IDF PATIENT/FAMILY HANDBOOK | CHAPTER III
X-Linked Agammaglobulinemia (XLA)
The basic defect in X-Linked Agammaglobulinemia is a failure of
B-lymphocyte precursors to mature into B-lymphocytes and
ultimately plasma cells. Since they lack the cells that are responsible
for producing immunoglobulins, these patients have severe
deficiencies of immunoglobulins.
Definition of X-Linked Agammaglobulinemia:
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 titled The Immune System and Primary
Immunodeficiency Diseases).
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, called
the plasma cells (see chapter titled The Immune
System and Primary Immunodeficiency Diseases).
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. Each
B-lymphocyte bears on its cell surface a sample
of the immunoglobulin that it is able to produce.
This cell surface immunoglobulin can bind
foreign substances, called antigens. When the
B-lymphocyte comes into contact with its specific
antigen, like the pneumococcus or tetanus toxoid,
it matures into an antibody secreting plasma cell.
Each B-cell makes a slightly different antibody (or
immunoglobulin) to allow the body to respond to
millions of different foreign substances.
Most patients with XLA have B-lymphocyte
precursors, but very few of these go on to become
B-lymphocytes. As a result, the underlying defect
in XLA is a failure of B-lymphocyte precursors
to mature into B-cells. Patients with XLA have
mutations in the gene that is necessary for the
normal development of B-lymphocytes. This gene,
discovered in 1993, is named BTK, or Bruton’s
Tyrosine Kinase, in honor of the discoverer of the
disorder, Dr. Ogden Bruton. As the name of the
disorder suggests, the BTK gene is located on the
X chromosome.
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Clinical Presentation of X-Linked
Agammaglobulinemia:
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. As a result, 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). Gastrointestinal infections
can also be a problem, especially with the parasite
Giardia. Giardia may cause abdominal pain,
diarrhea, poor growth or loss of serum proteins
like gamma globulin. Some patients with XLA also
have problems with skin infections.
In patients without antibodies, any of these infections
may 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.
On physical examination, most patients with XLA
have very small tonsils and lymph nodes (the
glands in your neck). This is because most of the
bulk of tonsils and lymph nodes is made up of
B-lymphocytes. In the absence of B-lymphocytes,
these tissues are reduced in size.
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Diagnosis of X-Linked Agammaglobulinemia:
The diagnosis of XLA should be considered in any
boy with recurrent or severe bacterial infections,
particularly if he has small or absent tonsils and
lymph nodes.
The first screening test should be an evaluation
of serum immunoglobulins. In most patients with
XLA all of the immunoglobulins (IgG, IgM and
IgA) are markedly reduced or absent. However,
there are exceptions; some patients make
some IgM or IgG. In addition, unaffected babies
make only small quantities of immunoglobulins
in the first few months of life, making it difficult
to distinguish an unaffected baby with a normal
delay in immunoglobulin production from a
baby with a true immunodeficiency. If the serum
immunoglobulins are low or if the physician
strongly suspects the diagnosis of XLA, the
number of B-cells in the peripheral blood should
be tested. A low percentage of B-cells (nearly
absent) in the blood is the most characteristic and
reliable laboratory finding in patients with XLA.
If a baby boy has a brother, maternal cousin or
maternal uncle with XLA, the newborn baby is at
risk to have XLA and his family and his physicians
should immediately determine the percentage
of B-cells in the blood so that treatment can be
started before an affected infant gets sick.
The diagnosis of XLA can be confirmed by
demonstrating the absence of BTK protein in
monocytes or platelets or by the detection of a
mutation in BTK in DNA. Almost every family has
a different mutation in BTK; however, members of
the same family usually have the same mutation.
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Inheritance of X-Linked Agammaglobulinemia:
X-Linked Agammaglobulinemia (XLA) is a genetic
disease and can be inherited or passed on in a
family. It is inherited as an X-linked recessive trait.
(For more information on how X-Linked recessive
traits are inherited, see chapter titled Inheritance.)
It is important to know the type of inheritance so
the family can better 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 titled Inheritance). In some
instances, it is also possible to determine if a fetus
of a carrier female will be born with XLA. Currently,
these genetic tests are being performed in only a
few laboratories.
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Treatment of X-Linked Agammaglobulinemia:
At this time, there is no way to cure patients who
have X-Linked Agammaglobulinemia (XLA). The
defective gene cannot be repaired or replaced, nor
can the maturation of B-lymphocyte 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 immunoglobulins (or
gamma globulins), and can be given directly
into the blood stream (intravenously) or under
the skin (subcutaneously) (see chapter titled
Specific Medical Therapy). The immunoglobulin
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. Immunoglobulin is particularly
effective in preventing the spread of infections
into the bloodstream and to deep body tissues or
organs. Some patients benefit from the use of oral
antibiotics every day to protect them from infection
or to treat chronic sinusitis or chronic bronchitis.
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
agammaglobulinemia patients can transmit the
diseases that they were designed to prevent.
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Expectations for X-Linked
Agammaglobulinemia Patients:
Most X-Linked Agammaglobulinemia (XLA)
patients who receive immunoglobulin on a
regular basis will be able to lead relatively
normal lives. They do not need to be isolated or
limited in their activities. Active participation in
team sports should be encouraged. Infections
may require some extra attention from time to
time, but children with XLA can participate in all
regular school and extracurricular activities, and
when they become adults can have productive
careers and families. A full active lifestyle is to be
encouraged and expected.
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