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Special Communication |

The Future of Research in Myasthenia

David P. Richman, MD1
[+] Author Affiliations
1Department of Neurology and Center for Neuroscience, University of California, Davis
JAMA Neurol. 2015;72(7):812-814. doi:10.1001/jamaneurol.2014.4740.
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This Special Communication reports on the latest research in myasthenia, which results from dysfunction of the neuromuscular synapse (ie, the neuromuscular junction), causing clinical “fatigue” that is defined as muscle weakness that worsens with muscle use and improves with rest.

Myasthenia results from dysfunction of the neuromuscular synapse (ie, the neuromuscular junction [NMJ]), causing clinical “fatigue,” which is defined as muscle weakness that worsens with muscle use and improves with rest. Electrodiagnostic testing demonstrates either decremental compound muscle action potentials in response to repetitive nerve stimulation at slow rates, generally 2 to 3 Hz, or increased synaptic jitter measured by single fiber electromyography. The majority of the myasthenic disorders result from dysfunction of the postsynaptic component of the NMJ, although involvement of either the synaptic cleft or the presynaptic motor nerve terminal can occasionally produce myasthenia.

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Neuromuscular Junction

A, In a mature neuromuscular junction, motor axonal action potentials mediated by voltage-gated sodium and potassium channels (VGSC and VGKC, respectively) activate nerve terminal voltage-gated calcium channels (VGCCs). Calcium influx initiates the release of vesicular acetylcholine (ACh), which diffuses across the synaptic cleft and binds to the tightly packed ACh receptor (AChR) located on the peaks of the folds of the end-plate membrane. This process activates the receptor’s ligand-gated ion channel, leading to depolarization of the end-plate membrane. The depolarization activates the muscle VGSC, initiating a muscle action potential. Acetylcholine is then hydrolyzed by acetylcholinesterase (AChE) in the muscle basal lamina. B, In the developing neuromuscular junction, the motor axonal growth cone releases agrin into the intercellular matrix when it reaches a developing myotube. Agrin binds to lipoprotein receptor-related protein 4 (lrp4), and the complex binds to muscle-specific kinase (MuSK), resulting in activation of MuSK, which self-phosphorylates and then initiates a series of phosphorylations beginning with DOK7 and ending with rapsyn and the δ subunit of AChR. This process induces AChR clustering, the first step in the development of both the postsynaptic and presynaptic portions of the mature neuromuscular junction. The agrin-lrp4-MuSK interaction also appears to be required for maintenance of the mature synapse. P indicates phosphate.

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