Muscle-Specific Kinase Myasthenia Gravis

Abstract

Thirty to fifty percent of patients with acetylcholine receptor (AChR) antibody (Ab)-negative myasthenia gravis (MG) have Abs to muscle specific kinase (MuSK) and are referred to as having MuSK-MG. MuSK is a 100 kD single-pass post-synaptic transmembrane receptor tyrosine kinase crucial to the development and maintenance of the neuromuscular junction. The Abs in MuSK-MG are predominantly of the IgG4 immunoglobulin subclass. MuSK-MG differs from AChR-MG, in exhibiting more focal muscle involvement, including neck, shoulder, facial and bulbar-innervated muscles, as well as wasting of the involved muscles. MuSK-MG is highly associated with the HLA DR14-DQ5 haplotype and occurs predominantly in females with onset in the fourth decade of life. Some of the standard treatments of AChR-MG have been found to have limited effectiveness in MuSK-MG, including thymectomy and cholinesterase inhibitors. Therefore, current treatment involves immunosuppression, primarily by corticosteroids. In addition, patients respond especially well to B cell depletion agents, e.g., rituximab, with long-term remissions. Future treatments will likely derive from the ongoing analysis of the pathogenic mechanisms underlying this disease, including histologic and physiologic studies of the neuromuscular junction in patients as well as information derived from the development and study of animal models of the disease.

Keywords: animal models; muscle specific kinase; myasthenia gravis; neuromuscular junction; pathogenesis; review; treatment.

FIGURE 1

Developing NMJ: The motor axon growth cone releases agrin into the intercellular matrix when it reaches a developing myotube. Agrin binds lrp4 and the complex binds MuSK resulting in activation of MuSK, which self-phosphorylates and then initiates a series of phosphorylations beginning with Dok7 and ending with rapsyn and 8 subunit of AChR. This process induces dense AChR clustering, the first step in the development of both the postsynaptic and presynaptic portions of the mature NMJ. From Richman (66) with permission.

FIGURE 2

Mature NMJ: Motor axon action potentials reach the motor nerve terminal leading to release of vesicles of acetylcholine (ACh), which diffuses across the synaptic clef to bind to the tightly packed acetylcholine receptors (AChR) located on the peaks of the folds of the endplate membrane. After AChR activation, ACh is then hydrolyzed by acetylcholinesterase (AChE) in the muscle basal lamina. VGSC, voltage-gated sodium channels; VGKC, voltage-gated potassium channels; VGCC, voltage-gated calcium channels. From Richman (66) with permission.

FIGURE 3

(A) Photomicrograph (x80) of longitudinal frozen section of diaphragm muscle stained immunohistochemically with alpha-bungarotoxin to label AChR (red) and anti-synapsin plus anti-neurofilament Abs to label presynaptic nerve terminals and axons (green), demonstrating pretzel appearance of endplate membrane. (B) Electron micrograph (×5000) of transverse section of diaphragm muscle neuromuscular junction demonstrating highly folded endplate membrane. [Modified from (63) with permission].

FIGURE 4

MuSK Structure (Modified from 15). FLR, Frizzled-like region.