Agammaglobulinemia
Agammaglobulinemia is an inherited immunodeficiency disorder characterized by abnormally low levels of antibodies (immunoglobulins) in the blood, leading to a heightened vulnerability to infections. Primarily affecting males due to its X-linked inheritance, this condition is linked to mutations in the Bruton's tyrosine kinase (Btk) gene, which is essential for the normal development and maturation of B cells—immune cells responsible for producing antibodies. Symptoms typically manifest in early childhood and include recurrent respiratory infections, chronic diarrhea, and various bacterial infections.
Diagnosis is often based on a history of frequent infections, along with laboratory tests that reveal low B cell counts and antibody levels. While there is currently no cure, treatment focuses on managing symptoms and reducing infection frequency, predominantly through intravenous immunoglobulin (IVIg) therapy, which provides the antibodies the body lacks. Antibiotics are also utilized to treat infections as they arise. Genetic counseling is recommended for families with a history of the condition, and advancements such as routine newborn screening may improve early detection and overall health outcomes for individuals with agammaglobulinemia. Future potential treatments, including gene therapy, are still under research.
Agammaglobulinemia
- ANATOMY OR SYSTEM AFFECTED: Blood, immune system
- ALSO KNOWN AS: Bruton syndrome, Bruton’s agammaglobulinemia, congenital agammaglobulinemia, sex-linked agammaglobulinemia, X-linked agammaglobulinemia
Definition
Agammaglobulinemia is an inherited disorder in which the levels of antibodies (immunoglobulins) in the blood are abnormally low. Without these protective antibodies, persons with agammaglobulinemia are at high risk for infection.
Agammaglobulinemia is a primary immunodeficiency syndrome (in which a part of the immune system is missing or not working correctly). Primary immunodeficiencies are inherited, so the cause of the immune deficiency is considered primary, that is, it is not caused by drug treatment, another disease, or environmental exposure to toxins.
Causes
Agammaglobulinemia is usually inherited on the X chromosome (X-linked); thus, mostly males are affected. The gene called Bruton’s tyrosine kinase (Btk) is responsible for this condition. When Btk is abnormal or mutated, the B cells (or B lymphocytes) do not develop normally and do not mature. B cells are the immune cells that are responsible for making antibodies. Antibodies play a critical role in recovery from certain infections and also protect against getting these infections again. In the past, agammaglobulinemia was often mistaken for a more severe deficiency of the immune system—severe combined immunodeficiency (SCID), popularly known as bubble-boy syndrome—in which both B and T cells are affected.
Agammaglobulinemia can also be inherited on autosomal chromosomes (non-sex chromosome). These forms of agammaglobulinemia are usually referred to as autosomal recessive agammaglobulinemia. The clinical presentation of these disorders is the same as X-linked agammaglobulinemia. The autosomal recessive agammaglobulinemias are a rare group of disorders, caused by various defects in the development of mature B cells, including defects in the following genes (and the proteins for which they encode): CD79A (Ig alpha), IGHM (C), VpreB/ 5 (pseudolight chain), and BLNK (B cell linker, a protein associated with Btk).
Risk Factors
Because agammaglobulinemia is an inherited disorder, there are no risk factors.
Symptoms
Typical symptoms of agammaglobulinemia include frequent bouts of bronchitis, chronic diarrhea, conjunctivitis (eye infection), otitis media (middle-ear infection), pneumonia, sinusitis, skin infection, and upper respiratory tract infection. Infections usually begin early in life (by the age of four years). Additional symptoms include bronchiectasis (damage or enlargement of the small air sacs in the lungs) and unexplained asthma.
Screening and Diagnosis
A diagnosis is usually made based on a person’s history of repeated infections of the respiratory tract and most typically throughout childhood. The most commonly reported bacterial infections are pneumococcal (Streptococcus pneumoniae), Staphylococcus, and Haemophilus influenzae.
A lack of, or a deficiency in, B cells or antibodies in the blood is a strong indicator of agammaglobulinemia. A Western blot test can determine the lack of the Btk protein, another indicator of X-linked agammaglobulinemia. Flow cytometry to assess Btk protein expression is also used as a diagnostic tool. To confirm a diagnosis, a genetic blood test can be performed to identify the specific Btk mutation.
Treatment and Therapy
Because there is no cure for agammaglobulinemia, the main goal of therapy is to reduce the frequency and severity of infections. However, people can be given the antibodies they lack. This treatment, called intravenous immunoglobulin (IVIg), helps boost the immune system. Regular treatment with IVIg, generally every three to four weeks for life, can increase the person’s life span and quality of life.
Additionally, antibiotics are often given to treat bacterial infections. If long-term treatment is needed, local antibiotics (such as lotions and drops) are used whenever possible before systemic antibiotics (in pill form) are prescribed.
People are now diagnosed earlier in life. Early diagnosis generally leads to early treatment. The advent of IVIg and improvements in the treatment of infection allow more people to avoid long-term pulmonary (lung) insufficiency and live a relatively healthy life.
A possible treatment of the future may be gene therapy, which has the potential to cure agammaglobulinemia. However, this technology is in its early stages and not ready to be applied to agammaglobulinemia therapy.
Affected persons should not receive live vaccines (such as measles, mumps, rubella vaccine, or MMR), polio vaccine, varicella (chickenpox) vaccine, or the intranasal influenza vaccine (FluMist). Treatment with IVIg is usually a necessity; without treatment, most severe infections are fatal.
Prevention and Outcomes
If a person has a relative with X-linked agammaglobulinemia and plans to have children, genetic counseling before pregnancy is recommended. The impact of early recognition and effective treatments on life span and quality of life (and healthcare costs) can affect public health interventions. The Centers for Disease Control and Prevention developed a population-based public health framework to improve health outcomes of primary immunodeficiency diseases such as agammaglobulinemia. Initial findings indicate that routine newborn screening for agammaglobulinemia, IVIg therapy, and improved antibiotics appear to reduce the burden of the disease.
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