Disease Description
X-Linked Agammaglobulinemia was the first immunodeficiency to
be identified. It is sometimes called Bruton Type Agammaglobulinemia,
X-Linked Infantile Agammaglobulinemia, or Congenital Agammaglobulinemia.
It is an inherited disorder localized to the central region of
the long arm of the X chromosome and is thus found in males.
However, this X-linked pattern of transmission cannot be demonstrated
in all families, possibly because of small family size, and because
in a certain percentage of cases, a new mutation in the gene
locus on the X chromosome has occurred. The gene locus is a specific
enzyme (BtK) which prompts B-cells to become mature and able
to produce antibodies.
Persons with X-Linked Agammaglobulinemia are unable to produce
antibodies (or binding proteins) that comprise the gammaglobulins
(immunoglobulins) in blood plasma. Most of these patients have
pre B-lymphocytes, but very few of these immature B-cells go
on to become mature B-lymphocytes. A few B-cells are present
in the bone marrow and circulation, but they may be reduced 100
fold or more. Other histologic (tissue) hallmarks of the disease
are lack of germinal centers (lymphocyte-producing cells) in
the lymph nodes or spleen, and in the absence of tonsils and
adenoids.
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Clinical Signs and Symptoms
These male patients are prone to develop serious, pyogenic (pus
producing) bacterial or viral infections. This process begins
in infancy or early childhood, typically at 6 to 9 months of
age, when maternally derived IgG antibodies have catabolized
(broken down). Common sites are the inner ear, sinuses, and respiratory
tract, leading to recurrent problems such as sinusitis, rhinitis
(nasal infection), pyoderma (skin infection), conjunctivitis
(eye infection), osteomyelitis (bone infection) meningitis (spinal
cord infection), sepsis (bloodstream infection), bronchitis,
and pneumonia. Recurrent gastrointestinal infections occur occasionally,
resulting in diarrhea. Since X-Linked Agammaglobulinemia patients
have no antibodies, infections can go beyond the mucosal surface
and into the bloodstream and internal organs.
Bacteria which are particularly common causes of infection in
these patients include pneumococcus, streptococcus, staphylococcus,
Pseudomonas aeruginosa, and Hemophilus influenzae. Giardia lamblia
can cause gastrointestinal infections, but it is not nearly as
common in X-Linked Agammaglobulinemia as in Common Variable Immunodeficiency
or Selective IgA Deficiency.
While the cellular immunity (immune response of T-cells and
not antibodies) of these patients is generally intact and they
are able to cope with most viral infections, there are some exceptions.
These patients are quite susceptible to a few viruses that cause
serious, life threatening illness. Examples are the hepatitis
virus, poliomyelitis virus, and enterovirus (ECHO virus). Resistance
to such infections as measles, chicken pox, tuberculosis, histoplasmosis,
and Pneumocystis carinii pneumonia is usually normal.
Besides signs of recurrent infections, other physical findings
include growth failure, rales and wheezes, and the absence of
tonsils and adenoids. While these patients test negative for
rheumatoid factor, they may develop a joint disease, especially
in the knees, resembling juvenile rheumatoid arthritis, which
frequently clears with administration of gammaglobulin. In some
cases, this arthritic manifestation may be due to mycoplasma
infections and responds to appropriate antibiotics.
Other unusual features described in these patients include autoimmune
hemolytic anemia (red blood cell breakdown), glomerulonephritis
(kidney inflammation), neutropenia (decreased neutrophils in
blood), and dermatomyositis (skin and muscle inflammation). A
chronic progressive encephalitis (brain infection) possibly caused
by a virus used to be relatively common, but with the increased
use of intravenous gammaglobulin , the incidence appears to be
greatly reduced.
Malignancies, including leukemia, lymphoma, and possibly colon
cancer in the older subjects, have been reported in a small percentage
of X-Linked Agammaglobulinemia patients.
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Diagnosis
A diagnosis of X-Linked Agammaglobulinemia is established by
several tests which measure the mounts of immunoglobulin in the
blood. In these patients, tests will show marked decreases or
absences of all five immunoglobulin classes. IgG is generally
less than 200 mg/dl, with IgA, IgM, IgD, and IgE usually low
or absent.
For some patients for whom the exact diagnosis is still unclear,
it may be important to test the function of these immunoglobulins
that are present. These patients are unable to respond with antibody
formation following immunization. Confirmation of this disease
can be made by genetic studies, analyzing the gene which produces
the B-cell enzyme BtK. When a specific defect is found in the
affected male, research laboratories can then test female members
to diagnose those who carry the abnormal X chromosomes.
White blood cell counts are normal, but B-lymphocytes, measured
by immunofluorescent techniques in the laboratory are usually
absent. T-cell development, as well as T-cell responses are normal.
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Treatment
There is no cure for X-Linked Agammaglobulinemia at this time.
Treatment focuses on providing antibody replacement through gammaglobulin
therapy. This treatment helps these patients by providing them
with the antibodies they cannot make to protect against the spread
of infections into the bloodstream and to body organs and tissues.
The usual treatment is intravenous immunoglobulin given at a
dose of 300 mg/kg every 3 weeks, or 400 mg/kg or more monthly.
The goal is to maintain serum IgG levels above 500 mg/dl. However,
this serum IgG level may not be sufficient to eradicate chronic
sino-pulmonary infections or to prevent development of secondary
bronchiectasis (widening and scaring of bronchial airways), postural
drainage and prophylactic and/or continuous broad spectrum antibiotics
are indicated.
In patients who have developed recurrent or chronic infections,
it may be necessary to obtain specimens of sputum, stool, or
the infected tissue in order to allow institution of specific
antibiotic therapy. In the case of chronic sinusitis or bronchiectasis
(widening of airways), postural drainage and prophylactic and/or
continuous broad spectrum antibiotics are indicated.
These patients should not be given live viral vaccines because
they could develop the disease for which the vaccination was
given. Polio is an example. Some research laboratories are attempting
gene therapy experiments to transfer a normal gene into cultured
B-cells; the results are still very preliminary and have not
yet been attempted in patients.
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