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Review
. 2021 Aug 3;11(8):1035.
doi: 10.3390/brainsci11081035.

Presynaptic Paraneoplastic Disorders of the Neuromuscular Junction: An Update

Maria Pia Giannoccaro  1   2 , Patrizia Avoni  1   2 , Rocco Liguori  1   2
Affiliations
Review

Presynaptic Paraneoplastic Disorders of the Neuromuscular Junction: An Update

Maria Pia Giannoccaro et al. Brain Sci. .

Abstract

The neuromuscular junction (NMJ) is the target of a variety of immune-mediated disorders, usually classified as presynaptic and postsynaptic, according to the site of the antigenic target and consequently of the neuromuscular transmission alteration. Although less common than the classical autoimmune postsynaptic myasthenia gravis, presynaptic disorders are important to recognize due to the frequent association with cancer. Lambert Eaton myasthenic syndrome is due to a presynaptic failure to release acetylcholine, caused by antibodies to the presynaptic voltage-gated calcium channels. Acquired neuromyotonia is a condition characterized by nerve hyperexcitability often due to the presence of antibodies against proteins associated with voltage-gated potassium channels. This review will focus on the recent developments in the autoimmune presynaptic disorders of the NMJ.

Keywords: CASPR2; Lambert Eaton myasthenic syndrome; immune checkpoint inhibitors; neuromuscular junction; neuromyotonia; paraneoplastic syndrome; presynaptic disorders.

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Conflict of interest statement

M.P.G. and P.A. report no conflicts of interest in this work. R.L. reports personal fees from Argenx, Biogen, Sanofi-Genzyme, Argon Healthcare s.r.l., Amicus Therapeutics s.r.l. and Alfasigma for Advisory Board consultancy and Lecture fees from Dynamicom Education, SIMG Service, Adnkronos Salute Unipersonale s.r.l. and DOC Congress s.r.l., outside the submitted work.

Figures

Figure 3
Figure 3
Pathophysiology of neuromyotonia. (A) Schematic overview of the VGKC complex in the juxtaparanodal region of myelinated axons (modified from [144]). CASPR2, together with contactin-2 and other proteins, is fundamental for clustering Kv1 channels. CASPR2 antibodies could interfere with CASPR2-contactin-2 interaction leading to Kv expression down-regulation with consequent impairment of action potential repolarisation and excessive or prolonged release of acetylcholine. (B) This leads to prolonged EPP and repetitive nerve firing. The EMG shows myokymic discharges (doublets, triplets, and multiplets).
Figure 1
Figure 1
Pathophysiology of LEMS. In normal conditions, the depolarization of the presynaptic nerve terminal leads to calcium ions influx, acetylcholine (ACh) release, and binding to the ACh receptors (AChR) with a consequent influx of positively charged ions, mainly sodium, generation of an endplate potential (EPP) and muscle contraction. In LEMS, voltage gated calcium channel (VGCC) antibodies block calcium influx causing a reduction of the ACh released at the presynaptic terminal with consequent reduction of the EPP amplitude. High-frequency repetitive nerve stimulation however can increase the EPP amplitude through calcium accumulation in the presynaptic terminal and increased ACh release.
Figure 2
Figure 2
Effect of 3,4-diamniopyride treatment in LEMS. 3,4-diaminopyridine (3,4-DAP) blocks the efflux of potassium (K+) prolonging the presynaptic depolarization, which in turn prolongs the VGCCs opening time, allowing the influx of an increased amount of calcium ions with consequently increased ACh release.
See this image and copyright information in PMC

References

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