Clinical characteristics.

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. 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. Common factors known to trigger episodes include fever, fasting, decreased oral intake, vomiting, infections, and ingestion of large amounts of fructose. 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. In untreated individuals, clinical manifestations 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.

Diagnosis/testing.

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.

Management.

Treatment of manifestations: Management of acute crisis includes increasing frequency of carbohydrate feedings; intake of glucose polymers; restriction of fructose, sucrose, glycerol, and sorbitol; measurement of blood gas, serum glucose, blood urea nitrogen, electrolytes, lactate, complete blood count, blood culture, and urine ketones; treatment with antipyretics for fever that do not contain fructose, sucrose, glycerol, and/or sorbitol. Acute inpatient treatment includes intravenous glucose with transition to feeds as tolerated; sodium bicarbonate may be required for treatment of acidemia. 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; routine immunizations, including influenza vaccine to reduce the risk of infection; appropriate management of acute intercurrent illnesses; planning prior to procedures and surgeries to prevent hypoglycemia; written protocols for medical management of illness or catabolic stressors and to optimize social and school services; developmental and educational support as needed; transitional care plan.

Surveillance: Monitor growth and developmental milestones in children at each visit; neuropsychologic testing as needed; assess quality of life issues for individuals and their parents/caregivers; monitor 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 a 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: 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.

Pregnancy management: For a pregnant woman with FBP1 deficiency, consider referral to a high-risk obstetric center and consultation with a metabolic physician. Frequent 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. If both parents are known to be heterozygous for an FBP1 pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting biallelic pathogenic variants and being affected, a 50% chance of inheriting a heterozygous pathogenic variant and being an asymptomatic carrier, and a 25% chance of inheriting neither of the familial pathogenic variants and 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 and prenatal/preimplantation genetic testing are possible.

Suggestive Findings

FBP1 deficiency should be suspected in individuals with the following clinical and metabolic findings.

Clinical findings

• Episodes of acute crisis manifesting as respiratory distress or hyperventilation, apneic spells, seizures, and/or lethargy/coma, most commonly in neonates and infants. The course of illness is precipitous and may be lethal if untreated, especially in neonates and infants.
• Other features may include episodic irritability, somnolence, hypotonia, tachycardia, dyspnea, and hyperhidrosis.
• Hepatomegaly is common during acute illness.
• Normal development and growth between crises

Metabolic findings

• 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 >4 mmol/L; reference range: 0.5-2.2 mmol/L), pH <7.35, with possible elevated lactate-to-pyruvate ratio, bicarbonate <20 mmol/L, and hyperalaninemia
  • Ketosis (Individuals with normal to low ketones have been reported.)
• Urine organic acids show elevated glycerol 3-phosphate and glycerol during acute crisis; glycerol 3-phosphate concentration returns to normal following resolution of metabolic crisis [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"). Most standard biochemical tests for plasma triglycerides cannot distinguish between glycerol and triglycerides, leading to an overestimation of triglyceride levels because of the high glycerol concentration 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 mg/dL)
• Increased free fatty acids in plasma (in some individuals)

Establishing the Diagnosis

The diagnosis of FBP1 deficiency is established in a proband with suggestive clinical and metabolic findings and biallelic pathogenic (or likely pathogenic) variants in FBP1 identified by molecular genetic testing (see Table 1) and/or deficient FBP1 enzyme activity in liver or mononuclear white blood cells. Molecular genetic testing is generally preferred because of its widespread availability and accuracy.

Note: (1) Per American College of Medical Genetics and Genomics / Association for Molecular Pathology variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of biallelic FBP1 variants of uncertain significance (or of one known FBP1 pathogenic variant and one FBP1 variant of uncertain significance) does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see Option 1), whereas comprehensive genomic testing does not (see Option 2).

Clinical Description

The manifestations of fructose-1,6-bisphosphatase 1 (FBP1) deficiency are generally episodic, occurring 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.

Onset. 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 respiratory distress or hyperventilation, apneic spells, seizures, and/or lethargy/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]. Elevation of creatine kinase has been noted in at least one individual in acute crisis [Bhai et al 2018]. This may indicate rhabdomyolysis secondary to energy deficiency.

Acute crises are more frequent in early life – neonatal period, infancy, and early childhood. With age, the frequency of attacks decreases, and episodes are characterized by irritability, somnolence, hypotonia, tachycardia, dyspnea, and hyperhidrosis. Reports of adults presenting in acute crisis are scarce [Moon et al 2011, Fawdry et al 2022].

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].

Growth and development. 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 those who receive treatment, obesity may develop, which is suspected to be due to overtreatment with carbohydrate-based diet.

Prognosis 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 clinically relevant 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

FBP1 deficiency is rare. Approximately 190 affected individuals have been reported to date.

Estimated prevalence of FBP1 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].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in a child diagnosed with FBP1 deficiency, 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].

Treatment of Manifestations

There is no cure for FBP1 deficiency. However, treatment during acute crises and routine dietary management can ameliorate and/or prevent long-term manifestations of this disorder. An international survey of 126 affected individuals 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].

Surveillance

No formal guidelines for long-term surveillance for individuals with FBP1 deficiency exist. Table 7 summarizes long-term surveillance based on the natural history of the disorder.

Agents/Circumstances to Avoid

Avoid ingestion of food items or medicines that contain fructose, sucrose, glycerol, and/or sorbitol, especially during acute crises in infancy or early childhood.

Although small amounts of fructose (≤2 g/kg/day) are well tolerated by individuals with FBP1 deficiency, single ingestion of high doses 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

It is appropriate to evaluate 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 (frequent feedings and avoidance of fasting) and prompt treatment of infections / febrile illnesses.

For newborns who may be at risk for FBP1 deficiency, it is important to avoid fasting, to feed regularly, and to monitor for hypoglycemia and acidosis while awaiting results of biochemical and/or molecular genetic testing. Monitoring for hypoglycemia can include use of bedside glucometers and clinical monitoring for lethargy, poor intake, vomiting, hypothermia, and/or tachypnea. A low threshold for starting an intravenous infusion of 5%-10% dextrose may prevent an acute crisis, especially in newborns who have low birth weight, are preterm, or have a diabetic mother.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Although successful pregnancies have been reported in women with FBP1 deficiency [Åsberg et al 2010], certain precautions should be taken:

• Pre-pregnancy
  • Counseling that emphasizes the importance of frequent eating in preventing hypoglycemia and the use of blood glucose monitoring for early detection of hypoglycemia
  • Consider referral to a high-risk obstetric center and consultation with a metabolic physician.
• During pregnancy
  • Frequent home glucose monitoring for early detection of hypoglycemia
  • Maintenance of glycemic control by taking uncooked cornstarch at night as needed [Krishnamurthy et al 2007, Sugita et al 2014]
  • In the third trimester when the physiologic requirements of energy are highest, increase in dietary intake and glucose monitoring as needed
• During labor. Continuous glucose infusion to maintain euglycemia

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

Fructose-1,6-bisphosphatase 1 (FBP1) deficiency is inherited in an autosomal recessive manner.

Parents of a proband

• The parents of an affected child are presumed to be heterozygous for an FBP1 pathogenic variant.
• If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for an FBP1 pathogenic variant and to allow reliable recurrence risk assessment.
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
  • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

• If both parents are known to be heterozygous for an FBP1 pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting biallelic pathogenic variants and being affected, a 50% chance of inheriting a heterozygous pathogenic variant and being an asymptomatic carrier, and a 25% chance of inheriting neither of the familial pathogenic variants and being unaffected and not a carrier.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. Unless an affected individual's reproductive partner also has FBP1 deficiency or is a carrier, offspring will be obligate heterozygotes (carriers) for an FBP1 pathogenic variant.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of an FBP1 pathogenic variant.

Carrier Detection

Molecular genetic carrier testing for at-risk relatives requires prior identification of the FBP1 pathogenic variants in the family.

Biochemical enzyme-based testing is not reliable for carrier detection.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk sibs for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• It is appropriate to offer FBP1 molecular genetic testing for reproductive partners of individuals known to have FBP1 deficiency or to be heterozygous for an FBP1 pathogenic variant.

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Molecular genetic testing. Once the FBP1 pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Note: Biochemical testing is not a reliable method for prenatal diagnosis, as FBP1 enzyme activity has been reported to be low in human placenta [Papamarcaki & Tsolas 1991].

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

Fructose-1,6-bisphosphatase 1 (FBP1) is a key enzyme of the gluconeogenic pathway. Its deficiency impairs glucose production from all gluconeogenic precursors, including dietary fructose. As a result, euglycemia in persons with FBP1 deficiency depends on glycogen stores in the liver. During glycemic stress (including catabolic states such as infections and fasting), glycogen stores are depleted and the gluconeogenic substrates pyruvate, alanine, and glycerol accumulate (see Figure 1). The subsequent conversion of pyruvate into lactate and acetyl-coenzyme A results in lactic acidemia and ketosis.

Figure 1.

Pathophysiology of fructose-1,6-bisphosphatase 1 deficiency Aldo A = aldolase A; DHAP = dihydroxyacetone phosphate; FBPase = fructose-1,6-bisphosphatase; G3P = glyceraldehyde 3-phosphate; GAH = glyceraldehyde; LDH = lactate dehydrogenase; PC = pyruvate (more...)

Deficient conversion of glucose-1-phosphate to glucose also activates the pentose phosphate pathway, causing both the production of ribose-5-phosphate and the synthesis of purines and pyrimidines. The subsequent breakdown of purines and pyrimidines results in hyperuricemia.

Mechanism of disease causation. Loss of function

FBP1-specific laboratory technical considerations. FBP1 comprises one noncoding exon (exon 1) and seven coding exons.

Acknowledgments

The authors would like to acknowledge our senior colleagues, Dr Ishwar Chander Verma, Dr Ratna D Puri, and Dr Renu Saxena, for rendering support in writing this article. Significant contributions from other colleagues, Dr Pratibha Bhai, Dr Deepti Gupta, Dr Ranjana Mishra, Dr Vibha Jain, and Dr Jyotsna Verma, are also gratefully acknowledged.

Revision History

• 7 July 2026 (sw) Comprehensive update posted live
• 5 December 2019 (bp) Review posted live
• 20 May 2019 (sbm) Original submission

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