Hereditary Hemochromatosis
What is hereditary hemochromatosis?Hereditary hemochromatosis (HH) is an inherited disease in which the body becomes incapable of absorbing iron properly and the blood becomes overloaded with iron, and is thereby considered an iron overload disorder. It is caused by a mutation in the HFE gene.
This disease has a range of symptoms, with some individuals living without any apparent symptoms, while others experience more severe symptoms such as tissue and organ damage due to the high levels of iron. The targeted tissues include the liver, heart, and pancreas, as well as the skeletal system, as arthritis has been reported in some individuals with hemochromatosis [1]. While the inheritance of the genes for HH are common, the severe symptoms are quite rare, with only 10% of individuals with the genes developing extreme iron overload and the associated organ damage [2]. The reasons for the lack of penetrance, or the proportion of individuals that have the genotype and express the phenotype, are largely unknown at this time. |
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DiagnosesOn the severe end of the symptom spectrum, hereditary hemochromatosis is diagnosed via the presence of cirrhosis (liver damage and scarring), diabetes, and a bronze-like skin coloration (shown in the figure to the left). In addition, individuals with HH may show abnormally high levels of iron on routine blood tests. Patients with HH have also experienced increased fatigue, arthritis, and heart failure [2].
However, when these symptoms are not present the simplest way to diagnose a risk for HH is to confirm the presence of HFE mutations via genetic family history screening. TreatmentThere is no cure for hereditary hemochromatosis. However, the high levels of iron in the blood can be regulated by the regular donation of blood or by undergoing a therapeutic phlebotomies [3].
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The HFE Gene
The HFE gene encodes for a protein found primarily on liver and intestinal cells that functions in detecting the amount of iron in the body. It also regulates the production of hepcidin, a protein produced by the liver that is considered the ultimate regulator of iron uptake [4].
The HFE gene is found on the short arm of the sixth chromosome [4]. While there are a variety of mutations that can occur in the HFE gene (eg. H63D and S65C), the most prevalent is the C282Y mutation [5]. The C282Y mutation is caused by a missense mutation where a guanine is changed to an adenine, causing a substitution of cystein with tyrosine at amino acid position 282 in the HFE gene [2]. Individuals who are homozygous, or have two copies, of the C282Y mutation in the HFE gene are susceptible to the symptoms of hereditary hemochromatosis. C282Y homozygotes account for 80%-85% of patients with HH [2]. The other well known mutatons, H63D and S65C, are generally not associated with iron overload unless they are inherited alongside a C282Y mutation [6].
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Location of the HFE gene on the sixth chromosome
Diagram of the HFE protein. The Cys282 -> Tyr282 substitution is the cause of the C282Y mutation. Image credit: [2]
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Inheritance patternHereditary hemochromatosis demonstrates an autosomal recessive inheritance pattern meaning that two recessive alleles must be inherited, one from each parent. Individuals heterozygous for HH carry one dominant allele in addition to one of the recessive mutations. People with this genotype are considered carriers for the disease and are not likely to develop any symptoms. They may, however, pass down the mutated allele to one or more of their children.
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References
Header Image Credit:
http://whatways.com/wp-content/uploads/2014/01/blood-cells.jpg
1. Allen, K.J., Gurrin, L.C., Constantine, C.C., Osborne, N.J., Delatycki, M.B., Nicoll, A.J., McLaren, C.E., Bahlo, M., Nisselle, A.E., Vulpe,C.D., Anderson, G.J., Southey, M.C., Giles, G.G., English, D.R., Hopper, J.L., Olynyk, J.K., Powell, L.W., Gertig, D.M. (2008) . Iron-overload-related disease in HFE hereditary hemochromatosis. New England Journal of Medicine, 358(3), 221-30. doi: 10.1056/NEJMoa073286
2. Bacon, B.R., Adams, P.C., Kowdley, K.V., Powell, L.W., Tavill, A.S. (2011). Diagnosis and management of hemochromatosis: 2011 practice guideline by the American Association for the Study of Liver Diseases. Hepatology, 54(1), 328-43. doi: 10.1002/hep.24330
3. Hemochromatosis Information Society: http://www.hemoinfo.org/treatment/
4. Genetics Home Reference: http://ghr.nlm.nih.gov/gene/HFE
5. Swinkels, D.W., Janssen, M.C., Bergmans, J., Marx, J.J. (2006). Hereditary hemochromatosis: genetic complexity and new diagnostic approaches. Clinical Chemistry, 52(6), 950-68.
6. Piperno, A., Arosio, C., Fossati, L., Vigano, M., Trombini, P., Vergani, A., and Mancia, G. (2000). Two novel nonsense mutations of HFE gene in five unrelated Italian patients with hemochromatosis. Gastroenterology, 119(2), 441-445.
http://whatways.com/wp-content/uploads/2014/01/blood-cells.jpg
1. Allen, K.J., Gurrin, L.C., Constantine, C.C., Osborne, N.J., Delatycki, M.B., Nicoll, A.J., McLaren, C.E., Bahlo, M., Nisselle, A.E., Vulpe,C.D., Anderson, G.J., Southey, M.C., Giles, G.G., English, D.R., Hopper, J.L., Olynyk, J.K., Powell, L.W., Gertig, D.M. (2008) . Iron-overload-related disease in HFE hereditary hemochromatosis. New England Journal of Medicine, 358(3), 221-30. doi: 10.1056/NEJMoa073286
2. Bacon, B.R., Adams, P.C., Kowdley, K.V., Powell, L.W., Tavill, A.S. (2011). Diagnosis and management of hemochromatosis: 2011 practice guideline by the American Association for the Study of Liver Diseases. Hepatology, 54(1), 328-43. doi: 10.1002/hep.24330
3. Hemochromatosis Information Society: http://www.hemoinfo.org/treatment/
4. Genetics Home Reference: http://ghr.nlm.nih.gov/gene/HFE
5. Swinkels, D.W., Janssen, M.C., Bergmans, J., Marx, J.J. (2006). Hereditary hemochromatosis: genetic complexity and new diagnostic approaches. Clinical Chemistry, 52(6), 950-68.
6. Piperno, A., Arosio, C., Fossati, L., Vigano, M., Trombini, P., Vergani, A., and Mancia, G. (2000). Two novel nonsense mutations of HFE gene in five unrelated Italian patients with hemochromatosis. Gastroenterology, 119(2), 441-445.
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Genetics 564 Assignment, Spring 2014 University of Wisconsin - Madison Last Updated: 7-30-2015 |
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