NORD gratefully acknowledges William JH Griffiths PhD FRCP, Consultant Hepatologist, Addenbrooke's Hospital, Cambridge, UK, for assistance in the preparation of this report.
Ferroportin disease, also known as hemochromatosis type 4, is a rare genetic disorder characterized by the abnormal accumulation of iron in the body. Ferroportin disease is caused by mutations of the SLC40A1 gene. The specific symptoms associated with ferroportin disease can vary greatly from one person to another. Some individuals may only have elevated levels of ferritin, a protein that binds to iron and is used as an indicator of the body's iron stores in the blood plasma. Other individuals may develop symptoms similar to classic hereditary hemochromatosis
Ferroportin disease is classified as an iron overload disorder, a group of disorders characterized by the abnormal accumulation of iron in the body. It is a separate, distinct disorder from classic hereditary hemochromatosis. Ferroportin disease is caused by mutations in a different gene and is inherited in a different manner from other forms of hemochromatosis.
The symptoms of ferroportin disease vary greatly from one person to another. Researchers believe that different mutations of the SLC40A1 gene are associated with different symptoms. Generally, ferroportin disease is separated into two main forms.
Some individuals with ferroportin disease develop a mild form of the disorder. These individuals have elevated levels of ferritin in the blood plasma (hyperferritinemia) and low level of saturated transferrin (the protein that carries iron in the blood). As affected individuals age, mild liver damage (hepatic fibrosis) may occur.
Other individuals develop a form of ferroportin disease that resembles the more common classic form of hemochromatosis (hemochromatosis type 1). The transferrin saturation is significantly elevated in this form. Symptoms associated with this form include joint pain, abnormalities in the heart’s rhythm or heartbeat pattern (arrhythmias), and diabetes. Liver damage is more prevalent in this form of ferroportin disease and can progress to cause scarring (cirrhosis) of the liver.
Ferroportin disease is caused by mutations of the SLC40A1 gene. These mutations are inherited as autosomal dominant traits. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.
Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50 percent for each pregnancy regardless of the sex of the resulting child.
Investigators have determined that the SLC40A1 gene is located on the long arm (q) of chromosome 2 (2q32). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 2q32” refers to band 32 on the long arm of chromosome 2. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
The SLC40A1 gene contains instructions for creating ferroportin, a specialized protein that is crucial to the proper export of iron from cells. Ferroportin also plays a role in the proper breakdown (metabolism) of iron. Iron is a critical mineral that is found in all cells of the body and is essential for the body to function and grow properly. Iron is found many types of food including red meat, poultry, eggs and vegetables. Iron levels must remain in a specific range within the body, otherwise they can cause anemia (due to low iron levels) or damage affected organs (due to high iron levels).
Mutations of the SLC40A1 gene result in low levels of functional ferroportin. The lack of functional ferroportin ultimately results in the abnormal accumulation of iron in the cells and tissues of the body. Different mutations of the SLC40A1 gene affect the ferroportin protein in different ways, altering the export and metabolism of iron accordingly. Researchers believe that the different ways in which SLC40A1 mutations affect ferroportin account for the two different forms of the disorder.
Ferroportin disease affects males and females in equal numbers. The exact incidence of ferroportin disease is unknown. Researchers believe that the disorder occurs more frequently than has been reported in the medical literature. Ferroportin affects individuals of all races and ethnicities. Some researchers believe that ferroportin disease is the most common form of hereditary iron overload after classic (type 1) hemochromatosis.
A diagnosis of ferroportin disease is made based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. A family history with affected individuals in successive generations is highly suggestive (autosomal dominant inheritance). Blood tests can reveal certain findings associated with ferroportin disease including high levels of ferritin in the blood and, in the milder form of the disease, low or normal saturation of transferrin, another protein that plays a role in the proper transport of iron within the body. Molecular genetic testing for mutations of the SLC40A1 gene is available and necessary to confirm the diagnosis.
The treatment of ferroportin disease is directed toward the specific symptoms that are apparent in each individual. Specific treatment may depend on the severity and form of ferroportin disease.
Individuals with the form of ferroportin disease that resembles classic hemochromatosis may be treated with regular phlebotomy, a procedure in which blood is removed via a vein. Individuals with the mild form of ferroportin disease may not necessarily require treatment and phlebotomy in these individuals is often complicated by anemia.
Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.
Additional therapies have been used to treat individuals with disorder of iron overload. Such therapies include iron chelators and antioxidants. Iron chelators are drugs that bind to the excess iron in the body allowing it to be dissolved in water and excreted from the body through the kidneys. Antioxidants such as vitamin E are substances that are believed to protect cells from damage from unstable molecules called free radicals.
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