X-linked agammaglobulinemia (also called
X-linked hypogammaglobulinemia, XLA,
Bruton type agammaglobulinemia, Bruton syndrome, or Sex-linked agammaglobulinemia
[1]83) is a rare
X-linked genetic disorder that affects the body's ability to fight infection. XLA patients do not generate mature
B cells.
[2] 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.
[3] Patients typically present in early childhood with recurrent
infections, particularly with extracellular, encapsulated
bacteria.
[4] 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.
[4]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.[4] 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.[5] 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 [4]. 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.
