Abstract
Muscle Specific Kinase myasthenia gravis (MuSK-MG) is an autoimmune disease that impairs neuromuscular transmission leading to generalized muscle weakness. Compared to the more common myasthenia gravis with antibodies against the acetylcholine receptor (AChR), MuSK-MG affects mainly the bulbar and respiratory muscles, with more frequent and severe myasthenic crises. Treatments are usually less effective with the need for prolonged, high doses of steroids and other immunosuppressants to control symptoms. Under physiological condition, MuSK regulates a phosphorylation cascade which is fundamental for the development and maintenance of postsynaptic AChR clusters at the neuromuscular junction (NMJ). Agrin, secreted by the motor nerve terminal into the synaptic cleft, binds to low density lipoprotein receptor-related protein 4 (LRP4) which activates MuSK. In MuSK-MG, monovalent MuSK-IgG4 autoantibodies block MuSK-LRP4 interaction preventing MuSK activation and leading to the dispersal of AChR clusters. Lower levels of divalent MuSK IgG1, 2, and 3 antibody subclasses are also present but their contribution to the pathogenesis of the disease remains controversial. This review aims to provide a detailed update on the epidemiological and clinical features of MuSK-MG, focusing on the pathophysiological mechanisms and the latest indications regarding the efficacy and safety of different treatment options.
Highlights
Muscle Specific Kinase myasthenia gravis (MuSK-MG) is an autoimmune disease that impairs neuromuscular transmission leading to generalized muscle weakness
This review aims to provide a detailed update on the epidemiological and clinical features of MuSK-MG, focusing on the pathophysiological mechanisms and the latest indications regarding the efficacy and safety of different treatment options
MuSK Myasthenia Gravis: An Update 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 acetylcholine receptor (AChR) at the neuromuscular junction (NMJ)
Summary
Like other diseases that affect neuromuscular transmission, the main clinical characteristic of MuSK-MG is the fluctuating weakness and fatigability of the skeletal muscles, which improve with rest and worsen after exercise. Proximal limb involvement can be mild or even absent while respiratory distress and other bulbar symptoms, such as difficulties in swallowing, chewing, and speaking, can be severe and rapidly progressive. The misinterpretation of these symptoms, which could support a diagnosis of a primary myopathy or motor neuron disorder (Huijbers et al, 2016), may contribute to a delay in the recognition and treatment of MuSK-MG patients. The weakness of neck and axial muscles is usually associated with bulbar symptoms and, in patients with a long history of severe disease, facial and tongue atrophy represents a common finding (Evoli et al, 2003; Farrugia et al, 2006b). It is clinically associated with non-fluctuating weakness, myopathic changes in the electrophysiology recordings, and fatty tissue infiltration at the muscle MRI scans
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