agammaglobulinaemia

Agammaglobulinaemia is a group of primary immunodeficiency disorders characterized by very low or absent immunoglobulins due to defective B cell development. The most common form is X-linked agammaglobulinaemia (XLA), also known as Bruton's agammaglobulinaemia, caused by mutations in the BTK gene. Less common autosomal recessive forms result from mutations in other genes involved in early B cell maturation, including IGHM, IGLL1, CD79A, and CD79B.

BTK encodes Bruton’s tyrosine kinase, a key component of B cell receptor signaling required for the progression from pre-B cells to mature B cells. Consequently, affected individuals have very low or absent CD19+ B cells and markedly reduced levels of all immunoglobulin isotypes (IgG, IgA, IgM). T cell numbers and function are typically normal, but antibody responses to vaccines are poor.

Clinical presentation usually appears after about six months of age, when maternal antibodies wane. Patients experience recurrent bacterial infections, particularly of the sinopulmonary tract and middle ear, pneumonia, and may have chronic or prolonged infections. Failure to thrive and, with ongoing infection, bronchiectasis can occur if untreated.

Diagnosis rests on laboratory findings of severely reduced immunoglobulins with absent or very low B cells, normal T cell numbers, and poor vaccine responses. Confirmation is by genetic testing for BTK mutations, and, in autosomal cases, by identifying mutations in the relevant genes.

Management centers on lifelong immunoglobulin replacement therapy (intravenous or subcutaneous) to maintain protective IgG levels, plus prompt treatment of infections and, when appropriate, antibiotic prophylaxis. Live vaccines are contraindicated. With regular Ig replacement, life expectancy can approach that of the general population; untreated disease leads to recurrent infections and progressive lung damage. Genetic counselling and family testing are recommended.