism (ALDOB), and both restrict fructose. The discriminators are that FBP1 deficiency causes hypoglycemia even without fructose exposure — it is a fasting disorder, not only a fructose-exposure disorder — and that hypoglycemia, metabolic acidosis, and seizures are significantly more common in FBP1 deficiency when the two are compared directly.
Show evidence (1 reference)
PMID:39036704 SUPPORT Human Clinical
"By comparing to phenotypes of HFI patients, FBP1D patients were more likely to present hypoglycemia, metabolic acidosis, and seizures (all p-value < 0.05)."
Provides a direct phenotypic comparison between the two fructose-metabolism disorders.
Mitochondrial disorders and glycogen storage diseases
Overlapping Features Because lactic acidosis with hypoglycemia and hepatomegaly is shared with mitochondrial energy defects and the hepatic glycogenoses, FBP1 deficiency is routinely misdiagnosed as one of these first, delaying diagnosis by years.
Show evidence (1 reference)
PMID:25601412 SUPPORT Human Clinical
"However, diagnosis was made late at a mean age of 3 years, as mitochondrial defects or glycogen storage diseases were firstly suspected."
Directly identifies the two disease groups that are mistakenly diagnosed first, and quantifies the resulting delay.
{ }

Source YAML

click to show 
name: Fructose-1,6-Bisphosphatase Deficiency
creation_date: "2026-08-01T22:30:00Z"
category: Metabolic Disorder
synonyms:
- FBPase deficiency
- FBP1 deficiency
- FBP1D
- Fructose-1,6-diphosphatase deficiency
description: >-
  Fructose-1,6-bisphosphatase (FBPase) deficiency is a rare autosomal recessive
  inborn error of gluconeogenesis caused by biallelic pathogenic variants in
  FBP1. FBPase catalyzes the hydrolysis of fructose-1,6-bisphosphate to
  fructose-6-phosphate, the penultimate committed step of hepatic
  gluconeogenesis. Loss of this step leaves the liver unable to generate glucose
  from lactate, glycerol, and gluconeogenic amino acids once glycogen stores are
  exhausted, so patients are well between episodes but decompensate acutely when
  a catabolic stress — fever, fasting, vomiting, intercurrent infection, or a
  large fructose load — raises gluconeogenic demand. The resulting crisis is a
  stereotyped combination of ketotic hypoglycemia and lactic acidosis with
  hyperventilation, apnea, seizures, and lethargy or coma. Hepatomegaly,
  transaminase elevation, and hepatic steatosis are also characteristic, and are
  increasingly recognized as persisting between crises rather than being confined
  to them. Management is preventive — avoidance of fasting, restriction of
  fructose, sucrose, glycerol, and sorbitol, and aggressive intravenous glucose
  during acute illness — and prognosis with treatment is generally good.
parents:
- hereditary disease
- metabolic disorder
- Inborn Error of Carbohydrate Metabolism
disease_term:
  preferred_term: fructose-1,6-bisphosphatase deficiency
  term:
    id: MONDO:0009251
    label: fructose-1,6-bisphosphatase deficiency
classifications:
  icimd_category:
  - classification_value: gluconeogenesis
    notes: >-
      FBP1 deficiency blocks the penultimate committed reaction of
      gluconeogenesis and is classified in the ICIMD gluconeogenesis category
      (WP-007).
references:
- reference: PMID:31804789
  title: Fructose-1,6-Bisphosphatase 1 Deficiency.
  tags:
  - GeneReviews
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    FBP1 deficiency is inherited in an autosomal recessive manner; affected
    individuals carry biallelic pathogenic FBP1 variants.
  evidence:
  - reference: PMID:31804789
    reference_title: Fructose-1,6-Bisphosphatase 1 Deficiency.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      FBP1 deficiency is inherited in an autosomal recessive manner.
    explanation: >-
      GeneReviews states the mode of inheritance directly. Evidence source is
      OTHER because GeneReviews is a synthesizing clinical review rather than a
      primary cohort report.
prevalence:
- population: Chinese population
  measure_type: POINT_PREVALENCE
  prevalence_class: BELOW_1_IN_1000000
  rate_per_100000: 0.076
  notes: >-
    Estimated at 1/1,310,034 from curated FBP1 variant allele frequencies in a
    Chinese cohort plus ChinaMAP and gnomAD, using carrier-frequency,
    permutation-combination, and Bayesian methods.
  evidence:
  - reference: PMID:39036704
    reference_title: >-
      Fructose-1,6-bisphosphatase deficiency: estimation of prevalence in the
      Chinese population and analysis of genotype-phenotype association.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The estimated Chinese FBP1D prevalence was 1/1,310,034.
    explanation: >-
      Reports the population point-prevalence estimate used for the normalized
      rate.
- population: Worldwide
  measure_type: BIRTH_PREVALENCE
  prevalence_class: BAND_1_9_PER_1000000
  rate_low: 0.11
  rate_high: 0.29
  notes: >-
    Frequently quoted incidence range of 1/350,000 to 1/900,000; recorded as a
    range because the two bounds derive from different case ascertainment rather
    than a single population denominator.
  evidence:
  - reference: PMID:28420223
    reference_title: >-
      Clinical and Molecular Characterization of Patients with Fructose
      1,6-Bisphosphatase Deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      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.
    explanation: >-
      States the commonly cited incidence range for the disorder.
pathophysiology:
- name: FBP1 Fructose-1,6-Bisphosphatase Deficiency
  biological_scale: MOLECULAR
  conforms_to: "metabolic_intoxication_decompensation#Enzymatic Block in Intermediary Metabolism"
  role: trigger
  description: >-
    Biallelic loss-of-function FBP1 variants deplete cytosolic
    fructose-1,6-bisphosphatase activity in the liver. The enzyme hydrolyzes
    fructose-1,6-bisphosphate to fructose-6-phosphate, the irreversible step that
    commits carbon to glucose synthesis rather than back to glycolysis, so its
    loss is an enzymatic block in the last steps of gluconeogenesis. Residual
    activity in patient leukocytes is typically under 10% of normal.
  genes:
  - preferred_term: FBP1
    term:
      id: hgnc:3606
      label: FBP1
  molecular_functions:
  - preferred_term: fructose 1,6-bisphosphate 1-phosphatase activity
    term:
      id: GO:0042132
      label: fructose 1,6-bisphosphate 1-phosphatase activity
    modifier: DECREASED
  biological_processes:
  - preferred_term: gluconeogenesis
    term:
      id: GO:0006094
      label: gluconeogenesis
    modifier: DECREASED
  cellular_components:
  - preferred_term: cytosol
    term:
      id: GO:0005829
      label: cytosol
  cell_types:
  - preferred_term: Hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  evidence:
  - reference: PMID:25601412
    reference_title: >-
      Fructose 1,6-bisphosphatase deficiency: clinical, biochemical and genetic
      features in French patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Disease is mainly revealed by hypoglycemia and lactic acidosis, both
      symptoms being characteristic for an enzymatic block in the last steps of
      the gluconeogenesis.
    explanation: >-
      Identifies the proximal lesion as an enzymatic block in the terminal steps
      of gluconeogenesis, the trigger node of this pathograph.
  - reference: PMID:25601412
    reference_title: >-
      Fructose 1,6-bisphosphatase deficiency: clinical, biochemical and genetic
      features in French patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Enzyme activity in leukocytes was dramatically decreased (<10%).
    explanation: >-
      Quantifies the residual enzyme activity in the French diagnostic cohort,
      supporting the DECREASED modifier on fructose 1,6-bisphosphate
      1-phosphatase activity.
  downstream:
  - target: Impaired Hepatic Gluconeogenesis
    causal_link_type: DIRECT
    description: >-
      Loss of the fructose-1,6-bisphosphatase step directly interrupts flux
      through hepatic gluconeogenesis.
    evidence:
    - reference: PMID:25601412
      reference_title: >-
        Fructose 1,6-bisphosphatase deficiency: clinical, biochemical and genetic
        features in French patients.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Disease is mainly revealed by hypoglycemia and lactic acidosis, both
        symptoms being characteristic for an enzymatic block in the last steps of
        the gluconeogenesis.
      explanation: >-
        Directly links the enzymatic block to failure of gluconeogenesis.
- name: Impaired Hepatic Gluconeogenesis
  biological_scale: CELLULAR
  description: >-
    With the fructose-1,6-bisphosphatase step blocked, the hepatocyte cannot
    convert lactate, glycerol, and gluconeogenic amino acids into glucose.
    Glycogenolysis still works, so glucose homeostasis is maintained in the fed
    and early-fasted state; the defect becomes clinically apparent only once
    glycogen stores run down and the liver must switch to de novo glucose
    production. Neonates are especially vulnerable because glycogen stores are
    small.
  biological_processes:
  - preferred_term: gluconeogenesis
    term:
      id: GO:0006094
      label: gluconeogenesis
    modifier: DECREASED
  - preferred_term: glucose homeostasis
    term:
      id: GO:0042593
      label: glucose homeostasis
    modifier: ABNORMAL
  cell_types:
  - preferred_term: Hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  evidence:
  - reference: PMID:31804789
    reference_title: Fructose-1,6-Bisphosphatase 1 Deficiency.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Acute crises are most common in early childhood; nearly half of affected
      children have hypoglycemia in the neonatal period (especially the first
      four days) resulting from deficient glycogen stores.
    explanation: >-
      Attributes neonatal hypoglycemia specifically to exhaustion of glycogen
      stores in the setting of a gluconeogenic block, supporting the
      glycogen-dependent buffering described in this node. Evidence source is
      OTHER because GeneReviews is a synthesizing review.
  downstream:
  - target: Gluconeogenic Substrate Accumulation and Energy Deficit
    causal_link_type: DIRECT
    description: >-
      Carbon entering gluconeogenesis stalls proximal to the block, so lactate,
      glycerol, and glycerol-3-phosphate accumulate while glucose output falls.
    evidence:
    - reference: PMID:29203193
      reference_title: >-
        Fructose-1,6-bisphosphatase deficiency as a cause of recurrent
        hypoglycemia and metabolic acidosis: Clinical and molecular findings in
        Malaysian patients.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        In four patients, genetic study was prompted by detection of glycerol or
        glycerol-3-phosphate in urine organic acids analysis.
      explanation: >-
        Detection of urinary glycerol and glycerol-3-phosphate is direct human
        evidence that gluconeogenic substrates accumulate behind the block.
  - target: Fasting Hypoglycemia
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Once hepatic glycogen is exhausted, the blocked gluconeogenic pathway
      cannot sustain blood glucose.
    intermediate_mechanisms:
    - Depletion of hepatic glycogen stores during fasting or catabolic stress removes the glycogenolytic buffer that masks the gluconeogenic block.
    evidence:
    - reference: PMID:31804789
      reference_title: Fructose-1,6-Bisphosphatase 1 Deficiency.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Acute crises are most common in early childhood; nearly half of affected
        children have hypoglycemia in the neonatal period (especially the first
        four days) resulting from deficient glycogen stores.
      explanation: >-
        Names glycogen-store depletion as the intermediate that converts the
        gluconeogenic block into hypoglycemia. Evidence source is OTHER because
        GeneReviews is a synthesizing review.
- name: Gluconeogenic Substrate Accumulation and Energy Deficit
  biological_scale: ORGANISM
  conforms_to: "metabolic_intoxication_decompensation#Toxic Metabolite Accumulation and Energy Deficit"
  role: amplifier
  description: >-
    Substrates that would normally be consumed by gluconeogenesis build up behind
    the block. Lactate accumulates and drives a high-anion-gap lactic acidosis;
    glycerol and glycerol-3-phosphate spill into urine (and can produce spurious
    pseudo-hypertriglyceridemia on glycerol-blanked triglyceride assays); urate
    rises. A catabolic stress — fever, fasting, reduced intake, vomiting,
    infection, or a large fructose load — sharply increases demand for hepatic
    glucose output and converts the compensated state into a crisis.
  biological_processes:
  - preferred_term: generation of precursor metabolites and energy
    term:
      id: GO:0006091
      label: generation of precursor metabolites and energy
    modifier: DECREASED
  - preferred_term: fructose metabolic process
    term:
      id: GO:0006000
      label: fructose metabolic process
    modifier: ABNORMAL
  cell_types:
  - preferred_term: Hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  evidence:
  - reference: PMID:29203193
    reference_title: >-
      Fructose-1,6-bisphosphatase deficiency as a cause of recurrent hypoglycemia
      and metabolic acidosis: Clinical and molecular findings in Malaysian
      patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      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.
    explanation: >-
      Documents accumulation of gluconeogenic substrates proximal to the block,
      including the glycerol-driven pseudo-hypertriglyceridemia artifact.
  - reference: PMID:31804789
    reference_title: Fructose-1,6-Bisphosphatase 1 Deficiency.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Common factors known to trigger episodes include fever, fasting, decreased
      oral intake, vomiting, infections, and ingestion of large amounts of
      fructose.
    explanation: >-
      Identifies the catabolic and fructose-load stressors that amplify the block
      into an acute crisis. Evidence source is OTHER because GeneReviews is a
      synthesizing review.
  downstream:
  - target: Acute Metabolic Decompensation
    causal_link_type: DIRECT
    description: >-
      Accumulating lactate plus failure of glucose output produces the acute
      decompensated state.
    evidence:
    - reference: PMID:25601412
      reference_title: >-
        Fructose 1,6-bisphosphatase deficiency: clinical, biochemical and genetic
        features in French patients.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        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.
      explanation: >-
        Links catabolic triggers acting on the metabolic block to the onset of
        decompensation.
  - target: Hepatic Steatosis and Liver Injury
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Chronic carbon accumulation behind the block is associated with fatty liver,
      but the connecting steps are not established. Endoplasmic reticulum stress
      and de novo lipogenesis activation have been postulated on the basis of
      Fbp1 knockout mice; this edge is deliberately typed as having unknown
      intermediates.
    hypothesis_groups:
    - fbp1_steatosis_er_stress_dnl
    evidence:
    - reference: PMID:34687058
      reference_title: >-
        Fructose-1,6-bisphosphatase deficiency causes fatty liver disease and
        requires long-term hepatic follow-up.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        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.
      explanation: >-
        The authors state explicitly that no clear pathophysiological basis is
        known and offer a mouse-derived postulate, so the intermediate steps of
        this edge are unknown. Graded INDIRECT because the quote reaches this
        edge only through an extrapolation from Fbp1 knockout mice, which is
        also why the edge is typed as having unknown intermediates.
- name: Fasting Hypoglycemia
  biological_scale: ORGANISM
  description: >-
    Blood glucose falls when fasting outlasts hepatic glycogen. Because
    lipolysis and ketogenesis remain intact, the hypoglycemia is ketotic — a key
    discriminator from fatty-acid oxidation defects, which give hypoketotic
    hypoglycemia. Between episodes children are asymptomatic and normoglycemic.
  biological_processes:
  - preferred_term: glucose homeostasis
    term:
      id: GO:0042593
      label: glucose homeostasis
    modifier: ABNORMAL
  evidence:
  - reference: PMID:31804789
    reference_title: Fructose-1,6-Bisphosphatase 1 Deficiency.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Fructose-1,6-bisphosphatase 1 (FBP1) deficiency is characterized by
      episodic acute crises of lactic acidosis and ketotic hypoglycemia,
      manifesting as respiratory distress or hyperventilation, apneic spells,
      seizures, and/or lethargy/coma.
    explanation: >-
      Establishes ketotic hypoglycemia as the defining episodic metabolic
      abnormality. Evidence source is OTHER because GeneReviews is a synthesizing
      review.
  - reference: PMID:31804789
    reference_title: Fructose-1,6-Bisphosphatase 1 Deficiency.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In between acute episodes, children are asymptomatic.
    explanation: >-
      Supports the episodic rather than continuous character of the
      hypoglycemia. Evidence source is OTHER because GeneReviews is a
      synthesizing review.
  downstream:
  - target: Acute Metabolic Decompensation
    causal_link_type: DIRECT
    description: >-
      Hypoglycemia is one of the two defining biochemical components of the
      decompensated crisis.
    evidence:
    - reference: PMID:31804789
      reference_title: Fructose-1,6-Bisphosphatase 1 Deficiency.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Fructose-1,6-bisphosphatase 1 (FBP1) deficiency is characterized by
        episodic acute crises of lactic acidosis and ketotic hypoglycemia,
        manifesting as respiratory distress or hyperventilation, apneic spells,
        seizures, and/or lethargy/coma.
      explanation: >-
        Pairs ketotic hypoglycemia with lactic acidosis as the crisis phenotype.
        Evidence source is OTHER because GeneReviews is a synthesizing review.
- name: Acute Metabolic Decompensation
  biological_scale: ORGANISM
  conforms_to: "metabolic_intoxication_decompensation#Acute Metabolic Decompensation"
  role: central_effector
  description: >-
    The central effector is a stereotyped crisis of ketotic hypoglycemia plus
    high-anion-gap lactic acidosis, usually with hepatomegaly and transaminase
    elevation. Unlike the urea-cycle and organic-acidemia conformers of this
    module, hyperammonemia is not a feature; the acid load is lactate and
    ketoacid. First decompensation is almost always before two years of age.
  biological_processes:
  - preferred_term: glucose homeostasis
    term:
      id: GO:0042593
      label: glucose homeostasis
    modifier: ABNORMAL
  evidence:
  - reference: PMID:29203193
    reference_title: >-
      Fructose-1,6-bisphosphatase deficiency as a cause of recurrent hypoglycemia
      and metabolic acidosis: Clinical and molecular findings in Malaysian
      patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All the patients presented with recurrent episodes of hypoglycemia,
      metabolic acidosis, hyperlactacidemia and hepatomegaly.
    explanation: >-
      Defines the composite decompensation phenotype in a molecularly confirmed
      patient series.
  - reference: PMID:29203193
    reference_title: >-
      Fructose-1,6-bisphosphatase deficiency as a cause of recurrent hypoglycemia
      and metabolic acidosis: Clinical and molecular findings in Malaysian
      patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All of them had the first metabolic decompensation prior to 2 years old.
      The common triggering factors were vomiting and infection.
    explanation: >-
      Supports the early-childhood timing and the catabolic triggers of the
      decompensated state.
  downstream:
  - target: Acute Metabolic Encephalopathy and Multiorgan Crisis
    causal_link_type: DIRECT
    description: >-
      Neuroglycopenia and acidosis produce the neurologic and systemic
      manifestations of the crisis.
    evidence:
    - reference: PMID:31804789
      reference_title: Fructose-1,6-Bisphosphatase 1 Deficiency.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Fructose-1,6-bisphosphatase 1 (FBP1) deficiency is characterized by
        episodic acute crises of lactic acidosis and ketotic hypoglycemia,
        manifesting as respiratory distress or hyperventilation, apneic spells,
        seizures, and/or lethargy/coma.
      explanation: >-
        Enumerates the neurologic and respiratory manifestations that the
        decompensated state produces. Evidence source is OTHER because
        GeneReviews is a synthesizing review.
- name: Hepatic Steatosis and Liver Injury
  biological_scale: TISSUE
  description: >-
    Liver involvement is near-universal and is not confined to crises. In a
    French series every one of 18 patients had liver abnormalities — hepatomegaly
    (8/18), transaminase elevation (6/15), or a bright (steatotic) liver on
    ultrasound (7/11) — during routine follow-up as well as during acute episodes
    (hepatomegaly 10/17, transaminase elevation 13/16, bright liver 4/14), and
    acute liver failure occurred in 6/14 during crises. This reframes FBP1
    deficiency as a chronic hepatic disorder warranting long-term liver
    surveillance, not only an episodic hypoglycemic one.
  cell_types:
  - preferred_term: Hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  evidence:
  - reference: PMID:34687058
    reference_title: >-
      Fructose-1,6-bisphosphatase deficiency causes fatty liver disease and
      requires long-term hepatic follow-up.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Interestingly, all 18 patients had liver abnormalities either during
      follow-up
    explanation: >-
      Establishes that liver abnormalities were universal in the 18-patient
      multicenter series and occurred on routine follow-up, not only during
      crises. The per-finding counts quoted in the node description come from the
      bracketed figures in the same sentence.
- name: Acute Metabolic Encephalopathy and Multiorgan Crisis
  biological_scale: ORGANISM
  conforms_to: "metabolic_intoxication_decompensation#Neurological Injury and Multiorgan Crisis"
  role: consequence
  description: >-
    Neuroglycopenia combined with lactic acidosis produces hyperventilation,
    apneic spells, seizures, and lethargy or coma. Most treated children have
    normal growth and psychomotor development, but profound or prolonged
    hypoglycemia can leave permanent neurological deficit, and untreated
    continued catabolism progresses to multiorgan failure involving liver, brain,
    and later heart, with high mortality.
  evidence:
  - reference: PMID:31804789
    reference_title: Fructose-1,6-Bisphosphatase 1 Deficiency.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In untreated individuals, clinical manifestations worsen progressively as
      continued catabolism leads to multiorgan failure (especially liver, brain,
      and later heart).
    explanation: >-
      Supports progression from decompensation to multiorgan crisis when
      untreated. Evidence source is OTHER because GeneReviews is a synthesizing
      review.
  - reference: PMID:29203193
    reference_title: >-
      Fructose-1,6-bisphosphatase deficiency as a cause of recurrent hypoglycemia
      and metabolic acidosis: Clinical and molecular findings in Malaysian
      patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      One patient had short stature and another had neurological deficit
      following status epilepticus due to profound hypoglycemia.
    explanation: >-
      Documents permanent neurological injury attributable to profound
      hypoglycemia in a molecularly confirmed patient.
mechanistic_hypotheses:
- hypothesis_group_id: fbp1_steatosis_er_stress_dnl
  hypothesis_label: ER stress and de novo lipogenesis as the basis of FBP1-deficiency fatty liver
  status: EMERGING
  description: >-
    The steatosis of FBP1 deficiency has no established pathophysiological
    explanation. The leading proposal, extrapolated from Fbp1 knockout mice, is
    that the gluconeogenic block drives endoplasmic reticulum stress and
    activation of de novo lipogenesis in hepatocytes. This has not been
    demonstrated in human liver tissue.
  evidence:
  - reference: PMID:34687058
    reference_title: >-
      Fructose-1,6-bisphosphatase deficiency causes fatty liver disease and
      requires long-term hepatic follow-up.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      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.
    explanation: >-
      States both the absence of an established mechanism and the specific
      mouse-derived hypothesis. Graded INDIRECT because the mechanism is offered
      as a postulate extrapolated from Fbp1 knockout mice and has not been
      demonstrated in human liver tissue.
discussions:
- discussion_id: fbp1_steatosis_mechanism_model_translation
  prompt: >-
    Does the endoplasmic reticulum stress and de novo lipogenesis mechanism
    observed in Fbp1 knockout mice actually account for the fatty liver seen in
    human FBP1 deficiency?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Hepatic Steatosis and Liver Injury
  rationale: >-
    Human evidence establishes that steatosis is present and clinically important
    (all 18 patients in the French series had liver abnormalities), but the
    proposed mechanism rests entirely on an Fbp1 knockout mouse and is stated by
    the authors as a postulate. Mice tolerate the gluconeogenic block differently
    from humans and the human hepatic lipid phenotype has not been
    mechanistically characterized, so the translational validity of the
    ER-stress/DNL chain is the open question rather than the existence of the
    phenotype.
  proposed_experiments:
  - experiment_id: fbp1_human_liver_er_stress_dnl
    name: ER stress and de novo lipogenesis profiling in human FBP1-deficient liver
    description: >-
      Characterize endoplasmic reticulum stress markers and de novo lipogenesis
      flux in liver biopsy or explant tissue from individuals with FBP1
      deficiency, against age-matched non-steatotic control liver.
    decision_criterion: >-
      Elevated ER-stress markers and increased lipogenic flux in human
      FBP1-deficient liver would support the mouse-derived mechanism; their
      absence would refute it and require an alternative explanation for the
      steatosis.
  - experiment_id: fbp1_mouse_human_liver_omics_comparison
    name: Cross-species hepatic lipidomic and transcriptomic comparison
    description: >-
      Compare hepatic lipidomic and transcriptomic signatures between
      FBP1-deficient human liver and Fbp1 knockout mouse liver to establish which
      features of the mouse phenotype are conserved in humans.
    decision_criterion: >-
      Concordant lipid species and lipogenic transcriptional programs across
      species would justify using the mouse as a mechanistic model; divergence
      would bound its translational use.
  - experiment_id: fbp1_steatosis_metabolic_control_cohort
    name: Longitudinal association of steatosis severity with metabolic control
    description: >-
      Determine whether steatosis severity tracks with metabolic control (fasting
      avoidance, fructose and sucrose restriction, crisis frequency) in a
      longitudinal patient cohort with serial hepatic imaging.
    decision_criterion: >-
      If steatosis severity is independent of metabolic control, the fatty liver
      is a constitutive consequence of the enzyme defect rather than of
      accumulated decompensations.
phenotypes:
- name: Hypoglycemia
  description: >-
    Recurrent hypoglycemia, ketotic in character, is the cardinal manifestation
    and typically the presenting problem.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Ketotic hypoglycemia
    term:
      id: HP:0012734
      label: Ketotic hypoglycemia
  evidence:
  - reference: PMID:31804789
    reference_title: Fructose-1,6-Bisphosphatase 1 Deficiency.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Fructose-1,6-bisphosphatase 1 (FBP1) deficiency is characterized by
      episodic acute crises of lactic acidosis and ketotic hypoglycemia,
      manifesting as respiratory distress or hyperventilation, apneic spells,
      seizures, and/or lethargy/coma.
    explanation: >-
      Names ketotic hypoglycemia as a defining feature of the disorder. Evidence
      source is OTHER because GeneReviews is a synthesizing review.
  - reference: PMID:29203193
    reference_title: >-
      Fructose-1,6-bisphosphatase deficiency as a cause of recurrent hypoglycemia
      and metabolic acidosis: Clinical and molecular findings in Malaysian
      patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All the patients presented with recurrent episodes of hypoglycemia,
      metabolic acidosis, hyperlactacidemia and hepatomegaly.
    explanation: >-
      All seven molecularly confirmed patients had recurrent hypoglycemia,
      supporting the VERY_FREQUENT band.
- name: Lactic Acidosis
  description: >-
    High-anion-gap lactic acidosis accompanies the hypoglycemic crises and
    reflects lactate accumulation behind the gluconeogenic block.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Lactic acidosis
    term:
      id: HP:0003128
      label: Lactic acidosis
  evidence:
  - reference: PMID:29203193
    reference_title: >-
      Fructose-1,6-bisphosphatase deficiency as a cause of recurrent hypoglycemia
      and metabolic acidosis: Clinical and molecular findings in Malaysian
      patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All the patients presented with recurrent episodes of hypoglycemia,
      metabolic acidosis, hyperlactacidemia and hepatomegaly.
    explanation: >-
      Hyperlactacidemia with metabolic acidosis was present in all patients in
      the series, supporting the VERY_FREQUENT band.
- name: Metabolic Acidosis
  description: >-
    High-anion-gap metabolic acidosis, driven by lactate and ketoacids, is a core
    laboratory feature of the acute crisis.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Metabolic acidosis
    term:
      id: HP:0001942
      label: Metabolic acidosis
  evidence:
  - reference: PMID:28420223
    reference_title: >-
      Clinical and Molecular Characterization of Patients with Fructose
      1,6-Bisphosphatase Deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The present study describes the clinical features of four Chinese pediatric
      patients who presented with hypoglycemia, hyperlactacidemia, metabolic
      acidosis, and hyperuricemia.
    explanation: >-
      Metabolic acidosis was present in all four molecularly characterized
      patients.
- name: Hepatomegaly
  description: >-
    Liver enlargement is present both during acute crises (10/17 patients) and on
    interval follow-up (8/18 patients).
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Hepatomegaly
    term:
      id: HP:0002240
      label: Hepatomegaly
  evidence:
  - reference: PMID:29203193
    reference_title: >-
      Fructose-1,6-bisphosphatase deficiency as a cause of recurrent hypoglycemia
      and metabolic acidosis: Clinical and molecular findings in Malaysian
      patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All the patients presented with recurrent episodes of hypoglycemia,
      metabolic acidosis, hyperlactacidemia and hepatomegaly.
    explanation: >-
      Hepatomegaly was present in all seven patients of the Malaysian series;
      the larger French series found it in a majority but not all, so the band is
      set to FREQUENT rather than VERY_FREQUENT.
- name: Hepatic Steatosis
  description: >-
    Fatty liver, detected as a bright liver on ultrasound or as steatosis on
    biopsy, is characteristic and can persist between crises.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Hepatic steatosis
    term:
      id: HP:0001397
      label: Hepatic steatosis
  evidence:
  - reference: PMID:34687058
    reference_title: >-
      Fructose-1,6-bisphosphatase deficiency causes fatty liver disease and
      requires long-term hepatic follow-up.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Initial reports described cases of liver steatosis, when liver biopsy was
      necessary to confirm the diagnosis by an enzymatic study.
    explanation: >-
      Documents hepatic steatosis on biopsy in the disorder; the bright-liver
      counts reported in the same series (7/11 on follow-up, 4/14 during crises)
      support the FREQUENT band.
- name: Elevated Hepatic Transaminases
  description: >-
    Transaminase elevation occurs in the majority of patients during acute crises
    (13/16) and in a substantial fraction between them (6/15).
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Elevated circulating hepatic transaminase concentration
    term:
      id: HP:0002910
      label: Elevated circulating hepatic transaminase concentration
  evidence:
  - reference: PMID:34687058
    reference_title: >-
      Fructose-1,6-bisphosphatase deficiency causes fatty liver disease and
      requires long-term hepatic follow-up.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Interestingly, all 18 patients had liver abnormalities either during
      follow-up
    explanation: >-
      Establishes universal liver involvement in the series; transaminase
      elevation is one of the three enumerated abnormalities, with the counts
      given parenthetically in the same sentence.
- name: Acute Hepatic Failure
  description: >-
    Acute liver failure can complicate a metabolic crisis; it was reported in
    6 of 14 patients evaluated during acute crises in the French hepatic
    follow-up cohort.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Acute hepatic failure
    term:
      id: HP:0006554
      label: Acute hepatic failure
  evidence:
  - reference: PMID:34687058
    reference_title: >-
      Fructose-1,6-bisphosphatase deficiency causes fatty liver disease and
      requires long-term hepatic follow-up.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      acute liver failure [n = 6/14] ... bright liver [n = 4/14]
    explanation: >-
      Directly reports acute liver failure in 6 of 14 patients assessed during
      acute crises.
- name: Hyperuricemia
  description: >-
    Urate elevation accompanies the metabolic crisis, reflecting increased
    nucleotide turnover and reduced renal urate clearance in the setting of
    lactic acidosis.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Hyperuricemia
    term:
      id: HP:0002149
      label: Hyperuricemia
  evidence:
  - reference: PMID:28420223
    reference_title: >-
      Clinical and Molecular Characterization of Patients with Fructose
      1,6-Bisphosphatase Deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The present study describes the clinical features of four Chinese pediatric
      patients who presented with hypoglycemia, hyperlactacidemia, metabolic
      acidosis, and hyperuricemia.
    explanation: >-
      Hyperuricemia was part of the presenting biochemical picture in all four
      patients.
- name: Hyperventilation
  description: >-
    Respiratory compensation for the metabolic acidosis presents as
    hyperventilation or respiratory distress during crises.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Hyperventilation
    term:
      id: HP:0002883
      label: Hyperventilation
  evidence:
  - reference: PMID:31804789
    reference_title: Fructose-1,6-Bisphosphatase 1 Deficiency.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Fructose-1,6-bisphosphatase 1 (FBP1) deficiency is characterized by
      episodic acute crises of lactic acidosis and ketotic hypoglycemia,
      manifesting as respiratory distress or hyperventilation, apneic spells,
      seizures, and/or lethargy/coma.
    explanation: >-
      Lists hyperventilation among the manifestations of the acute crisis.
      Evidence source is OTHER because GeneReviews is a synthesizing review.
- name: Apnea
  description: >-
    Apneic spells occur during acute crises, particularly in infants.
  phenotype_term:
    preferred_term: Apnea
    term:
      id: HP:0002104
      label: Apnea
  evidence:
  - reference: PMID:31804789
    reference_title: Fructose-1,6-Bisphosphatase 1 Deficiency.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Fructose-1,6-bisphosphatase 1 (FBP1) deficiency is characterized by
      episodic acute crises of lactic acidosis and ketotic hypoglycemia,
      manifesting as respiratory distress or hyperventilation, apneic spells,
      seizures, and/or lethargy/coma.
    explanation: >-
      Lists apneic spells among the crisis manifestations. Frequency is omitted
      because no source quantifies it. Evidence source is OTHER because
      GeneReviews is a synthesizing review.
- name: Seizure
  description: >-
    Seizures occur during hypoglycemic and acidotic crises; status epilepticus
    from profound hypoglycemia can cause permanent deficit.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:39036704
    reference_title: >-
      Fructose-1,6-bisphosphatase deficiency: estimation of prevalence in the
      Chinese population and analysis of genotype-phenotype association.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      By comparing to phenotypes of HFI patients, FBP1D patients were more likely
      to present hypoglycemia, metabolic acidosis, and seizures (all p-value <
      0.05).
    explanation: >-
      Seizures were significantly enriched in FBP1 deficiency relative to
      hereditary fructose intolerance across 122 collected patients.
- name: Lethargy
  description: >-
    Lethargy progressing to coma reflects neuroglycopenia during decompensation.
  phenotype_term:
    preferred_term: Lethargy
    term:
      id: HP:0001254
      label: Lethargy
  evidence:
  - reference: PMID:31804789
    reference_title: Fructose-1,6-Bisphosphatase 1 Deficiency.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Fructose-1,6-bisphosphatase 1 (FBP1) deficiency is characterized by
      episodic acute crises of lactic acidosis and ketotic hypoglycemia,
      manifesting as respiratory distress or hyperventilation, apneic spells,
      seizures, and/or lethargy/coma.
    explanation: >-
      Lists lethargy and coma among the crisis manifestations. Evidence source is
      OTHER because GeneReviews is a synthesizing review.
- name: Intellectual Disability
  description: >-
    A minority of affected children have intellectual disability, attributed to
    early and prolonged hypoglycemia rather than to a primary developmental
    effect of the enzyme defect.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:31804789
    reference_title: Fructose-1,6-Bisphosphatase 1 Deficiency.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      While the majority of affected children have normal growth and psychomotor
      development, a few have intellectual disability, presumably due to early
      and prolonged hypoglycemia.
    explanation: >-
      "A few" against a majority-normal background supports the OCCASIONAL band.
      Evidence source is OTHER because GeneReviews is a synthesizing review.
biochemical:
- name: Lactate
  presence: INCREASED
  context: >-
    Elevated blood lactate is a core laboratory hallmark of the acute crisis and
    reports accumulation of gluconeogenic substrate behind the FBPase block.
  evidence:
  - reference: PMID:29203193
    reference_title: >-
      Fructose-1,6-bisphosphatase deficiency as a cause of recurrent hypoglycemia
      and metabolic acidosis: Clinical and molecular findings in Malaysian
      patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All the patients presented with recurrent episodes of hypoglycemia,
      metabolic acidosis, hyperlactacidemia and hepatomegaly.
    explanation: >-
      Hyperlactacidemia in all patients supports elevated lactate as a core
      biochemical finding.
  readouts:
  - target: Gluconeogenic Substrate Accumulation and Energy Deficit
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Rising lactate reports accumulation of gluconeogenic carbon proximal to the
      fructose-1,6-bisphosphatase step.
    evidence:
    - reference: PMID:25601412
      reference_title: >-
        Fructose 1,6-bisphosphatase deficiency: clinical, biochemical and genetic
        features in French patients.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Disease is mainly revealed by hypoglycemia and lactic acidosis, both
        symptoms being characteristic for an enzymatic block in the last steps of
        the gluconeogenesis.
      explanation: >-
        Explicitly interprets lactic acidosis as characteristic of the terminal
        gluconeogenic block.
- name: Glucose
  presence: DECREASED
  context: >-
    Low blood glucose during fasting or catabolic stress, with preserved ketone
    production.
  evidence:
  - reference: PMID:31804789
    reference_title: Fructose-1,6-Bisphosphatase 1 Deficiency.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Fructose-1,6-bisphosphatase 1 (FBP1) deficiency is characterized by
      episodic acute crises of lactic acidosis and ketotic hypoglycemia,
      manifesting as respiratory distress or hyperventilation, apneic spells,
      seizures, and/or lethargy/coma.
    explanation: >-
      Establishes hypoglycemia as a defining biochemical abnormality. Evidence
      source is OTHER because GeneReviews is a synthesizing review.
  readouts:
  - target: Fasting Hypoglycemia
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Falling glucose during fasting reports failure of hepatic glucose output
      once glycogen is exhausted.
    evidence:
    - reference: PMID:31804789
      reference_title: Fructose-1,6-Bisphosphatase 1 Deficiency.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Acute crises are most common in early childhood; nearly half of affected
        children have hypoglycemia in the neonatal period (especially the first
        four days) resulting from deficient glycogen stores.
      explanation: >-
        Ties measured hypoglycemia to glycogen exhaustion unmasking the
        gluconeogenic block. Evidence source is OTHER because GeneReviews is a
        synthesizing review.
- name: Urinary glycerol and glycerol-3-phosphate
  presence: INCREASED
  context: >-
    Glycerol and glycerol-3-phosphate on urine organic acid analysis are a
    practical diagnostic clue and can trigger molecular testing; the same
    glycerol elevation can produce spurious pseudo-hypertriglyceridemia.
  evidence:
  - reference: PMID:29203193
    reference_title: >-
      Fructose-1,6-bisphosphatase deficiency as a cause of recurrent hypoglycemia
      and metabolic acidosis: Clinical and molecular findings in Malaysian
      patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      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.
    explanation: >-
      Documents both the urinary finding and the pseudo-hypertriglyceridemia
      artifact in molecularly confirmed patients.
  readouts:
  - target: Gluconeogenic Substrate Accumulation and Energy Deficit
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Urinary glycerol species report accumulation of a gluconeogenic substrate
      that cannot be consumed once the FBPase step is blocked.
    evidence:
    - reference: PMID:39036704
      reference_title: >-
        Fructose-1,6-bisphosphatase deficiency: estimation of prevalence in the
        Chinese population and analysis of genotype-phenotype association.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The genotype-phenotype association analyses showed that patients carrying
        homozygous c.841G>A were more likely to present increased urinary
        glycerol
      explanation: >-
        Independently confirms increased urinary glycerol as an FBP1-deficiency
        biochemical phenotype and links it to genotype.
- name: Uric acid
  presence: INCREASED
  context: >-
    Hyperuricemia is part of the presenting biochemical profile during metabolic
    crises.
  evidence:
  - reference: PMID:28420223
    reference_title: >-
      Clinical and Molecular Characterization of Patients with Fructose
      1,6-Bisphosphatase Deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The present study describes the clinical features of four Chinese pediatric
      patients who presented with hypoglycemia, hyperlactacidemia, metabolic
      acidosis, and hyperuricemia.
    explanation: >-
      Hyperuricemia was documented in all four molecularly characterized
      patients.
- name: Fructose-1,6-bisphosphatase enzyme activity
  presence: DECREASED
  context: >-
    Enzyme activity measured in liver or mononuclear white blood cells is
    dramatically reduced and is diagnostic; a single blood sample can support
    simultaneous enzyme assay and molecular analysis.
  evidence:
  - reference: PMID:25601412
    reference_title: >-
      Fructose 1,6-bisphosphatase deficiency: clinical, biochemical and genetic
      features in French patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Enzyme activity in leukocytes was dramatically decreased (<10%).
    explanation: >-
      Directly supports reduced enzyme activity as the biochemical readout of the
      molecular lesion.
  readouts:
  - target: FBP1 Fructose-1,6-Bisphosphatase Deficiency
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Leukocyte or hepatic FBPase activity below about 10% of normal reports the
      primary enzymatic lesion.
    evidence:
    - reference: PMID:31804789
      reference_title: Fructose-1,6-Bisphosphatase 1 Deficiency.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        The diagnosis of FBP1 deficiency is established in a proband with
        suggestive clinical and metabolic findings and biallelic pathogenic
        variants in FBP1 identified by molecular genetic testing and/or deficient
        FBP1 activity in liver or mononuclear white blood cells.
      explanation: >-
        Establishes deficient FBP1 activity in liver or leukocytes as a
        diagnostic readout of the lesion. Evidence source is OTHER because
        GeneReviews is a synthesizing review.
genetic:
- name: FBP1
  association: Causal biallelic variant
  relationship_type: CAUSATIVE
  gene_term:
    preferred_term: FBP1
    term:
      id: hgnc:3606
      label: FBP1
  notes: >-
    Fructose-1,6-bisphosphatase deficiency is caused by biallelic pathogenic
    variants in FBP1. The reported spectrum includes missense, frameshift,
    splice-site, and copy-number variants, including whole-exon and intragenic
    deletions; population-specific hotspots exist (c.490G>A and c.355G>A are
    enriched in Chinese individuals).
  evidence:
  - reference: PMID:29203193
    reference_title: >-
      Fructose-1,6-bisphosphatase deficiency as a cause of recurrent hypoglycemia
      and metabolic acidosis: Clinical and molecular findings in Malaysian
      patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Biallelic mutations in FBP1 gene (MIM*611570) were identified in all seven
      patients confirming the diagnosis of FBPase deficiency.
    explanation: >-
      Directly supports FBP1 as the causal gene with biallelic inheritance in a
      molecularly confirmed series.
  - reference: PMID:25601412
    reference_title: >-
      Fructose 1,6-bisphosphatase deficiency: clinical, biochemical and genetic
      features in French patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We described the first intragenic deletion in FBP1
      (g.97,364,754_97,382,011del) in homozygous state.
    explanation: >-
      Supports copy-number variation as part of the FBP1 mutational spectrum,
      which matters because exon-level deletions are missed by sequencing alone.
  - reference: PMID:39036704
    reference_title: >-
      Fructose-1,6-bisphosphatase deficiency: estimation of prevalence in the
      Chinese population and analysis of genotype-phenotype association.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In the Chinese population, c.490G>A and c.355G>A had significantly higher
      AFs than in the non-Finland European population
    explanation: >-
      Supports population-specific FBP1 variant hotspots.
environmental:
- name: Fasting and catabolic stress
  description: >-
    Fever, fasting, decreased oral intake, vomiting, and intercurrent infection
    raise demand for hepatic gluconeogenesis and precipitate acute crises. These
    are the dominant triggers in every reported series.
  influences_mechanisms:
  - target: Acute Metabolic Decompensation
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      Fasting, fever, reduced intake, vomiting, and infection directly
      precipitate acute metabolic decompensation when glycogen is exhausted and
      gluconeogenic demand rises.
    evidence:
    - reference: PMID:31804789
      reference_title: Fructose-1,6-Bisphosphatase 1 Deficiency.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Common factors known to trigger episodes include fever, fasting, decreased
        oral intake, vomiting, infections, and ingestion of large amounts of
        fructose.
      explanation: >-
        Directly supports the link from fasting and catabolic stress to acute
        metabolic decompensation. Evidence source is OTHER because GeneReviews is
        a synthesizing review.
  evidence:
  - reference: PMID:31804789
    reference_title: Fructose-1,6-Bisphosphatase 1 Deficiency.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Common factors known to trigger episodes include fever, fasting, decreased
      oral intake, vomiting, infections, and ingestion of large amounts of
      fructose.
    explanation: >-
      Enumerates the catabolic triggers. Evidence source is OTHER because
      GeneReviews is a synthesizing review.
  - reference: PMID:25601412
    reference_title: >-
      Fructose 1,6-bisphosphatase deficiency: clinical, biochemical and genetic
      features in French patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      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.
    explanation: >-
      Independently confirms the trigger profile in the French cohort.
- name: Large fructose load
  description: >-
    Ingestion of a large amount of fructose precipitates crises. Small amounts
    (up to about 2 g/kg/day) are generally tolerated, but a single high dose
    (>1 g/kg) is harmful, especially in young children — which is also why
    diagnostic fructose challenge testing is contraindicated.
  influences_mechanisms:
  - target: Acute Metabolic Decompensation
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      A large fructose load directly precipitates acute metabolic
      decompensation in FBPase deficiency.
    evidence:
    - reference: PMID:31804789
      reference_title: Fructose-1,6-Bisphosphatase 1 Deficiency.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Although small amounts of fructose (≤2 g/kg/day) are generally well
        tolerated, single ingestion of a high dose of fructose (>1g/kg) is harmful,
        especially in younger children.
      explanation: >-
        Directly supports the link from a large fructose load to acute metabolic
        decompensation. Evidence source is OTHER because GeneReviews is a
        synthesizing review.
  evidence:
  - reference: PMID:31804789
    reference_title: Fructose-1,6-Bisphosphatase 1 Deficiency.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Although small amounts of fructose (≤2 g/kg/day) are generally well
      tolerated, single ingestion of a high dose of fructose (>1g/kg) is harmful,
      especially in younger children.
    explanation: >-
      Quantifies the fructose exposure threshold that triggers harm. Evidence
      source is OTHER because GeneReviews is a synthesizing review.
treatments:
- name: Acute intravenous glucose and bicarbonate
  description: >-
    Acute crises are treated with intravenous glucose, transitioning to feeds as
    tolerated, with sodium bicarbonate added if acidemia requires correction.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
    therapeutic_agent:
    - preferred_term: glucose
      term:
        id: CHEBI:17234
        label: glucose
  target_mechanisms:
  - target: Fasting Hypoglycemia
    treatment_effect: BYPASSES
    description: >-
      Exogenous glucose supplies the glucose that the blocked gluconeogenic
      pathway cannot produce.
    evidence:
    - reference: PMID:31804789
      reference_title: Fructose-1,6-Bisphosphatase 1 Deficiency.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Acute inpatient treatment includes intravenous glucose with transition to
        feeds as tolerated; sodium bicarbonate may be required for treatment of
        acidemia.
      explanation: >-
        Specifies intravenous glucose as the acute treatment that substitutes for
        absent endogenous glucose production. Evidence source is OTHER because
        GeneReviews is a synthesizing review.
  evidence:
  - reference: PMID:31804789
    reference_title: Fructose-1,6-Bisphosphatase 1 Deficiency.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Acute inpatient treatment includes intravenous glucose with transition to
      feeds as tolerated; sodium bicarbonate may be required for treatment of
      acidemia.
    explanation: >-
      Directly supports the acute inpatient regimen. Evidence source is OTHER
      because GeneReviews is a synthesizing review.
- name: Fasting avoidance with frequent feeds and uncooked cornstarch
  description: >-
    Long-term prevention of hypoglycemia rests on avoiding fasting, frequent
    meals, and uncooked cornstarch overnight to provide slow-release glucose
    across the overnight fast.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Dietary Intervention
    term:
      id: NCIT:C15447
      label: Dietary Intervention
  target_mechanisms:
  - target: Fasting Hypoglycemia
    treatment_effect: BYPASSES
    description: >-
      Continuous exogenous carbohydrate supply keeps the fast from ever
      outlasting glycogen stores, so the gluconeogenic block is never unmasked.
    evidence:
    - reference: PMID:31804789
      reference_title: Fructose-1,6-Bisphosphatase 1 Deficiency.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Long-term management includes prevention of hypoglycemia with avoidance
        of fasting, frequent meals, (including use of uncooked cornstarch
        overnight), and restriction of foods or medicines that contain fructose,
        sucrose, glycerol, and/or sorbitol
      explanation: >-
        Directly supports fasting avoidance and cornstarch as the preventive
        strategy against hypoglycemia. Evidence source is OTHER because
        GeneReviews is a synthesizing review.
  evidence:
  - reference: PMID:31804789
    reference_title: Fructose-1,6-Bisphosphatase 1 Deficiency.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Long-term management includes prevention of hypoglycemia with avoidance of
      fasting, frequent meals, (including use of uncooked cornstarch overnight),
      and restriction of foods or medicines that contain fructose, sucrose,
      glycerol, and/or sorbitol
    explanation: >-
      Directly supports the long-term dietary management plan. Evidence source is
      OTHER because GeneReviews is a synthesizing review.
- name: Restriction of fructose, sucrose, glycerol, and sorbitol
  description: >-
    Foods and medicines containing fructose, sucrose, glycerol, or sorbitol are
    restricted because each feeds carbon into the pathway proximal to the
    enzymatic block. Antipyretics must be checked for these excipients.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Dietary Intervention
    term:
      id: NCIT:C15447
      label: Dietary Intervention
  target_mechanisms:
  - target: Gluconeogenic Substrate Accumulation and Energy Deficit
    treatment_effect: INHIBITS
    description: >-
      Limiting intake of substrates that must traverse the blocked step reduces
      further accumulation behind it.
    evidence:
    - reference: PMID:31804789
      reference_title: Fructose-1,6-Bisphosphatase 1 Deficiency.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        treatment with antipyretics for fever that do not contain fructose,
        sucrose, glycerol, and/or sorbitol
      explanation: >-
        Shows the restriction extends to medication excipients, supporting
        substrate restriction as the mechanism-targeted intervention. Evidence
        source is OTHER because GeneReviews is a synthesizing review.
  evidence:
  - reference: PMID:31804789
    reference_title: Fructose-1,6-Bisphosphatase 1 Deficiency.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Management of acute crisis includes increasing frequency of carbohydrate
      feedings; intake of glucose polymers; restriction of fructose, sucrose,
      glycerol, and sorbitol
    explanation: >-
      Directly supports substrate restriction as a core management measure.
      Evidence source is OTHER because GeneReviews is a synthesizing review.
- name: Genetic counseling
  description: >-
    Autosomal recessive recurrence counseling, carrier testing for at-risk
    relatives, and prenatal or preimplantation testing once the familial variants
    are known. Presymptomatic molecular testing of at-risk sibs allows preventive
    measures before a first crisis.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:31804789
    reference_title: Fructose-1,6-Bisphosphatase 1 Deficiency.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Offer molecular genetic testing for the familial FBP1 pathogenic variants
      to apparently asymptomatic older and younger at-risk sibs of an affected
      individual in order to identify as early as possible those who would
      benefit from prompt initiation of measures to prevent acute crises and
      prompt treatment of infections/febrile illnesses.
    explanation: >-
      Supports cascade testing of at-risk relatives as an actionable preventive
      measure. Evidence source is OTHER because GeneReviews is a synthesizing
      review.
diagnosis:
- name: Molecular genetic testing of FBP1
  description: >-
    Identification of biallelic pathogenic FBP1 variants establishes the
    diagnosis. Testing should cover copy-number variation, since whole-exon and
    intragenic deletions are part of the spectrum and are missed by sequencing
    alone.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C19770
      label: Molecular Analysis
  evidence:
  - reference: PMID:31804789
    reference_title: Fructose-1,6-Bisphosphatase 1 Deficiency.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The diagnosis of FBP1 deficiency is established in a proband with
      suggestive clinical and metabolic findings and biallelic pathogenic
      variants in FBP1 identified by molecular genetic testing and/or deficient
      FBP1 activity in liver or mononuclear white blood cells.
    explanation: >-
      Directly states the diagnostic criteria. Evidence source is OTHER because
      GeneReviews is a synthesizing review.
  - reference: PMID:39036704
    reference_title: >-
      Fructose-1,6-bisphosphatase deficiency: estimation of prevalence in the
      Chinese population and analysis of genotype-phenotype association.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Genetic sequencing could effectively help to diagnose FBP1D.
    explanation: >-
      Supports sequencing as the practical diagnostic route given nonspecific
      clinical manifestations.
- name: Enzyme activity assay in leukocytes or liver
  description: >-
    Measurement of fructose-1,6-bisphosphatase activity in mononuclear white
    blood cells or liver confirms the enzymatic lesion. A leukocyte assay avoids
    liver biopsy and can be run on the same blood sample used for molecular
    analysis. NCIT has no clinical-action term for an enzyme activity assay, so
    the generic Diagnostic Procedure term is used with a specific preferred_term.
  diagnosis_term:
    preferred_term: enzyme activity assay
    term:
      id: NCIT:C18020
      label: Diagnostic Procedure
  evidence:
  - reference: PMID:25601412
    reference_title: >-
      Fructose 1,6-bisphosphatase deficiency: clinical, biochemical and genetic
      features in French patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      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.
    explanation: >-
      Directly supports the combined single-sample leukocyte enzyme plus
      molecular diagnostic strategy.
- name: Urine organic acid analysis
  description: >-
    Detection of glycerol or glycerol-3-phosphate on urine organic acid analysis
    is a practical trigger for targeted FBP1 testing in a child with recurrent
    hypoglycemia and acidosis.
  diagnosis_term:
    preferred_term: urine organic acid analysis
    term:
      id: NCIT:C18020
      label: Diagnostic Procedure
  evidence:
  - reference: PMID:29203193
    reference_title: >-
      Fructose-1,6-bisphosphatase deficiency as a cause of recurrent hypoglycemia
      and metabolic acidosis: Clinical and molecular findings in Malaysian
      patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In four patients, genetic study was prompted by detection of glycerol or
      glycerol-3-phosphate in urine organic acids analysis.
    explanation: >-
      Directly supports urine organic acid analysis as the finding that prompted
      molecular diagnosis in over half the series.
differential_diagnoses:
- name: Hereditary Fructose Intolerance
  description: >-
    Also a defect of fructose metabolism (ALDOB), and both restrict fructose. The
    discriminators are that FBP1 deficiency causes hypoglycemia even without
    fructose exposure — it is a fasting disorder, not only a fructose-exposure
    disorder — and that hypoglycemia, metabolic acidosis, and seizures are
    significantly more common in FBP1 deficiency when the two are compared
    directly.
  evidence:
  - reference: PMID:39036704
    reference_title: >-
      Fructose-1,6-bisphosphatase deficiency: estimation of prevalence in the
      Chinese population and analysis of genotype-phenotype association.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      By comparing to phenotypes of HFI patients, FBP1D patients were more likely
      to present hypoglycemia, metabolic acidosis, and seizures (all p-value <
      0.05).
    explanation: >-
      Provides a direct phenotypic comparison between the two fructose-metabolism
      disorders.
- name: Mitochondrial disorders and glycogen storage diseases
  description: >-
    Because lactic acidosis with hypoglycemia and hepatomegaly is shared with
    mitochondrial energy defects and the hepatic glycogenoses, FBP1 deficiency is
    routinely misdiagnosed as one of these first, delaying diagnosis by years.
  evidence:
  - reference: PMID:25601412
    reference_title: >-
      Fructose 1,6-bisphosphatase deficiency: clinical, biochemical and genetic
      features in French patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      However, diagnosis was made late at a mean age of 3 years, as mitochondrial
      defects or glycogen storage diseases were firstly suspected.
    explanation: >-
      Directly identifies the two disease groups that are mistakenly diagnosed
      first, and quantifies the resulting delay.
clinical_trials: []
datasets: []
📚

References & Deep Research

References

1
PMID:31804789
Fructose-1,6-Bisphosphatase 1 Deficiency.
No top-level findings curated for this source.