Atransferrinemia is an extremely rare genetic disorder characterized by low levels of healthy, functional red cells in the blood (hypochromic, microcytic anemia) and by the accumulation of excess iron in the body (hemosiderosis). Symptoms may vary based upon the severity of anemia and upon the extent of iron accumulation in the body and the specific organs affected. Common symptoms include recurrent infections and growth delays. Atransferrinemia is principally caused by mutations of the transferrin (TF) gene and is inherited as an autosomal recessive trait. Atransferrinemia is classified as an iron overload disorder. A milder form of atransferrinemia, known as hypotransferrinemia, is caused by mutations in the same gene.
The symptoms and severity of atransferrinemia vary from one person to another depending upon the specific location and extent of iron accumulation in the body. Some individuals may develop mild symptoms, others may develop serious, life-threatening complications.
Affected individuals often develop severe microcytic hypochromic anemia, a condition characterized by abnormally small red cells (erythrocytes) that are insufficiently filled with hemoglobin. Red cells are blood cells that deliver oxygen throughout the body. Hemoglobin is the iron-rich, oxygen-bearing protein in blood. Microcytic hypochromic anemia may be associated with pallor and fatigue. Some affected individuals may have a slightly enlarged liver (hepatomegaly).
Atransferrinemia is also often associated with growth delays and recurrent infections. Additional symptoms depend upon the location and extent of iron accumulation in the body. Atransferrinemia can potentially affect the liver, heart, joints, pancreas, kidneys and thyroid. Iron accumulation can damage affected organs and can cause scarring (cirrhosis) of the liver, arthritis, an underactive thyroid (hypothyroidism) and heart abnormalities. In severe cases, affected individuals can develop life-threatening complications such as pneumonia or an impaired ability to circulate blood to the lungs and the rest of the body, resulting in fluid buildup in the heart, lungs and various body tissues (congestive heart failure).
Atransferrinemia / hypotransferrinemia is principally caused by mutations of the transferrin (TF) gene. It is inherited as an autosomal recessive trait. 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.
Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents both to pass the defective gene and, therefore, to have an affected child is 25 percent with each pregnancy. The risk to have a child who is a carrier like the parents is 50 percent with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25 percent. The risk is the same for males and females.
Investigators have determined that the transferrin (TF) gene is located at band 21 on the long arm (q) of chromosome 3 (3q21). 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 3q21” refers to band 21 on the long arm of chromosome 3. The numbered bands help to specify the location of the thousands of genes that are present on each chromosome.
The TF gene contains instructions for producing a protein called transferrin. This protein is essential for the proper transport of iron within the body. Mutations of the TF gene result in deficient levels of functional transferrin, which ultimately results in the accumulation of excess iron in various organs of the body. Iron accumulation damages the tissue of affected organs, causing the characteristic symptoms of atransferrinemia.
Researchers have determined that the absence of transferrin results in an inability of the body to deliver iron to immature red cells in the bone marrow. The lack of delivery of iron to these immature cells causes the body to increase the absorption of iron in the intestines significantly, resulting in the iron overload that characterizes atransferrinemia.
Atransferrinemia is an extremely rare disorder. Approximately 10 cases in 8 families have been reported in the medical literature. Because atransferrinemia may go unrecognized or misdiagnosed, determining its true frequency in the general population is difficult. Atransferrinemia affects males and females in equal numbers. Atransferrinemia was first described in the medical literature in 1961.
A diagnosis of atransferrinemia is made based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. Laboratory tests can reveal low or undetectable levels of transferrin in the blood.
The treatment of atransferrinemia is directed toward the specific symptoms that are apparent in each individual. Affected individuals have been treated with infusions of plasma or of a urified form of transferrin (apotransferrin) that may correct certain symptoms (e.g., anemia, growth deficiencies) associated with the disorder. As the liver synthesizes most transferrin, liver transplantation theoretically could supply a cure; its use has not been reported. In long-term survival with atransferrinemia, iron toxicity to tissues, rather than anemia, is the principal cause of illness. Approaches to off-loading excess body iron stores are not well worked out (see below).
Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.
Iron chelators are drugs that are often used to treat other disorders of iron overload. Iron chelators bind to the excess iron in the body allowing it to be dissolved in water and excreted from the body through the kidneys. The role, if any, that iron chelators may play in the treatment of individuals with atransferrinemia is unknown. For the possible use of liver transplantation, see “Treatment”, above.
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Orphanet Encyclopedia. Atransferrinemia. February 2005. Available at: http://www.orpha.net/consor/cgi-bin/index.php?lng=EN Accessed on: April 18, 2010.
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