Bruton Type Agammaglobulinemia

Definition

Definition of Bruton Type Agammaglobulinemia
X-linked agammaglobulinemia (XLA), or Bruton agammaglobulinemia, is an inherited immunodeficiency disease caused by mutations in the gene coding for Bruton tyrosine kinase (BTK). The disease was first elucidated by Bruton in 1952, for whom the gene is named. BTK is critical to the maturation of pre-B cells to differentiating mature B cells. The BTK gene defect has been mapped to the long arm of the X chromosome at band Xq21.3 to Xq22, spanning 37.5kb with 19 exons forming 659 amino acids to complete the BTK cytosolic tyrosine kinase. A database of BTK mutations (BTKbase: Mutation registry for X-linked agammaglobulinemia) lists 544 mutation entries from 471 unrelated families showing 341 unique molecular events. No single mutation accounts for more than 3% of mutations in patients. In addition to mutations, a number of variants or polymorphisms have been found.

Symptoms

Symptoms of Bruton Type Agammaglobulinemia
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.

Causes

Causes of Bruton Type Agammaglobulinemia
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.

Diagnosis

Diagnosis of Bruton Type Agammaglobulinemia
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.

Prognosis

Prognosis of Bruton Type Agammaglobulinemia
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.

Treatment

Treatment of Bruton Type Agammaglobulinemia
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.

Prevention

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