tetanus toxin tetanus toxin, also known as tetanospasmin is a potent neurotoxin produced by clostridium tetani and causes the disease state, tetanus. the ld50 of this toxin has been measured to be approximately 1 ng/kg, making it second only to botulinum toxin d as the deadliest toxin in the world. it functions very similarly to botulinum neurotoxin by attaching and endocytosing into the presynaptic nerve terminal and interfering with snare proteins. it differs from botulinum neurotoxin in a few ways, most apparently in its end state, wherein tetanospasmin causes spastic paralysis as opposed to the flaccid paralysis demonstrated with botulinum neurotoxin. latrotoxin latrotoxin (α-latrotoxin) found in venom of widow spiders also affects the neuromuscular junction by causing the release of acetylcholine from the presynaptic cell. mechanisms of action include binding to receptors on the presynaptic cell activating the ip3/dag pathway and release of calcium from intracellular stores and pore formation resulting in influx of calcium ions directly. either mechanism causes increased calcium in presynaptic cell, which then leads to release of synaptic vesicles of acetylcholine. latrotoxin causes pain, muscle contraction and if untreated potentially paralysis and death. snake venom snake venoms act as toxins at the neuromuscular junction and can induce weakness and paralysis. venoms can act as both presynaptic and postsynaptic neurotoxins. presynaptic neurotoxins, commonly known as β-neurotoxins, affect the presynaptic regions of the neuromuscular junction. the majority of these neurotoxins act by inhibiting the release of neurotransmitters, such as acetylcholine, into the synapse between neurons. however, some of these toxins have also been known to enhance neurotransmitter release. those that inhibit neurotransmitter release create a neuromuscular blockade that prevents signaling molecules from reaching their postsynaptic target receptors. in doing so, the victim of these snake bite suffer from profound weakness. such neurotoxins do not respond well to anti-venoms. after one hour of inoculation of these toxins, including notexin and taipoxin, many of the affected nerve terminals show signs of irreversible physical damage, leaving them devoid of any synaptic vesicles. postsynaptic neurotoxins, otherwise known as α-neurotoxins, act oppositely to the presynaptic neurotoxins by binding to the postsynaptic acetylcholine receptors. this prevents interaction between the acetylcholine released by the presynaptic terminal and the receptors on the postsynaptic cell. in effect, the opening of sodium channels associated with these acetylcholine receptors is prohibited, resulting in a neuromuscular blockade, similar to the effects seen due to presynaptic neurotoxins. this causes paralysis in the muscles involved in the affected junctions. unlike presynaptic neurotoxins, postsynaptic toxins are more easily affected by anti-venoms, which accelerate the dissociation of the toxin from the receptors, ultimately causing a reversal of paralysis. these neurotoxins experimentally and qualitatively aid in the study of acetylcholine receptor density and turnover, as well as in studies observing the direction of antibodies toward the affected acetylcholine receptors in patients diagnosed with myasthenia gravis. diseases main article: neuromuscular junction disease any disorder that compromises the synaptic transmission between a motor neuron and a muscle cell is categorized under the umbrella term of neuromuscular diseases. these disorders can be inherited or acquired and can vary in their severity and mortality. in general, most of these disorders tend to be caused by mutations or autoimmune disorders. autoimmune disorders, in the case of neuromuscular diseases, tend to be humoral mediated, b cell mediated, and result in an antibody improperly created against a motor neuron or muscle fiber protein that interferes with synaptic transmission or signaling. myasthenia gravis myasthenia gravis is an autoimmune disorder where the body makes antibodies against either the acetylcholine receptor (achr) (in 80% of cases), or against postsynaptic muscle-specific kinase (musk) (0–10% of cases). in seronegative myasthenia gravis low density lipoprotein receptor-related protein 4 is targeted by igg1, which acts as a competitive inhibitor of its ligand, preventing the ligand from binding its receptor. it is not known if seronegative myasthenia gravis will respond to standard therapies. neonatal mg neonatal mg is an autoimmune disorder that affects 1 in 8 children born to mothers who have been diagnosed with myasthenia gravis (mg). mg can be transferred from the mother to the fetus by the movement of achr antibodies through the placenta. signs of this disease at birth include weakness, which responds to anticholinesterase medications, as well as fetal akinesia, or the lack of fetal movement. this form of the disease is transient, lasting for about three months. however, in some cases, neonatal mg can lead to other health effects, such as arthrogryposis and even fetal death. these conditions are thought to be initiated when maternal achr antibodies are directed to the fetal achr and can last until the 33rd week of gestation, when the γ subunit of achr is replaced by the ε subunit. lambert-eaton myasthenic syndrome lambert–eaton myasthenic syndrome (lems) is an autoimmune disorder that affects the presynaptic portion of the neuromuscular junction. this rare disease can be marked by a unique triad of symptoms: proximal muscle weakness, autonomic dysfunction, and areflexia. proximal muscle weakness is a product of pathogenic autoantibodies directed against p/q-type voltage-gated calcium channels, which in turn leads to a reduction of acetylcholine release from motor nerve terminals on the presynaptic cell. examples of autonomic dysfunction caused by lems include erectile dysfunction in men, constipation, and, most commonly, dry mouth. less common dysfunctions include dry eyes and altered perspiration. areflexia is a condition in which tendon reflexes are reduced and it may subside temporarily after a period of exercise. 50–60% of the patients that are diagnosed with lems also have present an associated tumor, which is typically small-cell lung carcinoma (sclc). this type of tumor also expresses voltage-gated calcium channels. oftentimes, lems also occurs alongside myasthenia gravis. treatment for lems consists of using 3,4-diaminopyridine as a first measure, which serves to increase the compound muscle action potential as well as muscle strength by lengthening the time that voltage-gated calcium channels remain open after blocking voltage-gated potassium channels. in the us, treatment with 3,4-diaminopyridine for eligible lems patients is available at no cost under an expanded access program. further treatment includes the use of prednisone and azathioprine in the event that 3,4-diaminopyridine does not aid in treatment. neuromyotonia neuromyotonia (nmt), otherwise known as isaac's syndrome, is unlike many other diseases present at the neuromuscular junction. rather than causing muscle weakness, nmt leads to the hyperexcitation of motor nerves. nmt causes this hyperexcitation by producing longer depolarizations by down-regulating voltage-gated potassium channels, which causes greater neurotransmitter release and repetitive firing. this increase in rate of firing leads to more active transmission and as a result, greater muscular activity in the affected individual. nmt is also believed to be of autoimmune origin due to its associations with autoimmune symptoms in the individual affected. congenital myasthenic syndromes congenital myasthenic syndromes (cms) are very similar to both mg and lems in their functions, but the primary difference between cms and those diseases is that cms is of genetic origins. specifically, these syndromes are diseases incurred due to mutations, typically recessive, in 1 of at least 10 genes that affect presynaptic, synaptic, and postsynaptic proteins in the neuromuscular junction. such mutations usually arise in the ε-subunit of achr, thereby affecting the kinetics and expression of the receptor itself. single nucleotide substitutions or deletions may cause loss of function in the subunit. other mutations, such as those affecting acetylcholinesterase and acetyltransferase, can also cause the expression of cms, with the latter being associated specifically with episodic apnea. these syndromes can present themselves at different times within the life of an individual. they may arise during the fetal phase, causing fetal akinesia, or the perinatal period, during which certain conditions, such as arthrogryposis, ptosis, hypotonia, ophthalmoplegia, and feeding or breathing difficulties, may be observed. they could also activate during adolescence or adult years, causing the individual to develop slow-channel syndrome. treatment for particular subtypes of cms (postsynaptic fast-channel cms) is similar to treatment for other neuromuscular disorders. 3,4-diaminopyridine, the first-line treatment for lems, is under development as an orphan drug for cms in the us, and available to eligible patients under an expanded access program at no cost.