Agammaglobulinemia

What are the other Names for this Condition? (Also known as/Synonyms)

• Bruton’s Agammaglobulinemia
• Congenital Agammaglobulinemia
• X-Linked Agammaglobulinemia 

What is Agammaglobulinemia? (Definition/Background Information)

• Agammaglobulinemia is a condition in which there are very low levels of immunoglobulins in the body. Immunoglobulins are a type of antibodies that protect the body from infections. As a result, individuals with Agammaglobulinemia are highly susceptible to infection from bacteria and viruses, and are often unable to fight these infections on their own
• Agammaglobulinemia can be categorized into the following types:
  • Early-onset Bruton’s Agammaglobulinemia (X-Linked Agammaglobulinemia or XLA)
  • Early-onset Agammaglobulinemia not due to Bruton’s       
  • Adult-onset common variable immunodeficiency
• Bruton’s Agammaglobulinemia is the most common cause of Agammaglobulinemia, especially in children. When clinicians refer to Agammaglobulinemia, they usually mean Bruton’s Agammaglobulinemia. It is a rare X-linked genetic disorder, which usually presents after 6 months of age
• Since the mutation is located on the X chromosome, males inherit the disorder, because they only have one X-chromosome, which is defective. Females have two X-chromosomes and even if one is defective, the other good chromosome may dominate and not let the condition get manifested
• Individuals with the disorder have difficulties producing the antibodies (gamma globulins) in blood plasma. They often experience frequent infections such as a bronchitis, diarrhea, eye infections, ear infections, and sinus infections
• The treatment options for Agammaglobulinemia may include antibody replacement through gamma globulin therapy and treating infections with appropriate antibiotics
• The prognosis for Agammaglobulinemia is generally good with appropriate therapy. Without treatment, deadly infections may develop and the condition may progress to chronic infections and decrease the lifespan of the individual

Who gets Agammaglobulinemia? (Age and Sex Distribution)

• Agammaglobulinemia (Bruton’s) occurs in males, because it is an X-linked disorder. Since males only have one copy of the X chromosome, they develop the disorder if they inherit the mutated X chromosome. Very rarely, it is seen in females, who have both the X chromosomes that are defective
• This genetic disorder is usually seen in infants aged 6 months and older, when their mother’s immunoglobulins levels start decreasing. Very rarely, inherited Agammaglobulinemia is seen in adults
• Usually, no racial or ethnic preference is noticed. It may occur worldwide with no geographical restriction. However, some reports suggest that it may be more prevalent in certain regions and races

What are the Risk Factors for Agammaglobulinemia? (Predisposing Factors)

The risk factors of Bruton’s Agammaglobulinemia include:

• Individuals with a positive family history (especially mother) of Bruton’s Agammaglobulinemia are at a higher risk of inheriting this X-linked disorder
• Males are at a higher risk of inheriting the disorder, because they only have one X chromosome. If they inherit an X chromosome with the mutation, the likelihood of developing the disease is high.
• However, sometimes it can come in any individual due to a new mutation of the X chromosome. In this situation, the mother is not a carrier of the disease (not inherited).

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases ones chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others. 

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider. 

What are the Causes of Agammaglobulinemia? (Etiology)

The causative factors of Bruton’s Agammaglobulinemia include mutations in the BTK gene, located on the X chromosome.

• These mutations prevent the development and regulation of B lymphocytes
• Pre-B-lymphocytes are unable to mature into B lymphocytes. When B lymphocytes do not mature, there is very low antibody production, thus making it difficult to ‘fight-off’ bacterial and viral infections

What are the Signs and Symptoms of Agammaglobulinemia?

The signs and symptoms of Bruton’s Agammaglobulinemia arise mainly due to the individual’s decreased ability to defend himself/herself against infections. They are usually observed in children aged between 3 to 5 years. The signs and symptoms are due to the infections, which again vary from individual to another. The infections may include:

• Infections of the sinus
• Diarrhea
• Eye, ear infections
• Respiratory infection, bronchitis, pneumonia
• Infection of the skin and bones
• Blood infection (sepsis)
• Meningitis - infection of the meninges, the tissue covering the brain and the spinal cord
• Growth retardation due to repeated infections
• Bronchiectasis (chronic irreversible inflammatory changes of the lung passages) due to repeated infections of the lung
• Other illnesses seen in these individuals are believed to be autoimmune related. They include:
  • Inflammation of the kidneys (glomerulonephritis)
  • Inflammation of the skin, muscle, and joints       

How is Agammaglobulinemia Diagnosed?

The following procedures may be used to diagnose Bruton’s Agammaglobulinemia:

• Thorough evaluation of the individual’s medical history, review of medical records, and a thorough physical examination including skin, lungs, oral cavity, ears, etc.
• During history taking, the physician may want to know the following:
  • When the symptoms began and whether they are becoming worse
  • About one’s personal and family history of infections        
• Appropriate consultation is often necessary very early in life to prevent complications
• Blood tests are performed to check the immunoglobulins in the body
• Flow cytometry is also done to measure the levels of B lymphocytes that are circulating in blood
• Other tests that may be done include immunoelectrophoresis and quantification of immunoglobulins
• If the individual has an active infection, then appropriate tests, such as blood culture, urine culture and throat culture, may be undertaken 

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis. 

What are the possible Complications of Agammaglobulinemia?

Individuals with Bruton’s Agammaglobulinemia may experience complications, such as:

• Bronchiectasis
• Arthritis
• Eczema
• Chronic sinus disease
• Chronic pulmonary disease
• If infections become frequent and disabling, the quality of life is affected

How is Agammaglobulinemia Treated?

Treatment for Bruton’s Agammaglobulinemia varies, depending on each individual’s specific condition. Before the start of treatment, the physician may undertake to assess the following parameters:

• Age
• Overall health status
• Medical history
• Tolerance to medicine
• Extent of the disease

Based on this, the following treatment options for Agammaglobulinemia may be undertaken, such as:

• Antibody replacement through gamma globulin therapy, which can be administered intravenously (through the veins) or subcutaneously (under the skin)
• Prompt treatment of infections with antibiotics and appropriate supportive care
• Appropriate treatment of associated complications such as bronchiectasis

How can Agammaglobulinemia be Prevented?

• Currently, there are no specific methods or guidelines to prevent Bruton’s Agammaglobulinemia, an X-linked genetic condition
• Genetic testing of the expecting parents (and related family members) and prenatal diagnosis (molecular testing of the fetus during pregnancy) may help in understanding the risks better and plan accordingly.
• If there is a family history of the condition, then genetic counseling will help assess risks, before planning for a child
• Active research is currently being performed to explore the possibilities for treatment and prevention of inherited and acquired genetic disorders
• In individuals who already have the illness, avoiding live viral vaccinations is important to prevent unnecessary infections

What is the Prognosis of Agammaglobulinemia? (Outcomes/Resolutions)

The prognoses for Bruton’s Agammaglobulinemia include:

• Generally, individuals who have been diagnosed early in their life and with immunoglobulin replacements have a good outlook and are able to lead relatively normal lives
• Without suitable treatment, infections may develop quickly in an individual with Agammaglobulinemia, which may become fatal
• There are no restrictions for children to participate in regular activities when they are being treated with immunoglobulin replacements 

Additional and Relevant Useful Information for Agammaglobulinemia:

The following DoveMed website link is a useful resource for additional information:

https://www.dovemed.com/diseases-conditions/infection-center/