The whole cascade converges into the phosphorylation of the AChR subunits and rapsyn; rapsyn is a structural protein that self-aggregates providing a scaffold that anchors AChRs with the actin cytoskeletonthrough the mediation of microtubule actin cross-linking factor 1 (MACF1)to form the mature clusters (Borges and Ferns,2001; Lee et al.,2009; Zuber and Unwin,2013; Oury et al.,2019; Xing et al.,2019;Figure 1C). To prevent the formation of AChR clusters in extrasynaptic sites, and to reduce the risk of tetanic contraction caused by an overstimulation of the muscle, several negative regulators control the clustering pathway and the expression of AChRs on the muscle membrane. regarding the efficacy and safety of different treatment options. Keywords:myasthenia gravis, MuSK, autoantibodies, neuromuscular junction, acetylcholine receptor == Overview == Myasthenia gravis with antibodies against Muscle Specific Kinase myasthenia gravis (MuSK-MG) is an autoimmune disease that impairs transmission at the neuromuscular junction (NMJ), leading to generalized weakness and Homocarbonyltopsentin fatigability of skeletal muscles. MuSK-MG represents an important subgroup of autoimmune myasthenia affecting 570% of patients (depending on geographical location) who are negative for the more common antibodies against the acetylcholine receptor (AChR; Hoch et al.,2001; Vincent and Leite,2005). Compared to the form with AChR antibodies, MuSK-MG differs in terms of epidemiology, clinical features, pathogenic mechanisms, and response to treatment. Autoantibodies, which are mainly of the monovalent IgG4 subclass, target and block the function of MuSK, a tyrosine kinase located on the muscle post-synaptic membrane, disrupting a finely tuned pathway that regulates the development and maintenance of high-density clusters of AChRs at the NMJ. IgG1, 2 and 3 MuSK antibodies are also shownin vitroto be potentially pathogenic but their mechanismsin vivohave not been identified. The following review will describe the clinical and pathophysiological features of MuSK-MG, focusing on the effect of the autoantibodies on the AChR clustering pathway, and the main principles of diagnosis and treatment. == Epidemiology == Several epidemiological studies have been carried out since MuSK antibodies were discovered in 2001 (Hoch et al.,2001) and the incidence of MuSK-MG appears to Homocarbonyltopsentin vary widely across countries (Vincent et al.,2008). Therefore, the Homocarbonyltopsentin general prevalence of the disease is difficult to estimate due to this variability. Mediterranean countries, especially Italy, Turkey, and Greece, present the highest frequency of MuSK-MG (Evoli et al.,2003; Tsiamalos et al.,2009). On the other hand, prevalence appears to be lower among those populations that live at northern latitudes (Niks et al.,2007; Vincent et al.,2008) and higher in people of Afro-American origin (Oh et al.,2009). Considering this particular ethnic-geographical distribution, together with the association with HLA class II DR14 DQ5 (Niks et al.,2006; Bartoccioni et al.,2009; Alahgholi-Hajibehzad et al.,2013), genetic background is likely to play a significant part in the etiology of MuSK-MG although otherand still undeterminedenvironmental factors are likely to be involved. Association with thymus pathology (either thymic hyperplasia or thymoma) offers only hardly ever been reported and this has a direct implication on restorative management of individuals as thymectomy is not indicated in the current medical practice (Marx et al.,2013; Clifford et al.,2019). MuSK-MG affects predominantly ladies (up to 9:1 female:male percentage), especially young females in their third decade (Evoli et al.,2003; Guptill et al.,2011) and it is reported hardly ever in elders and children (Pasnoor et al.,2010; Skjei et al.,2013). This is in contrast with the distribution of AChR-MG in which an increase of incidence in older males has been observed over the last few decades (Carr et al.,2010). == Clinical Features == Like additional diseases that impact neuromuscular transmission, the main medical characteristic of MuSK-MG is the fluctuating weakness and fatigability of the skeletal muscle tissue, which improve with rest and get worse after exercise. However, a analysis Homocarbonyltopsentin of MuSK-MG can be demanding as clinical indications of the CDC42 disease, and pattern of muscle mass involvement can differ in several.