Disorders of Fructose Metabolism 2026: A Survey of the Molecular, Biochemical, and Pathophysiological Bases

• DOI: https://doi.org/10.22533/at.ed.15953226210115

• Palavras-chave: Metabolismo da frutose, Intolerância Hereditária à Frutose, Frutosúria Essencial, variantes do gene ALDOB.

• Keywords: Fructose metabolism, Hereditary Fructose Intolerance, Essential Fructosuria, ALDOB gene variants.

• Abstract:     Fructose is a monosaccharide widely present in the human diet, whose metabolism involves specific pathways predominantly in enterocytes, the liver, and the kidneys. Genetic alterations in the enzymes responsible for this metabolism can result in metabolic disorders with a variable clinical spectrum, particularly relevant during the neonatal and pediatric periods. Among these conditions, Hereditary Fructose Intolerance (HFI) stands out as an inborn error of metabolism with autosomal recessive inheritance caused by mutations in the ALDOB gene, as well as Essential Fructosuria, which results from deficiency of fructokinase (KHK) and is classically considered clinically benign. In HFI, aldolase B deficiency leads to the accumulation of fructose-1-phosphate, resulting in depletion of ATP and inorganic phosphate, with a direct impact on gluconeogenesis, glycogenolysis, and glycogenesis, culminating in severe hypoglycemia, hepatic and renal dysfunction, growth retardation, and risk of death when not diagnosed early. This review aims to compile and update current knowledge on the main disorders of fructose metabolism, with emphasis on HFI, addressing its pathophysiological mechanisms, genotype–phenotype correlations, the most frequent molecular variants. The biochemical and laboratory aspects of Essential Fructosuria are also discussed, highlighting its importance in the differential diagnosis with diabetes mellitus. Finally, the relevance of early molecular diagnosis, the use of targeted genetic panels, and the strict exclusion of fructose, sucrose, and sorbitol are emphasized as fundamental strategies to reduce morbidity and mortality, ensure appropriate genetic counseling, and enable individualized clinical management of affected patients.