X-linked agammaglobulinemiax-linked agammaglobulinemia, x-linked agammaglobulinemia of bruton
X-linked agammaglobulinemia XLA is a rare genetic disorder discovered in 1952 that affects the body's ability to fight infection As the form of agammaglobulinemia that is X-linked, it is much more common in males In people with XLA, the white blood cell formation process does not generate mature B cells, which manifests as a complete or near-complete lack of proteins called gamma globulins, including antibodies, in their bloodstream B cells are part of the immune system and normally manufacture antibodies also called immunoglobulins, which defend the body from infections by sustaining a humoral immunity response Patients with untreated XLA are prone to develop serious and even fatal infections A mutation occurs at the Bruton's tyrosine kinase Btk gene that leads to a severe block in B cell development at the pre-B cell to immature B cell stage and a reduced immunoglobulin production in the serum Btk is particularly responsible for mediating B cell development and maturation through a signaling effect on the B cell receptor BCR Patients typically present in early childhood with recurrent infections, in particular with extracellular, encapsulated bacteria XLA is deemed to have a relatively low incidence of disease, with an occurrence rate of approximately 1 in 200,000 live births and a frequency of about 1 in 100,000 male newborns It has no ethnic predisposition XLA is treated by infusion of human antibody Treatment with pooled gamma globulin cannot restore a functional population of B cells, but it is sufficient to reduce the severity and number of infections due to the passive immunity granted by the exogenous antibodies
XLA is caused by a mutation on the X chromosome of a single gene identified in 1993 which produces an enzyme 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 It is the first known immune deficiency, and is classified with other inherited genetic defects of the immune system, known as primary immunodeficiency disorders
- 1 Signs and symptoms
- 2 Genetics
- 3 Diagnosis
- 4 Treatment
- 41 Other considerations
- 5 See also
- 6 References
- 7 External links
Signs and symptoms
Affects males 50% of the time if mother is a carrier for the gene Children are fine until 6–9 months of age Present with recurrent infections with Streptococcus pneumoniae, Haemophilus influenzae, Mycoplasma pneumoniae, hepatitis virus, and enterovirus CNS infections Examination shows lymphoid hypoplasia tonsils and adenoids, no splenomegaly or lymphadenopathy There is significant decrease in all immunoglobulins
Most antibodies are gamma globulins Antibodies are made mainly by plasma cells, which are daughter cells of the B cell line The Btk enzyme plays an essential role in the maturation of B cells in the bone marrow, and when mutated, immature pro-B lymphocytes are unable to develop into pre-B lymphocytes, which normally develop into mature naive B cells that leave the bone marrow into the blood stream
The disorder is inherited in an X-linked recessive fashion as the gene linked to it is on the X chromosome and is almost entirely limited to the sons of asymptomatic female carriers 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 for mutations in the other X chromosome, so they are less likely to be symptomatic
There is 30-50% chance of XLA patients having a positive family history of genetic inheritance The rest of the cases occur as random mutations If a carrier female gives birth to a male child, there is a 50% chance that the male will have XLA A carrier female has a 25% chance overall of giving birth to an affected male child 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 arise only 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 This is due to humoral immunodeficiency 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 pregnancyAlthough the symptoms of a XLA and other primary immune diseases PID include repeated and often severe infections, the average time for a diagnosis of a PID can be up to 10 years
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 live a 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
Muscle injections of immunoglobulin IMIg were common before IVIg was prevalent, but are less effective and much more painful; hence, IMIg is now uncommonSubcutaneous treatment SCIg was recently approved by the US Food and Drug Administration 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 possibleOne 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 Enterovirus family, and mostly to: polio virus, coxsackie virus hand, foot, and mouth disease and Echoviruses 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 mature B cells and so HLA co-receptors needed for the viral infection Patients with XLA are also more likely to have a history of septic arthritis
It is not known if XLA patients are able to generate an allergic reaction, as they lack functional IgE antibodiesThere 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 However, while XLA is a congenital disorder, with known genetic causes, CVID may occur in adulthood and its causes are not yet understood XLA was also historically mistaken as Severe Combined Immunodeficiency SCID, a much more severe immune deficiency "Bubble boys"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
- Intravenous immunoglobulin IVIg
- Hypogammaglobulinemia CVID
- ^ James, William D; Berger, Timothy G; et al 2006 Andrews' Diseases of the Skin: clinical Dermatology Saunders Elsevier ISBN 0-7216-2921-0
- ^ a b c d e f g h i X-Linked Agammaglobulinemia Patient and Family Handbook for The Primary Immune Diseases Third Edition 2001 Published by the Immune Deficiency Foundation
- ^ a b c d Chun, Jin-Kyong; Lee, Taek Jin; Song, Jae Woo; Linton, John A; Kim, Dong Soo 2008-02-29 "Analysis of Clinical Presentations of Bruton Disease: A Review of 20 Years of Accumulated Data from Pediatric Patients at Severance Hospital" Yonsei Medical Journal 49 1: 28–36 doi:103349/ymj200849128 ISSN 0513-5796 PMC 2615253 PMID 18306466
- ^ Mahmoudi, Massoud 2007 Allergy and Asthma: Practical Diagnosis and Management McGraw-Hill Professional ISBN 978-0-07-147173-2
- ^ Bruton OC 1952 "Agammaglobulinemia" Pediatrics 9 6: 722–8 PMID 14929630 Reproduced in Buckley CR 1998 "Agammaglobulinemia, by Col Ogden C Bruton, MC, USA, Pediatrics, 1952;9:722-728" Pediatrics 102 1 Pt 2: 213–5 PMID 9651432
- ^ Faulkner GC, Burrows SR, Khanna R, Moss DJ, Bird AG, Crawford DH February 1999 "X-Linked agammaglobulinemia patients are not infected with Epstein-Barr virus: implications for the biology of the virus" Journal of Virology 73 2: 1555–64 PMC 103980 PMID 9882361
- GeneReviews/NCBI/NIH/UW entry on X-Linked Agammaglobulinemia
|GTP-binding protein regulators|
|Signal transducing adaptor proteins||
|See also intracellular signaling peptides and proteins|
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