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Disease Information

Inherited Immunodeficiencies: Autosomal Recessive Agammaglobulinemia

Definition

Autosomal recessive agammaglobulinemia is a term used to describe a group of inherited disorders of the immune system that affect males and females equally. These disorders are 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). The autosomal recessive forms of agammaglobulinemia are caused by mutations (mistakes) in one of several different genes including µ heavy chain, λ5, Igα and BLNK. These mistakes result 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 autosomal recessive agammaglobulinemia is suspected in patients who have recurrent infections, low serum immunoglobulin levels (IgG, IgA, IgM), few to absent CD19+ B cells in the peripheral blood (<1 percent) and normal Btk (the gene that is abnormal in the X-linked form of agammaglobulinemia). The most consistent finding in autosomal recessive agammaglobulinemia is the absence of B cells. Patients with autosomal recessive agammaglobulinemia 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 one of the genes responsible for autosomal recessive agammaglobulinemia).

Incidence

The autosomal recessive forms of agammaglobulinemia are very rare. Less than 25 cases have been described.

Influencing Factors

Pattern of inheritance
Autosomal recessive agammaglobulinemia occurs if two abnormal genes, one from each parent, are present in the patient. Each parent carries an abnormal gene but does not have any physical symptoms of the disorder itself. For each pregnancy, there is a 25 percent chance of having an unaffected child, a 25 percent chance that the child will inherit the problem and a 50 percent chance that the child will be a carrier, like their parents, for autosomal recessive agammaglobulinemia. Each pregnancy carries the same risks or chance, and one pregnancy is not influenced by another.

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 the X-linked form of agammaglobulinemia. These patients have mutations in the gene called Btk (see section on X-linked agammaglobulinemia). Of the remaining 15 percent of patients, approximately half have defects in genes that are known to be responsible for autosomal recessive agammaglobulinemia. The other half may have autosomal recessive forms of agammaglobulinemia caused by genes that have not yet been identified or they may have B cell defects that are caused by a combination of genetic and environmental factors.

Clinical Features and Symptoms

Patients with autosomal recessive agammaglobulinemia are usually well the first few months of life because they are protected by immunoglobulins (antibodies) from the mother. Most patients develop recurrent bacterial infections in the first few months of life and all have been recognized as having immunodeficiency before 5 years of age. Patients with autosomal recessive agammaglobulinemia tend to have earlier infections and more severe infections than patients with the X-linked form of the disease.

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. Most patients with autosomal recessive 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 all forms of 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 autosomal recessive 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 genes that cause autosomal recessive agammaglobulinemia in the normal immune system
  • Identifying additional genes that can cause autosomal recessive agammaglobulinemia
  • Improving therapy for affected patients, including stem cell transplants
  • Identifying ways to improve early diagnosis

 

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