Autoimmune Channelopathies at Neuromuscular Junction

Abstract

The neuromuscular junction, also called myoneural junction, is a site of chemical communication between a nerve fiber and a muscle cell. There are many types of channels at neuromuscular junction that play indispensable roles in neuromuscular signal transmission, such as voltage-gated calcium channels and voltage-gated potassium channels on presynaptic membrane, and acetylcholine receptors on post-synaptic membrane. Over the last two decades, our understanding of the role that autoantibodies play in neuromuscular junction disorders has been greatly improved. Antibodies against these channels cause a heterogeneous group of diseases, such as Lambert-Eaton syndrome, Isaacs' syndrome and myasthenia gravis. Lambert-Eaton syndrome is characterized by late onset of fatigue, skeletal muscle weakness, and autonomic symptoms. Patients with Isaacs' syndrome demonstrate muscle cramps and fasciculation. Myasthenia gravis is the most common autoimmune neuromuscular junction channelopathy characterized by fluctuation of muscle weakness. All these disorders have a high risk of tumor. Although these channelopathies share some common features, they differ for clinical features, antibodies profile, neurophysiological features, and treatments. The purpose of this review is to give a comprehensive insight on recent advances in autoimmune channelopathies at the neuromuscular junction.

Keywords: Isaacs' syndrome; Lambert-Eaton syndrome (LEMS); channelopathies; myasthenia gravis (MG); neuromuscular junction (NMJ).

Figure 1

Synaptic ultrastructure at the NMJ. A representative electron micrograph of a human NMJ synapse. Asterisks represent the synaptic cleft.

Figure 2

Channels and channelopathies at NMJ. NMJ channels and their associated human diseases are indicated in green and blue letters, respectively. The entry of calcium ions (Ca²⁺) through VGCCs depolarize the nerve terminal, resulting in the release of ACh from synaptic vesicles into synaptic cleft. In repolarization process, potassium ions (K⁺) leak out to the extracellular through VGKCs, accompanied by a recovery of resting potential and a halt of substantial ACh release. Diffused ACh are captured by AChR leading to muscle contraction. LEMS and Isaacs' syndrome are caused by antibodies against VGCCs and VGKCs, respectively. MG is mainly caused by antibodies against AChR, MuSK, and LRP4.