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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.
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.
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 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.
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.
Parents of a child with XLA should consider genetic counseling if they are planning to have more children.
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.
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.
absence or severe deficiency of the plasma protein gamma globulin. There are three main types: transient, congenital, and acquired. The transient type occurs in early infancy, because gamma globulins are not produced in the fetus and the gamma globulins derived from the maternal blood are soon depleted. This temporary deficiency of gamma globulin lasts for the first 6 to 8 weeks, until the infant begins to synthesize the protein. Congenital agammaglobulinemia is a rare condition, occurring in males, and resulting in decreased or absent production of antibodies. Acquired agammaglobulinemia is secondary to other disorders and is usually a hypogammaglobulinemia, that is, a deficiency rather than total absence of this plasma protein. It is often secondary to malignant diseases such as leukemia, myeloma, and lymphoma, and to diseases associated with hypoproteinemia such as nephrosis and liver disease. Some patients have a family history of rheumatoid arthritis or allergies. This seems to indicate the presence of genetic factors in the development of agammaglobulinemia.
Symptoms. Because gamma globulin is so important in the production of antibodies and thus in the body's ability to defend itself against infection, it follows that a deficiency or absence of gamma globulin would result in severe and recurrent infections. The infections are usually bacterial rather than viral in origin and are extremely difficult to eliminate. The condition is often complicated by local damage to tissues because of scarring and repeated infection. Disorders of connective tissue such as scleroderma, arthritis, and lupus erythematosus are also frequent complications.
Treatment. Replacement therapy with human gamma globulin is effective in preventing severe infections. The aim is to maintain the gamma globulin level above 150 mg per 100 mL of blood. The optimal dose is determined by the patient's response. Antibiotics are also given and are continued until all signs of infection have disappeared. The prevention and management of infections requires close collaboration between all members of the health care team. The administration of live vaccines is contraindicated.
common variable agammaglobulinemia common variable immunodeficiency.
X-linked agammaglobulinemia a primary X-linked immunodeficiency disorder characterized by absence of circulating B lymphocytes, plasma cells, or germinal centers in lymphoid tissues, very low levels of circulating immunoglobulins, susceptibility to bacterial infection, and symptoms resembling rheumatoid arthritis. Pre-B cells apparently fail to differentiate into mature B cells, express surface immunoglobulins, and produce antibody.
X-linked agammaglobulinemia (XLA),
an X-linked recessive B-cell immune deficiency condition, with hypo- or agammaglobulinemia; the immune deficiency becomes apparent as maternally transmitted immunoglobulin levels decline in early infancy.
Synonym(s): Bruton agammaglobulinemia
X-linked agammaglobulinemiaAn X-linked disease with defective humoral immunity due to an intrinsic B-cell gene defect that 'maps' to chromosome Xq21.3-22 Clinical Recurrent pyogenic infections, affecting boys by 5-6 months of life, coincident with fall in IgG acquired in utero Lab ↓ B cells, ↓ Igs, intact T-cell function Management Antibiotics, monthly injections of gammaglobulins Prognosis Death in early childhood, often due to fulminant lung infection
X-link·ed a·gam·ma·glob·u·li·ne·mi·a(XLA, X-LA) (lingkt ā-gamă-glob-yū-li-nēmē-ă)
B-cell immune deficiency condition, with hypo- or agammaglobulinemia; the immune deficiency becomes apparent as maternally transmitted immunoglobulin levels decline in early infancy.