Which are the causes of Agammaglobulinemia?

Agammaglobulinemia is a rare genetic disorder that affects the immune system's ability to produce antibodies, leading to a weakened immune response. This condition is primarily caused by mutations in the genes responsible for the development and maturation of B cells, a type of white blood cell that produces antibodies.

1. X-Linked Agammaglobulinemia (XLA): The most common form of agammaglobulinemia is XLA, which is caused by mutations in the BTK gene located on the X chromosome. As this disorder is X-linked, it predominantly affects males. The BTK gene provides instructions for producing a protein called Bruton's tyrosine kinase, which is essential for B cell development and function. Without functional BTK, B cells fail to mature, resulting in a severe deficiency of antibodies.

2. Autosomal Recessive Agammaglobulinemia: This form of agammaglobulinemia is caused by mutations in other genes involved in B cell development, such as the μ heavy chain gene (IGHM), λ5 gene (IGLL1), and Ig-α gene (CD79A). Autosomal recessive agammaglobulinemia affects both males and females equally, as it is not linked to the sex chromosomes.

3. Autosomal Dominant Agammaglobulinemia: In rare cases, agammaglobulinemia can be inherited in an autosomal dominant pattern. This means that a single copy of the mutated gene from either parent is sufficient to cause the disorder. Mutations in the gene encoding the transcription factor interferon regulatory factor 4 (IRF4) have been associated with this form of agammaglobulinemia.

4. Sporadic Agammaglobulinemia: In some instances, agammaglobulinemia can occur sporadically without a clear genetic cause. These cases may be caused by de novo mutations that arise during early embryonic development or other unknown factors affecting B cell development.

Agammaglobulinemia typically manifests in early childhood, with affected individuals experiencing recurrent and severe bacterial infections. The absence or extremely low levels of antibodies in the blood make it difficult for the immune system to fight off infections effectively. Common infections associated with agammaglobulinemia include pneumonia, sinusitis, ear infections, and gastrointestinal infections.

Early diagnosis of agammaglobulinemia is crucial to initiate appropriate treatment strategies. Treatment often involves regular infusions of immunoglobulins (antibodies) derived from healthy donors to provide the necessary immune protection. Additionally, prophylactic antibiotics may be prescribed to prevent infections. In some cases, gene therapy and bone marrow transplantation may be considered as potential treatment options.

In conclusion, agammaglobulinemia is primarily caused by genetic mutations affecting B cell development and maturation. X-Linked Agammaglobulinemia (XLA) is the most common form, while autosomal recessive and autosomal dominant forms also exist. Sporadic cases may occur without a clear genetic cause. Early diagnosis and appropriate treatment are essential to manage the condition and prevent severe infections.