X-Linked Agammaglobulinemia (XLA)

What Is Agammaglobulinemia?

Agammaglobulinemia is more commonly known as X-Linked agammaglobulinemia (XLA), Bruton’s agammaglobulinemia, or congenital agammaglobulinemia. It is a disorder caused by the body’s inability to produce B cells or immunoglobulins (antibodies) that the B cells make. When B Cells or immunoglobulin levels are below the normal range, it can cause recurrent infections (like the flu, strep throat, etc.), allergies, asthma, and a weakened immune system. The most commonly recognized clinical feature of agammaglobulinemia is recurrent infection.

Immunoglobulins are the main components of immune response and can recognize antigens (foreign substances) to trigger an immune response and eliminate the infection. B cells are the specialized immune cells that mature into antibody-producing cells (plasma cells) during a pathogenic attack. The key function of antibodies is to recognize and kill foreign pathogens (bacteria or viruses) by binding to them and neutralizing their ability to cause infection. 

Who Can Get XLA?

XLA is a congenital (at birth) condition that is caused by the result of a mutated gene. The mutated gene responsible for XLA codes for the protein Bruton tyrosine kinase, or BTK gene, is located on the X chromosome. XLA is an X-linked recessive disease, making it a male-prominent condition. It is more likely to occur in males (85% chance) compared to females (15% chance). The overall frequency of X-linked agammaglobulinemia is 1 in 100,000 male newborns and 1 in 200,000 live births. 

Agammaglobulinemia is considered a primary immunodeficiency disease. It can manifest in infants right after the maternal antibodies wear off at the age of 6 months. 

Causes of XLA

In males (who only have one X chromosome), one altered copy of the BTK gene in each cell is enough to cause the condition. In females (who have two X chromosomes), a mutation would have to occur in both copies of the BTK gene to cause the disorder. Because the likelihood of females having two altered copies of this gene is low, males are affected by X-linked recessive disorders much more often than females. A characteristic of X-linked inheritance is that males cannot pass X-linked traits to their male children.

Affected individuals may not have an apparent family history of XLA. In most of these cases, the affected person’s mother is a silent carrier of one altered BTK gene. The carrier females have no clinical manifestation, but they have a 25% chance of giving birth to a child that has this disease. In other cases, the affected individual would not have inherited the gene from their mother; rather, they would have a new mutation in the BTK gene. 

Agammaglobulinemia is mainly caused by a mutation in a gene responsible for B cells development. Typically, B cells are the essential component of the immune system that are differentiated into a fully matured form called plasma cells. The plasma cells produce immunoglobulins (antibodies) against pathogens. 

The mechanism of the B cells development, maturation, and proliferation processes are regulated by highly specialized genes in the bone marrow. One of the most crucial genes is the BTK gene, called Bruton’s kinase tyrosine. 

The BTK gene produces BTK proteins that are essential components during the B-cells maturation process and promote the transformation of pro-B-cells into pre-B-cells. 

In XLA, a mutation in the BTK gene ultimately stops the B cell’s development and maturation process. In this rare disorder, people have fewer or no circulatory B cells, resulting in fewer immunoglobulins (hypogammaglobulinemia) or a lack of immunoglobulins (agammaglobulinemia) in the body. 

Risk Factors

Certain risk factors that make people more vulnerable to XLA are sex, age, race, and positive family history (carrier mother or father with XLA). It should be noted that the risk factors do not guarantee that an individual will always get agammaglobulinemia disorder from a carrier parent. But there are chances that new sporadic mutations may occur on X-chromosomes, hence leading to the onset of agammaglobulinemia. 

Age

The symptoms of agammaglobulinemia appear at the age of 6 months when the placental immunoglobulins (IgG) run out. At the initial stages of life, the mother provides passive immunity to the fetus by transferring immunoglobulins through the placenta and protecting the newborn baby from various fatal infections. 

After 6 months, when the maternal immunoglobulins (IgG) start depleting, children become prone to common bacterial infections. Within 2 years, more than approximately 50% of XLA children get serious, recurrent bacterial infections such as pneumonia, bronchitis, ear infections, etc. 

Sex

Men have only one X-chromosome, and therefore, the chances of getting XLA become higher in the male population when they receive a mutated X-chromosome from a carrier mother. 

The onset of agammaglobulinemia genetic disorder may only occur in females if both X-chromosomes that are inherited are mutated, which happens rarely. 

Race

There is no accurate link found between race and the onset of agammaglobulinemia. Studies have concluded that agammaglobulinemia genetic disorder can occur worldwide without any geographical limitations. The prevalence of XLA among one race over another is undetermined at this time.

Family History

Individuals with a previous positive family history of agammaglobulinemia are at a higher risk of developing XLA. The chances are only higher in males receiving mutated X-chromosomes from carrier mothers. 

Signs and Symptoms

The clinical manifestation of agammaglobulinemia is a predisposition towards recurrent infections, which the body defends by antibody response. The symptoms of agammaglobulinemia may vary from patient to patient and could be severe if not treated properly. 

Common bacterial infections include: 

• Eczema
• Bronchitis
• Meningitis
• Pharyngitis
• Pneumonia
• Strep throat
• Ear infections
• Fatigue and fever
• Skin infections/rash
• Sinus infections (sinusitis)
• Blood infection (like sepsis or bacteremia)

Other symptoms can include ear or skin infections, gastrointestinal problems, allergies, asthma, and diarrhea. These bacterial infections are commonly caused by various encapsulated bacteria including Staphylococcus aureus, E.coli, Streptococcus pneumonia, and mycoplasma. 

Newborns less than 6 months old with XLA typically do not show any symptoms. Without immunoglobulins, children with XLA are at high risk of developing various common bacterial or viral infections. In agammaglobulinemia, the most common sites that are highly affected during severe bacterial infections are: 

• Upper respiratory tract
• Gastrointestinal tract
• Joints
• Skin
• Lungs

Individuals with agammaglobulinemia show growth retardation because of frequent and repetitive bacterial or viral infections. BTK mutation also leads to reduced size in the tonsils, the intestinal Peyer patches, the lymph nodes, the adenoids, and the spleen.

Children with XLA often experience several viral infections caused by the poliomyelitis virus, echovirus, and enterovirus family. XLA patients with protozoal infections caused by Giardia may have chronic gastrointestinal infections (diarrhea). XLA could be fatal if left untreated, and there are higher possibilities that an individual with XLA may experience severe life-threatening infections and a low survival rate. 

Common viral infections include: 

• Polio
• Hepatitis
• Dermatomyositis-like symptoms (such as difficulty swallowing, muscle weakness, and reddish skin)

Diagnosis

It is important to diagnose XLA disorder accurately at an initial stage to overcome future complications. Clinically, agammaglobulinemia can be diagnosed through several screening procedures that mainly rely on:

• Physical examination and patient’s medical history. Physicians generally ask patients about the infections they have encountered recently and medication they have taken. They also physically examine the patient’s skin, ears, lungs, oral cavity, etc. 
• Complete blood count (CBC) with differential diagnosis and quantification of serum gamma globulins to check the level of immunoglobulins (IgG, IgA, IgM) in the serum. If the level of immunoglobulins is low or found to be nearly absent, then a B-lymphocyte phenotyping procedure is recommended. The lymphocyte phenotyping procedure is used to check the level of mature B cells and normal T cells in the peripheral blood through flow cytometry. 
• Serum-specific antibody titers against immunization. Patients with XLA usually don’t produce antibodies in response to vaccination against diphtheria or tetanus.  
• Genetic testing to check the mutation in the BTK gene on X-chromosomes and running molecular analysis in the laboratory. Different mutations may exist in every family’s BTK gene, but the same family members usually have the same mutation. 
• Previous family history (if this disorder is already present in their family).

Furthermore, various other molecular diagnostic procedures are performed to evaluate the agammaglobulinemia genetic disorder. However, any delay in the diagnosis of agammaglobulinemia would be detrimental to the prognosis and the patient’s life.

Treatment

Early diagnosis of agammaglobulinemia and several treatment therapies (antibiotics and immunoglobulin replacement therapy) may help to enhance life expectancy and allow agammaglobulinemia patients to live a relatively normal and active life. There is no curative therapy for agammaglobulinemia genetic disorder. The goal of currently available treatment therapy is to boost the immune system of an individual with XLA and prevent recurrent infections.

The selection of the right treatment for XLA mainly depends on various parameters such as:

• Patient’s age
• Patient’s previous medical history
• Current health condition
• The extent of the disease
• Tolerance for a specific medicine

The main goals for treatment are to prevent organ damage, decrease disease severity, reduce morbidity, treat any infections, and improve health-related quality of life. 

Bacterial infections are treated with antibiotics. Those who get severe or frequent bacterial infections may need to take antibiotics for several months at a time to prevent them from recurring. Antibiotics are also prescribed for prophylaxis in order to prevent life-threatening infections such as sinopulmonary infection, sepsis, or pneumonia. Antibiotics include amoxicillin, intravenous ceftriaxone, and amoxicillin/clavulanate. 

The first and foremost goal is to protect patients from getting bacterial infections by maintaining good hygiene (frequent hand washing) and drinking treated water. To minimize risk for infection, it is important to avoid crowds, unhygienic street foods, certain vaccines, etc.  To avoid unnecessary infections and severe complications, it is recommended that patients with XLA avoid taking live attenuated vaccines for polio, rubella (MMR), measles, mumps, rotavirus, varicella, etc. It is best to notify your physician prior to taking any vaccines entirely. Live vaccines may make someone who is immunocompromised ill because of underlying problems with their immune response.

Immunoglobulin Replacement Therapy (IRT)

Immunoglobulin replacement therapy (IRT) is a standard, lifelong, and life-saving treatment for XLA. IRT not only boosts the patient’s immune system but also improves the patient’s survival rate and quality of life by providing the missing immunoglobulins in the body. It is recommended for XLA patients in many cases. This will help replace and replenish what the body is not making. IRT can be given to agammaglobulinemia patients either intravenously (through the veins), subcutaneously (under the skin), or intramuscularly (into the muscle). 

Injected immune globulin comes from the blood plasma of healthy donors. Some may only need a single injection of IRT. Others may need to stay on this treatment for a year or more. Blood tests may be warranted every few months to check levels until they are normalized. 

Intravenous Immunoglobulin (IVIG) Therapy Procedures

Intravenous immunoglobulin (IVIG) therapy is administered in the veins every 3 to 4 weeks. The dose is typically calculated based on the patient’s weight. 

Subcutaneous Immunoglobulin (SCIG) Therapy Procedures

An alternative to IVIG therapy, subcutaneous immunoglobulin therapy (SCIG), may be chosen as an option due to IVIG adverse reactions or difficulty with IV access. Immunoglobulins (IgG) are administered via injection under the skin of agammaglobulinemia patients every 1 to 2 weeks. This is also dosed based on the patient’s weight.

SCIG therapy is just as safe as IVIG therapy and has fewer systemic side effects and only slight changes in serum concentration compared to IVIG. XLA patients can easily take this therapy at home by following procedures provided by their healthcare provider. 

Intramuscular Immunoglobulin Therapy Procedures

Another alternative to IVIG therapy is intramuscular immunoglobulin therapy. Immunoglobulins (IgG) are administered via injection into the muscle of agammaglobulinemia patients. Injections should be made in the upper thigh or deltoid muscle of the upper arm. This is also dosed based on the patient’s weight. 

Drawbacks of IRT Therapy

• IRT therapy is prepared from a donor pool; it does not provide immunity to unexposed pathogens. 
• IVIG and SCIG therapies only replace IgG immunoglobulins, not other immunoglobulin isotypes such as IgA and IgM. 
• IRT is usually very expensive, especially in areas with poor medical facilities. 
• During IRT therapy, XLA patients may experience local side effects such as tiredness, swelling, and erythema, but the symptoms can easily resolve within a few hours.

Complications

Any delay in early diagnosis often leads to severe complications in the agammaglobulinemia condition and reduced life expectancy. The most common and long-term complications experienced by an individual with XLA are chronic lung diseases such as bronchiectasis. 

Studies report approximately 50% of agammaglobulinemia patients suffer from chronic lung infections, and its incidence is higher in XLA patients above 20 years old. Other complications experienced by patients with XLA may include:

• Chronic pulmonary infections
• Chronic sinus infections
• Arthritis
• Eczema

Getting treated for infections and taking immunoglobulin therapy can reduce the risk of these complications.

XLA disorder may increase the risk for colorectal cancer. The risk of developing lymphoproliferative disorders and gastric cancer is also higher in an individual with agammaglobulinemia. 

Prognosis

Over the last two decades, early agammaglobulinemia diagnosis, therapeutic measures, and IRT have significantly improved the overall prognosis and survival rate in children with XLA. 

XLA patients seem to do better and survive into their late 40s due to early diagnosis and regular treatment therapy compared to those who delayed their agammaglobulinemia treatment. The prognosis rate is generally better as long as the XLA patient is diagnosed and treated during childhood (typically before the age of 5). However, the life expectancy of patients with agammaglobulinemia can be reduced due to recurrent bacterial or viral infections. Those who get many severe infections will have a worse outlook than those who don’t get as many infections.

The life expectancy and prognosis of agammaglobulinemia may rely upon the individual’s immunodeficiency, its type, and severity. The majority of mortalities have been caused due to viral and pulmonary infections. However, most individuals with XLA who get immunoglobulin regularly will be able to live everyday lives. Catching this condition early and getting on antibiotics or immunoglobulin treatment can limit infections, prevent complications, and improve life expectancy.

Genetic counseling can assist expected parents to check the risk of agammaglobulinemia in developing fetuses (prenatal diagnosis) and plan treatment therapy accordingly. Testing for agammaglobulinemia disorder at birth can also help in the management of this genetic disorder at an early stage and may increase the survival rate. 

Follow-up

Agammaglobulinemia is a rare inherited disorder of the immune system and requires a high level of control and management. Patients with XLA should regularly get a follow-up with their physician. The following should be monitored in order to evaluate the immune response:

• Pulmonary status (especially for chronic lung disease)
• Cerebrospinal fluid (CSF) analyses
• Growth and development
• Immunoglobulin levels

It is recommended that patients get these tests done periodically for every age group, keep signs and symptoms in check, and have their physicians devise respective treatment criteria (IVIG and antibiotics) as needed.