What Is Agammaglobulinemia? Understanding This Rare Condition
Agammaglobulinemia is a rare inherited immunodeficiency disorder characterised by severely low or absent levels of antibodies (immunoglobulins) in the blood. This condition affects the body’s ability to fight bacterial infections effectively, making individuals extremely vulnerable to serious and recurrent infections.
The term “agammaglobulinemia” literally means “absence of gamma globulins” – the proteins that contain our infection-fighting antibodies. This condition affects approximately 5-10 people per million in the UK, making it one of the rarer primary immunodeficiencies.
Types of Agammaglobulinemia
There are several forms of agammaglobulinemia, with the most common being:
X-linked Agammaglobulinemia (XLA): Also known as Bruton’s agammaglobulinemia, this accounts for approximately 85% of all agammaglobulinemia cases and affects only boys.
Autosomal Recessive Agammaglobulinemia (ARA): This rarer form can affect both boys and girls and accounts for up to 15% of cases.
How Does Agammaglobulinemia Affect the Immune System?
To understand agammaglobulinemia, it’s essential to know how our immune system normally works. Antibodies are made by white blood cells called B-cells or B-lymphocytes. In agammaglobulinemia, genetic mutations block the development of normal, mature B-cells that would normally make antibodies.
The Role of Antibodies
There are three major types of immunoglobulin:
- Immunoglobulin G (IgG) – the most abundant immunoglobulin, found in blood and tissue fluids, functioning mainly against bacteria and some viruses
- Immunoglobulin A (IgA) – found in blood, tears, and saliva, protecting the respiratory, reproductive, urinary, and digestive systems
- Immunoglobulin M (IgM) – found in the blood, functioning similarly to IgG but formed earlier in the immune response
Recognising the Symptoms of Agammaglobulinemia
Early Warning Signs
Children with agammaglobulinemia typically begin showing symptoms after 6-9 months of age when maternal antibodies wear off. The most common early indicators include:
- Recurrent ear infections (otitis media)
- Persistent sinus infections leading to sinusitis
- Frequent chest infections including bronchitis and pneumonia
- Throat infections such as tonsillitis or laryngitis
- Severe or persistent diarrhoea
Common Infection Patterns
People with agammaglobulinemia experience repeated, severe, or persistent infections affecting surfaces exposed to bacteria, particularly the mucosal surfaces of the lungs and gut.
Respiratory infections commonly involve:
- Streptococcus pneumoniae
- Haemophilus influenzae
- Staphylococcus aureus
Gastrointestinal infections often include:
- Campylobacter
- Salmonella
- Giardia parasites
Physical Signs to Watch For
Very small or absent tonsils and lymph nodes may be physical signs of agammaglobulinemia, since these are sites where B-cells would normally be present.
Understanding the Causes: Genetics Behind Agammaglobulinemia
X-linked Agammaglobulinemia (XLA)
XLA is caused by mutations in the Bruton tyrosine kinase (BTK) gene, located on the long arm of the X-chromosome. More than 544 mutation entries from 471 unrelated families have been documented, showing 341 unique molecular events.
How XLA Is Inherited: XLA follows an X-linked recessive pattern of inheritance. For every boy conceived to a carrier mother, there is a 50/50 chance he will have XLA. Affected fathers can have carrier daughters, but their sons will not be affected by XLA.
Autosomal Recessive Forms
Autosomal recessive agammaglobulinemia is caused by genes affecting B-cell development, involving genes mapped to different chromosomes including 22q11.21 (IGLL1), 14q32.33 (IGHM), and 9q34.13 (LCRR8).
Diagnosis: How Is Agammaglobulinemia Identified?
When to Suspect Agammaglobulinemia
Antibody deficiency will be considered in individuals presenting with repeated, severe, or persistent infections. These individuals will usually be referred to a specialist for further assessment, following which an immunologist should be consulted.
Diagnostic Tests
Blood Tests Include:
- Immunoglobulin levels: Assessment of IgG, IgA, and IgM levels
- Lymphocyte counts: Checking how many B-lymphocytes and T-cells are present in the blood. In agammaglobulinemia, mature B-lymphocytes are not present, but T-cell levels remain normal
- Functional antibody testing: Testing how well existing antibodies react to microbes
Genetic Testing: A definitive diagnosis is made by looking for mutations in the BTK gene using genetic analysis.
UK Diagnostic Pathway
In the UK, diagnosis typically follows this pathway:
- GP referral following recurrent infections
- Specialist immunology consultation
- Comprehensive blood testing
- Genetic confirmation
- Family screening when appropriate
Treatment Options: Managing Agammaglobulinemia in the UK
Primary Treatment: Immunoglobulin Replacement Therapy
The main treatment for agammaglobulinemia involves replacing missing antibodies using immunoglobulin (Ig) replacement therapy. This treatment is available through the NHS and can be administered in two ways:
Intravenous Immunoglobulin (IVIG):
- Administered every 2-4 weeks through a needle in the arm or hand
- Usually given in hospital day units
- Takes 2-6 hours per infusion
Subcutaneous Immunoglobulin (SCIG):
- Injected under the skin in the lower stomach or thigh
- Given daily or weekly, depending on the individual
- Can often be administered at home
Monitoring Treatment Effectiveness
The dose is monitored by looking at how well the treatment protects against infections, with adequate therapy reducing the rate and severity of bacterial infections and potentially preventing them entirely.
Regular monitoring includes:
- Blood tests every 3-6 months to check IgG levels and possible complications
- Assessment of infection frequency and severity
- Lung function tests when necessary
Additional Treatments
Antibiotic Therapy: Antibiotics are often needed to treat breakthrough bacterial infections, with some individuals requiring daily antibiotics for chronic conditions.
Physiotherapy: Patients with bronchiectasis may need physiotherapy to help clear airways and remove mucus from lung airways.
Living With Agammaglobulinemia: What to Expect
Quality of Life
Although not a cure, immunoglobulin replacement therapy is often enough to keep patients healthy so that those affected can lead full and relatively normal lives.
Education and Activities
Children with agammaglobulinemia should take part in regular school activities, including exercise, and do not need to be limited in what they can do. However, schools should be informed of the diagnosis for appropriate support.
Travel Considerations
People with agammaglobulinemia can travel safely, though those planning long vacations (over 3 weeks) need to arrange treatment in their destination country.
Potential Complications and Long-term Outlook
Respiratory Complications
Bronchiectasis: Chronic lung or sinus disease may develop if diagnosis is delayed, potentially reducing exercise ability.
Other Potential Issues
- Joint problems: Arthritis affecting the knees can occur, usually only in individuals not receiving adequate immunoglobulin therapy
- Gastrointestinal issues: Inflammatory bowel disease can occur and is thought to be a complication of repeated bowel infections
Life Expectancy
The life expectancy of people with agammaglobulinemia is normal – the same range as that for the general population when properly treated.
Support and Resources in the UK
NHS Services
The NHS provides comprehensive care for agammaglobulinemia through:
- Specialist immunology centres across the UK
- Home treatment services for subcutaneous immunoglobulin
- Multidisciplinary care teams including immunologists, nurses, and physiotherapists
UK Support Organisations
Immunodeficiency UK Immunodeficiency UK is a national patient organisation for individuals and families in the UK with primary and secondary immunodeficiency. They provide:
- Patient information booklets
- Advocacy and support services
- Benefits advice and guidance
- Educational resources for families
Website: immunodeficiencyuk.org Charity Number: 1193166
Primary Immunodeficiency Association (PIA) The PIA provides information about various primary immunodeficiencies including agammaglobulinemia.
Financial Support
Prescription Charges: Currently, primary immunodeficiencies are not covered by medical exemption certificates for free prescriptions, but Immunodeficiency UK is campaigning for this change.
Disability Living Allowance: Some individuals may qualify for DLA or Personal Independence Payment (PIP).
Vaccination Considerations
Safe Vaccinations
Not all vaccines are safe for patients with agammaglobulinemia, and any recommended vaccinations should be discussed with the clinical immunology team before administration.
Important Notes
- Live vaccines are generally contraindicated
- Killed or inactivated vaccines may be given but may not provide protection
- The aim is to achieve a T-cell response since there are no B-cells to make antibodies
Research and Future Treatments
Current Research Directions
Gene Therapy: While there are no clinical trials of gene therapy for agammaglobulinemia at present, significant laboratory work is ongoing, and trials may start in the not-too-distant future.
Stem Cell Transplantation: Haematopoietic stem cell transplantation has been considered for many combined primary immunodeficiencies and is being extended to other immunodeficiencies.
Staying Informed
To stay updated on research:
- Contact your immunology centre about ongoing studies
- Use PubMed to search for research papers on agammaglobulinemia
- Follow Immunodeficiency UK for research updates
Frequently Asked Questions
Can women be affected by agammaglobulinemia?
While X-linked agammaglobulinemia only affects males, women can be carriers and may be affected by autosomal recessive forms.
Is agammaglobulinemia curable?
Currently, there is no cure for agammaglobulinemia, but affected individuals can lead normal, productive lives with proper treatment.
How effective is treatment?
Immunoglobulin therapy is highly effective, and those affected can live normal, healthy lives if treatment starts early in childhood before recurrent infections develop.
Can people with agammaglobulinemia have children?
Yes, with appropriate genetic counselling. Prenatal genetic diagnosis is available for families where agammaglobulinemia has been diagnosed.
Key Takeaways
- Agammaglobulinemia is a rare but serious primary immunodeficiency affecting antibody production
- Early diagnosis and treatment with immunoglobulin replacement therapy enables normal life expectancy
- The NHS provides comprehensive care through specialist immunology centres
- Strong support networks exist through UK organisations like Immunodeficiency UK
- With proper management, individuals can lead full, active lives including education, work, and travel
Getting Help and Support
If you suspect you or a family member may have agammaglobulinemia:
- Speak to your GP about recurrent or severe infections
- Request referral to a specialist immunology service
- Contact support organisations for information and advice
- Connect with other families through patient groups
Emergency Contact: Always seek immediate medical attention for signs of serious infection, including high fever, difficulty breathing, or signs of sepsis.
This information is for guidance only and should not replace professional medical advice. Always consult your healthcare provider for personalised treatment recommendations.
Sources: Information compiled from NHS resources, Immunodeficiency UK, medical literature, and specialist immunology sources.
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