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LRBA deficiency
This condition occurs when there are changes in the LRBA gene, impacting the immune system's ability to regulate itself. It can affect various parts of the body and typically presents in childhood, requiring specialised care.
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Overview
LRBA deficiency is a rare inherited disorder that primarily affects the immune system. Individuals with this condition can experience a variety of symptoms, including immune dysregulation, meaning the immune system does not function correctly, and autoimmune features where the body's immune system mistakenly attacks its own healthy tissues [PMID:28790071]. The condition typically presents in early childhood, though symptoms can vary widely in severity and type among affected individuals. Because the immune system has a widespread role, LRBA deficiency can impact many different organ systems.
This condition is considered rare, meaning it affects a small number of people in the population. Accurate diagnosis is important for guiding appropriate medical care and surveillance.
Symptoms & clinical features
The symptoms of LRBA deficiency are diverse, reflecting the broad role of the immune system. Common manifestations include autoimmune conditions, such as inflammatory bowel disease, which can cause significant digestive issues. Cytopaenias, which are low counts of certain blood cells (like red blood cells, white blood cells, or platelets), are also frequently observed [PMID:29074815]. These can lead to anaemia, increased risk of infection, or easy bruising and bleeding.
Some individuals may experience hypogammaglobulinaemia, a condition where the body does not produce enough antibodies, making them more susceptible to infections. Other symptoms can include enlarged lymph nodes, spleen, or liver, as well as skin rashes and lung problems. The range of symptoms means that presentation can be complex and may require assessment by multiple medical specialists.
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Affected organs
LRBA deficiency can affect many different parts of the body. The gastrointestinal tract is frequently impacted, leading to inflammatory bowel disease-like symptoms such as chronic diarrhoea, abdominal pain, and poor growth. Blood components are also commonly affected, resulting in conditions like autoimmune haemolytic anaemia (where the immune system destroys red blood cells) or immune thrombocytopaenia (where platelets are attacked).
Other organs that may be involved include the lungs, leading to recurrent infections or interstitial lung disease; the skin, causing various rashes; and the endocrine system, potentially resulting in conditions like type 1 diabetes. Lymph nodes, the spleen, and the liver can also become enlarged due to immune system overactivity.
Risks & severity
The severity of LRBA deficiency can vary considerably between individuals, even within the same family. Some people may have relatively mild symptoms, while others experience severe, life-threatening complications. The condition typically presents in childhood, with some reports indicating presentation as early as infancy [PMID:28790071]. The chronic nature of the symptoms and the risk of recurrent infections or severe autoimmune flares mean that ongoing medical management is generally required.
Long-term risks are associated with uncontrolled inflammation, recurrent infections, and the potential for organ damage due to autoimmune attacks. The exact prevalence of LRBA deficiency is not well established, but it is considered a rare disease. The variability in symptoms makes predicting individual prognosis challenging, but early diagnosis and consistent management can help improve outcomes.
Genetic causes
LRBA deficiency is caused by pathogenic variants in the LRBA gene. This gene provides instructions for making a protein called LPS responsive beige-like anchor protein. The LRBA protein plays a crucial role in the immune system, particularly in the function of regulatory T cells, which are vital for controlling immune responses and preventing autoimmunity [PMID:29074815].
Specifically, the LRBA protein is involved in transporting and stabilising another important protein called CTLA-4, which helps to 'put the brakes' on immune cell activity. When the LRBA gene has a pathogenic variant, the LRBA protein may be non-functional or absent. This can lead to reduced levels of CTLA-4 on the cell surface, causing immune cells to become overactive and unregulated. This dysregulation is thought to be the underlying mechanism for the autoimmune and inflammatory features observed in LRBA deficiency.
- LRBA LPS responsive beige-like anchor protein
Inheritance pattern
LRBA deficiency follows an autosomal recessive inheritance pattern. This means that an individual must inherit two copies of the altered LRBA gene - one from each parent - to develop the condition. Parents who each carry one copy of the altered gene are known as carriers; they typically do not show symptoms of the condition themselves because they have one working copy of the gene.
For carrier parents, there is a 25% chance with each pregnancy that their child will inherit two altered copies of the gene and be affected by LRBA deficiency. There is a 50% chance the child will be a carrier like the parents, and a 25% chance the child will inherit two working copies of the gene and not be a carrier or be affected. Family members of an affected individual may wish to discuss genetic counselling to understand their own carrier status and risks.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
Diagnosis & testing
Diagnosis of LRBA deficiency typically begins with clinical suspicion based on a combination of persistent infections, autoimmune features, and immune dysregulation. Blood tests may reveal low blood cell counts or abnormal antibody levels, which can point towards an underlying immune disorder. Imaging studies might be used to assess organ involvement, such as inflammation in the bowel or lung changes.
Confirmation of LRBA deficiency is made through genetic testing, specifically by sequencing the LRBA gene to identify pathogenic variants. In the UK, genetic testing for primary immunodeficiencies, including LRBA deficiency, can be accessed through the NHS Genomic Medicine Service (GMS). Referrals for genetic testing are generally made by a clinical immunologist or a clinical geneticist, often through R-codes like R140 (Immunodeficiency, primary, with lymphoproliferation and/or autoimmune features) or R117 (Chronic Diarrhoea with an immunodeficiency component) depending on the predominant symptoms.
Management & lifestyle
Management of LRBA deficiency is complex and focuses on addressing the specific symptoms experienced by each individual. It typically involves a multidisciplinary team including immunologists, gastroenterologists, and haematologists. Treatment strategies can include immunosuppressive medications to control autoimmune responses and inflammation, and immunoglobulin replacement therapy for those with low antibody levels to help prevent infections.
In some cases, specific therapies targeting the CTLA-4 pathway, such as abatacept, have shown promising results by helping to restore immune regulation [PMID:28790071]. Haematopoietic stem cell transplantation (HSCT) may also be considered for individuals with severe, life-threatening forms of the disease. Regular monitoring for complications and infections is an integral part of ongoing care, guided by NHS clinical pathways for primary immunodeficiencies. Lifestyle adjustments, such as infection avoidance strategies and nutritional support, are often important for overall well-being.
UK care pathway
In the UK, individuals suspected of having LRBA deficiency would typically be referred to a clinical immunologist or paediatric immunologist for initial assessment. If an underlying genetic cause is suspected, they would then be referred to a Clinical Genetics service or a specialist immunology centre within the NHS Genomic Medicine Service (GMS). Genetic testing for LRBA deficiency falls under various GMS R-codes, such as R140 or R117, depending on the presenting symptoms. Genetic counsellors play a vital role in explaining the condition, inheritance patterns, and implications for families.
Frequently asked questions
What does 'autosomal recessive' inheritance mean?
Autosomal recessive means that a person must inherit two altered copies of the LRBA gene - one from each parent - to develop LRBA deficiency. Parents who carry one altered copy usually do not have symptoms themselves.
How common is LRBA deficiency?
LRBA deficiency is considered a rare condition. The exact number of people affected is not precisely known, but it is recognised as one of the less common primary immunodeficiencies.
Can LRBA deficiency be cured?
Currently, there is no definitive cure for LRBA deficiency, but treatments are available to manage symptoms and improve quality of life. In some severe cases, bone marrow transplant (haematopoietic stem cell transplantation) may be considered, which can offer a potential long-term solution.
What kind of specialist doctors treat LRBA deficiency?
Individuals with LRBA deficiency are typically cared for by a team of specialists, including clinical immunologists, gastroenterologists, haematologists, and clinical geneticists, depending on their specific symptoms and needs.
Is there support available for families affected by LRBA deficiency?
Yes, various patient advocacy groups and charities in the UK provide support, information, and resources for individuals and families living with rare immune conditions, including LRBA deficiency. Genetic counsellors can also help connect families with appropriate support networks.
References
- Jamee M, Hosseinzadeh S, Sharifinejad N. Comprehensive comparison between 222 CTLA-4 haploinsufficiency and 212 LRBA deficiency patients: a systematic review. Clinical and experimental immunology. 2021. PMID: 33788257