X-linked agammaglobulinemia

X-linked agammaglobulinemia
Other names	X-linked hypogammaglobulinemia, Bruton type agammaglobulinemia, Bruton syndrome, sex-linked agammaglobulinemia[1]: 83
The disorder is passed on in an X-linked recessive pattern
Specialty	Immunology

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,^[2] 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.^[3] XLA is deemed to have a relatively low incidence of disease, with an occurrence rate of approximately 1 in 200,000 live births^[4] and a frequency of about 1 in 100,000^[5] 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.^[3]

XLA is caused by a mutation on the X chromosome (Xq21.3-q22) of a single gene identified in 1993 which produces an enzyme 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.^[6] It is the first known immune deficiency, and is classified with other inherited (genetic) defects of the immune system, known as primary immunodeficiency disorders.