Hereditary fructose intolerance

Hereditary fructose intolerance (aldolase B deficiency) becomes symptomatic in infancy, when fructose-, sucrose- or sorbitol-containing foods are introduced during weaning. Affected infants develop nausea, vomiting, sweating, abdominal pain, hepatomegaly, and growth restriction. Ingestion of fructose provokes acute hypoglycaemia that is refractory to glucagon, and large loads may cause lethargy, seizures and progressive coma. Untreated disease progresses to chronic hepatic and renal injury, whereas early, sustained dietary restriction carries an excellent prognosis. Fructose-1,6-bisphosphatase deficiency, is a disorder of gluconeogenesis characterised by recurrent episodes of lactic acidosis and ketotic hypoglycaemia. Acute crises arise most commonly in early childhood, with nearly half of affected children having neonatal hypoglycemia.

The estimated prevalence of hereditary fructose intolerance is 1:18,000 to 1:31,000. Fructose-1,6-bisphosphatase deficiency is considerably rarer, with only 190 cases reported to date. The prevalence is estimated to be 1:350,000 in the Dutch population and less than 1:900,000 in the French population.

Both disorders are caused by biallelic germline pathogenic variants. Hereditary fructose intolerance results from loss of function of aldolase B, encoded by ALDOB (9q31.1); accumulated fructose-1-phosphate inhibits gluconeogenesis and glycogenolysis, depletes hepatic ATP and impairs protein glycosylation. Fructose-1,6-bisphosphatase deficiency results from loss of fructose-1,6-bisphosphatase, encoded by FBP1, a key gluconeogenic enzyme; its deficiency blocks gluconeogenesis, so fasting or intercurrent illness precipitates ketotic hypoglycaemia and lactic acidosis. Sequence analysis identifies most ALDOB pathogenic variants.

Both hereditary fructose intolerance (ALDOB) and fructose-1,6-bisphosphatase deficiency (FBP1) are inherited in an autosomal recessive manner. For a couple who are both heterozygous carriers, each child has a 25% risk of being affected. Prenatal molecular testing is technically possible once the familial pathogenic variants have been identified.

No consensus clinical diagnostic criteria have been established; the diagnosis rests on molecular genetic testing, supported by characteristic biochemical findings. In hereditary fructose intolerance, fructose exposure provokes hypoglycaemia, lactic acidaemia, hypophosphataemia, hyperuricaemia and hyperalaninaemia, whereas fructose-1,6-bisphosphatase deficiency presents with lactic acidosis and ketotic hypoglycaemia. Deficient hepatic aldolase B activity on liver biopsy can confirm hereditary fructose intolerance when molecular testing is inconclusive.

Main differential diagnoses include:

• Fructose malabsorption: fructose-triggered gastrointestinal symptoms from intestinal transporter dysfunction, without hepatic or renal injury.
• : infantile hepatic dysfunction and hypoglycaemia triggered by galactose, not fructose; GALT.
• Hepatic : fasting hypoglycaemia, hepatomegaly and lactic acidosis without a fructose trigger; G6PC1, SLC37A4 and others.
• : fasting hypoketotic hypoglycaemia with Reye-like illness; ACADM, ACADVL.
• : progressive hepatic failure with renal Fanconi tubulopathy; FAH.

• Molecular genetic testing establishes a definitive diagnosis and distinguishes the condition from disorders with overlapping presentations.
• Identification of the germline pathogenic variants supports condition-specific monitoring and long-term management decisions, made by the treating physicians in consultation with the affected individual.
• Once the familial variants are known, testing of at-risk relatives can clarify their carrier or affected status and inform reproductive planning.

• Gaughan S, Ayres L, Baker PR II. Hereditary Fructose Intolerance. 2015 Dec 17 [Updated 2021 Feb 18]. In: Adam MP, Bick S, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. Available from:
• Bijarnia-Mahay S, Bhatia S, Arora V. Fructose-1,6-Bisphosphatase 1 Deficiency. 2019 Dec 5 [Updated 2026 Jul 7]. In: Adam MP, Bick S, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. Available from:
• Lieu EL, Kelekar N, Bhalla P, Kim J. Fructose and Mannose in Inborn Errors of Metabolism and Cancer. Metabolites. 2021;11(8):479. PMID: .