Hereditary fructose intolerance
|Classification and external resources|
Hereditary fructose intolerance (HFI) is an inborn error of fructose metabolism caused by a deficiency of the enzyme aldolase B. Individuals affected with HFI are asymptomatic until they ingest fructose, sucrose, or sorbitol. If fructose is ingested, the enzymatic block at aldolase B causes an accumulation of fructose-1-phosphate. This accumulation has downstream effects on gluconeogenesis and regeneration of adenosine triphosphate (ATP). Symptoms of HFI include vomiting, hypoglycemia, jaundice, hemorrhage, hepatomegaly, hyperuricemia and potentially kidney failure. While HFI is not clinically a devastating condition, there are reported deaths in infants and children as a result of the metabolic consequences of HFI. Death in HFI is always associated with problems in diagnosis.
HFI is an autosomal recessive condition caused by mutations in the ALDOB gene, located at 9q22.3. Diagnosis of HFI is typically suspected based on dietary history, especially in infants who become symptomatic after breast feeding is supplemented by fructose containing foods. This suspicion is typically confirmed by molecular analysis. Treatment of HFI is based around strict avoidance of fructose in the diet. Older patients with HFI typically self-select a diet low in fructose, even before being diagnosed.
The key identifying feature of HFI is the appearance of symptoms with the introduction of fructose to the diet. Affected individuals are asymptomatic and healthy, provided they do not ingest foods containing fructose or any of its common precursors, sucrose and sorbitol. In the past, infants often became symptomatic when they were introduced to formulas that were sweetened with fructose or sucrose. These sweeteners are not common in formulas used today. Symptoms such as vomiting, nausea, restlessness, pallor, sweating, trembling and lethargy can also first present in infants when they are introduced to fruits and vegetables. These can progress to apathy, coma and convulsions if the source is not recognized early.
When patients are diagnosed with HFI, a dietary history will often reveal an aversion to fruit and other foods that contain large amounts of fructose. Most adult patients do not have any dental caries.
After ingestion, fructose is converted to fructose-1-phosphate by the liver by fructokinase. Deficiencies of fructokinase cause essential fructosuria, a clinically benign condition characterized by the excretion of unmetabolized fructose in the urine. Fructose-1-phosphate is metabolized by aldolase B into dihydroxyacetone phosphate and glyceraldehyde. HFI is caused by a deficiency of aldolase B.
A deficiency of aldolase B results in an accumulation of fructose-1-phosphate, and trapping of phosphate (fructokinase requires adenosine triphosphate (ATP)). The downstream effects of this enzyme block are the inhibition of glucose production and reduced regeneration of ATP.
DNA Variants of Aldolase B
As of 1991, eight structural defects of the aldolase B gene have been identified in HFI patients.
Mutations of the Aldolase Be Gene in Hereditary Fructose Intolerance
|Mutation||DNA Change||Protein Change||Frequency||Occurrence|
|A149P||G -> C exon 5||Ala -> Pro||67%||Europe|
|A174D||C -> A exon 5||Ala -> Asp||16%||Europe|
|C240stop||C -> A exon 7||Truncation AA 240||2 alleles|
|G12||Deletion of gGTA intron 2/exon 3||Splice site loss||2 alleles|
|F13||Deletion 1.65 kb intron 3/exon 5||Truncation||1 allele|
|d4||Deletion of CAAA exon 4||Truncation AA 132||1 allele|
|G10||Deletion 1.4 kb intron 5/exon 5||Truncation||1 allele|
|L288dC||Deletion of C exon 8||Truncation AA 296||3 alleles|
While the majority of aldolase B alleles among patients with HFI could be identified with simple noninvasive screening methods, among Caucasians of Northern European descent, as many as 29% of the subjects studied were compound heterozygotes for some other as yet unidentified mutations. Whether the remaining mutations are few or numerous and varied remains to be determined. In the meantime, European investigators suggest that the four reported mutations most common among European subjects could be easily screened for with a diagnostic kit containing allele specific oligonucleotide probes.
Because of the ease of therapy (dietary exclusion of fructose), HFI can be effectively managed if properly diagnosed. In HFI, the diagnosis of homozygotes is difficult, requiring a genomic DNA screening with allele specific probes or an enzyme assay from a liver biopsy. Once identified, parents of infants who carry mutant aldolase B alleles leading to HFI, or older individuals who have clinical histories compatible with HFI can be identified and counselled with regard to preventive therapy: dietary exclusion of foods containing fructose, sucrose, or sorbitol. If possible, individuals who suspect they might have HFI, should avoid testing via fructose challenge as the results are non-conclusive for individuals with HFI and even if the diagnostic administration fructose is properly controlled, profound hypoglycemia and its sequelae can threaten the patient's well-being. 
Treatment of HFI depends on the stage of the disease, and the severity of the symptoms. Stable patients without acute intoxication events are treated by careful dietary planning that avoids fructose and its metabolic precursors. Fructose is replaced in the diet by glucose, maltose or other sugars. Management of patients with HFI often involves dietitians who have a thorough knowledge of what foods are acceptable.
- Kaiser, Ursula B.; Hegele, Robert A. (December 1991). "Case report: Heterogeneity of aldolase B in hereditary fructose intolerance". The American Journal of Medical Sciences 302 (6): 364–368. doi:10.1097/00000441-199112000-00008. PMID 1772121.
- Steinmann, Beat; Santer, Rene (2012). "Disorders of Fructose Metabolism". In Saudubray, Jean-Marie; van den Berghe, Georges. Inborn Metabolic Diseases: Diagnosis and Treatment (5th ed.). New York: Springer. pp. 157–165. ISBN 978-3-642-15719-6. Unknown parameter
- Online 'Mendelian Inheritance in Man' (OMIM) 229600
- Cross NCP, deFranchis R (1990). Molecular analysis of aldolase B genes in hereditary fructose intolerance. Lancet. pp. 355; 306–309.
- Boston University HFI Lab
- What is Dietary Fructose Intolerance?
- Food-Info.net Fructose Intolerance (with list of acceptable and non-acceptable carbohydrates)
- What is Fructose Intolerance?
- Case Study
- HFI-Info Discussion Board