Fructose-1,6-Bisphosphatase Deficiency

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.