Neuromuscular junction disease

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Neuromuscular junction disease
Classification and external resources
MeSH D020511

Neuromuscular junction disease is a medical condition where the normal conduction through the neuromuscular junction fails to function correctly.

Neuromuscular junction diseases[edit]

The neuromuscular junction is a specialized synapse between a neuron and the muscle it innervates. It allows efferent signals from the nervous system to contact muscle fibers causing them to contract. In vertebrates, the neuromuscular junction is always excitatory, therefore to stop contraction of the muscle, inhibition must occur at the level of the efferent motor neuron. In other words the inhibition must occur at the level of the spinal cord.

Release of acetylcholine vesicles from the presynaptic terminal occurs only after adequate depolarization of the efferent nerve. Once a motor nerve action potential reaches the presynaptic nerve terminal it causes an increase in intracellular calcium concentration by causing an increase in ion conductance through voltage gated calcium channels. This increase in calcium concentration allows the acetylcholine vesicles to fuse with the plasma membrane at the presynaptic membrane, in a process calledexocytosis, thus releasing acetylcholine into the synapse. Once acetylcholine is present in the synapse it is able to bind to nicotinic acetylcholine receptors increasing conductance of certain cations, sodium and potassium in the postsynaptic membrane and producing an excitatory end plate-current. As cations flow into the postsynaptic cell, this causes a depolarization, as the membrane voltage increases above normal resting potential. If the signal is of sufficient magnitude, than an action potential will be generated post synaptically. The action potential will propagate through the sarcolemma to the interior of the muscle fibers eventually leading to an increase in intracellular calcium levels and subsequently initiating the process of Excitation–contraction coupling. Once coupling begins it allows the sarcomeres of the muscles to shorten, thus leading to the contraction of the muscle.

Neuromuscular junction diseases are a result of a malfunction in one or more steps of the above pathway. As a result normal functioning can be completely or partially inhibited, with the symptoms largely presenting themselves as problems in mobility and muscle contraction as expected from disorders in motor end plates. Neuromuscular junction diseases can also be referred to as end plate diseases or disorders.

Among neuromuscular diseases some can be autoimmune disease, or hereditary disorders. They can affect either presynaptic mechanisms or postsynaptic mechanisms, preventing the junction from functioning normally. The most studied diseases affecting the human acetylcholine receptor are Myasthenia Gravis and some forms of congenital Myasthenic Syndrome. Other diseases include the Lambert-Eaton syndrome and botulism.

History[edit]

Before 1921, the mechanism of the neuromuscular junction was largely uncertain, physiologists disagreed as to whether transmission across synapses was electrical or biochemical. Otto Loewi, also referred to as the father of neuroscience shared the noble prize with Henry Dale in 1936 for a discovery he made in 1921. Otto Loewi had formulated an experiment wherein he confirmed that neuronal transmission was chemical. He did this by dissecting two hearts out of frogs. The first was dissected with the vagus nerve that when stimulated causes heart rate to decrease, and the other without the vagus nerve. When he stimulated the vagus nerve of the first heart thus causing it to slow down its heart rate he then transferred some of the liquid bathing that heart and applied to the second heart. This caused the second heart to slow down its beat as well, signifying that transmission across neuronal synapses must be chemical.

The discovery of chemical transmission in 1921 paved the way for modern understanding of neuronal to muscle transmission and our knowledge of the subject has taken huge leaps in the past 90 years allowing us to diagnose differences in diseases in the junction, to study the structure and function of acetylcholine receptors on the post synaptic membrane and intimately analyze the mechanisms of the pathway that allows us to maintain motor control over extrinsic muscle groups.

Following the breakthrough made by Otto Loewi in 1921, several studies pushed the envelope on discovering the mechanism occurring at the neuromuscular junction. With the knowledge that acetylcholine was an integral part of the system scientists began to dig further into the controversy this junction had provided.

Below is a summary of the events and studies that grew to be landmark discoveries in the process of demystifying this subject.
Up until the 1950s some issues were still not clarified. Especially how acetylcholine was liberated and why, how it was transported and the manner that it caused the current to be transferred through the motor end plate. Quotes from the textbook of physiology written by Fulton in 1949 can reveal some of the knowledge present at the time.

  • "How the nerve impulse produces the end-plate potential has not been settled..."
  • "The electrical theory holds that currents from... nerve terminals are adequate to set up the end-plate potential..."
  • "The chemical theory holds that the transmitter is acetylcholine..."
  • "Nachmansohn … proposes that acetylcholine is liberated in the (muscle) end-plate by... current from the nerve ending."[1][2]

In their 1951 work, Fatt and Katz suggested that the release of acetylcholine from the presynaptic membrane largely caused the increase in conductance for ions to permeate through on the post synaptic membrane.[3] Combining the ideas from that journal entry with an entry written four years later, two important conclusion were drawn. First, acetylcholine function behaved independently from electrical excitation, using unique receptors in its reactions across the synapse.[4] Second, the authors of these articles also deduced from statistically analyzing the circuits involved that the end plate potential formed a non-linear relationship with the amount of quanta that was released.[4] The next important step in discovering the process occurring at the NMJ, was support for the hypothesis that transmission across the synapse occurred via vesicles enclosing the acetylcholine.[5]

This allowed further studies to develop studying quantal analysis of miniature electric post synaptic potentials and the relationship with acetylcholine release. These studies came in from multiple sources: (Castillo, Katz 1954, 1955), (J.C.Eccles 1945), (M.J.Dennis, K.Miledi 1974) and (A.W.Liley 1956).

All these studies confirmed our current knowledge of motor end plate transmission, and quantified the release of transmitters across the neuromuscular junction. Fatt and Katz provided what some consider to be the most important pieces of the puzzle, catalyzing investigation into the subject. They answered questions previously puzzling the scientific community and put forward new insights that questioned scientists even further.[2]

Basis of neuromuscular junction function[edit]

Motor nerve properties[edit]

Skeletal muscle fibers are innervated by motor neuron arriving from the anterior horn of the spinal cord. They are usually myelinated and the action potential traverses the axons using salutatory conduction to achieve speed in transmission and decreasing current loss during transmission. At the distal ends of these motor nerves the fibers branch into many thousands of thinner fibers. In mature mammalian muscle each single muscle fiber is innervated by only one nerve terminal. However it has been found that the “extra ocular muscles, tensor tympani, stapedius, some laryngeal muscles and some muscles in the tongue contain fibers with multiple muscle synaptic contacts”.[6]

The nerve terminal[edit]

Acetylcholine is stored in vesicle in the presynaptic membrane. They are usually aligned at higher concentrations near release sites, called active zone. This is the site will the fusion of the vesicles and the plasma membrane will allow the release of the neurotransmitter into the synapse. The post synaptic membrane has many folds in which acetylcholine receptors are located in high concentrations. The distance between across the synapse is between 20 nm to 60 nm.CITATION
The release of the transmitter require calcium influx through channels that are present at high densities at the active zones. The vesicles undergo a process usually described as docking, followed by priming and then finally fusion and release of contents into the synapse. For this process an assembly of normally functioning proteins is essential for the release of acetylcholine into the synapse. The influx of calcium in the presynaptic cell triggers the completion of the assembly reaction. It interacts with synaptotagmin, the calcium sensor and an assembled SNARE complex. SNAP-25, and syntaxin-1 are essential proteins in this process as they form the precursor intermediate complex, later incorporating synaptobrevin-2. Eventually through mechanisms that are still considered theory today the SNARE complex allows the vesicles to fuse and release its contents. More importantly it is important to recognize the conserved components of this fusion machinery, namely SNARE’s, Munc19/nSec1, and Rab3 which are all critically involved in the synaptic vesicle exocytosis process. Therefore these proteins also serve as possible points of malfunction in neuromuscular junction diseases. .[7]
After releasing their contents into the synaptic cleft, synaptic vesicle membrane seems to follow one of three processes to accomplish recycling. The first involves synaptic vesicles completely fusing with the plasma membrane, followed by recycling of membrane components via a clathrin-dependent mechanism. The vesicles first lose their coat of clathrin and move into the interior of the nerve terminal. They are then fused with endosomes and new vesicles bud from this process. As the new vesicles accumulate acetylcholine through active transport and translocate back to the active zones by diffusion or via a cytoskeletal movement. This is important since several of the synaptic vesicle-associated proteins are target for proteolytic cleavage by botulinum toxins.[6] Synaptic vesicles may also recycle through the “kiss and run” mechanism or the “kiss and stay” mechanism.[8] The former two are much faster mechanisms and are predicted to be less present at the neuromuscular junction.[6]

Postsynaptic structure[edit]

Post synaptically the membrane is folded into secondary synaptic folds with a concentration of around 20,000 receptors per micrometer.[9] There is also a large decrease in receptor density moving away from the end plate, which can be up to one thousand times lower. This emphasizes the importance and necessity of the nicotinic receptors in the mechanism to ensure transmission of the signal from the nerve to the muscles. The acetylcholine receptor belongs to a large superfamily of neurotransmitter receptors, called Cys-loop receptors. It is a ligand gated ion channel composed of five protein subunits symmetrically arranged with an opening through the middle. Acetylcholine binds to the N termini of each of the two alpha subunits results in a change in the conformation of the receptor. This allows the diffusion of sodium and potassium across its membrane.[10]

Classification[edit]

There are two ways to classify neuromuscular diseases. The first relies on its mechanism of action, or how the action of the diseases affects normal functioning (whether it is through mutations in genes or more direct pathways such as poisoning). This category divides neuromuscular diseases into three broad categories: immune-mediated disease, toxic/metabolic and congenital syndromes.

The second classification method divides the diseases according to the location of their disruption. In the neuromuscular junction, the diseases will either act on the presynaptic membrane of the motor neuron, the synapse separating the motor neuron from the muscle fiber, or the postsynaptic membrane (the muscle fiber).

Immune-mediated[edit]

Immune-mediated diseases include a variety of diseases not only affecting the neuromuscular junction. Immune-mediated disorders range from simple and common problems such as allergies to disorders such as HIV/AIDS. Within this classification, autoimmune disorders are considered to be a subset of immune-mediated syndromes. Autoimmune diseases occur when the body's immune system begins to target its own cells, often causing harmful effects.

The neuromuscular junction diseases present within this subset are myasthenia gravis, and Lambert-Eaton syndrome.[11] In each of these diseases, a receptor or other protein essential to normal function of the junction is targeted by antibodies in an autoimmune attack by the body.

Toxic/metabolic[edit]

Metabolic diseases are usually a result of abnormal functioning of one of the metabolic processes required for regular production and utilization of energy in a cell. This can occur by damaging or disabling an important enzyme, or when a feedback system is abnormally functioning. Toxic diseases are a result of a form of poison that effects neuromuscular junction functioning. Most commonly animal venom or poison, or other toxic substances are the origin of the problem.

Neuromuscular junction diseases in this category include snake venom poisoning, botulism, arthropod poisoning, organophosphates and hypermagnesemia.[12] Organophosphates are present in many insecticides and herbicides. They are also the basis of many nerve gases.[13] Hypermagnesmia is a condition where the balance of magnesium in the body is unstable and concentrations are higher than normal baseline values.[14]

Congenital[edit]

Congenital syndromes affecting the neuromuscular junction are considered a very rare form of disease, occurring in 1 out of 200,000 in the United Kingdom.[15] These are genetically inherited disorders. Symptoms are seen early since the affected individuals carry the mutation from birth. Congenital syndromes are usually classified by the location of the affected gene products. Congenital syndromes can have multiple targets affecting either the presynaptic, synaptic or postsynaptic parts of the neuromuscular junction.[16] For example, if the malfunctioning or inactive protein is acetylcholinesterase, this would be classified as a synapse congenital syndrome.[15]

Presynaptic[edit]

The diseases that act on the presynaptic membrane are autoimmune neuromyotonia, Lambert-Eaton syndrome, congenital myasthenia gravis and botulism.[17] All of these disorders negatively affect the presynaptic membrane in some way. Neuromyotonia causes antibodies to damage the normal function of potassium rectifier channels, while Lambert-Eaton syndrome causes antibodies to attack presynaptic calcium channels.[18] Congenital myasthenia gravis is a large group of diseases, since the genetic defects can affect any point in the chain of events leading to successful transmission across the junction. One discovered type of congenital myasthenia gravis can affect the junction presynaptically by a mutation in the gene encoding choline acetyl transferase.[15] This protein is an enzyme that is responsible for catalyzing the reaction that combines acetyl-coenzyime A with choline, yielding acetylcholine.[19]

There are many mechanisms through which presynaptic function can be impaired. Most often this causes a decrease in the release of acetylcholine. It can also impair vesicle exocytosis by interfering with the complex guiding vesicle fusion and release of contents. Mechanism of action can also impair the calcium channels that induce exocytosis of the vesicles. Other ion channels can also be disrupted, such as the potassium channels causing inefficient repolarization at the presynaptic membrane as in neuromyotonia.[17]

Synapse[edit]

At the synaptic cleft, the neurotransmitter normally diffuses across the synapse to eventually contact postsynaptic receptors. However, after exiting the presynaptic membrane, the neurotransmitters can be hindered by a subset of diseases that interfere with the transmission of the neurotransmitter across the synapse. The mechanism currently known that operates via the synaptic cleft causing impairment of normal functioning is another congenital myasthenia gravis.[18] This mechanism is the only currently known disease that acts on the synapse.[20] It acts by impairing the function of the enzyme that breaks down acetylcholine causing it to become very hypertonic at the synapse.[20] This increase in acetylcholine in the synapse disrupts normal functioning of the junction,.[21][22]

Postsynaptic[edit]

The highest number of diseases affect the neuromuscular junction postsynaptically. In other words, it is the most susceptible to negative intervention.[18] The targets of these postsynaptic diseases can be multiple different proteins. Immune mediated Myasthenia Gravis being the most common, effecting the acetylcholine receptors at the post synaptic membrane.[23] All the diseases that affect the postsynaptic membrane are forms of myasthenia gravis.[17] Here is a list of the diseases: Myasthenia Gravis, Neonatal Myasthenia Gravis, Drug Induced Myasthenia Gravis and several types of Congenital myasthenia where the product of the mutated gene is a postsynaptic protein.[24]

Most common diseases[edit]

Myasthenia gravis[edit]

Myasthenia gravis is the most common neuromuscular disease affecting function of the end plate in patients. It is present in 100 people out of 1,000,000 in the population, and its onset is usually in either younger or older individuals.[25]

Acquired myasthenia gravis is the most common neuromuscular junction disease.[18] Important observations were made by Patrick and Lindstrom in 1973 when they found that antibodies attacking the acetylcholine receptors were present in around 85% of cases of myasthenia gravis.[26][27] The remaining diseases were also a result of antibody attacks on vital proteins, but instead of the acetylcholine receptor, the culprits were MuSK, a muscle-specific serum kinase, and lipoprotein receptor-related protein.[27] So these mechanisms describe myasthenia gravis that is acquired, and not congenital, affecting the these vital proteins by an immunological response against self-antigens. The cases not caused by antibodies against the acetylcholine receptors became by convention called seronegative myasthenia gravis.[28] The term seronegative came about because scientists would be testing for acetylcholine receptor antibodies in patients that had myasthenia gravis resulting in negative tests in the serum. This does not imply that there are no antibodies present, but this terminology only became present because scientists were testing for the wrong antigen.[27][29]

Neonatal myasthenia gravis is a very rare condition in which a mother with myasthenia gravis passes down her antibodies to her infant through the placenta, causing the it to be born with antibodies that will attach self-antigens.[20]

Drug-induced myasthenia gravis is also a very rare condition in which pharmacological drugs cause a blockade or disruption of the NMJ machinery.[20] Robert W. Barrons summarizes the possible causes of drug-induced myasthenia gravis: "Prednisone was most commonly implicated as aggravating myasthenia gravis, and D-penicillamine was most commonly associated with myasthenic syndrome. The greatest frequency of drug-induced neuromuscular blockade was seen with aminoglycoside-induced postoperative respiratory depression. However, drugs most likely to impact myasthenic patients negatively are those used in the treatment of the disease. These include overuse of anticholinesterase drugs, high-dose prednisone, and anesthesia and neuromuscular blockers for thymectomy."[30]
.

Lambert-Eaton myasthenic syndrome (LEMS)[edit]

Lambert-Eaton myasthenic syndrome (LEMS) is similar to myasthenia gravis in that it is an immune-mediated response acting against a specific protein in the neuromuscular junction. The difference is that LEMS is a result of an autoimmune response on the voltage gated calcium channels of the presynaptic membrane.[25] The antibodies attack the voltage gated calcium channels of the P/Q type.[23] Abnormal activity of this ion channel, which usually causes the initiates the process of acetylcholine vesicles from the presynaptic membrane once the membrane is sufficiently depolarized, causes less acetylcholine to be released into the synapse.[20] LEMS is about 20 times more rare than myasthenia gravis.[31]

LEMS also differs from myasthenia gravis in that it is usually associated with small-cell lung cancer, which is present in 60% percent of patients.[31] It seems that as cancer develops, the body will begin to develop antibodies against the cancer, and in some cases the antibodies can also attack the calcium channels present at the presynaptic membrane.[20] In the cases where no cancer is present in the patient, there is usually an underlying different autoimmune disease which causes the immune system to become hyperactive attacking its own antigens.[31]

Other diseases[edit]

Neuromyotonia[edit]

Neuromyotonia is classified into three types.[25] The most common form of this disease is acquired neuromyotonia, which is the result of an autoimmune attack on rectifier voltage-gated potassium channels.[20] This causes the presynaptic membrane to remain hyperpolarized, making it difficult for adequate depolarizations to occur.[17]

Congenital myasthenia[edit]

This is the most complex and diverse congenital myasthenic syndrome.[15] Since this is a genetic disorder, there are infinite possibilities of genes that could be mutated in different ways that could disrupt normal functioning of the neuromuscular junction. Around 11 gene targets have been specified.[32] Its prevalence in the population is very difficult to measure since it is a rare genetic disorder that presents itself as a neuromuscular junction disorder, but in the United Kingdom, estimates are 1 in 200,000 of the population.[15] The major signs that indicate a congenital syndrome are symptoms present at birth, such as weakness and a depressive response to repetitive nerve stimulation.[15]

Since the disease is genetic in nature and is not immune-mediated, any serum test will show up negative since congenital myasthenia is not a result of antibodies attacking the vital proteins of the NMJ.[18] Knowledge of this disease is very plastic as new genes that could be effected could be discovered as we gain more insight into the different types.

Botulism[edit]

Neurotoxin may act on the neuromuscular junction either post synaptically or presynaptically as there are several different forms of toxins that the NMJ is sensitive to.[25] Common mechanisms of action include blockage of acetylcholine release at the synapse thus causing the NMJ to become abnormal in function.[20]

Detection[edit]

Common symptoms[edit]

Tests[edit]

  • Repetitive nerve stimulation
  • Electromyography (EMG)
  • Nerve conduction studies
  • Exercise testing
  • Single-fiber EMG

Treatment[edit]

Symptomatic treatment[edit]

Cholinesterase inhibitors at AChR

Immunosuppressive treatment[edit]

  • Thymectomy
  • Medical therapy: corticosteroids, non-streroidal immunosuppression
  • Short-term treatment: plasmapherisis, IVIG

Trivalent botulinum antitoxin[edit]

References[edit]

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