Bruton's agammaglobulinemia

Definition

Bruton's agammaglobulinemia is a disorder that is present at birth (congenital) and is characterized by low or completely absent levels of immunoglobulins in the bloodstream. Bruton's agammaglobulinemia is also known as X-linked agammaglobulinemia (XLA).

Description

Children with XLA have very low, or completely absent, levels of immumoglobulins in their blood. Immunoglobulins are protein molecules in blood serum that function like antibodies. Without them, the body lacks a fully functioning immune system. Individuals with XLA are vulnerable to repeated, potentially fatal, bacterial infections.

Although persons with XLA carry the genes to produce immunoglobulins, a genetic defect on the X chromosome prevents their formation. This defect is not associated with the immunoglobulins themselves, but rather with the B cells in the bloodstream that ordinarily secrete the immunoglobulins.

B cells are a type of white blood cell. They are the sole producers of immunoglobulins in the body. B cells are produced in the bone marrow and carried to the spleen, lymph nodes, and other organs as they mature. The maturation process depends on an enzyme called Bruton's agammaglobulinemia tyrosine kinase (Btk). If Btk is missing or defective, the B cells cannot mature and cannot produce immunoglobulins.

The gene that controls the production of Btk is on the X chromosome. Certain changes (mutations) in this gene result in defective Btk. Males have one X and one Y chromosome (XY). Females have two X chromosomes (XX). The mother passes one of her two X chromosomes down to her child, and the father passes either an X or a Y chromosome to the child. The mutated gene that produces XLA is a recessive gene. This means that as long as one good copy is present, the disease will not occur. Boys only have one copy of the gene, because they only have one X chromosome. Girls have two copies of the gene. This means that for boys to have XLA they must only inherit one copy of the defective gene, but for girls to have the disease they have to inherit two copies, one from each parent. This is why diseases associated with X linked genes are usually much more common in boys than in girls. To date, no cases of XLA in girls have actually been reported.

Demographics

XLA occurs in one in every 50,000 to one in every 100,000 newborns. Males are overwhelmingly more likely to have it than girls. Children who have an affected relative are more likely to be at risk, because the defect causing the disorder is inherited.

Causes and symptoms

XLA is caused by a defect in the gene that controls the production of the enzyme Btk. This defect blocks B cells from maturing. Only mature B cells produce immunoglobulins. Because other portions of the immune system are functional, people with XLA can fight off some types of infection, such as fungal and most viral infections. Immunoglobulins, however, are vital for combating bacterial infections.

Infants with XLA usually do not show symptoms of the disorder during the first six months of life, because immunoglobulins from their mothers are circulating in their bloodstreams. Over time, their immunoglobulin levels begin to decrease because they cannot successfully produce their own. As the immunoglobulin levels decrease, the baby becomes increasingly vulnerable to bacterial infections.

Common symptoms of immunoglobulin deficiency usually appear after the infant is six months old. They include frequent ear and sinus infections, pneumonia , and gastroenteritis . Certain viruses, such as hepatitis and polio viruses, can also pose a threat. Children with XLA often have small tonsils and lymph nodes and may develop chronic skin infections. Approximately 20 percent of these children develop arthritis, possibly as a result of joint infections.

When to call the doctor

If a child has had many more infections, especially serious infections, than is normal for a child of his or her age there may be an immune system problem such as XLA and a doctor should be consulted.

Diagnosis

Frequent bacterial infections, a lack of mature B cells, and low-to-nonexistent levels of immunoglobulins point to a diagnosis of XLA. A sample of the child's blood serum can be analyzed for the presence of immunoglobulins by a technique called immunoelectrophoresis. To make a definitive diagnosis, the child's X chromosome is analyzed for defects in the Btk gene. Similar analysis can be used for prenatal diagnosis or to detect carriers of the defective gene.

Treatment

Treatment of XLA consists of regular intravenous doses of commercially prepared gamma globulin (sold under the trade names Gamimune or Gammagard) to ward off infections. Antibiotics are used to treat infections as they occur. Children with XLA must be treated promptly for even minor cuts and scrapes and taught to avoid crowds and people with active infections.

Prognosis

Prior to the era of gamma globulin and antibiotic treatment, approximately 90 percent of XLA individuals died before the age of eight. Early diagnosis and therapy in the early 2000s allows most individuals with XLA to reach adulthood and lead relatively normal lives. Infants who develop polio or persistent viral infections, however, have a poorer prognosis.

Prevention

There is no known way to prevent XLA. However, if an individual believes a family member may have XLA, it is possible to get genetic counseling prior to pregnancy to determine if the individual is a carrier of the gene. If the person is a carrier various options can be discussed.

KEY TERMS

Antibody —A special protein made by the body's immune system as a defense against foreign material (bacteria, viruses, etc.) that enters the body. It is uniquely designed to attack and neutralize the specific antigen that triggered the immune response.

Bcell —A type of white blood cell derived from bone marrow. B cells are sometimes called B lymphocytes. They secrete antibodies and have a number of other complex functions within the human immune system.

Bruton's agammaglobulinemia tyrosine kinase (Btk) —An enzyme vital for the maturation of B cells.

Carrier —A person who possesses a gene for an abnormal trait without showing signs of the disorder. The person may pass the abnormal gene on to offspring. Also refers to a person who has a particular disease agent present within his/her body, and can pass this agent on to others, but who displays no symptoms of infection.

Enzyme —A protein that catalyzes a biochemical reaction without changing its own structure or function.

Immunoglobulin G (IgG) —Immunoglobulin type gamma, the most common type found in the blood and tissue fluids.

Mutation —A permanent change in the genetic material that may alter a trait or characteristic of an individual, or manifest as disease. This change can be transmitted to offspring.

X chromosome —One of the two sex chromosomes (the other is Y) that determine a person's gender. Normal males have both an X and a Y chromosome, and normal females have two X chromosomes.

Parental concerns

Children with XLA can have normal lives. Most medical care can be managed on an outpatient basis or even by home care. Special attention needs to be paid to the beginning of infections so that they can be treated promptly, but in general, children should be encouraged to participate in normal activities such as school and play . Usually, children with XLA are not given any vaccines containing live viruses (such as measles , mumps , or polio) because there is a small but dangerous risk that the child will actually get the disease that the vaccine was intended to prevent.

Resources

ORGANIZATIONS

Immune Deficiency Foundation. 40 W. Chesapeake Ave Suite 308 Towson, MD 21204. Web site: <www.primaryimmune.org>.

WEB SITES

Chin, Terry. "Agammaglobulinemia." Available online at <www.emedicine.com/ped/topic54.htm> (accessed October 27, 2004).

"X-Linked Agammaglobulinemia." Children's Hospital and Health System. Available online at <www.chw.org/display/PPF/DocID/2229/router.asp> (accessed October 27, 2004).

Tish Davidson, A.M. Julia Barrett

X-Linked Agammaglobulinemia

Definition

X-linked agammaglobulinemia (XLA) or Bruton's agammaglobulinemia is present at birth (congenital) and is characterized by low or completely absent levels of immunoglobulins in the bloodstream. Immunoglobulins are protein molecules in blood serum that function like antibodies. Without them, the body lacks a fully functioning immune system. Persons with XLA are vulnerable to repeated, potentially fatal bacterial infections.

Description

XLA occurs in one in 50,000 to one in 100,000 newborns. Almost all persons with the disorder are males. Although persons with XLA carry the genes to produce immunoglobulins, a genetic defect on the X chromosome prevents their formation. This defect is not associated with the immunoglobulins themselves, but rather with the B cells in the bloodstream that ordinarily secrete the immunoglobulins.

B cells are a type of white blood cell. They are the sole producers of immunoglobulins in the body. B cells are produced in the bone marrow and carried to the spleen, lymph nodes, and other organs as they mature. The maturation process depends on an enzyme called Bruton's agammaglobulinemia tyrosine kinase (Btk). If Btk is missing or defective, the B cells cannot mature and cannot produce immunoglobulins.

The gene for Btk is on the X chromosome. Certain changes (mutations) in this gene result in defective Btk. Since the gene is carried on the X chromosome, XLA individuals are almost always male. Females have two X chromosomes, which means they have two copies of the Btk gene, one of which is normal. Males have only one X chromosome.

Causes and symptoms

XLA is caused by a defect in the gene that codes for Btk. This defect leads to blocked maturation of B cells, the cells that produce immunoglobulins. Because other portions of the immune system are functional, people with XLA can fight off some types of infection, such as fungal and most viral infections. Immunoglobulins, however, are vital to combat bacterial infections. Infants with XLA usually do not show symptoms during the first six months of life because immunoglobulins from their mothers are circulating in their bloodstreams. As the mother's supply decreases, the baby becomes increasingly vulnerable to bacterial infections.

Common symptoms of immunoglobulin deficiency appear after the infant is six months old. They include frequent ear and sinus infections, pneumonia, and gastroenteritis. Certain viruses, such as hepatitis and polio viruses, can also pose a threat. Children with XLA grow slowly, have small tonsils and lymph nodes, and may develop chronic skin infections. Approximately 20% of these children develop arthritis, possibly as a result of joint infections.

Diagnosis

Frequent bacterial infections, a lack of mature B cells, and low-to-nonexistent levels of immunoglobulins point to a diagnosis of XLA. A sample of the infant's blood serum can be analyzed for the presence of immunoglobulins by a technique called immunoelectrophoresis. To make a definitive diagnosis, the child's X chromosome is analyzed for defects in the Btk gene. Similar analysis can be used for prenatal diagnosis or to detect carriers of the defective gene.

Treatment

Treatment of XLA consists of regular intravenous doses of commercially prepared gamma globulin (sold under the trade names Gamimune or Gammagard) to ward off infections. Antibiotics are used to treat infections as they occur. Children with XLA must be treated promptly for even minor cuts and scrapes, and taught to avoid crowds and people with active infections.

Prognosis

Prior to the era of gamma globulin and antibiotic treatment, approximately 90% of XLA individuals died before age 8. Early diagnosis and current therapy allows most individuals with XLA to reach adulthood and lead relatively normal lives. Infants who develop polio or persistent viral infections, however, have a poorer prognosis.

Prevention

Parents of a child with XLA should consider genetic counseling if they are planning to have more children.

Resources

ORGANIZATIONS

Immune Deficiency Foundation. 25 W. Chesapeake Ave., Suite 206, Towson, MD 21204. (800) 296-4433. 〈http://www.primaryimmune.org〉.

National Organization for Rare Disorders. P.O. Box 8923, New Fairfield, CT 06812-8923. (800) 999-6673. 〈http://www.rarediseases.org〉.

KEY TERMS

Antibody— A molecule that is produced by the immune system in response to a protein, called an antigen, that is not recognized as belonging in the body.

B cell— A type of lymphocyte, or white blood cell, that is a key component of the body's immune system. Mature B cells produce immunoglobulins.

Bruton's agammaglobulinemia tyrosine kinase (Btk)— An enzyme vital for the maturation of B cells.

Carrier— A person who has a genetic defect but does not develop any symptoms or signs of the defect. The carrier's offspring may inherit the defect and develop the associated disorder.

Enzyme— A protein molecule that prompts rapid biochemical reactions.

Immunoglobulin— A protein molecule formed by mature B cells in response to foreign proteins in the body. There are five types of immunoglobulins, but the major one is gamma globulin or immunoglobulin G.

Mutation— A change in a gene that alters the function or other characteristics of the gene's product.

X chromosome— One of the two sex chromosomes (the other is Y) that determine a person's gender. Normal males have both an X and a Y chromosome, and normal females have two X chromosomes.