Atransferrinemia

(Iron transport deficiency Anemia)

Synonyms of Atransferrinemia

 congenital atransferrinemia
 hereditary atransferrinemia
 hypotransferrinemia

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).

The symptoms of Atransferrinemia are quite variable and depend on the severity of the anemia
and the extent of accumulation of iron in the body caused by the condition. Symptoms may also
vary depending on the organ affected by Atransferrinemia. Some of the symptoms are frequent
infections and growth retardation. This disease is primarily caused by mutation of transferrin
gene and is an autosomal recessive condition. This disease can also be classified as an iron
overload disorder.

Disease presentation: Signs and symptoms

As stated, symptoms of Atransferrinemia are significantly variable and depend on the extent of
iron accumulation in the body. Some people may have extremely mild symptoms whereas some
people may have serious complications with this disease. Affected individuals usually develop
severe microcytic hypochromic anemia in which there are extremely small erythrocytes which
are inadequately filled hemoglobin which may cause severe fatigue. Some people may also have
hepatomegaly.

Other symptom of Atransferrinemia is growth retardation and frequent infections.

Atransferrinemia tends to affect the liver, heart, pancreas, kidneys as well as thyroid. This
abnormal accumulation of iron can also cause cirrhosis of the liver and arthritis as well as
hypothyroidism and cardiac abnormalities. In acute cases of Atransferrinemia, there may be
development of pneumonia, circulatory problems, fluid buildup in the heart, lungs, as well as
congestive heart failure.
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)

Pathophysiology: Cause

Atransferrinemia is caused due to mutation of the transferrin gene and is an autosomal recessive
trait meaning that the defective genes need to be inherited from both parents to have this
condition. The function of the transferrin gene is to carry instructions for the cells to produce
protein called as transferrin which is responsible for control of iron in the body. Mutation of this
gene results in depletion of functional transferrin causing accumulation of excess iron in the
body which in turn affects various organs in the body.

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.

Treatment

The treatment of Atransferrinemia is aimed at treating the symptoms that an individual

experiences. The treatment may consist of plasma infusions or transferring infusions to control
iron buildup in the body to treat certain symptoms like growth retardation or anemia. Liver
transplantation is also an option as most of transferring is synthesized in the liver, although it has
not been proven as of yet. Apart from this, genetic counseling is also of help in dealing with the
symptoms of Atransferrinemia. Other than this, treatment is only supportive and symptomatic for
Atransferrinemia.

Diagnosis

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.

Standard Therapies

Treatment

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.

Investigational Therapies

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.

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All

studies receiving U.S. Government funding, and some supported by private industry, are posted
on this government web site.

Picture of Blood- Okay

Case Study
Morphologic presentation