(also called '''X-linked hypogammaglobulinemia,''' '''XLA''', '''Bruton type agammaglobulinemia''') is a rare s, particularly with extracellular, encapsulated
Bacteria . XLA is an
X-linked disorder, and therefore is almost always limited to males. It occurs in a frequency of about 1 in 100,000 male newborns, and has no ethnic
Predisposition . XLA is treated by infusion of human antibody. Treatment with pooled gamma globulin cannot restore a functional population of
B Cell s, but it is sufficient to reduce the severity and number of infections due to the
Passive Immunity granted by the exogenous antibodies.
X-Linked Agammaglobulinemia Patient and Family Handbook for The Primary Immune Diseases. Third Edition. 2001. Published by the Immune Deficiency Foundation
XLA is caused by a mutation on the
X Chromosome of a single
Gene identified in 1993 and known as
Bruton's Tyrosine Kinase , or Btk. XLA was first characterized by Dr.
Ogden Bruton in a ground-breaking research paper published in 1952 describing a boy unable to develop immunities to common childhood diseases and infections. Bruton's paper describes the first known
Immune Deficiency . XLA is classified with other inherited (genetic) defects of the
Immune System , known as
Primary Immunodeficiency disorders.Bruton, Ogden C. [http://pediatrics.aappublications.org/cgi/content/full/102/1/S1/213 ''Agammaglobulinemia'']
The gene Bruton's tyrosine kinase (Btk) plays an essential role in the maturation
B Cell s in the
Bone Marrow , and when mutated, immature pre-B lymphocytes are unable to develop into mature B cells that leave the bone marrow into the blood stream. The disorder is X-linked (it is on the
X Chromosome ), and is almost entirely limited to the sons of
Asymptomatic female
Carrier s . This is because males have only one copy of the X chromosome, while females have two copies; one normal copy of an X chromosome can compensate in for mutations in the other X chromosome. Females carriers have a 50% chance of giving birth to a male child with XLA.
An XLA patient will pass on the gene, and all of his daughters will be XLA carriers, meaning that any male grandchildren from an XLA patient's daughters have a 50% chance of inheriting XLA. A female XLA patient can only arise as the child of an XLA patient and a carrier mother. XLA can also rarely result from a spontaneous mutation in the
Fetus of a non-carrier mother.
XLA diagnosis usually begins due to a history of recurrent infections, mostly in the
Respiratory Tract , through childhood. The diagnosis is probable when blood tests show the complete lack of circulating B cells (determined by the B cell marker
CD19 and/or
CD20 ), as well as low levels of all
Antibody classes, including
IgG ,
IgA ,
IgM ,
IgE and
IgD .
When XLA is suspected, it is possible to do a
Western Blot test to determine whether the Btk protein is being expressed. Results of a genetic blood test confirm the diagnosis and will identify the specific Btk mutation, however its cost prohibits its use in routine screening for all pregnancies. Women with an XLA patient in their family should seek genetic counseling before pregnancy.
The most common treatment for XLA is an
Intravenous infusion of
Immunoglobulin (
IVIg , human IgG antibodies) every 3-4 weeks, for life. IVIg is a human product extracted and pooled from thousands of
Blood donations. IVIg does not cure XLA but increases the patient's lifespan and quality of life, by generating
Passive Immunity , and boosting the
Immune System . With treatment, the number and severity of infections is reduced. With IVIg, XLA patients may a live relatively healthy life. A patient should attempt reaching a state where his
IgG blood count exceeds 800 mg/Kg. The dose is based on the patient's weight and IgG blood-count. The dosing rule of thumb is 1g of IVIg for every 2kg of patient's weight.
Muscle injections of immunoglobulin (IMIg) were common before IVIg was prevalent, but are less effective and much more painful, hence, IMIg is now uncommon.
Subcutaneous treatment (SCIg) was recently approved by the
FDA , which is recommended in cases of severe adverse reactions to the IVIg treatment.
Antibiotics are another common supplementary treatment. Local antibiotic treatment (drops, lotions) are preferred over systemic treatment (pills) for long term treatment, if possible.
One of the future prospects of XLA treatment is
Gene Therapy , which could potentially cure XLA. Gene therapy technology is still in its infancy and may cause severe complications such as cancer and even death. Moreover, the long term success and complications of this treatment are, as yet, unknown.
Serology (detection on antibodies to a specific
Pathogen or
Antigen ) is often used to diagnose viral diseases. Because XLA patients lack antibodies, these tests always give a negative result regardless of their real condition. This applies to standard
HIV tests. Special blood tests (such as the
Western Blot based test) are required for proper viral diagnosis in XLA patients.
It is not recommended and dangerous for XLA patients to receive live attenuated
Vaccines such as live
Polio , or the
Measles ,
Mumps ,
Rubella (
MMR Vaccine ). Special emphasis is given to avoiding the oral live attenuated
SABIN-type Polio Vaccine that has been reported to cause polio to XLA patients. Furthermore, it is not known if active
Vaccines in general have any beneficial effect on XLA patients as they lack normal ability to maintain
Immune Memory .
XLA patients are specifically susceptible to viruses of the ,
Coxsackie Virus (hand, foot, and mouth disease) and
Echovirus es. These may cause severe
Central Nervous System conditions as chronic
Encephalitis ,
Meningitis and death. An experimental anti-viral agent,
Pleconaril , is active against
Picornaviruses . XLA patients, however, are apparently immune to the
Epstein-Barr Virus (EBV), as they lack
B Cells needed for the viral infection.
It is not known if XLA patients are able to generate an
Allergic Reaction , as they lack functional
IgE antibodies.
There is no special hazard for XLA patients in dealing with pets or outdoor activities.
Unlike in other primary
Immunodeficiencies XLA patients are at no greater risk for developing
Autoimmune illnesses.
Agammaglobulinemia (XLA) is similar to the primary immunodeficiency disorder
Hypogammaglobulinemia (
CVID ), and their clinical conditions and treatment are almost identical. XLA was also historically mistaken as Severe Combined Immunodeficiency (
SCID ), a much more severe immune deficiency.
A strain of
Laboratory Mouse , XID, is used to study XLA. These mice have a mutated version of the mouse Btk gene, and exhibit a similar, yet milder, immune deficiency as in XLA.
