Fructose 1-phosphate aldolase deficiency or hereditary fructose intolerance (HFI) is an autosomal recessive disorder, caused by the deficiency in aldolase B (fructose-1, 6-bisphosphate aldolase), an enzyme responsible for the cleavage of fructose-1-phosphate. HFI is a metabolic disorder that usually manifests around 4-6 months of age when weaning is started. The inheritance pattern is autosomal recessive, and there is a 25% chance of having a child with HFI if both parents are heterozygotes.
The mainstay of treatment is the dietary restriction of fructose, sorbitol, and sucrose. Life expectancy is normal in these individuals if appropriate precautionary measures are taken. The disorder leads to toxic accumulation of fructose-1-phosphate in the liver and renal tubules.
HFI is caused by the deficiency of aldolase B, an isoenzyme that is expressed in the liver, kidney, and intestinal tissue, which is important in fructose metabolism. The enzyme catalyzes different reactions including cleavage of fructose-1-phosphate and reversible cleavage of fructose-1, 6-bisphosphate (FBP) into glyceraldehyde phosphate and dihydroxyacetone phosphate (DHAP).
The aldolase B gene is located on chromosome 9q22, and various mutations have been identified. The most frequent of these mutations is A150P, A149P, and A174D. The severity of the disease depends on the aldolase B activity and it can remain undiagnosed in some individuals due to self-imposed dietary restriction.
Aldolase B is the key enzyme in fructose metabolism, and its deficiency can lead to a toxic accumulation of fructose-1-phosphate. Fructose is rapidly converted into fructose-1-phosphate by fructokinase, leading to depletion of inorganic phosphate and ATP. This lethal cascade leads to increased production of uric acid and a release of magnesium along with impaired protein synthesis and metabolic disturbances, which are believed to be responsible for hepatic and renal dysfunction.
Aldolase B is responsible for the reversible conversion of fructose-1-phosphate to 3 carbon sugars. In individuals deficient in aldolase B activity, this causes an accumulation of fructose-1-phosphate, leading to subsequent inhibition of both glycolytic and gluconeogenesis pathways, thus causing hypoglycemia in individuals.
The pathogenesis for renal tubular dysfunction is believed to be due to decreased activity of vacuolar-ATPase, responsible for endosomal acidification, and proton secretion, because of the deficiency of the aldolase enzyme leading to renal tubular dysfunction.
Characteristic Metabolic Disturbances
Characteristic Clinical Findings
Histological findings on liver biopsy:
Electron microscopy/ultrastructural findings on liver biopsy:
It is important to evaluate dietary history for the patient. Symptoms generally appear when weaning is started in an infant around 4-6 months of age. Clinically, it can range from recurrent vomiting, abdominal bloating and diarrhea, yellow discoloration of eyes (jaundice), hepatomegaly, and failure to thrive in infants. Depending on the activity level of the aldolase B enzyme, the symptoms may vary, and commonly these individuals form an aversion to food rich in fructose and sucrose. Some cases remain undiagnosed for many years.
The diagnosis of HFI is primarily based on clinical findings and metabolic disturbances observed in individuals after the ingestion of fructose, sucrose, or sorbitol containing food. The fructose tolerance test (FTT), is the standard diagnostic test. It is not routinely recommended due to resulting hypoglycemia and hypophosphatemia in adults, as well as the difficulty in performing the test in infants and children. A non-invasive test for HFI is molecular genetic testing for the ALDOB gene. An invasive test for HFI is a liver biopsy and check for aldolase B activity.
In an emergency, the patient can present with lethargy, seizures, comatose, or with hepatic and renal failure. The management in the acute setting includes intravenous glucose (dextrose) administration, correction of possible metabolic acidosis, and supportive treatment. Such individuals need active management and a multi-specialty team approach.
The mainstay of treatment for HFI is dietary adherence, as well as the prevention of acute manifestations. Care should be taken to avoid fructose-containing fluids. As these individuals adhere to a specific diet, this can lead to micronutrient deficiencies, which can be prevented by daily supplementation with multivitamins (folate and vitamin C).
Fructose intolerance has an excellent prognosis, provided the individual follows strict dietary compliance. If the disorder is diagnosed early in its course, and management is initiated in a timely manner, then the individual can have normal cognitive development and life span.
If dietary restrictions are not followed it can lead to serious complications such as:
Patient and family education on proper management, especially compliance with dietary restriction is essential for patients affected with this disease. Early diagnosis and management have profound effects on the neurodevelopment of these patients. Genetic counseling is recommended in families proven to have a genetic mutation of the ALDOB gene.
Fructose 1-phosphate aldolase deficiency or HFI is a relatively rare autosomal recessive disorder, but the timely diagnosis is imperative to avoid morbidity and mortality associated with this condition. The condition is best managed by an inter-professional team that includes a geneticist, dietician, pediatrician, hepatologist, nephrologist, and nurse.
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