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| '''For patient information, click [[X-linked agammaglobulinemia (patient information)|here]]''' | | '''For patient information, click [[X-linked agammaglobulinemia (patient information)|here]]''' |
| {{X-linked agammaglobulinemia}} | | {{X-linked agammaglobulinemia}} |
| {{CMG}} | | {{CMG}} '''Associate Editor-In-Chief:''' {{CZ}} |
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| '''Associate Editor-In-Chief:''' {{CZ}}
| | {{SK}} Bruton agammaglobulinemia |
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| | ==[[X-linked agammaglobulinemia overview|Overview]]== |
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| | ==[[X-linked agammaglobulinemia historical perspective|Historical Perspective]]== |
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| ==Overview== | | ==[[X-linked agammaglobulinemia classification|Classification]]== |
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| '''X-linked agammaglobulinemia''' (also called '''X-linked hypogammaglobulinemia,''' '''XLA''', '''Bruton type agammaglobulinemia''') is a rare [[X-linked]] genetic disorder that affects the body's ability to fight infection (origin of the name: A=no, gammaglobulin=Antibody). XLA patients do not generate mature [[B cell]]s. B cells are part of the immune system and normally manufacture antibodies (also called [[immunoglobulin]]s) which defends the body from infections (the [[humoral]] response). Patients with untreated XLA are prone to develop serious and even fatal infections.<ref name=ConleyXLA>[http://www.stjude.org/disease-summaries/0,2557,449_2164_6526,00.html XLA information by St. Jude Children's Hospital]</ref> Patients typically present in early childhood with recurrent [[infection]]s, particularly with extracellular, encapsulated [[bacteria]].<ref name=IDF/> 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.<ref name= IDF>[http://www.immunedisease.com/US/patients/IDF/agamma.html X-Linked Agammaglobulinemia] Patient and Family Handbook for The Primary Immune Diseases. Third Edition. 2001. Published by the Immune Deficiency Foundation</ref>
| | ==[[X-linked agammaglobulinemia pathophysiology|Pathophysiology]]== |
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| 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.<ref name=IDF/> 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.<ref name= BrutonsPaper>Bruton, Ogden C. [http://pediatrics.aappublications.org/cgi/content/full/102/1/S1/213 ''Agammaglobulinemia'']</ref>
| | ==[[X-linked agammaglobulinemia causes|Causes]]== |
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| ==Genetics== | | ==[[X-linked agammaglobulinemia differential diagnosis|Differentiating X-linked agammaglobulinemia from other Diseases]]== |
| 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 [[asymptomatic carrier|carrier]]s .<ref name= IDF/> 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.
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| 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.
| | ==[[X-linked agammaglobulinemia epidemiology and demographics|Epidemiology and Demographics]]== |
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| {| align="left" style="border: 1px solid {{{border|gray}}}; background-color: {{{color|#fdffe7}}};"
| | ==[[X-linked agammaglobulinemia risk factors|Risk Factors]]== |
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| |align="center"|[[Image:XlinkRecessive.jpg|250px]]
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| |align="center"|[[Image:Xlinkrecessivefather.jpg|250px]]
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| ==Diagnosis ==
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| 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]], [[Immunoglobulin A | IgA]], [[IgM]], [[Immunoglobulin E | IgE]] and [[Immunoglobulin D | IgD]].<ref name= IDF/>
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| 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,<ref name= IDF/> 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.
| | ==[[X-linked agammaglobulinemia screening|Screening]]== |
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| ==Treatment== | | ==[[X-linked agammaglobulinemia natural history, complications and prognosis|Natural History, Complications and Prognosis]]== |
| The most common treatment for XLA is an [[intravenous]] infusion of [[immunoglobulin]] ([[Intravenous 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]].<ref name= IDF/> 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.
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| Muscle injections of immunoglobulin (IMIg) were common before IVIg was prevalent, but are less effective and much more painful, hence, IMIg is now uncommon.
| | ==Diagnosis== |
| | [[X-linked agammaglobulinemia history and symptoms|History and Symptoms]] | [[X-linked agammaglobulinemia physical examination|Physical Examination]] | [[X-linked agammaglobulinemia laboratory findings|Laboratory Findings]] | [[X-linked agammaglobulinemia serology|Serology]] | [[X-linked agammaglobulinemia chest x ray|Chest X Ray]] | [[X-linked agammaglobulinemia CT|CT]] | [[X-linked agammaglobulinemia other imaging findings|Other Imaging Findings]] | [[X-linked agammaglobulinemia other diagnostic studies|Other Diagnostic Studies]] |
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| [[Injection (medicine)|Subcutaneous]] treatment (SCIg) was recently approved by the [[FDA]], which is recommended in cases of severe adverse reactions to the IVIg treatment.
| | ==Treatment== |
| | | [[X-linked agammaglobulinemia medical therapy|Medical Therapy]] | [[X-linked agammaglobulinemia surgery|Surgery]] | [[X-linked agammaglobulinemia primary prevention|Primary Prevention]] | [[X-linked agammaglobulinemia secondary prevention|Secondary Prevention]] | [[X-linked agammaglobulinemia cost-effectiveness of therapy|Cost-Effectiveness of Therapy]] | [[X-linked agammaglobulinemia future or investigational therapies|Future or Investigational Therapies]] |
| [[Antibiotics]] are another common supplementary treatment. Local antibiotic treatment (drops, lotions) are preferred over systemic treatment (pills) for long term treatment, if possible.
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| 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.
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| == Other considerations == | |
| [[Serology]] (detection on antibodies to a specific [[pathogens|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. | |
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| It is not recommended and dangerous for XLA patients to receive live attenuated vaccines such as live [[polio vaccine|polio]], or the [[measles]], [[mumps]], [[rubella]] ([[MMR vaccine]]).<ref name= IDF/> Special emphasis is given to avoiding the oral live attenuated [[Polio#Sabin.27s_.22oral_polio_vaccine.22|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.
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| XLA patients are specifically susceptible to viruses of the [[Enterovirus]] family, and mostly to: [[polio virus]], [[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.
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| It is not known if XLA patients are able to generate an [[allergic reaction]], as they lack functional [[Immunoglobulin E | IgE]] antibodies.
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| There is no special hazard for XLA patients in dealing with pets or outdoor activities.<ref name= IDF/>
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| Unlike in other primary immunodeficiencies XLA patients are at no greater risk for developing [[autoimmune]] illnesses.
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| Agammaglobulinemia (XLA) is similar to the primary immunodeficiency disorder Hypogammaglobulinemia (CVID), and their clinical conditions and treatment are almost identical. However, while XLA is a congenital disorder, with known genetic causes, CVID may occur in adulthood and its causes are not yet understood.
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| XLA was also historically mistaken as Severe Combined Immunodeficiency (SCID), a much more severe immune deficiency ("Bubble boys").
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| 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.
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| ==See also==
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| *[[Intravenous immunoglobulin]] (IVIg)
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| *Hypogammaglobulinemia (CVID)
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| ==References==
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| {{reflist|2}}
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| ==External links== | | ==Case Studies== |
| *[http://bioinf.uta.fi/BTKbase/ BTKBASE - Mutation Databse]
| | [[X-linked agammaglobulinemia case study one|Case #1]] |
| *[http://health.groups.yahoo.com/group/XLA_community/ XLA patients community]
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| *[http://www.ipopi.org International Patient Organisation for Primary Immunodeficiencies]
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| *[http://www.primaryimmune.org The Immune Deficiency Foundation]
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| *[http://www.healthatoz.com/healthatoz/Atoz/ency/x-linked_agammaglobulinemia.jsp More info]
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| {{Immune disorders}} | | {{Immune disorders}} |