Continuing Education Activity
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. To avoid the morbidity and mortality associated with this condition, it must be promptly diagnosed and managed. This activity reviews the evaluation and management of HFI and highlights the role of the interprofessional team in evaluating and treating patients with this condition.
- Explain the role of aldolase B in fructose metabolism.
- Describe the pathophysiology of fructose 1-phosphate aldolase deficiency.
- Review the long term management of patients with fructose 1-phosphate aldolase deficiency.
- Summarize interprofessional team strategies for improving care coordination and communication and improve outcomes in cases of fructose 1-phosphate aldolase deficiency.
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 a 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 are 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.
HFI has an autosomal recessive inheritance pattern affecting both genders equally. The prevalence of the disease is estimated to be around 1 in 20,000 births in the US, and 1 in 26,100 live births in Europe.
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
- Lactic acidosis
Characteristic Clinical Findings
- Nausea, vomiting
- Abdominal distress
- Chronic growth restriction
- Failure to thrive
Histological Findings on Liver Biopsy
- Giant cell transformation along with steatosis, fibrosis, and cirrhosis
Electron Microscopy/Ultrastructural Findings on Liver Biopsy
- Concentric and irregularly disposed membranous arrays present in the glycogen areas of most hepatocytes
- Marked rarefaction of the cytoplasm (‘fructose holes’)
History and Physical
It is important to evaluate the dietary history of 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 (icterus), 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.
In heterozygous individuals (carriers), they are generally asymptomatic but hyperuricemia is observed in some of the cases with a predisposition to gouty arthritis.
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 a check for aldolase B activity.
Treatment / Management
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).
- Infectious hepatitis, sepsis, or disseminated intravascular coagulation
- Autoimmune liver disease
- Neonatal hemochromatosis
- Toxic ingestion
- Alpha-1-antitrypsin deficiency
- Urea cycle disorders
- Citrin deficiency
- Fatty acid oxidation disorders (including MCAD deficiency, LCHAD deficiency, and VLCAD deficiency)
- Maple syrup urine disease
- Wilson disease
- Glycogen storage disease (GSD)
- Disorders of mitochondrial DNA depletion
- Transaldolase deficiency
- Congenital disorders of glycosylation
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:
- Severe hypoglycemia possibly leading to coma
- Lactic acidosis
- Hepatic dysfunction
- Renal dysfunction and metabolic abnormalities
Deterrence and Patient Education
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.
Pearls and Other Issues
- Early diagnosis and treatment of the condition have an excellent prognosis. Multi-specialty care is needed.
- HFI is an autosomal recessive disorder. Genetic counseling is important as both the parents of the affected individual are obligate heterozygotes (carriers) and there is a 25% chance of having a child with HFI, 50% chance of being a carrier, and 25% chance of not being affected.
- Educating the child and adults regarding the importance of dietary restriction and adherence is needed. The primary objective of dietary restriction is to reduce morbidity and mortality associated with this disorder.
- HFI in a pregnant mother does not pose any risk to the mother or child if strict dietary adherence is practiced during the pregnancy.
Enhancing Healthcare Team Outcomes
Fructose 1-phosphate aldolase deficiency or HFI is a relatively rare autosomal recessive disorder, but a timely diagnosis is imperative to avoid morbidity and mortality associated with this condition. The condition is best managed by an interprofessional team that includes a geneticist, dietician, pediatrician, hepatologist, nephrologist, and nurse.