The Role of Mutations on HLA Genes in Lambert-Eaton Myasthenic Syndrome

Lambert-Eaton myasthenic syndrome (LEMS) is a rare presynaptic disorder of neuromuscular transmission in which quantal release of acetylcholine (ACh) is impaired, causing a unique set of clinical characteristics, which include proximal muscle weakness, depressed tendon reflexes, posttetanic potentiation, and autonomic changes. [1] The initial presentation can be similar to that of myasthenia gravis (MG), but the progressions of the 2 diseases have some important differences. LEMS disrupts the normally reliable neurotransmission at the neuromuscular junction (NMJ). This disruption is thought to result from an autoantibody-mediated removal of a subset of the P/Q-type Ca2+ channels involved with neurotransmitter release.

Neuromuscular Junction Disorders

The neuromuscular junction (NMJ) is a critical component of the motor unit that is made up of the distal, unmyelinated nerve terminal, synaptic space, and end-plate region of the muscle fiber. Contraction of muscle fiber involves a coordinated series of steps that ultimately generates an action potential at the muscle end plate (also known as an end-plate potential). Normally the end-plate potential substantially exceeds the threshold necessary to trigger an action potential in the muscle fiber, and this difference is termed the safety factor of neuromuscular transmission. Disorders that affect the NMJ reduce this safety factor, a change that results in fatigable weakness.

Chemotherapy-Induced Peripheral Neuropathy: Mechanisms and Clinical Assessment

Antineoplastic drugs may be neurotoxic and the clinical features frequently include distal sensory loss and neuropathic pain. This is related to a direct damage in sensory neurons and non-selective degeneration of sensory nerve fibers. Due to different mechanisms, there are agents that affects also motor or autonomic nerves. In the case of immune checkpoint inhibitors, an inflammatory response attacks the muscle, motor neurons or neuromuscular transmission. We present an easy-to-read article to understand first symptoms of chemotherapy-induced neuropathy (CIN) with describing each agent and the course of neuropathy as well as the clinical assessment with neurophysiological techniques. In addition, skin biopsy allows us to examine histological changes such as reinnervation. Neuroprotection with antioxidant therapy is possible but more effort in this field is needed.

DYNAMICS OF NEUROMUSCULAR TRANSMISSION REPRODUCED BY CALCIUM-DEPENDENT SERIAL TRANSITIONS IN THE VESICLE FUSION COMPLEX

Neuromuscular transmission, from spontaneous release to facilitation and depression was accurately reproduced by a mechanistic kinetic model of sequential maturation transitions in the molecular fusion complex. The model incorporates three predictions. First, sequential calcium-dependent forward transitions take vesicles from docked to pre-primed to primed states, followed by fusion. Second, pre-priming and priming are reversible. Third, fusion and recycling are unidirectional. The model was fed with experimental data from previous studies while the backward (β) and recycling (ρ) rate constant values were fitted. Classical experiments were successfully reproduced when every forward (α) rate constant had the same value, and both backward rate constants were 50-100 times larger. Such disproportion originated an abruptly decreasing gradient of resting vesicles from docked to primed states. Simulations also predict that: i. Spontaneous release reflects primed to fusion spontaneous transitions. ii. Calcium elevations synchronize the series of forward transitions that lead to fusion. iii Facilitation reflects a transient increase of priming following calcium-dependent transitions. iv. Backward transitions and recycling restore the resting state. v. Depression reflects backward transitions and slow recycling after intense release. Such finely-tuned kinetics offers a mechanism for collective non-linear transitional adaptations of a homogeneous vesicle pool to an ever-changing pattern of electrical activity.

Appraisal of a novel pedagogical approach to demonstrating neuromuscular transmission to medical students

Although traditional didactic lecturing is the principal instructional approach used in numerous medical schools, this method has several limitations. Experiential learning approaches place students in the center of the learning process and creates a positive and supportive classroom learning environment. In this article, we propose an active pedagogical approach for teaching a basic physiology concept, namely, neuromuscular transmission (NMT), and we evaluate the effectiveness of this approach among undergraduate medical students. One-hundred forty-two undergraduate medical students were involved in this study ( cohort A, n = 62; cohort B, n = 80). Cohort A received a didactic lecture on NMT and subsequently tested their knowledge of the topic via test 1, after which their perceptions of didactic lectures were recorded. The students were then asked to participate in a touch-and-go (TAG) active-learning session regarding NMT, after which their learning was subsequently tested by taking test 2. Their perceptions about the TAG game were also recorded. Students in cohort B were first administered test 1 regarding NMT. Then, they were asked to attend a didactic lecture blended with a TAG active-learning session, after which test 2 was administered, and their perceptions were recorded. Both the didactic lecture and active learning sessions facilitated student learning regarding the concepts involved in NMT. A comparison of the lecture followed by the game used in cohort A with the game blended lecture used in cohort B revealed no significant differences. However, both formats created a positive influence on students’ interest in learning the concept, and the students preferred active learning over didactic sessions alone.

Presynaptic Paraneoplastic Disorders of the Neuromuscular Junction: An Update

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.

The Safety Factor for Neuromuscular Transmission: Effects of Dimethylsulphoxide, Cannabinoids and Synaptic Homeostasis

Background In myasthenia gravis, impaired postsynaptic sensitivity to acetylcholine results in failure of neuromuscular transmission and fatiguing muscle weakness. Objective Develop an ex vivo muscle contraction assay to test cannabinoids and other substances that might act on the myasthenic neuromuscular junction to restore control of the muscle. Methods Tubocurarine was added to an ex vivo, mouse phrenic nerve-hemidiaphragm muscle preparation to reduce acetylcholine sensitivity. This produced a myasthenia-like decrement in twitch force during a train of 10 nerve impulses (3 / sec). Endplate potential (EPP) recordings were used to confirm and extend the findings. Results Surprisingly, addition to the bath of dimethylsulphoxide (DMSO), at concentrations as low as 0.1%(v/v), partially reversed the decrement in nerve-evoked force. Intracellular electrophysiology, conducted in the presence of tubocurarine, showed that DMSO increased the amplitudes of both the spontaneous miniature EPP (MEPP) and the (nerve-evoked) EPP. In the absence of tubocurarine (synaptic potentials at physiological levels), an adaptive fall in quantal content negated the DMSO-induced rise in EPP amplitude. The effects of cannabinoid receptor agonists (solubilized with DMSO) in the contraction assay do not support their further exploration as useful therapeutic agents for myasthenia gravis. CP 55,940 (a dual agonist for cannabinoid receptor types 1 and 2) reversed the beneficial effects of DMSO. Conclusions: We demonstrate a powerful effect of DMSO upon quantal amplitude that might mislead pharmacological studies of synaptic function wherever DMSO is used as a drug vehicle. Our results also show that compounds targeting impaired neuromuscular transmission should be tested under myasthenic-like conditions, so as to avoid confounding effects of synaptic homeostasis.