What is X-Linked Agammaglobulinemia?
X-linked agammaglobulinemia or XLA is a frequent immune system disorder in children that stops them from creating antibodies, which are proteins that help fight off infections. People with this condition need lifelong treatment with an immune system protein called immunoglobulin to live healthily.
XLA happens when a gene called Bruton’s tyrosine kinase, which helps develop B cells, isn’t working correctly. B cells are responsible for producing antibodies that help the body fight off infections. But, in people with XLA, these B cells can’t mature into cells that make antibodies, because of a genetic defect. As a result, there are very few or no antibodies in their blood.
This absence of antibodies makes people with XLA highly susceptible to certain bacterial infections, viruses, and chronic diarrhea caused by a parasite named Giardia lamblia.
People with XLA usually start experiencing recurring respiratory infections like sinusitis and middle ear infections after 6 to 9 months of age, when the protective maternal antibodies naturally disappear. The disorder is often suspected when the person needs hospitalization and intravenous antibiotics to treat bacterial pneumonia. Usually, XLA is diagnosed before the age of five, though it can sometimes appear later in life.
Despite the lack of a cure for XLA, early treatment with immunoglobulin and antibiotics can prevent and manage infections. This lifelong treatment can be expensive, but it’s essential. If the diagnosis is delayed, chronic and hard-to-treat infections can cause damage to vital organs, which can’t be reversed.
What Causes X-Linked Agammaglobulinemia?
XLA, also known as Bruton’s disease, is caused by changes or mutations in a specific gene called Bruton’s Tyrosine Kinase gene (Btk). This gene is found on the X chromosome, which is one of the sex chromosomes, and that’s why it affects mostly boys. There are hundreds of different types of mutations that can cause XLA. These mutations can occur anywhere between positions 101349447 to 101390796 on the X chromosome. However, no single mutation is found in more than 3% of known cases.
The Btk gene gives instructions for making a protein, named BTK, that is crucial for maturing a type of immune cell called B cells. A mutation in the Btk gene interferes with the production of this BTK protein, preventing the B cells from developing fully. As a result, there are not enough mature B cells in the body to properly fight infections, leading to a severe lack or significant decrease in all types of antibodies in the blood.
Most cases of this disease are due to mutations in the Btk gene and are linked to the X chromosome. However, about 10% of the cases result from changes in other genes that are not sex-linked. This other form of the disease is called autosomal recessive agammaglobulinemia (ARA) and it happens in girls. It is similar to XLA in boys. The genes involved in ARA help the BTK protein facilitate the maturation of B cells. Therefore, mutations in these genes can also interfere with B cell development.
Risk Factors and Frequency for X-Linked Agammaglobulinemia
X-linked agammaglobulinemia (XLA) is a condition that only affects males. The number of people affected by XLA and how often it occurs varies significantly. One estimate places the rate of XLA at 1 in 190,000 live births, with about 1 in 100,000 newborn boys being affected. The estimated prevalence is somewhere between 1 and 9 out of every 1,000,000 people. There’s no specific racial group that’s more likely to have XLA, but it’s reported most often in people of the White race.
There are several alternative names for this condition, including Bruton agammaglobulinemia, Btk agammaglobulinemia, Bruton tyrosine kinase agammaglobulinemia, agammaglobulinemia of Bruton, and congenital agammaglobulinemia.
Signs and Symptoms of X-Linked Agammaglobulinemia
For anyone who could potentially have X-linked agammaglobulinemia (XLA), a genetic disorder that weakens the immune system, it is necessary to conduct a detailed medical history and physical exam.
If XLA is suspected in infants or very young children, doctors will often ask the parents or caregivers about the child’s health history, including past and current illnesses, hospital stays, vaccinations, allergies, and medicines they have taken. Information about the child’s diet, home environment, activities, and travels can also be helpful in making a diagnosis.
If a patient often suffers from long-lasting or repeated infections such as conjunctivitis, respiratory tract infections, skin infections, ear infections, or diarrhea, this can signal XLA. Positive cultures for certain bacteria, or a record of needing IV antibiotics or multiple hospital stays before the age of 3, can provide additional clues. Developmental delays can also be a sign of XLA.
Doctors will also carefully evaluate the child’s respiratory, lymphatic, gastrointestinal, and skin systems for any symptoms. Infants with XLA are typically born healthy, and outward symptoms may not appear until they are 6-8 months old. This is because, up until that point, they are still protected by their mother’s antibodies.
A physical exam will reveal that patients typically have underdeveloped (hypoplastic) lymphoid tissues. Signs such as difficult-to-see tonsils, non-palpable lymph nodes, ear infections, eardrum perforation, nasal discharge, extended breathing times, cough, increased respiratory effort, or high-pitched breathing sounds can all hint at XLA. These symptoms may also prompt doctors to conduct additional tests (like lung function tests, CT scans, biopsies), especially if lung disease (like bronchiectasis) is suspected. More tests may be needed if the patient has abdominal bloating, as this could indicate an enlarged liver or spleen.
Lastly, the family’s medical history, including previous infections, hospital stays, surgeries, immunodeficiency diagnoses or symptoms, the health statuses of living relatives, and causes of death can also aid in diagnosing XLA.
Testing for X-Linked Agammaglobulinemia
To definitively diagnose X-linked agammaglobulinemia (XLA), a condition that affects the body’s ability to fight off infections, a series of laboratory tests are required. These tests include measuring levels of specific proteins called immunoglobulins, counting different types of white blood cells, assessing the body’s response to certain vaccines, and doing advanced genetic analysis.
A typical set of tests may consider the levels of three types of proteins (called IgG, IgM, and IgA), the number of certain types of cell (B cells), how the body responds to vaccines, and whether there is a particular protein (BTK) in certain cells. Finally, these tests would include sequencing the Btk gene, which instructs how to make this crucial protein.
In a male patient who has frequently experienced bacterial infections, these tests might show lower-than-typical protein levels, absence of mature B cell numbers, little to no increase in the body’s response to vaccines, low or no levels of the BTK protein, and mutated sequences of the Btk gene.
Even if the Btk gene mutations are found, on its own, this is not enough to diagnose XLA.
In addition to these lab findings, certain symptoms can suggest an XLA diagnosis in boys with lower-than-typical B cell levels include having had several serious infections that required hospitalization before the age of 5 years, a poor response to vaccines, and the absence of certain lymph nodes and tonsils.
It’s important to note that if a test’s results are abnormal, the tests should be run again to confirm the diagnosis. This double-checking helps prevent false diagnoses and ensures accurate treatment.
Treatment Options for X-Linked Agammaglobulinemia
While there isn’t a cure for XLA, or X-linked agammaglobulinemia, managing the condition involves preventing and managing infections.
This disease management strategy involves several steps:
* First, regular treatment using immunoglobulin, which are proteins in your blood that fight infections. This is delivered through either an intravenous (IV) infusion, which means it’s injected directly into your veins, or a subcutaneous injection, which is given under your skin.
* Second, antibiotics may be used to both prevent and treat bacterial infections.
* Close supervision is necessary to handle any complications that arise from receiving the immunoglobulin treatment, complications from infections, or the start of any clinical disease, such as autoimmune diseases, inflammatory diseases, or cancers.
* Lastly, patient support is important and may include nutritional, social, psychological, and educational help.
Patients are also advised about the importance of getting all the vaccinations that don’t contain live bacteria or viruses. Several vaccines fall in this category such as oral polio vaccine (OPV), measles/mumps/rubella (MMR), chickenpox (Varivax), BCG, yellow fever, and rotavirus (Rota-Teq).
When dealing with immunoglobulin therapy, there are several factors to consider. Both intravenous (IVIG) and subcutaneous (SCIG) therapies are suitable, and the decision between the two depends on the specifics of each patient’s situation. IVIG might be preferred if a larger volume of the medicine is required. SCIG, on the other hand, has been reported to have fewer side effects and allows for stable levels of immunoglobulin in the blood after the injection.
The side effects of immunoglobulin therapy can vary but are often not severe and only temporary. Symptoms can include headaches, fever, muscle pain, changes in blood pressure, nausea, and chest discomfort. Allergic reactions resembling an anaphylactic reaction can also occur during the infusion. If a patient experiences any of these symptoms, the treatment may need to be paused until the side effects can be managed.
Despite being less frequent, delayed side effects are of greater concern. These include problems like clot formation due to thickening of the blood, kidney failure related to the body’s reaction to certain types of treatments, low sodium levels in the blood, destruction of red blood cells, inflammation of the lining of the brain and spinal cord, and lower than normal levels of white blood cells. To avoid these reactions, a regimen that has previously been tolerated well by the patient, with attention to preparation and infusion speed, should be maintained.
What else can X-Linked Agammaglobulinemia be?
If a doctor suspects XLA, or X-linked Agammaglobulinemia, they will think about other conditions that can cause similar symptoms before making a diagnosis. The following are some of the other conditions:
- Autosomal recessive agammaglobulinemia (ARA)
- Common variable immunodeficiency disease (CVID)
- Transient hypogammaglobulinemia of infancy (THI)
- X-linked hyper IgM syndrome (Hyper-IgM)
- X-linked lymphoproliferative disease (X-LPD)
- Severe combined immunodeficiency disease (SCID)
What to expect with X-Linked Agammaglobulinemia
Before the use of regular immunoglobulin replacement therapy, most children with XLA – a condition that severely weakens the immune system – passed away before reaching only 10 years old. These deaths were usually due to complications from lung disease, severe widespread infections known as sepsis, or meningitis, which is an infection that inflames the brain and spinal cord membranes.
Despite chronic lung disease continuing to be a serious concern, patients with XLA now often live into adulthood, thanks to improvements in medical treatment practices. If diagnosed early, namely before the age of five, these individuals can have a far better prognosis. By receiving regular immunoglobulin replacement therapy – a treatment that boosts the immune system – and taking prescribed antibiotics to treat or prevent infections, affected individuals can anticipate a normal quality of life and a life expectancy beyond the age of 40.
Possible Complications When Diagnosed with X-Linked Agammaglobulinemia
: Patients with XLA, or X-linked agammaglobulinemia, have to manage both the inherent complications of their condition and the side effects of the treatments necessary to manage it.
Individuals with XLA are especially prone to infections that keep coming back, which can lead to persistent illness and damage to organs. For instance, constant episodes of acute pneumonia can develop into a chronic lung condition called bronchiectasis, which can decrease a person’s lifespan. The longer it takes to diagnose and start treating chronic infections, the more risk there is of them becoming serious and life-threatening, such as spreading to joints or major organs.
Besides infections, people with XLA are also at greater risk of developing cancer, inflammatory disorders and autoimmune conditions, although these are less common complications.
Treatment Side Effects
Patients with XLA rely on regular replacement of immunoglobulins, specific proteins that our immune system uses to fight off bacteria and viruses. While this treatment can improve life expectancy, reduce infection rates and severity, decrease the frequency of hospital visits, and lower the need for antibiotics, it also has its share of side effects that require diligent monitoring.
Doctors can manage these side effects by altering parameters involved in the immunoglobulin replacement therapy, such as the time between infusions, the method of administration, the delivery rate, and the specific product used for replacement.
Immunoglobulins given in this therapy come from the serum of many healthy donors, who are screened for any transmissible diseases. The donor serum is treated to retain high amounts of IgG while minimizing IgA and IgM, reducing the chance of severe allergic reactions or kidney damage.
How often patients need infusions depends on how it is administered- intravenously (through a vein) or subcutaneously (under the skin). IV infusions can be spaced up to a month apart, whereas subcutaneous infusions need to be repeated every week.
The rate at which the immunoglobulins are delivered also plays a role in its efficacy, as too high a rate can increase the risk of complications.
The type of immunoglobulin product and its specific composition, including additives that enhance delivery and reduce clumping, may also influence its tolerability.
Possible complications from the immunoglobulin replacement therapy include immediate reactions like headaches, which can be managed with over-the-counter medication and may be avoided by reducing the rate of infusion.
Further side effects may include nausea, discomfort, fever, chest tightness, and migraines. Different parts of the body can be affected in varying ways:
- Cardiovascular reactions: Increased heart rate, palpitations, flushing, and low blood pressure
- Neurologic reactions: Anxiety, nervousness, irritability, tremors, fainting, and seizures
- Respiratory reactions: Coughing, chest tightness, shortness of breath, wheezing, and bronchospasm
- Dermatological reactions: Redness of the skin, hives, and eczema
- Musculoskeletal reactions: Lower backache, joint pain, and muscle pain
- Gastrointestinal reactions: Abdominal pain, bloating, and liver dysfunction
Rarer, but more serious complications, such as aseptic meningitis, severe allergic reactions, Stevens-Johnson syndrome (a severe skin disorder), acute renal failure, acute respiratory distress syndrome, transfusion-associated lung injury, deep vein thrombosis, pulmonary edema, pulmonary embolism, cardiac arrest, and shock can also occur following a period of latency.
Preventing X-Linked Agammaglobulinemia
Patients and their families should be given resources and learning materials that explain various medical practices like vaccinations, the replacement of immunoglobulins (proteins that the immune system makes to attack viruses and bacteria), the use of antibiotics to prevent or treat infections, regular and urgent medical care, the importance of attending follow-up doctor appointments, teams of healthcare professionals, how to prepare for travel, why it’s important to keep records, getting support, and how to strongly stand up for your own health rights.
It’s equally important to thoroughly discuss the reasons why patients should avoid live virus vaccines, which are types of vaccines that use a weakened form of a virus or bacteria to stimulate your immune system. These include vaccines for diseases like polio, mumps, measles, rubella, rotavirus, yellow fever, and chickenpox.
When planning a trip, patients and families are advised to:
- Bring along a portable water filtration system, preventive antibiotics, and other medications.
- Familiarize themselves with the required vaccinations for traveling to foreign countries and be prepared to comply or get formal exceptions when necessary.
- Be equipped with a list of useful resources, including the locations, contact information, and hours of operation for medical facilities like infusion centers (for patients receiving immunoglobulin replacement therapy), doctors, and pharmacists (to get antibiotics needed to treat new infections), hospitals, medical specialists, emergency centers, therapists, and various support staff.
Keeping records of all aspects of patient care, care management, and follow-up details is encouraged. This list should include handy contacts and resources that may be of use to the patient.
When it comes to what information should be recorded, this can include the patient’s vaccination history, history of infections, details of doctor or emergency department visits, hospital stays, illnesses, school absences, visits to therapists and in-home care providers, lab test results, rate of growth, allergies, sensitivities, food likes and dislikes, medicines, dietary supplements, traveling history, and social activities and contacts.
