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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 cells.[1] B cells are part of the immune system and normally manufacture antibodies (also called immunoglobulins) which defends the body from infections (the humoral response). Patients with untreated XLA are prone to develop serious and even fatal infections.[2] Patients typically present in early childhood with recurrent infections, particularly with extracellular, encapsulated bacteria.[3] XLA is an X-linked disorder, and therefore is more common in 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 cells, but it is sufficient to reduce the severity and number of infections due to the passive immunity granted by the exogenous antibodies.[3]
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.[3] 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. Colonel Ogden C. Bruton first described the disease in 1952.[4] It is the first known immune deficiency, and is classified with other inherited (genetic) defects of the immune system, known as primary immunodeficiency disorders.
The gene Bruton’s tyrosine kinase (Btk) plays an essential role in the maturation of B cells 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 carriers [3]. 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. 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.[3]
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,[3] 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.[3] 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.[citation needed]
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