X-linked agammaglobulinemia
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[edit] Summary
X-linked agammaglobulinemia (XLA, Bruton type agammaglobulinemia) is a rare genetic disorder that causes an immune deficiency. XLA patients completely lack antibodies (of all sorts: IgG, IgM, IgA, IgE, IgD) and display absence of B lymphocytes in the blood. Patients typically present in early childhood with recurrent infections, particularly with extracellular, encapsulated bacteria. It is treated by a monthly infusion of human antibodies (IV-Ig). XLA is almost entirely limited to males, sons of healthy female carriers. It occurs in a frequency of about 1 in 100,000 male newborns, and has no ethnic predisposition.
See also hypogammaglobulinemia (CVID), a similar disorder, less characterised than XLA. agammaglobulinemia (XLA) and hypogammaglobulinemia (CVID) are often intermixed by physicians, as their clinical conditions and treatment are almost identical.
[edit] Genetics
XLA is caused by a mutation on X chromosome of a single gene - Btk (Bruton's tyrosine kinase). Btk has an essential role in the maturation B lymphocyte cells in the bone marrow, and when mutated, these lymphocytes do not mature into mature B cells. As the disorder is X-linked (on X chromosome),and rare, it is almost entirely limited to males, sons of healthy women carriers. This is due to the fact that males have only one copy of the X chromosome, while women have two copies and can compensate in the case of a single mutation. The disorder is recessive, hence female may serve as carriers, and while being healthy themselves, have a 50% of giving birth to an XLA boy. The genetics of the father does not count in this case. It occurs in about 1 in 100,000 male newborns, and has no ethnic predisposition.
[edit] Diagnosis
XLA diagnosis usually begins due to a history of recurrent infections, mostly in the respiratory tract, through childhood. The diagnosis is made by blood tests proving lack of IgG count and the B-cells (marker CD19) count. A genetic blood test exists to diagnose the specific Btk mutation, but 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.
[edit] Treatment
The most commonly used treatment is an intravenous administration of immunoglobulin (IV-Ig, human IgG antibodies) every 3-4 weeks for life. The IV-Ig is given as an infusion, and it takes several hours. The dose, measured in grams, is based on the patient's weight and IgG blood-count. IV-Ig does not cure XLA but increases the patient's lifespan and quality of life. With IV-Ig, XLA patients may a live relatively healthy life. IV-Ig was first introduced in the late 70s. Muscle injections (IM-Ig) were common before IV-Ig was prevalent. This treatment is both less effective and painful and is therefore uncommon now days. A new subcutaneous treatment (SC-Ig) was recently approved by the FDA, which is especially recommended in cases of severe adverse effects to the IV-Ig treatment. A patient should attempt reaching a state where his IgG blood count exceeds 800 mg/Kg. IV-Ig is not a drug, but a pure human body product extracted from thousands of blood donations, and is therefore expensive. It is a rather "healthy" treatment which boosts the human immune system.
Beside IgG administration, antibiotics are a common supplementry treatment. Local antibiotic treatment (drops, lotions) should be preferred over systemic treatment (pills) for long term treatment, if possible.
One of the future prospects of XLA treatment is gene therapy, ("a gene transplant"), which will cure XLA. This has yet to be accomplished, and gene therapy is still an immature method that might cause complications such as cancer and even death.
[edit] XLA Notes
1. It is not recommended and might be even dangerous for XLA patients to receive live attenuated vaccines. Special emphasis is given to avoiding Polio vaccinations (although this is based on old data, when XLA and SCID where confused to be the same disorder). Furthermore, it is not known if active vaccines have any beneficial effect on XLA patients.
2. Serology blood works (detection on antibodies to a specific pathogens) which are often used for viral diagnostics, are meaningless for XLA patients. These tests always come out negative regardless of the situation. This is especially important in the case of HIV blood tests, as the common test is based on Serology. XLA patients should make their physicians aware of this rare condition and ask for special blood tests (such as the "western blot" based blood test for HIV).
3. XLA patients should be aware that 100% of their daughters will be XLA carriers, which brings their male grandsons from their daughters to 50% of inheriting XLA.
4. XLA patients are the only people able to father a female XLA patient, in the theoretical (and extremely rare) case where the mother is a XLA carrier as well. In such a mate the chances for a female XLA patient are 50%.
5. XLA patients are apparently immune to the Epstein-Barr virus (EBV), as they lack B cells needed for the viral infection.
6. It is not known if XLA patients are able to have an allergic reaction and to what extent, as they lack the IgE antibodies that start such reactions.
7. XLA patients are able to able to get autoimmune illnesses, but unlike other immune deficiencies where the chances may be higher than normal people, this is probably not the case for XLA.
8. XLA patients and SCID patients (a much more serious immune deficiency) were historically mixed-up by researchers. This biased some of the old XLA research results.
9. Beside inheritance, XLA could also result from a spontaneous mutation in the fetus of a non-carrier mother. This however, is less common.
10. XLA was the first immune deficiency to be identified and described. The Btk gene that was found later on to responsible for XLA is named over discoverer - Bruton.
11. XID mice are lab mice mutated in the mouse version of the Btk gene. They have a similar immune deficiency as XLA, albeit milder. XID mice are used for biological research.
12. There is no special hazard for XLA patients in dealing with pets, given standard hygiene conditions. This is also true for hiking in nature (except third world countries which better be avoided)
[edit] IV-Ig Notes
1. IV-Ig is an infusion of IgG antibodies only. Therefor, peripherial tissues that are defended mainly by IgA antibodies, such as the eyes, lungs, gut and urinary tract are not fully protected by the IV-Ig treatment.
2. The IV-Ig bottles come with countless warnings of adverse effects. It is important to keep in mind that these warnings were composed by lawyers, not by physicians. XLA patients most likely will not develop the virulent adverse effect, anaphylactic shock, because they do not have the antibodies to react against the treatment. Anaphylactic shock is more likely to occur in IgA-deficient patients who do have other antibody types.
3. In case of recurring side effects, it is recommended to slow the pace of the IV-Ig administration, and to reduce the dosage. It is also advisable to change IV-Ig brand. some people react against to a specific brand.
4. If the XLA patient is also diabetic, he should take into consideration the medium in which the antibodies are solubilized in the IV-Ig treatment, as some brands solubilize antibodies with highly concentrated sugars (such as sucrose and maltose).
5. FDA guidelines for IV-IG state the product should be:
-
- Prepared out of at least 10,000 different human donors.
- All four IgG subgroups (1-4) should be present.
- The IgG should maintain biological activity and lifetime of at least 21 days.
- Does not contain samples which are HIV, Hepatitis B, Hepatitis C positive.
- Screened and treated in an manner that destroys viruses.
6. IV-Ig is also considered a modulator of the immune system and was shown to be beneficial in treating noumerous Autoimmune diseases such as Rheumatoid Arthritis (RH), Lupus (SLE), Multiple sclerosis (MS), Myasthenia Gravis, Pemphigus, Polymyositis (PM), Dermatomyositis (DM), Granulomatosis (WG), Churg-Strauss, Chronic Infammatory Demyelinating Polyneuropathy and more.
7. IV-Ig could be given to pregnant women.
8. IV-Ig is also used as a treatment for unexplained recurring miscarriages. The effectiveness of the therapy is controversial.
9. For more data see: Intravenous immunoglobulin
[edit] Related sicknesses and recommended medicine
1. Ear infections, especially at childhood: Amoxycillin antibiotic pills. Ear drops are not useful and ear-suction (the common treatment) is not recommended.
2. Sinusitis and mucus: Pseudoephedrine. (causes sleeplessness)
3. Eye infection: Chloramphenicol antibiotic eye-drops.
4. Urinary tract infection: Ofloxacin antibiotic pills.
