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Diseases of the Neuromuscular Junction

David Lipsitz, DVM, DACVIM (Neurology)

Veterinary Specialty Hospital, San Diego, CA, USA

The neuromuscular junction (NMJ) consists of the amount of ACh released and the amount of nAChRs but
efferent nerve terminals, the neuromuscular cleft, and there is normally an abundance of both, resulting in a
the postsynaptic membrane. As an action potential large safety factor for neuromuscular transmission.
reaches the presynaptic nerve terminal, voltage‐gated Acetylcholinesterase then breaks down the ACh (pro-
2+
calcium channels open, allowing Ca ion efflux into the ducing choline and esterase) and the ACh diffuses away
2+
presynaptic nerve terminal. This Ca influx allows syn- from the synapse, allowing the sodium channels to close.
aptic vesicles containing neurotransmitter to dock and New ACh molecules are synthesized when the choline
fuse with the sarcolemma in the process of exocytosis, is transported, through reuptake into the presynaptic
thereby releasing the neurotransmitter acetylcholine terminal.
(ACh) into the synaptic cleft. Fusion of the vesicular The clinical presentation in animals with neuromus-
and plasma membranes is mediated by SNARE (soluble cular transmission disease is very similar regardless of
N‐ethylmaleimide‐sensitive fusion) proteins. Some of whether the disorder is presynaptic (i.e., botulism) or
the SNARE proteins that are used for synaptic vesicle postsynaptic (i.e., myasthenia gravis). There is usually a
exocytosis include synaptobrevin (VAMP1), syntaxin 1a, symmetric progressive generalized weakness in all limbs.
and synaptosome‐associated protein 25 (SNAP‐25). Exercise intolerance is often seen as well. Tendon reflexes
These SNARE proteins may be the target of many disease may or may not be intact. There is often facial muscle,
processes and toxins. laryngeal, pharyngeal or esophageal weakness associated
The ACh released from these vesicles then diffuses with these disorders. Sensory function is unaffected, as
through the synaptic cleft and binds to the nicotinic ace- would be expected.
tylcholine receptors (nAChRs) located on the specially
folded postsynaptic muscle fiber sarcolemma. The adult
nACHR has been shown to have four different protein Myasthenia Gravis
subunits (α, β, δ, ε). The receptor is arranged in the fashion
of five subunits: 2 α1, β1, δ, ε. These subunits span the Myasthenia gravis (MG) is a neuromuscular transmis-
lipid bilayer, creating a water‐filled pore which forms a sion disorder caused by a reduction in the number of
“hydrophobic girdle” that acts as a barrier to ion per- functional nAChRs on the postsynaptic membrane. It is
meation. When ACh binds to the receptor, it undergoes usually the result of an acquired autoimmune disease
conformational change that allows a preferential influx and much less commonly a congenital disorder.
of Na+ > Ca++ and an efflux of potassium. This region is
also closely associated with a high density of sodium Clinical Presentation
channels in order to promote and amplify the signal to
assure the propagation of an action potential to generate Myasthenia gravis should be a consideration in any animal
muscle contraction. As the sodium ions move into the being examined for focal or generalized neuromuscular
muscle membrane, local depolarization occurs in what is weakness. The clinical signs may be focal in nature and
termed an endplate potential (EPP) which spreads across limited to esophageal dilation leading to regurgitation,
the surface of the sarcolemma, with the ensuing excita- pharyngeal dysfunction causing dysphagia and laryngeal
tion‐contraction coupling allowing the muscle fiber to paresis/paralysis causing dysphonia (voice change).
contract. The magnitude of the EPP is dependent on the Multiple cranial nerve abnormalities may also occur in

Clinical Small Animal Internal Medicine Volume I, First Edition. Edited by David S. Bruyette.
© 2020 John Wiley & Sons, Inc. Published 2020 by John Wiley & Sons, Inc.
Companion website: www.wiley.com/go/bruyette/clinical