Fructose-1,6-Bisphosphatase Deficiency
Summary
Clinical characteristics.
Fructose-1,6-bisphosphatase (FBP1) deficiency is characterized by episodic acute crises of lactic acidosis and ketotic hypoglycemia, manifesting as hyperventilation, apneic spells, seizures, and/or coma. Acute crises are most common in early childhood; nearly half of affected children have hypoglycemia in the neonatal period (especially the first 4 days) resulting from deficient glycogen stores. Factors known to trigger episodes include fever, fasting, decreased oral intake, vomiting, infections, and ingestion of large amounts of fructose.
In untreated individuals, symptoms worsen progressively as continued catabolism leads to multiorgan failure (especially liver, brain, and later heart). Morbidity and mortality are high. Sepsis, blindness, and Reye syndrome-like presentation have been reported.
In between acute episodes, children are asymptomatic. While the majority of affected children have normal growth and psychomotor development, a few have intellectual disability, presumably due to early and prolonged hypoglycemia.
Diagnosis/testing.
The diagnosis of FBP1 deficiency is established in a proband with suggestive clinical and metabolic findings by identification of EITHER biallelic FBP1 pathogenic variants on molecular genetic testing OR deficient fructose-1,6-bisphosphatase 1 (FBP1) activity in liver or mononuclear white blood cells. Molecular genetic testing is generally preferred because of its widespread availability and accuracy.
Management.
Treatment of manifestations: Intervention (oral or IV glucose) should take place early in an acute crisis while the blood glucose is normal due to the possibility of delayed hypoglycemia, which only occurs relatively late in the course of acute metabolic decompensation.
The mainstay of routine daily management is prevention of hypoglycemia by avoiding fasting (including use of uncooked cornstarch overnight), consuming frequent meals, and appropriate management of acute intercurrent illnesses.
Prevention of primary manifestations: Routine daily management to prevent hypoglycemia, attention to agents/circumstances to avoid, and routine immunizations, including annual influenza vaccine to reduce the risk of infection, which can precipitate hypoglycemia.
Surveillance: Long-term monitoring of developmental milestones in affected children and quality of life issues for affected individuals and their parents/caregivers; monitoring for excessive weight gain at each visit.
Agents/circumstances to avoid: Food items or medicines that contain fructose, sucrose, glycerol, and/or sorbitol, especially during acute crisis in infancy or early childhood. Although small amounts of fructose (≤2 g/kg/day) are generally well tolerated, single ingestion of high dose of fructose (>1g/kg) is harmful, especially in younger children. Fructose tolerance testing ("fructose challenge") to diagnose FBP1 deficiency can be hazardous and should not be performed.
Evaluation of relatives at risk: When the familial FBP1 variants are known, it is appropriate to clarify the genetic status of 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 preventive measures.
Pregnancy management: For a pregnant woman with FBP1 deficiency, consider referral to a high-risk obstetric center and consultation with a metabolic physician. Home glucose monitoring and consumption of uncooked cornstarch at night as needed as carbohydrate requirements increase during pregnancy. During labor, continuous glucose infusion is recommended to maintain euglycemia.
Genetic counseling.
FBP1 deficiency is inherited in an autosomal recessive manner. When both parents are known to be heterozygous for an FBP1 pathogenic variant, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the FBP1 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible.
Diagnosis
Formal diagnostic criteria for fructose-1,6-bisphosphatase (FBP1) deficiency have not been established.
Suggestive Findings
FBP1 deficiency should be suspected in individuals with the following characteristic clinical features and metabolic findings.
Clinical features
- Episodes of acute crisis may manifest as hyperventilation, apneic spells, seizures, and/or coma, most commonly in neonates and infants. The course of illness is precipitous and may be lethal, especially in neonates and infants.
- Other features can include episodic irritability, tachycardia, hypotonia, and hyperhidrosis.
- Hepatomegaly is common.
- Inter-crisis periods are uneventful with normal development and growth.
Metabolic findings. A strong clinical suspicion should arise in individuals with recurrent episodes of ketotic hypoglycemia with lactic acidosis and urinary organic acid analysis showing a glycerol and glycerol-3-phosphate peak. Although this combination is fairly specific for FBP1 deficiency, establishing the diagnosis requires enzyme assay and/or molecular genetic testing (see Establishing the Diagnosis).
- Hypoglycemia (plasma glucose <40mg/dL in neonates; <60 mg/dL in older infants, children, and adults; reference range 70-120 mg/dL)
- High anion-gap metabolic acidosis
- Lactic acidemia (plasma lactate >2.5 mmol/L; reference range: 0.5-2.2 mmol/L) with possible elevated lactate:pyruvate ratio and hyperalaninemia.
- Ketosis (individuals with low ketones have been reported)
- Elevated glycerol 3-phosphate is an important biomarker for this disorder on urine organic acid analysis. Glycerol 3-phosphate is more specific as glycerol is also elevated in glycerol kinase deficiency (see NROB1-Related Adrenal Hypoplasia Congenita) [Nakai et al 1993]. It is important to collect the urine sample in the period of crisis, as the glycerol 3-phosphate level returns to normal once the individual is in the well state [Moey et al 2018].
- Pseudo-hypertriglyceridemia. Although plasma triglycerides are commonly increased, it is not the triglycerides but the glycerol levels that are high (often referred to as "pseudo-hypertriglyceridemia"). The commonly available biochemical assays for plasma triglycerides cannot differentiate glycerol from triglycerides, and hence overestimate the triglyceride levels due to the high concentration of glycerol in plasma [Afroze et al 2013]. Glycerol blanking methods can be used to measure the true levels of triglycerides [Cole 1990].
- Hyperuricemia (plasma uric acid >5.0 mg/dL; reference range 2.0-5.0 mmol/L
- Increased free fatty acids (in some cases)
Establishing the Diagnosis
The diagnosis of fructose-1,6-bisphosphatase 1 deficiency is established in a proband with suggestive clinical and metabolic findings by identification of EITHER biallelic FBP1 pathogenic variants on molecular genetic testing (Table 1) OR deficient fructose-1,6-bisphosphatase 1 (FBP1) activity in liver or mononuclear white blood cells. Molecular genetic testing is generally preferred because of its widespread availability and accuracy.
Molecular Genetic Testing
When the clinical and metabolic findings suggest the diagnosis of fructose-1,6-bisphosphatase deficiency, molecular genetic testing approaches can include single-gene testing or use of a multigene panel:
- Single-gene testing. Sequence analysis of FBP1 detects small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. Perform sequence analysis first. If only one or no pathogenic variant is found, perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications.Note: Pathogenic variants reported frequently in individuals of certain ancestries are noted in Table 7. Given the rarity of fructose-1-6-bisphosphatase deficiency, the efficacy of targeted testing for specific pathogenic variants in individuals of these ancestries is not known.
- A multigene panel (such as one for hypoglycemia or lactic acidosis) that includes FBP1 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. Of note, given the rarity of fructose-1,6-bisphosphatase deficiency, some panels may not include FBP1. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see Table 1).For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
Table 1.
Molecular Genetic Testing Used in Fructose-1,6-Bisphosphatase Deficiency
| Gene 1 | Method | Proportion of Pathogenic Variants 2 Detectable by Method |
|---|---|---|
| FBP1 | Sequence analysis 3 | ~90% 4 |
| Gene-targeted deletion/duplication analysis 5 | ~10% 6 |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 2.
See Molecular Genetics for information on allelic variants detected in this gene.
- 3.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 4.
Kikawa et al [1997], Prahl et al [2006], Afroze et al [2013], Takagi et al [2013], Lebigot et al [2015], Santer et al [2016], Ijaz et al [2017], Bhai et al [2018], Moey et al [2018], Pinheiro et al [2019]
- 5.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
- 6.
Herzog et al [2001], Åsberg et al [2010], Lebigot et al [2015], Santer et al [2016], Bhai et al [2018]
Analysis of Fructose-1,6-Bisphosphatase (FBP1 or FBPase) Activity
While enzymatic activity in leukocytes and liver is very specific, testing is not widely available [Besley et al 1994, Lebigot et al 2015]: spectrophotometric analysis to estimate enzyme activity in leukocytes is performed in a few laboratories worldwide. The usual assay tests FBP1 activity by measuring the amount of NADPH formed – a nonspecific assay as NADPH may be formed from other reactions within the cells. Specificity can be achieved by testing for FBP1 activity in the presence and absence of AMP, a specific inhibitor for the enzyme [Lebigot et al 2015]. FBP1 stability in untreated blood samples at +4 °C lasts 24 hours, and therefore samples can be transported long distances to a reference laboratory.
Clinical Characteristics
Clinical Description
The manifestations of fructose-1,6-bisphosphatase (FBP1) deficiency are generally episodic due to lactic acidosis and ketotic hypoglycemia, which are often triggered by fasting or febrile infections. The episodes of acute crisis are most frequent in early life – neonatal period, infancy, and early childhood – and subsequently decrease in frequency. In FBP1 deficiency, several metabolic derangements can occur with or without hypoglycemia.
Classically, FBP1 deficiency manifests in the first year of life. Nearly half of affected infants present within the first four days of life with an acute crisis. Neonatal presentation results from hypoglycemia due to deficient glycogen stores [Steinmann & Santer 2016].
Acute crises are characterized by episodes of hyperventilation, apneic spells, seizures, and/or coma, often with hepatomegaly. Muscular hypotonia may also be present. This may be associated with transient liver dysfunction (transaminitis), which does not require specific treatment [Bhai et al 2018]. With age, the frequency of attacks decreases and episodes are characterized by irritability, somnolence, hypotonia, and dyspnea.
Factors known to trigger episodes include fever, fasting, decreased oral intake, vomiting, infections, and ingestion of large amounts of fructose. Episodes tend to be recurrent. Often four to five episodes occur before the correct diagnosis is established [Lebigot et al 2015].
In between crises, children are asymptomatic and the majority experience normal growth and psychomotor development [Steinmann & Santer 2016]. A few children with brain injury and/or intellectual disability have been reported, probably related to early and prolonged hypoglycemia [Li et al 2017, Moey et al 2018].
In untreated individuals, symptoms worsen progressively as continued catabolism leads to multiorgan failure (especially liver, brain, and later heart). Morbidity and mortality are high. Sepsis, blindness, and Reye syndrome-like presentation have been reported [Lebigot et al 2015, Bhai et al 2018].
Genotype-Phenotype Correlations
No genotype-phenotype correlations have been identified.
Nomenclature
Baker & Winegrad [1970] first described deficiency of hepatic fructose-1,6-bisphosphatase 1 (hence the eponymous Baker-Winegrad disease) in a child with hypoglycemia and metabolic acidosis on fasting.
Prevalence
Fructose-1,6-bisphosphatase deficiency is rare. Approximately 150 affected individuals have been reported to date.
An estimated prevalence of fructose-1,6-bisphosphatase deficiency is 1:350,000 in the Dutch population [Visser et al 2004] and <1:900,000 in the French population [Lebigot et al 2015]. The disorder may be more frequent in populations with higher rates of consanguinity [Santer et al 2016].
Differential Diagnosis
Table 2a provides a comparative analysis of disorders with clinical similarities to fructose-1,6-bisphosphatase (FBP1) deficiency. Table 2b compares the biochemical parameters of these disorders.
Information on mitochondrial respiratory chain and Krebs cycle disorders and fatty acid oxidation defects follows Table 2b.
Table 2a.
Disorders (and Associated Genes) of Interest in the Differential Diagnosis of Fructose-1,6-Bisphosphatase Deficiency
| Gene(s) | Disorder 1 | Differential Diagnosis Disorder: Features Overlapping w/FBP1 Deficiency | Distinguishing Between FBP1 Deficiency & Differential Diagnosis Disorder |
|---|---|---|---|
| ACAT1 | Beta-ketothiolase deficiency (OMIM 203750) | Ketolytic defect characterized by ketotic hypoglycemia or hyperglycemia & metabolic acidosis | In BKD: ↑ of specific metabolites on urine organic acids by GCMS can include 2-methylacetocetate, 2-methyl-3-hydroxybutyryl CoA, & tiglylglycine. |
| ALDOB | Hereditary fructose intolerance 2 |
|
|
| G6PC1 SLC37A4 | Glycogen storage disease type I 3 |
| Detection of glycerol in FBP1D (on urine organic acid analysis) is useful in differentiating the disorders. |
| PC | Pyruvate carboxylase deficiency 4 | Episodes of acute vomiting, tachypnea, & acidosis are usually precipitated by metabolic stress or infection; episodes may be very similar to FBP1D (w/↑ lactate-to-pyruvate ratio, hyperalaninemia, hypoglycemia, & metabolic acidosis). | The neurologic involvement, severe ID, & recurrent seizures characteristic of PCD types A & B are not observed in FBP1D. |
| PGM1 | PGM1-CDG (see Congenital Disorders of N-Linked Glycosylation and Multiple Pathway Overview) | Presents more commonly w/rhabdomyolysis; however, episodic hypoglycemia & metabolic acidosis may also occur. |
|
| Multiple | Fatty acid oxidation defects (FAODs) | FAODs can present in neonates w/hypoglycemia, hyperammonemia, & ↓/absent ketones. |
|
| Multiple | Mitochondrial respiratory chain disorders & Krebs cycle disorders | Multisystem involvement in which the most metabolically active organs are most affected (e.g., brain, liver, kidney, heart) | Mitochondrial disorders have a more chronic course than FBP1D. |
BKD = beta-ketothiolase deficiency; CDG = congenital disorder of glycosylation; FBP1D = FBP1 deficiency; FTT = failure to thrive; HFI = hereditary fructose intolerance; ID = intellectual disability; MS/MS = tandem mass spectrometry; PCD = pyruvate carboxylase deficiency
- 1.
Disorders included in this table are inherited in an autosomal recessive manner with the exception of mitochondrial respiratory chain and Krebs cycle disorders, which may be inherited in an autosomal recessive manner, an autosomal dominant manner, or by maternal inheritance.
- 2.
Hereditary fructose intolerance is due to deficiency of enzyme aldolase B, which facilitates the breakdown of fructose-1-phosphate into dihydroxyacetone phosphate and glyceraldehyde.
- 3.
GSDI is due to the deficiency of enzyme glucose-6-phosphatase.
- 4.
Pyruvate carboxylase enzyme aids in the irreversible carboxylation of pyruvate to oxaloacetate.
Table 2b.
Biochemical Parameters of Disorders in the Differential Diagnosis of Fructose-1,6-Bisphosphatase Deficiency
| Biochemical Parameter | FBP1 | BKT | HFI | GSDI | PCD | FAOD | Respiratory Chain Defects |
|---|---|---|---|---|---|---|---|
| ↑ lactate | Fasting | During crisis | Fasting | Permanent, also increased w/fasting | Permanent | Fasting | Permanent |
| Lactate/ pyruvate ratio | 20-40 | – | – | – | >30 | – | >20 |
| Ketosis | ↑↑/– | ↑↑ | ↑ | ↑↑/– | ↑↑↑ | – | ↑↑ |
| Triglycerides | Pseudo- hyper | ↑ | N | ↑ | N | N | N |
| Glucose | L | L | L | N/L | L/N/H | N/L | L |
| Ammonia | N | ↑ | N | N | ↑↑ | ↑ | N/↑↑ |
| Alanine | ↑↑ | N | ↑↑ | N | ↑↑ | N | ↑↑ |
| Citrulline | N | N | N | N | H | N | N |
| Liver dysfunction (transaminitis) | ↑/– | ↑ | ↑ | ↑ | ↑ | N | ↑/– |
| Uric acid | ↑ | N | N | ↑ | N | N | N |
| Organic acids in urine | Ketonuria, glycerol, glycerol-3-phosphate | 2-methylacetocetate, 2-methyl-3-hydroxybutyryl CoA, tiglylglycine | Ketonuria | Ketonuria | Lactate/ ketonuria | ↑ C16-C22 | Lactate |
↑ = increased; ↑↑ = moderately increased; ↑↑↑ = severely increased; BKT = beta-ketothiolase deficiency; FAOD = fatty acid oxidation defect; GSDI = glycogen storage disease type 1; H = high; HFI = hereditary fructose intolerance; L = low; N = normal; PCD = pyruvate carboxylase deficiency
Fatty acid oxidation defects (FAODs) are mitochondrial disorders caused by defective beta-oxidation of fatty acids. FAODs can present in neonates with hypoglycemia, hyperammonemia, and reduced/absent ketones. As ketones could be normal in FBP1 deficiency, diagnosis of FAOD is based on elevated acylcarnitine profiles on MS/MS.
Mitochondrial respiratory chain and Krebs cycle disorders. Mitochondrial respiratory chain disorders are a heterogeneous group of disorders that share involvement of the cellular bioenergetic machinery due to molecular defects affecting the mitochondrial oxidative phosphorylation system. The variable presentation can include neonatal metabolic acidosis with increased lactate. The usual disease course is a gradually progressive loss of developmental milestones; however, more rapid decline occurs with episodic crises. Urine organic acid profile may reveal distinctive elevation of fumaric acid or other Krebs cycle intermediates, reflecting the site of the enzyme deficiency. See Mitochondrial Disorders Overview.
Management
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in a child diagnosed with fructose-1,6-bisphosphatase (FBP1) deficiency who is not in acute crisis, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended [Wang et al 2017, Bhai et al 2018].
Note that the management of possible multisystem complications resulting from early and prolonged hypoglycemia are not discussed in this GeneReview.
Table 3.
Recommended Evaluations Following Initial Diagnosis of Fructose-1,6-Bisphosphatase Deficiency for a Child Not in Acute Crisis
| Evaluation/Concern | Comment |
|---|---|
| Consultation w/metabolic physician / biochemical geneticist & specialist metabolic dietician |
|
| Hepatomegaly |
|
| Developmental assessment | Referral to developmental pediatrician to assess motor, adaptive, cognitive, & speech/language skills; need for early intervention / special education |
| Consultation w/clinical geneticist &/or genetic counselor | Incl genetic counseling |
| Family support/resources | Assess:
|
- 1.
Elevation of CK has been noted in at least one individual in acute crisis [Bhai et al 2018]. This may indicate rhabdomyolysis secondary to energy deficiency.
- 2.
See pseudo-hypertriglyceridemia in Suggestive Findings.
Treatment of Manifestations
An international survey of 126 patients from 36 centers revealed widely varying practices of fructose/sucrose restriction; the authors concluded that internationally accepted guidelines for management and surveillance were needed [Pinto et al 2018].
Management of acute crises. Acute crises are more frequent in early life – neonatal period, infancy, and early childhood – with gradual decrease afterwards.
Intervention (oral glucose or IV dextrose) should take place early in an acute crisis while the blood glucose is normal due to the possibility of delayed hypoglycemia, which only occurs relatively late in the course of acute metabolic decompensation.
The family must be given the contact information for an expert metabolic center and a clear emergency outpatient treatment plan during illness (Table 4) and emergency letters/cards with information on principles of acute in-patient treatment (Table 5).
Emergency outpatient treatment. The threshold