Causes of myasthenia gravis
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In most cases of myasthenia gravis (MG), the neuromuscular disease has an autoimmune origin, meaning it’s caused by a mistaken attack by the body’s immune system. Self-reactive antibodies produced by the immune system are at the forefront of this attack, which affects the function of the neuromuscular junction — the region where nerve and muscle cells communicate to coordinate voluntary movements.
The disorder leads to symptoms of muscle weakness and fatigue that worsen with exercise and improve with rest. There are several types of MG.
It isn’t always clear why the self-reactive antibodies in MG arise, but their production has been linked to abnormalities in the thymus gland, an organ that’s part of the immune system. MG is caused by the immune system’s attack on various components of the neuromuscular junction.
More rarely, MG can arise as a consequence of genetic mutations that affect the function of proteins at the neuromuscular junction.
Self-reactive antibodies
For proper communication to occur at the neuromuscular junction, nerve cells release a chemical called acetylcholine that travels to the surface of a muscle cell. There it binds to acetylcholine receptors, known as AChRs, to elicit muscle contraction.
Although antibodies normally serve to protect the body against infections, in autoimmune diseases, the immune system wrongfully produces self-reactive antibodies or autoantibodies that target the body’s own healthy tissues.
The most common cause of MG is the production of autoantibodies that target AChRs at the neuromuscular junction, which occurs in about 85% of patients. When there is an insufficient number of receptors available for acetylcholine to bind to, muscles lose their ability to contract properly, leading to progressive muscle weakness and fatigue.
In about 6% of patients, antibodies targeting muscle-specific kinase or MuSK — another protein important for the function of the neuromuscular junction — are evident, which are thought to be the cause of MG for those individuals.
Still, about 10% of patients have double-seronegative myasthenia gravis, meaning that neither AChR nor MuSK autoantibodies can be found in their bloodstream.
More recent research has identified that in such cases, there may be antibodies against other proteins important for the formation and maintenance of the neuromuscular junction. These, namely, are agrin or low-density lipoprotein receptor-related protein 4 (LRP4), which may be the cause of the disease.
Thymus gland abnormalities
While the production of autoantibodies is known to drive myasthenia gravis symptoms in the majority of cases, their precise origin is not well established. However, researchers believe that abnormalities in the thymus gland may play a role.
Located in the chest between the lungs, the thymus gland is a component of the immune system that works to produce white blood cells that fight off infection. Early in life, the thymus is very active and produces a lot of immune cells, but its function gradually diminishes as a person gets older and other immune organs take over.
About 70% of MG patients have thymic hyperplasia, a condition in which the thymus is enlarged due to an increased number of cells in the organ, which indicates an overly active immune response. Moreover, about 10%-15% of patients have tumors in the thymus called thymomas, which are usually benign (noncancerous), but may still affect the gland’s function.
Given that, researchers believe the thymus may trigger or help maintain the production of the harmful self-reactive antibodies that drive MG. This particularly is thought to be the case among patients with antibodies targeting AChRs. Abnormalities leading to the production of anti-MuSK or other types of antibodies are poorly understood and seem not to involve the thymus.
Other causes
Most individuals living with MG have no family history of the disorder; it seems to occur spontaneously. While 3%-5% of patients have family members with MG or other autoimmune conditions, the inheritance pattern remains unclear.
About 10%-20% of babies born to mothers with MG will develop a temporary form of the disease called transient neonatal MG. That can happen because, during pregnancy, a mother’s autoantibodies may be transferred to her unborn child through the placenta. In most cases, babies with this form of MG will naturally recover in the weeks following birth, as their own antibodies replace their mother’s.
Some individuals have mutations in genes involved in nerve-muscle communication, and thus develop symptoms of MG that are not caused by an autoimmune response. This genetic condition is sometimes considered a heritable form of MG, called congenital MG. Patients with congenital MG typically start experiencing muscle weakness in early childhood.
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FAQs about myasthenia gravis causes
Myasthenia gravis can be diagnosed in people of all sexes, ages, races, and ethnicities, but is most commonly seen in adult women younger than 40 and in elderly men or those older than 60. There are no well-established clinical risk factors for the development of myasthenia gravis.
The main cause of myasthenia gravis is the immune system’s production of self-reactive antibodies that target acetylcholine receptors — proteins that are important for nerve-muscle communication. While the exact origin of these antibodies is not well established, it is thought that abnormalities in the thymus gland may be involved in their appearance.
In most cases, myasthenia gravis is caused by the immune system’s production of self-reactive antibodies that disrupt nerve-muscle communication, and thus it is considered an autoimmune disease. In rare cases, individuals may have genetic mutations that affect nerve-muscle communication, which is sometimes considered a heritable form of myasthenia gravis that is not autoimmune in nature.
Although the disease mechanisms of myasthenia gravis are not expected to cause pain, many patients report experiencing this symptom somewhat regularly. It is possible that pain arises secondarily to generalized muscle weakness, which can lead to changes in posture that cause non-specific muscle or joint aches.
Myasthenia gravis is generally not caused by genetic factors, and its symptoms more commonly emerge in adulthood. In rare cases, babies born to mothers with myasthenia gravis also may have the condition, but it is usually temporary and goes away in the first months of life. Individuals with congenital myasthenia gravis are born with mutations that affect nerve-muscle communication, but symptoms may not emerge until later in life.
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