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Mendelian susceptibility to mycobacterial disease
MSMD affects the immune system, leading to recurrent or severe infections from mycobacteria, which are common environmental bacteria. This condition often presents in childhood and requires careful management.
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Overview
Mendelian susceptibility to mycobacterial disease (MSMD) is a group of rare genetic disorders characterised by a specific defect in the immune system. This defect makes individuals highly susceptible to severe or recurrent infections, primarily by mycobacteria [PMID:33671239]. Mycobacteria are a type of bacteria commonly found in the environment, with some strains causing diseases like tuberculosis. People with MSMD struggle to fight off these infections, which can be life-threatening if not managed appropriately.
The condition can manifest in various ways, ranging from mild to severe, depending on the specific genetic change and its impact on the immune response. Although typically diagnosed in childhood, symptoms can sometimes emerge later in life. Prompt diagnosis and treatment are crucial for improving outcomes for individuals living with MSMD.
Symptoms & clinical features
The primary symptom of MSMD is an increased susceptibility to infections caused by mycobacteria. These can include infections from Mycobacterium bovis Bacille Calmette-Guérin (BCG), often administered as a tuberculosis vaccine, or atypical (non-tuberculous) mycobacteria found in the environment. Symptoms of these infections may include persistent fever, weight loss, swollen lymph nodes, and organ-specific issues depending on where the infection takes hold [PMID:24072238].
Some individuals with MSMD may also experience infections from other intracellular pathogens, such as Salmonella bacteria or certain viruses and fungi. The severity and recurrence of these infections can vary significantly among affected individuals, even within the same family. Recurrent infections often require prolonged antibiotic treatment.
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Affected organs
Mycobacterial infections in individuals with MSMD can affect various organs and systems throughout the body. Commonly affected sites include the lymph nodes, which may become swollen and painful. The lungs can also be impacted, leading to pneumonia-like symptoms. Other potential sites of infection include the bones, joints, skin, and internal organs such as the liver and spleen [PMID:24072238]. In some severe cases, disseminated infection can occur, spreading throughout the bloodstream and affecting multiple organ systems simultaneously, which can be life-threatening.
Risks & severity
MSMD presents with a spectrum of severity, from mild, localised infections to severe, disseminated disease that can be fatal if not treated. The lifetime risk of developing serious mycobacterial infections is significantly elevated for individuals with MSMD compared to the general population. The age of onset for symptoms is typically in early childhood, often following BCG vaccination, but can range from infancy to adulthood [PMID:24072238].
Specific genetic changes can influence the severity of the condition. For example, certain types of genetic alterations may lead to more profound immune dysfunction and, consequently, more severe or recurrent infections. Ongoing research aims to better understand these genotype-phenotype correlations to help predict disease course and guide management strategies.
Genetic causes
MSMD is caused by pathogenic variants in several genes that are critical for a specific part of the immune system known as the interferon-gamma (IFN-γ) pathway. This pathway is essential for the immune system to effectively combat intracellular pathogens like mycobacteria. Key genes implicated in MSMD include IFNGR1, IL12RB1, and STAT1.
Pathogenic variants in IFNGR1, for example, can lead to a faulty interferon-gamma receptor on immune cells. This receptor is responsible for receiving signals that activate other immune cells to fight infections. When the receptor doesn't function correctly, immune cells are less able to respond to mycobacterial threats. Similarly, variants in IL12RB1 affect the interleukin-12 receptor, which plays a crucial role in inducing the production of IFN-γ. STAT1 is another important gene in this pathway; variants in STAT1 can disrupt the signalling cascade that leads to an effective immune response against these pathogens.
- IFNGR1 interferon gamma receptor 1
- IL12RB1 interleukin 12 receptor subunit beta 1
- STAT1 signal transducer and activator of transcription 1
Inheritance pattern
MSMD can be inherited in either an autosomal dominant (AD) or autosomal recessive (AR) pattern, depending on the specific gene involved and the nature of the genetic change. In autosomal dominant inheritance, only one copy of the altered gene is needed for an individual to develop the condition. This means if one parent has the genetic variant, there is a 50% chance their child will also inherit the variant and be affected.
In autosomal recessive inheritance, an individual must inherit two copies of the altered gene - one from each parent - to develop the condition. Parents who each carry one copy of the altered gene are typically unaffected and are called carriers. If both parents are carriers, there is a 25% chance with each pregnancy that their child will inherit two altered copies and develop MSMD. Genetic counselling can help families understand their specific inheritance risks.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
Diagnosis & testing
A diagnosis of MSMD is often suspected in individuals experiencing recurrent, severe, or disseminated infections, particularly those caused by mycobacteria. Clinical evaluation includes a thorough review of medical history, infection patterns, and family history. Immune function tests may be performed to assess the response of the IFN-γ pathway.
Confirmation of MSMD relies on genetic testing to identify pathogenic variants in the causative genes (e.g., IFNGR1, IL12RB1, STAT1). In the UK, genetic testing for suspected MSMD is typically requested by a clinical immunologist or geneticist through the NHS Genomic Medicine Service. Relevant R-codes for genetic testing would fall under the inherited immunology or primary immunodeficiency panels. Referral to a clinical genetics service is essential for appropriate genetic testing and interpretation.
Management & lifestyle
Management of MSMD focuses on preventing and treating infections, as well as addressing the underlying immune defect where possible. This often involves long-term antibiotic prophylaxis to prevent mycobacterial infections and aggressive treatment of active infections with appropriate antimicrobial agents. Individuals with MSMD should generally avoid live bacterial vaccines, such as the BCG vaccine, due to the risk of severe infection.
In some cases, particularly for severe forms of MSMD, treatments like interferon-gamma therapy or hematopoietic stem cell transplantation (HSCT) may be considered. Interferon-gamma therapy aims to boost the immune response by providing the missing or deficient immune signalling molecule. HSCT, a more intensive treatment, can replace the faulty immune system with healthy cells. Management plans are highly individualised and developed by a team of specialists, including immunologists, infectious disease specialists, and geneticists, within the NHS framework.
UK care pathway
In the UK, individuals suspected of having MSMD would typically enter the NHS Genomic Medicine Service pathway. Initial assessment would usually be by a paediatrician or adult immunologist, followed by referral to a clinical genetics service. Genetic testing for primary immunodeficiencies, including MSMD, is available through NHS Genomic Laboratory Hubs, using relevant R-codes specified on the National Genomic Test Directory. Genetic counsellors play a vital role in providing information and support to families undergoing genetic testing and navigating a diagnosis.
Frequently asked questions
What kind of infections are common in MSMD?
Individuals with MSMD are primarily susceptible to infections caused by mycobacteria, which include both typical strains like those causing tuberculosis and atypical mycobacteria found in the environment. They may also be vulnerable to other intracellular pathogens like Salmonella and certain viruses or fungi.
Is MSMD contagious?
No, MSMD itself is not contagious. It is a genetic condition, meaning it is caused by changes in an individual's genes and cannot be passed from person to person like an infection. However, the infections that individuals with MSMD get, such as mycobacterial infections, can sometimes be contagious to others if they are not treated.
Can MSMD be cured?
Currently, there is no simple cure for MSMD. Management focuses on preventing and treating infections effectively. In some severe cases, hematopoietic stem cell transplantation (HSCT) may be considered, which can potentially correct the underlying immune defect. Research into new therapies is ongoing.
What should I do if my child has MSMD and is due for a vaccination?
If your child has MSMD, it is crucial to consult with their immunology specialist before any vaccinations are given. Live bacterial vaccines, such as the BCG vaccine for tuberculosis, are typically not recommended for individuals with MSMD due to the risk of severe infection. Your specialist will provide guidance on appropriate vaccination schedules.
How does MSMD affect daily life?
MSMD can significantly impact daily life due to the risk of recurrent and severe infections, often requiring long-term medication and close medical monitoring. Lifestyle adjustments, such as avoiding certain exposures and adhering to treatment plans, are important. Support from healthcare teams and patient advocacy groups can help manage these challenges.
References
- Mirzalieva O, Juncker M, Schwartzenburg J. ISG15 and ISGylation in Human Diseases. Cells. 2022. PMID: 35159348
- Bustamante J. Mendelian susceptibility to mycobacterial disease: recent discoveries. Human genetics. 2020. PMID: 32025907
- Rosain J, Kong XF, Martinez-Barricarte R. Mendelian susceptibility to mycobacterial disease: 2014-2018 update. Immunology and cell biology. 2019. PMID: 30264912
- Kumararatne DS. Mendelian susceptibility to mycobacterial disease. Respiration; international review of thoracic diseases. 2006. PMID: 16679750
- Cottle LE. Mendelian susceptibility to mycobacterial disease. Clinical genetics. 2011. PMID: 20718793
- Boisson-Dupuis S. The monogenic basis of human tuberculosis. Human genetics. 2020. PMID: 32055999
- Peñafiel Vicuña AK, Yamazaki Nakashimada M, León Lara X. Mendelian Susceptibility to Mycobacterial Disease: Retrospective Clinical and Genetic Study in Mexico. Journal of clinical immunology. 2023. PMID: 36044171
- Cornelissen HM, Glanzmann B, Van Coller A. Mendelian susceptibility to mycobacterial disease in tuberculosis-hyperendemic South Africa. South African medical journal = Suid-Afrikaanse tydskrif vir geneeskunde. 2021. PMID: 34949297