MEMD and complete ISGq15 deficiencyD84.8

MSMD (MSDM stands for"Mendelian susceptibility to mycobacterial diseases"; OMIM: 614889) due to ISG15 deficiency is a rare, autosomal-dominantly inherited, autoinflammatory disease that belongs to the type 1 interferonopathies. The interferon stimulated gene 15 (ISG15 gene) encodes ISG15, a ubiquitin-like protein (UBL) that is conjugated to diverse target proteins. ISG15 deficiency prevents the formation of "ubiquitin specific peptidase 18" (USP18), a negative regulator of the type I interferon signaling pathway. This leads to an amplification of the type I interferon-dependent immune response and decreased production of interferon-γ (Zhang X et al. 2015). The result is a largely selective impairment of antifungal immunity.

MSMD due to complete ISG15 defect is classified as a type 1 interferonopathy. These represent a group of rare, genetically and phenotypically heterogeneous disease patterns caused by a dysfunction of the innate immune system (Crow YJ 2011). With the exception of multifactorial SLE, these are very rare diseases. Pathogenetically, type 1 interferonopathies are based on disturbances in the metabolism and in the immunological recognition of intracellular nucleic acids

Laboratory and mutation analyses lead to a diagnosis. The IFN-gamma, IL12 p40 and IL12 p70 values can be measured in ELISA after whole blood activation by BCG, BCG+IL12 and BCG+IFN-gamma. The ISG15 deficiency patients produce only small amounts of IFN-gamma, but normal amounts of IL12p40 and IL12p70. There is only a relatively low susceptibility to viral infection. In contrast, however, the patients show an increased susceptibility to mycobacterial infections.

Other etiologies of the MSMD must be excluded.

BCG vaccination should be avoided in persons with a known ISG15 mutation. Treatment usually includes long-term antimicrobial therapy in combination with recombinant IFN-gamma.

With appropriate treatment, the prognosis is considered good.

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