Hereditary Fructose Intolerance (HFI) and the Aldolase B Gene
This website was constructed as a class project for Genetics 564, an undergraduate Genetics course at UW-Madison.
What is HFI?
Hereditary Fructose Intolerance (HFI) is a genetic disorder that affects approximately 1 in every 23,000 people worldwide [1]. This disorder is characterized by the body's inability to process fructose, sucrose, and sorbitol, which are present in fruits and many processed foods [2]. Affected individuals who consume these foods will usually present symptoms such as vomiting, nausea, abdominal pain, and low blood glucose [1-6]. High or prolonged consumption of problematic sugars can lead to stunted growth and liver damage [1,2]. This condition can be lethal without early dietary intervention [2]. The cause of the disorder is a mutation in the Fructose-1,6-bisphosphate Aldolase (more commonly known as Aldolase B) gene. The change renders it unable to make normal Aldolase B protein, which is essential for processing fructose in the body [4,6]. Currently, the only treatment available for those with HFI is dietary restriction of sugars [3].
What causes HFI?
The cause of HFI is a mutation to the Aldolase B gene (noted as ALDOB in humans), a 15,220 base pair gene located on the ninth chromosome [7]. Aldolase B protein is encoded by this gene. There are three different types of Aldolase proteins in the body (A, B, and C) but only mutated Aldolase B protein causes HFI [6]. The function of Aldolase B is to cleave fructose-1,6-bisphosphate in the liver and kidneys as part of the energy-yielding process of glycolysis. When it is unable to do so, fructose-1-bisphosphate accumulates in the liver, unable to proceed through glycolysis [1,6]. This causes liver damage and other HFI symptoms, so early dietary intervention is extremely important for individuals diagnosed with or suspected of having HFI [5]. For a review of the mechanics of HFI, see the video below.
How is HFI inherited?
HFI is inherited in an autosomal recessive pattern [1-6]. As shown in the diagram at the left (from Brussels Genetics), this means that two asymptomatic, mutation-bearing parents (carriers) can have an affected child if they both randomly pass on the ALDOB mutation. The likelihood of two carrier parents having an affected child is generally 25%.
Is there a test for HFI?
Infants and individuals who believe they may be carriers of the ALDOB mutation can be tested for HFI. Companies such as Counsyl, Integrated Genetics, and others offer genetic testing services, usually requiring just a blood sample [3]. HFI is consistently reported as a result of a mutation to ALDOB, but not every individual with HFI may have the same mutation to the gene. For example, some individuals have an insertion mutation (when one or more nucleotides are aberrantly inserted in the sequence, disrupting the rest of the coding sequence) and others have a deletion (the removal of a nucleotide, disrupting the coding sequence). There are seven mutations that have been seen in 82% of all reported HFI cases worldwide [2]. Unfortunately, individuals with very rare types of ALDOB mutations may not have a definitive, genetically identified diagnosis available. However, over 40 Aldolase B mutations have been identified as causes of HFI, and it is possible more will be discovered in the future [8]. Further confirmation of an HFI diagnosis could be pursued through a liver biopsy or an intravenous fructose test [3]. Both are risky procedures but they would detect abnormal Aldolase B activity in patients with very rare mutations [3].
Is HFI treatable?
Currently there is no cure or treatment for HFI [1]. Through maintaining a diet that minimizes fructose, sucrose, and sorbitol intake, HFI symptoms can be avoided. For more information on a healthy diet for individuals with HFI, visit the Project Inspiration and HFI Resources page.
References
1. James, C.L., Rellos, P., Ali, M., Heeley, A.F. & Cox, T.M. (1996). Neonatal screening for hereditary fructose intolerance: frequency of the most common mutant aldolase B allele (A149P) in the British population. Journal of Medical Genetics, 33(10), 837–841.
2. Cox, T.M. (1994). Aldolase B and fructose intolerance. The FASEB Journal, 8(1), 62-71.
3. Bouteldja, N. & Timson, D.J. (2009). The Biochemical Basis of Hereditary Fructose Intolerance. Journal of Inherited Metabolic Disorders, 33(2), 105-112. doi:
10.1007/s10545-010-9053-2.
4. Coffee, E.M. & Tolan, D.R. (2010). Mutations in the Promoter Region of the Aldolase B Gene that cause Hereditary Fructose Intolerance. Journal of Inherited Metabolic Disorders, 33(6), 715-725. doi: 10.1007/s10545-010-9192-5
5. Tolan, D.R. & Brooks, C.C. (1992). Molecular analysis of common aldolase B alleles for hereditary fructose intolerance in North Americans. Biochemical and Molecular Medicine, 48(1), 19–25.
6. Kajihara, S., Mukait, T., Arai, Y., Owada, M., Kitagawa, T. & Hori, K. (1990). Hereditary Fructose Intolerance Caused by a Nonsense Mutation of the Aldolase B Gene. American Journal of Human Genetics, 47(3), 562-567.
7. Genetics Home Reference. (2014). ALDOB. Retrieved February 3, 2014 from http://ghr.nlm.nih.gov/gene/ALDOB
8. Coffee, E.M., Yerkes, L., Ewen, E.P., Zee, T., Tolan, D.R. (2010). Increased prevalence of mutant null alleles that cause hereditary fructose intolerance in the American population. Journal of Inherited Metabolic Disorders, 33(1), 33–42. doi: 10.1007/s10545-009-9008-7
2. Cox, T.M. (1994). Aldolase B and fructose intolerance. The FASEB Journal, 8(1), 62-71.
3. Bouteldja, N. & Timson, D.J. (2009). The Biochemical Basis of Hereditary Fructose Intolerance. Journal of Inherited Metabolic Disorders, 33(2), 105-112. doi:
10.1007/s10545-010-9053-2.
4. Coffee, E.M. & Tolan, D.R. (2010). Mutations in the Promoter Region of the Aldolase B Gene that cause Hereditary Fructose Intolerance. Journal of Inherited Metabolic Disorders, 33(6), 715-725. doi: 10.1007/s10545-010-9192-5
5. Tolan, D.R. & Brooks, C.C. (1992). Molecular analysis of common aldolase B alleles for hereditary fructose intolerance in North Americans. Biochemical and Molecular Medicine, 48(1), 19–25.
6. Kajihara, S., Mukait, T., Arai, Y., Owada, M., Kitagawa, T. & Hori, K. (1990). Hereditary Fructose Intolerance Caused by a Nonsense Mutation of the Aldolase B Gene. American Journal of Human Genetics, 47(3), 562-567.
7. Genetics Home Reference. (2014). ALDOB. Retrieved February 3, 2014 from http://ghr.nlm.nih.gov/gene/ALDOB
8. Coffee, E.M., Yerkes, L., Ewen, E.P., Zee, T., Tolan, D.R. (2010). Increased prevalence of mutant null alleles that cause hereditary fructose intolerance in the American population. Journal of Inherited Metabolic Disorders, 33(1), 33–42. doi: 10.1007/s10545-009-9008-7
Site creator: Madeline Ford ([email protected]) Site last updated: 5/19/14