Disease Information

Inherited Immunodeficiencies: X-linked Agammaglobulinemia (XLA)

Alternate Names: XLA

Definition

X-linked agammaglobulinemia (XLA) is an inherited disorder of the immune system that affects males but not females. It is characterized by the onset of recurrent bacterial infections in the first few years of life due to the absence of antibodies (another name for immunoglobulins). X-linked agammaglobulinemia is caused by a mutation (mistake) in the XLA gene, Btk. This mistake results in the absence of a particular type of white blood cells, the B cells. B cells in the normal individual function as the precursors of antibody producing cells. 

The diagnosis of XLA is suspected in males who have recurrent infections, low serum immunoglobulin levels (IgG, IgA, IgM) and few to absent CD19+ B cells in the peripheral blood (<1 percent). The most consistent finding is the absence of B cells. Males with X-linked agammaglobulinemia are often noted to have small tonsils and very few lymph nodes (palpable glands in the neck and groin region). The diagnosis is confirmed by mutation detection  (laboratory test looking for a mistake in the Btk gene).

Incidence

X-linked agammaglobulinemia occurs with a frequency of about 3-6/million males in all racial and ethnic groups.

Influencing Factors

Pattern of Inheritance
The gene for X-linked agammaglobulinemia is found on the X chromosome. Because females have two X chromosomes, if they have a mutation on one X chromosome, they have a spare X that can help compensate for the mutation. Males have one X chromosome and one Y chromosome. Since they do not have a spare X chromosome, they show signs of a mutation inherited on the X chromosome. Although, a female who carries the mutation for Btk on one of her X chromosomes, shows no sign of immunodeficiency, her sons and daughters have a 50 percent chance of inheriting the X chromosome with the mutation (and a 50 percent chance of inheriting the normal X chromosome). The sons who inherit the mutant X chromosome with have X-linked agammaglobulinemia and the daughters who inherit the mutant X chromosome will be carriers like their mother. Carriers of XLA can be identified by mutation detection (a laboratory test). 

All of the daughters of a man with X-linked agammaglobulinemia will be carriers of XLA; but the sons, who have inherited his unaffected Y chromosome, will be normal. About 50 percent of patients with XLA will have a brother, cousin or uncle with XLA. In most remaining families, the affected individual represents the first sign of a new mutation (mistake) in the Btk gene in his family. We do not know what causes new mutations in most families.

Most patients (85 percent) who have the early onset of infections and profound hypogamma-globulinemia (low serum immunoglobulin levels) and absent B cells are males with X-linked agammaglobulinemia and mutations (mistakes) in the gene, Btk. However, there are some patients, both males and females, who have an autosomal recessive form of the disease (see section on autosomal recessive agammaglobulinemia).

Clinical Features and Symptoms

Males with X-linked agammaglobulinemia are usually well the first few months of life because they are protected by immunoglobulins (antibodies) from the mother. Typically, affected males develop recurrent bacterial infections in the first two years of life and 90 percent are recognized as having immunodeficiency before 5 years of age.

Recurrent otitis is the most common infection prior to diagnosis. Conjunctivitis (eye infections), diarrhea, and sinus, pulmonary (lung) and skin infections are also frequently seen. Over half of the patients with X-linked agammaglobulinemia are recognized to have immunodeficiency when they develop a severe life-threatening infection such as pneumonia, sepsis (blood stream infection) or meningitis.

Survival Rates

The prognosis for X-linked agammaglobulinemia has improved dramatically in the last 20 years as a result of earlier diagnosis, more liberal use of antibiotics, and intravenous gammaglobulin. Patients are encouraged to lead a normal a life as possible, which includes regular exercise and good health habits.

Treatment Strategies

Gammaglobulin replacement is the mainstay of treatment for patients with X-linked agammaglobulinemia. Patients receive intravenous gammaglobulin (IVIG) every 3-4 weeks. At our center, chronic prophylactic antibiotics are used for prevention of bacterial infections.

Patients should NOT receive the live (oral) polio vaccine.

Current Research

• Better understanding the role of the XLA gene (Btk) in the normal immune system
• Improving therapy for affected patients, including stem cell transplants
• Identifying ways to improve early diagnosis
• Identifying complications that arise in adults with X-linked agammaglobulinemia 

 

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