Bruton agammaglobulinemia Health Article

Definition

Bruton agammaglobulinemia is an X-linked genetic condition caused by an abnormality in a key enzyme needed for proper function of the immune system. People who have this disorder have low levels of protective antibodies and are vulnerable to repeated and potentially fatal infections.

Description

An integral aspect of the body's ability to resist and fight off infections by microorganisms (bacteria, viruses, parasites, fungi) is the immune system. The immune system is comprised of specialized cells whose function is to recognize organisms that are foreign to the body and destroy them. One set of specialized cells used to fight infection are the B cells. B cells circulate in the bloodstream and produce organism-fighting proteins called antibodies.

Antibodies are made of different classes of immunoglobulin that are produced within a B cell and are then released into the bloodstream, where they attach to invading microorganisms. There are antibodies specifically designed to combine with each and every microorganism, very similar to a lock and key. Once the antibodies attach to the microorganism, it triggers other specialized cells of the immune system to attack and destroy the invader, thus preventing or fighting an existing infection.

In order for antibodies to be produced by the body, the B cells must develop and mature so they are capable of producing the infection-fighting antibodies. When this process does not occur normally, the immune system can not work properly to fight off infection, a state known as immunodeficiency. Bruton agammaglobulinemia (also called X-linked agammaglobulinemia, or congenital agammaglobulinemia) is an inherited immunodeficiency characterized by failure to produce mature B cells and thus to produce the antibodies needed to fight infections. The abnormality in this disorder resides in Bruton tyrosine kinase (BTK, also known as BPK or ATK), an enzyme needed for maturation of B cells. As a result, people with this condition have low levels of mature B cells and the antibodies that they produce, making them vulnerable to frequent and sometimes dangerous infections.

Bruton agammaglobulinemia was the first immunodeficiency disease to be identified, reported by the physician Colonel Ogden C. Bruton in 1952. Bruton's patient, a four-year-old boy, was first admitted to Walter Reed Army Hospital because of an infected knee. The child recovered well when Bruton gave him antibiotics, but over the next four years he had multiple infections. Just at that time, a new instrument was installed in the hospital's laboratory that was able to measure levels of antibodies in the bloodstream. At first the technician believed the machine was defective because it did not detect gammaglobulins (the building blocks of antibodies) in the boy, but Bruton recognized the significance of this finding, and remarked, "Things began to click then. No gammaglobulins; can't build antibodies."

Genetic profile

Bruton agammaglobulinemia is inherited in an X-linked recessive manner; thus, almost all persons with the disorder are male. Females have two X chromosomes, which means they have two copies of the BTK gene, whereas males only have one X chromosome and one copy of the BTK gene. If a male has an altered BTK gene, he will have Bruton agammaglobulinemia. If a female has one altered BTK gene, she will be a carrier and will be at risk to pass the altered gene on to her children. If her son inherits the altered gene, he will be affected; if her daughter inherits the altered gene, she will be a carrier like her mother. Alternatively, if her son or daughter does not inherit the altered gene, they will not be affected and will not pass the altered gene on to their children. Since fathers only pass a Y chromosome to their sons and an X chromosome to their daughters, none of an affected male's sons will develop the disorder but all of the daughters will be carriers.

Mutations in the gene for BTK (located at Xq21.3-22) are responsible for the disease. Over 250 different mutations in BTK have been identified and they are spread almost evenly throughout the BTK gene. While this abnormal gene can be passed from parent to child, in half of the cases a child will show the disease without having a parent with the mutant gene. This is because new alterations in the BTK gene can occur. This new alteration can then be passed on to the affected individual's children.

Demographics

Bruton agammaglobulinemia occurs in all racial groups, with an incidence between one in 50,000 and one in 100,000 individuals.