Summary

X-linked agammaglobulinemia (XLA; also known as Bruton’s agammaglobulinemia) is the name for a condition that affects the body’s abliity to make antibodies and fight infections. It belongs to a group of conditions known as antibody deficiencies. XLA affects only boys and its features include repeated episodes of bacterial infections affecting the ears, sinuses, nose, eyes, skin and the gastrointestinal tract (gut). It is a rare condition with about 5–10 people in a million affected.

Antibodies belong to a particular type of protein, called immunoglobulin, normally found in blood and tissue fluids. There are three majot types of immunoglobulin, known as:

  • Immunoglobulin G (IgG) – the most abundant and common immunoglobulin, found in blood and tissue fluids. IgG functions mainlyagianst bacteria and soem viruses.
  • Immunoglobulin A (IgA) – found in blood, tears and saliva. It protects the tissues of the respiratory, reproductive, urinary and digestive systems.
  • Immunoglobulin M (IgM) – found in the blood. IgM functions in much the same way as IgG but is formed earlier in the immune response.

All types of immunoglobulin are made up of antibodies against the germs that an individual has met during the course of his or her life.

Antibodies are made by white blood cells called B-cells or sometimes referred to as B-lymphocytes. In XLA there are genetic changes known as mutations in the Bruton’s tyrosine kinase (BTK) gene. These mutations block the development of normal, mature B-cells that would normally make antibodies. As a result, people with XLA have very few mature B-cells and cannot make immunoglobulins; that is, the antibodies that are needed to protect the body against infections.

The aim of treatment in XLA is to replace the missing or defective antibodies with purified immunoglobulins from the blood of healthy donors in order to reduce the frequency and severity of infections. Although not a cure for XLA, immunoglobulin replacement therapy is often enough to keep patients healthy so that those affected can lead full and relatively normal lives. Children with XLA should take part in regular school activities, including exercise, and do not need to be limited in what they can do. It is important for the school to be aware of the diagnosis, however.

Antibiotics are often needed to treat breakthrough bacterial infections that will occur from time to time. A few individuals may need to take antibiotics every day to protect them from infection or to treat chronic sinusitis or chronic bronchitis. Patients with bronchiectasis (widening and scarring of the bronchial airways) may need help from a physiotherapist to help clear their airways.

Boys with XLA develop bacterial infections because they lack protective antibodies. Infections usually affect those surfaces that are exposed to bacteria, such as the mucosal surfaces of the lung and gut.  

In XLA, serious, bacterial infections may occur, such as meningitis or pneumonia. Such infections usually begin in infancy or early childhood, typically at 6 to 9 months of age when the protective antibodies that have passed from the mother to the unborn child via the placenta, are broken down. This leaves an affected boy with no antibodies ineffective at fighting infections.

People with XLA can have repeated, severe or persistent infections. Here are some common features that you may recognise and which may have led your clinician to a diagnosis of XLA:

  • Sinus infections causing sinusitis 
  • Inner ear infections, such as otitis media
  • Throat infections, such as tonsillitis or laryngitis
  • Chest infections, such as bronchitis or pneumonia
  • Stomach and intestinal infections, including giardiasis (a parasitic infection) resulting in persistent diarrhoea or weight loss
  • Skin infections, such as abscesses and boils
  • Eye infections, such as conjunctivitis
  • Urinary tract infection (cystitis)
  • Meningitis
  • Joint infections (osteomyelitis)
  • Blood poisoning (septicaemia)

Furthermore, very small or absent tonsils and lymph nodes (the glands in the neck) may be a physical sign of XLA, since these are the sites where the B-cells would normally be present.

Common causes of infections in XLA

Infections affecting the lung, ear and sinuses are commonly caused by these organisms:

  • Streptococcus pneumoniae
  • Haemophilus influenzae
  • Staphylococcus aureus

and infections in the gut by:

  • Campylobacter
  • Salmonella
  • Giardia.

People with XLA are usually able to cope with most viral infections, including measles and chicken pox, without any problems. In rare cases enteroviruses can cause serious infection but this is uncommon for those on adequate replacement immunoglobulin therapy.

Diagnosis

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 as immunologist should be consulted. 

Making the diagnosis

A clinical immunologist usually makes the diagnosis of XLA.

Diagnosis is confirmed by blood tests. Tests may be intensive at the beginning if this investigative process and may include an assessment of:

  • The levels of IgG, IgA and IgM
  • The function of any antibodies that are present, to see how well they react to microbes, if at all (unlikely in XLA).  This is doen by test immunisations using safe ‘dead’ or fragmented organism vaccines.
  • How many lymphocytes (the white blood cells involved in immunity) there are in the blood
  • How many B-lymphocytes are present in the blood, as well as the other major type of lymphocytes (needed to fight viruses) known as T-cells. In XLA, mature B-lymphocytes are not present in blood but T-cell levels will be normal.

A definite diagnosis is made by looking for mutations in the BTK gene using genetic analysis. When a specific defect is found, the doctors will often test female members of the family to diagnose those who carry the abnormal X-chromosomes.

XLA is caused by mutations in the BTK gene, which is present on an X-chromosomes. The gene makes the enzyme Bruton’s tyrosine kinase, which is needed to instruct B-cells to mature and produce antibodies.

More than 600 different mutations in the BTK gene have been found to cause XLA. Most mutations result in the absence of the BTK enzyme or an abnormal BTK protein that is quickly broken down in the cell. Without functional BTK enzyme there is no development of B-cells – and so a lack of antibodies – and this results in an increased susceptibility to bacterial infections.

XLA is an inherited condition, meaning it is passed through the generations. It follows what is called an X-linked recessive pattern of inheritance, with transfer of a defective gene on one of the two X chromosomes of a mother to a son. This means that for every boy who is conceived to a carrier mother there is a 50/50 chance that he will have XLA. This has implications for family planning. Mothers, their maternal aunts and sisters may be carriers and should receive genetic counselling. Daughters who are born to carrier mothers should also be tested once they are old enough to give informed consent as there is a 50/50 chance they might carry the faulty gene. Affected fathers can have carrier daughters but their sons will not be affected by XLA or be carriers of the condition.

Family planning

Prenatal genetic diagnosis is available for families in which XLA has already been diagnosed. Your health team will be able to refer you for advice about the risks of prenatal testing.

More information about the genetic aspects of XLA is available in our booklet ‘Genetic aspects of primary immunodeficiency’.

At present there is no cure for people with XLA but affected boys can grow up to lead normal productive lives if they keep to the treatments recommended and have regular check-ups with an immunologist.

The main treatment for XLA involves replacing the missing antibodies using immunoglobulin (Ig) replacement therapy. This treatment can be given intravenously (dripped into a vein through a needle in the arm or hand) or subcutaneously (injected under the skin in the lower stomach or thigh). This treatment is usually needed every day or every week for subcutaneous therapy or every 2–4 weeks for intravenous therapy, depending on the individual.

The dose is monitored by looking at how well the treatment protects against infections, since adequate therapy reduces the rate and severity of bacterial infections and may prevent them entirely.

The doctor will also do blood tests periodically (typically every 3–6 months, although this may be more frequent depending on your centre’s local policies) to check levels of IgG and for any possible complications.

Additional treatments focus on taking steps to reduce the number and severity of infections. They include prompt long-term treatment with broad-spectrum antibiotics or more specific antibiotics if the bugs causing the infection are known. If lung problems have developed, such as bronchiectasis, where the airways of the lungs become abnormally widened leading to a build-up of excess mucus, physical therapy, such as physiotherapy and specific exercises, may be needed to remove the mucus from the lung airways.   

Immunisations

Not all vaccines are safe to be administered to patients with XLA and therefore you should discuss any recommended or required vaccinations with your clinical immunology team before a vaccine is given.

Some people with XLA, but not all, may have or may develop other health problems. Monitoring is usually by clinical review (check-up), infrequent blood tests and for some people tests of breathing function.

Your clinical immunologist will be on the lookout for the complications and will work with other clinical specialists to offer you the most appropriate advice and treatments.

Lung and sinus problems

If chronic lung or sinus disease, such as bronchiectasis, has developed before diagnosis, those affected may have a reduced ability to exercise. Your doctor may refer you for ‘lung function tests’.

Lung function tests measure how well your lungs are working. You may be referred to a physiotherapist, and specific exercises may be recommended to remove the mucus from the lung airways to improve your lung health. People with chronic sinus disease may be referred to an ear, nose and throat (ENT) specialist for advice on other treatments, including physical treatments, to reduce the risk of further sinus damage.

Painful joints and arthritis in XLA

Joint disease (arthritis) usually affecting the knees can occur. This usually only occurs in individuals not receiving immunoglobulin replacement therapy and is thought to be related to infection with enteroviruses and mycoplasma.

Gut problems in XLA

Inflammatory bowel disease (such as Crohn’s disease) can occur in XLA and is thought to be a complication of repeated, severe or persistent bowel infection.

Other problems

Sometimes a condition known as neutropenia – a reduction in the number of neutrophils (a type of white blood cell) – can happen. This is usually temporary and is seen only in individuals not receiving immunoglobulin replacement therapy.

Here we post questions patients have asked us about X-linked agammaglobulinemia (XLA). Please do not hesitate to get in touch with us if you have a question.

Q. My son has XLA and my partner and I are planning to have another child. What are the options for conceiving a child unaffected by XLA?

A. If you have a child with XLA you can have Prenatal Genetic Diagnosis (PGD) which has been approved by the Human Fertilisation and Embryology Authority (HEFA). You will need to speak to your son’s immunologist who will refer you to a genetics team who will be able to advise on the pros and cons of PGD.

Q. Both my sons have XLA and one of them has 4 boys. Is it possible that my grandson has XLA?

A. XLA is an inherited condition, meaning it is passed down through the generations.  It follows what is called an X-linked recessive pattern of inheritance, with transfer of a defective gene on one of the two X chromosomes of a mother to a son.  In answer to your question affected fathers can have carrier daughters but their sons will not be affected by XLA or be carriers of the condition.

You can find out more information about the inheritance of XLA in these two booklets – Genetics of PID and the XLA condition specific booklet.

Q. My son has XLA, can I get a medical exemption certificate for him?

A. Currently primary immunodeficiencies are not covered by the medical exemption certificates in order to get free prescriptions but this is something Immunodeficiency UK is campaigning for with the Prescription Charges Coalition.  Please check this web page to see if your son might qualify for free prescriptions via another route.

Q: My son has XLA and has unilateral deafness.  At school, his teachers are reporting him as being very tired and showing a lack of concentration. Does he need extra support at school?  

A. Fatigue is commonly associated with chronic disorders and is not specific to having a PID, but is frequently seen in it. However, it is uncommon for children with well-managed XLA to have primary fatigue.  Unilateral deafness is also linked to concentration fatigue (the National Deaf Children’s Society website has more information) and special provisions may be needed in class to ensure your son is able to hear the teacher well. This webpage gives advice on what these could include.

Both having a PID and having unilateral deafness are covered under the Equality Act  . This emphasises a legal duty on education providers to make reasonable adjustments so that any special arrangements can be made. Also visit our webpage covering disability and PID for more information.

It might also be useful to speak again with your clinic to more fully discuss the deafness with the team looking after your son.  A paediatric immunodeficiency service will be part of a larger hospital with services to support sensory deficit and would agree that your son’s needs require a fuller assessment.  This would further strengthen your case for support in school.

Q. How many people per year are diagnosed with XLA?

A. This is not known at present. At the moment this incidence data is not readily available and there is still no way of capturing that in the UK reliably yet.

Q. How many people are currently affected by XLA in the UK?

A. About 1 in 100,000 people have XLA.

Q. What causes XLA?

A. A genetic change in the btk (Bruton’s Tyrosine Kinase) gene causes XLA.  This gene makes the enzyme Bruton’s tyrosine kinase, which is needed to instruct B-cells to mature and produce antibodies.

Q. What is the life expectancy of a person with XLA?

A. The life expectancy of people with XLA is normal – the same range as that for the general population.

Q. For XLA what tests will be undertaken regularly to ensure that there are no other health issues going on?

A. Doctors will monitor those affected for infection and the consequences of any infection. It’s important to attend any regular check ups. This is essential as reduced immune surveillance may increase cancer risk above the normal healthy population e.g. chronic gastritis may cause stomach cancer and colon cancer.  All XLA patients are monitored regularly using the appropriate tests as needed.

Q. What can we do to improve the general health of a person with XLA?

A. Following a healthy diet, avoiding getting infections and seeking help promptly when an infection happens will help keep you well. Take a look at ‘Keeping well and healthy when you have a PID’.

Q. Is there any point in taking supplements to boost what immune system XLA patients have?

A. There isn’t any evidence-based information on the use of supplements in XLA. Doctors will be keen to rule out if there are any deficiencies due to diet that could lead to secondary immune problems. 

Q. How effective is immunoglobulin as a long-term treatment for XLA?

A. Immunoglobulin therapy is a highly effective therapy and those affected are able to live a normal healthy life if it is started early in childhood before any recurrent infections set in.

Please take a look at our FAQs on immunoglobulin treatment here.

Q. Is there any treatment for XLA other than immunoglobulin?

A. Not at the present moment.

Q. Are there any plans/studies for gene therapy for XLA?

A. There are no clinical trials of gene therapy for XLA at present. However, there is quite a bit of work ongoing in the laboratory and so trials may start in the not too distant future.

Q. Are there any activities people with XLA should avoid?

A. No. There are some simple precautions that should be taken to avoid getting infections. Take a look at this webpage on ‘Keeping well’ and follow safety advice for going on holiday.

Q. Can people with XLA travel safely?

A. Yes absolutely. Take a look at our ‘Going on holiday’ section. People planning to take long vacations (over 3 weeks) need to arrange to have their treatment in the country they are staying in.

Q. Should we expect our GP to be knowledgeable about PIDs/XLA?

A. Unfortunately not. Collectively PIDs are rare and XLA even rarer. It is often down to parents and individuals to bring their GPs up to speed. They can do that by pointing them to sources of reliable sources information such as the Immunodeficiency UK website.

Q. Is there a way we can find out what research work is being undertaken about XLA?

A. One way is to ask your immunology centre if they are involved in any research. Also you can use the search engine called Pubmed and find papers related to XLA by putting in X-linked agammaglobulinemia or XLA in the search box. Immunodeficiency UK will also do its best to keep you updated on the results of any new research that is going on via its website. 

Q. How it is passed down genetically?

A. XLA is an X-linked recessive condition and so affects boys. Female members in an affected family may carry the gene and so mothers, maternal aunts and sisters may be carriers and should receive genetic counselling – the sisters once they are old enough to give informed consent.

Q. What are the chances of passing on XLA to our children?

A. Affected males will pass on the faulty gene to all of their daughters, who will be carriers of XLA, but their sons will not be affected by XLA or be carriers of the condition.

Q. Can XLA patients have genetic counselling?

A. Yes. Female members in an affected family may carry the gene and so mothers, maternal aunts and sisters may be carriers and should receive genetic counselling – the sisters once they are old enough to give informed consent. Genetic counsellors will advice on family planning issues and  prenatal genetic diagnosis is available for families in which XLA has already been diagnosed.

Q. I am a mum with sons affected by XLA.  Should I tell my sisters and other relatives that they should be tested for PID?

A. Yes your sisters may be carriers and if they have sons they should be tested. Please take a look at our XLA information sheet and information on genetic inheritance here. 

Q. I have XLA and my daughter is a carrier of XLA. What are the chances of her sons, my grandsons, having XLA and can they get treatment before they are born?

A. There is a 50/50 chance that a male child will be born with XLA. It is possible to test if the baby has XLA using non-invasive prenatal testing. It is not possible to give treatment before the baby is born to correct the inherited problem.

Q. Which vaccines can be given and which cannot for XLA?

A. In XLA, the aim is to achieve a T-cell response, since there are no B-cells to make antibodies. There are no specific contraindications, but many vaccines may not be helpful if they do not elicit good T-cell based protection. You should discuss immunisation with your centre.

You can download our information booklet here.