Neuromuscular junction disease

Neuromuscular junction

The neuromuscular junction is a specialized synapse between a neuron and the muscle it innervates, allowing efferent signals from the nervous system to contract muscle fibers. In vertebrates, this junction is always excitatory, so inhibition must occur at the level of the efferent motor neuron, specifically in the spinal cord. Release of acetylcholine vesicles from the presynaptic terminal occurs only after adequate depolarization of the efferent nerve.

When a motor nerve action potential reaches the presynaptic terminal, it increases intracellular calcium concentration by increasing ion conductance through voltage-gated calcium channels. This calcium rise allows acetylcholine vesicles to fuse with the plasma membrane via exocytosis, releasing acetylcholine into the synapse. Acetylcholine then binds to nicotinic acetylcholine receptors, increasing conductance of sodium and potassium in the postsynaptic membrane and producing an excitatory end-plate current.

Cation flow into the postsynaptic cell causes depolarization, and if the signal is sufficient, an action potential is generated. This action potential propagates through the sarcolemma, increasing intracellular calcium and initiating excitation–contraction coupling, which shortens sarcomeres and leads to muscle contraction. Neuromuscular junction diseases result from malfunction in one or more steps of this pathway, completely or partially inhibiting normal function.

Classification

Neuromuscular junction diseases can be classified by mechanism of action or by location of disruption. The mechanism-based classification divides diseases into three broad categories: immune-mediated disease, toxic/metabolic syndromes, and congenital syndromes. Immune-mediated diseases include autoimmune disorders where the body's immune system targets its own cells; within this subset are myasthenia gravis and Lambert-Eaton syndrome, where antibodies target a receptor or other essential protein.

Metabolic diseases result from abnormal functioning of metabolic processes required for energy production, often by damaging an enzyme or disrupting a feedback system. Toxic diseases arise from poisons affecting neuromuscular junction function, including snake venom, botulism, arthropod poisoning, organophosphates, and hypermagnesemia. Organophosphates are present in many insecticides, herbicides, and nerve gases. Hypermagnesemia is a condition where magnesium concentrations exceed normal baseline values.

The location-based classification divides diseases according to whether they act on the presynaptic membrane, the synapse, or the postsynaptic membrane.

Most common diseases

Myasthenia gravis is the most common neuromuscular junction disease, affecting 1 person out of 10,000 in the population, with onset typically in younger or older individuals. Acquired myasthenia gravis is the most common form. Antibodies attacking acetylcholine receptors are present in around 85% of cases; the remaining cases involve antibodies against MuSK, a muscle-specific serum kinase, or lipoprotein receptor-related protein. Cases not caused by acetylcholine receptor antibodies are termed seronegative myasthenia gravis, a term that arose because tests for acetylcholine receptor antibodies were negative, though other antibodies may be present.

Transient neonatal myasthenia gravis is a rare condition where a mother with myasthenia gravis passes antibodies to her fetus through the placenta, causing the newborn to have antibodies that attach to self-antigens at the neuromuscular junction; most cases resolve within 2 to 4 months as antibodies dissipate.