Mendelian susceptibility to mycobacterial disease

Mendelian Susceptibility to Mycobacterial Disease (MSMD) is a rare genetic disorder that affects the immune system, making individuals more susceptible to infections by weakly virulent mycobacteria, such as Mycobacterium avium, Mycobacterium bovis BCG (bacille Calmette-Guérin), and non-tuberculous environmental mycobacteria. Patients with MSMD also show increased susceptibility to the more virulent Mycobacterium tuberculosis. The disease is characterized by a selective predisposition to clinical disease caused by the aforementioned mycobacterial species, despite a generally normal resistance to other microbes, including other bacteria, viruses, fungi, and parasites.

Etiology

MSMD is caused by mutations in various genes involved in the Interferon-gamma (IFN-γ) pathway, which is crucial for the immune response against mycobacteria. These genes include IFNGR1 (Interferon Gamma Receptor 1), IFNGR2 (Interferon Gamma Receptor 2), STAT1 (Signal Transducer and Activator of Transcription 1), IL12B (Interleukin 12B), IL12RB1 (Interleukin 12 Receptor, Beta 1), and IRF8 (Interferon Regulatory Factor 8), among others. Mutations in these genes can lead to partial or complete defects in the IFN-γ signaling pathway, impairing the body's ability to mount an effective immune response against mycobacterial infections.

Clinical Presentation

The clinical manifestations of MSMD can vary widely among affected individuals, ranging from localized infections, such as lymphadenitis (inflammation of the lymph nodes), to severe disseminated infections. Symptoms typically appear in childhood, although cases with later onset have been reported. The severity of the disease depends on the specific genetic defect and its impact on the IFN-γ pathway.

Diagnosis

Diagnosis of MSMD is based on the clinical presentation, history of mycobacterial infections, and laboratory findings. Genetic testing is crucial for confirming the diagnosis and identifying the specific mutation(s) involved. Additional tests may include immune function tests, such as the quantification of IFN-γ production and response.

Treatment

Treatment of MSMD focuses on managing mycobacterial infections with appropriate antibiotics and preventing future infections. In cases of severe immune dysfunction, bone marrow transplantation may be considered. Interferon-gamma therapy has also been used in some cases to enhance the immune response against mycobacteria.

Prognosis

The prognosis for individuals with MSMD varies depending on the severity of the immune defect and the timeliness of diagnosis and treatment. With appropriate management, many patients can lead relatively normal lives. However, severe cases may have a poorer prognosis due to recurrent or disseminated infections.

NIH genetic and rare disease info

• NIH info on Mendelian susceptibility to mycobacterial disease

Mendelian susceptibility to mycobacterial disease is a rare disease.