Hereditary Fructose Intolerance

Clinical characteristics: Following dietary exposure to fructose, sucrose, or sorbitol, untreated hereditary fructose intolerance (HFI) is characterized by metabolic disturbances (hypoglycemia, lactic acidemia, hypophosphatemia, hyperuricemia, hypermagnesemia, hyperalaninemia) and clinical findings (nausea, vomiting, and abdominal distress; chronic growth restriction / failure to thrive). While untreated HFI typically first manifested when fructose- and sucrose-containing foods were introduced in the course of weaning young infants from breast milk, it is now presenting earlier, due to the addition of fructose-containing nutrients in infant formulas. If the infant ingests large quantities of fructose, the infant may acutely develop lethargy, seizures, and/or progressive coma. Untreated HFI may result in renal and hepatic failure. If identified and treated before permanent organ injury occurs, individuals with HFI can experience a normal quality of life and life expectancy.

Diagnosis/testing: The diagnosis of HFI is established in a proband with suggestive metabolic disturbances and clinical findings following dietary exposure to fructose, sucrose, or sorbitol and either biallelic pathogenic variants in ALDOB identified on molecular genetic testing or – now rarely – deficient hepatic fructose 1-phosphate aldolase (aldolase B) activity on liver biopsy. Note: Fructose tolerance testing ("fructose challenge") in the diagnosis of HFI should be avoided because it is dangerous and, when used in the past, could result in death.

Potential sources of fructose should be removed immediately if HFI is suspected.

Management: Treatment of manifestations: Acute manifestations (e.g., lethargy, seizures, or progressive coma and/or renal and hepatic failure) should be managed symptomatically in a hospital setting, including administration of intravenous glucose (dextrose), supportive treatment of hepatic and/or renal insufficiency, and treatment of metabolic acidosis, if present.

Prevention of primary manifestations: Dietary restriction of fructose, sucrose, sucralose, and sorbitol is the cornerstone of HFI treatment. During hospitalizations, special caution is advised to avoid use of fructose-containing intravenous fluids, as well as fructose-containing infant formulas and pharmaceuticals. Given that reduced fruit and vegetable intake is a dietary requirement, daily supplementation with a "sugar-free" multivitamin is recommended to prevent micronutrient deficiencies, specifically water-soluble vitamins.

Surveillance: No formal guidelines for surveillance exist. Once the diagnosis of HFI has been made, periodic evaluation of liver function, renal function, and growth is reasonable, particularly if compliance with the fructose/sucrose/sorbitol/sucralose-restricted diet is not absolute.

Agents/circumstances to avoid: Enteral or parenteral exposure to fructose, sorbitol, sucrose, sucralose, and polysorbate, including fructose, fructose-containing oligosaccharides, high-fructose corn syrup, honey, agave syrup, inverted sugar, maple-flavored syrup, molasses, palm or coconut sugar, and sorghum. In addition, medicines and formulas in which fructose/sucrose may not be listed as a primary component need to be avoided; examples include syrups, enema solutions, some immunoglobulin solutions, and many infant and pediatric nutritional drinks.

Although vaccinations are generally safe in children with HFI, the two potentially harmful vaccines are the sucrose-containing rotavirus vaccines, Rotarix^® pre-established oral suspension and RotaTeq^®, the only rotavirus vaccines approved for use in the US. Any individual with a severe adverse reaction immediately following administration of either vaccine should be thoroughly investigated for the possibility of HFI.

Evaluation of relatives at risk: Presymptomatic diagnosis of HFI is warranted for sibs of a proband in order to avoid life-threatening complications by restricting fructose intake as soon as possible.

Genetic counseling: HFI is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an ALDOB pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of inheriting neither pathogenic variant. Once the ALDOB 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.