IDF PATIENT/FAMILY HANDBOOK | CHAPTER II
X-LINKED AGAMMAGLOBULINEMIA
The basic defect in X-Linked Agammaglobulinemia is a failure of B-lymphocyte precursors to mature into Blymphocytes and ultimately plasma cells. Since they lack the cells that are responsible for producing gamma globulins, these patients have severe deficiencies of gamma globulins.
DEFINITION: X-Linked Agammaglobulinemia (XLA) was first described in 1952 by Dr. Ogden Bruton. This disease, sometimes called Bruton’s Agammaglobulinemia or Congenital Agammaglobulinemia, was one of the first immunodeficiency diseases to be identified. XLA is an inherited immunodeficiency disease in which patients lack the ability to produce antibodies, proteins that make up the gamma globulin or immunoglobulin fraction of blood plasma.
Antibodies are an integral part of the body’s defense mechanism against certain microorganisms (e.g. bacteria, viruses). Antibodies are important in the recovery from infections, and also protect against getting certain infections more than once. There are antibodies specifically designed to combine with each and every microorganism - much like a lock and key. When microorganisms, such as bacteria, land on a mucus membrane or enter the body, antibody molecules specific for that microorganism stick to the surface of the microorganism. Antibody bound to the surface of a microorganism can have one or more effects that are beneficial to the person. For example, some microorganisms must attach to body cells before they can cause an infection and antibody prevents the microorganism from “sticking” to the cells. Antibody attached to the surface of some microorganisms will also cause the activation of other body defenses (such as a group of blood proteins called serum complement) which can directly kill the bacteria or viruses. Finally, antibody coated bacteria are much easier for white blood cells (phagocytes) to ingest and kill than bacteria which are not coated with antibody. All of these actions prevent microorganisms from invading body tissues where they may cause serious infections (see chapter on Immune System).
The basic defect in XLA is an inability of the patient to produce antibodies. Antibodies are proteins that are produced by specialized cells in the body, the plasma cells (see chapter on the Normal Immune System). The development of plasma cells proceeds in an orderly fashion from stem cells located in the bone marrow. The stem cells give rise to immature lymphocytes called pro-B-lymphocytes. Pro-B-lymphocytes give rise to Pre-B-lymphocytes, which in turn give rise to B-lymphocytes. On contact with a foreign substance called an antigen (such as a microorganism) B-lymphocytes mature into the plasma cells that produce and secrete antibodies.
Most patients with XLA have B-lymphocyte precursors, but very few of these go on to become B-lymphocytes. Thus, the underlying defect in XLA is a failure of B-lymphocyte precursors to mature into B-cells. Patients with XLA have mutations in a gene that is necessary for the normal development of Blymphocytes. This gene, discovered in 1993, is named BTK, or Bruton’s Tyrosine Kinase, in honor of the discoverer of the disorder, Colonel Ogden Bruton, M.D. As the name of the disorder suggests, the BTK gene is located on the X chromosome.
CLINICAL PRESENTATION: Patients with X-Linked Agammaglobulinemia (XLA) are prone to develop infections because they lack antibodies. The infections frequently occur at or near the surfaces of mucus membranes, such as the middle ear, sinuses and lungs, but in some instances can also involve the bloodstream or internal organs. Thus patients with XLA may have infections that involve the sinuses (sinusitis) the eyes (conjunctivitis), the ears (otitis), the nose (rhinitis), the airways to the lung, (bronchitis), or the lung itself (pneumonia). They also may have recurrent gastrointestinal tract infections that can cause diarrhea (gastroenteritis). In patients without antibodies, any of these infections may also penetrate the mucosal surface, invade the bloodstream and spread to other organs deep within the body, such as the bones, joints or brain. Infections in XLA patients are usually caused by microorganisms that are killed or inactivated very effectively by antibodies in normal people.
The most common bacteria that cause infection are the pneumococcus, the streptococcus, the staphylococcus and Hemophilus influenzae. Some specific kinds of viruses may also cause serious infections in these patients.
DIAGNOSIS: When a patient is suspected of having X-Linked Agammaglobuline-mia (XLA), the diagnosis is established by several tests. In XLA all of the immunoglobulins (IgG, IgM, and IgA) are markedly reduced or absent in the blood. It is difficult to provide exact numbers for normal immunoglobulin levels because they vary with the age of the child. Since normal babies make only small quantities of immunoglobulins in the first few months of life, it is important to remember that it may be difficult to distinguish a very young baby (less than 6 months old) with XLA from a normal baby by only testing blood levels of immunoglobulins.
In some cases, tests may also be performed to see how well the patient’s immunoglobulins function as antibodies. For example, the patient’s blood may be tested to determine if he has responded with specific antibodies to the usual childhood immunizations (for example, tetanus and/or diphtheria), or the child may be immunized with these killed vaccines and then tested. The most characteristic laboratory feature of XLA is the absence of B-lymphocytes in the blood. Blood may be tested to determine if the patient has B-lymphocytes in many laboratories. This is the most reliable test, since it is not influenced by age, previous immunizations, or the IgG that the baby received across the placenta from the mother.
Finally, it is now possible to test the BTK gene for errors or mutations.
INHERITANCE: X- Linked Agammaglobulinemia (XLA) is a genetic disease and as such can be inherited or passed on in a family. It is inherited as an Xlinked recessive trait. A complete explanation of how X-Linked recessive traits are inherited is beyond the scope of this chapter (see chapter on Inheritance). It is important to understand the type of inheritance so that families can understand why a child has been affected, the risk that subsequent children may be affected, and the implications for other members of the family.
Now that the precise gene that causes XLA has been identified, it is possible to test the female siblings (sisters) of a patient with XLA, and other female relatives such as the child’s maternal aunts, to determine if they are carriers of the disease. Carriers of XLA have no symptoms, but have a 50% chance of transmitting the disease to each of their sons (see chapter on Inheritance). In some instances, it is also possible to determine if a fetus of a carrier female will be born with XLA. At the present time, these genetic tests are being performed in only a few laboratories.
TREATMENT: At the present time, there is no way to cure patients who have XLinked Agammaglobulinemia (XLA). The defective gene cannot be repaired or replaced, nor can the maturation of Blymphocyte precursors to B-lymphocytes and plasma cells be induced.
However, patients with XLA can be given some of the antibodies that they are lacking. The antibodies are supplied in the form of gamma globulins (or immunoglobulins) and can be given directly into the blood stream “intravenously” (see chapter on Specific Medical Therapy).
The gamma globulin preparations contain antibodies that substitute for the antibodies that the XLA patient can not make himself. They contain antibodies to a wide variety of microorganisms. Gamma globulin is particularly effective in preventing the spread of infections into the bloodstream and to deep body tissues or organs. Recurrent or chronic infections of the mucus membranes, such as sinusitis, occur in some patients with XLA despite the use of gamma globulin. In these patients, it may be necessary to obtain specimens of infected secretions such as sputum, stool, or occasionally the infected tissue itself. These specimens are cultured in the laboratory in order to identify exactly which microorganisms are responsible for causing the infection. The culture results will guide the specific course of therapy, which may include antibiotics.
Finally patients with XLA should not receive any live viral vaccines, such as live polio, or the measles, mumps, rubella (MMR) vaccine. Although uncommon, it is possible that live vaccines (particularly the oral polio vaccine) in agamma globulinemia patients can transmit the diseases that they were designed to prevent.
EXPECTATIONS: Most X-Linked Agammaglobulinemia (XLA) patients who are receiving gamma globulin on a regular basis will be able to lead relatively normal lives. They do not need to be isolated or limited in their activities. Infections may require some extra attention from time to time, but children with XLA can participate in all regular school and extracurricular activities, and adults can have productive careers and families. A full active lifestyle is to be encouraged and expected!