Causes and triggers of myasthenia gravis
Fact-checked by Mistaken immune attacks cause myasthenia gravis (MG), a disorder that affects the communication between nerves and muscles.
In MG, the immune system erroneously produces self-reactive antibodies that target proteins that help nerves send signals to muscles to support voluntary movements. Disrupting this communication leads to the characteristic MG symptoms of muscle weakness and fatigue.
Because it is driven by self-reactive immune activity, MG is classified as an autoimmune disease. It isn’t always clear why the immune system becomes dysregulated, but abnormalities in the thymus gland appear to play a role for many patients. Certain environmental triggers may also increase the risk of MG symptoms developing or getting worse.
Autoimmune causes
The autoimmune mechanism of MG involves the mistaken production of self-reactive antibodies, also called autoantibodies. Antibodies normally help protect the body against infections, but autoantibodies mistakenly attack the body’s own healthy tissues.
Autoantibodies in MG target proteins found at the neuromuscular junction (NMJ), where nerve and muscle cells communicate to facilitate muscle contractions and movement. The loss of these proteins disrupts nerve-muscle signaling, or neuromuscular transmission.
Each NMJ involves a nerve cell and a muscle cell separated by a small gap, or synapse. Normal neuromuscular transmission involves a few steps:
- The nerve cell releases a signaling molecule called acetylcholine into the synapse.
- Acetylcholine travels to the postsynaptic membrane, or the surface of the muscle cell.
- Acetylcholine binds to proteins called acetylcholine receptors (AChRs) on the muscle cell, signaling it to contract.
- A protein called acetylcholinesterase breaks down the remaining acetylcholine in the synapse, ending the signal.
Self-reactive antibodies in MG can cause neuromuscular transmission failure. The most common autoantibodies in MG target AChRs, disrupting the ability of acetylcholine to bind to muscle cells. Less often, MG-causing antibodies target other NMJ proteins, including muscle-specific kinase (MuSK) and low-density lipoprotein receptor-related protein 4 (LRP4). Both MuSK and LRP4 antibodies can prevent NMJs from forming and working correctly.
| Features | AChR antibodies | MuSK antibodies | LRP4 antibodies |
|---|---|---|---|
| Prevalence in MG | 80%-85% with generalized MG; 50%-70% with ocular MG | 5%-8% | 1%-5%; may co-exist with AChR or MuSK antibodies |
| Function of target protein | Helps muscle cells receive signals from nerves | Helps NMJs form and function | Helps NMJs form and function |
| Clinical features | Can cause weakness limited to the eyes or more widespread | More commonly affects muscles in the mouth and throat; may be more severe | May cause milder symptoms with earlier onset |
About 10% of patients have double-seronegative MG, meaning neither AChR nor MuSK autoantibodies are detectable in their bloodstream. Some of these individuals may have LRP4 antibodies, which are a more recent discovery, or other rare antibodies that affect NMJs. Scientists don’t entirely understand why the disease develops in seronegative patients.
Thymus gland abnormalities
Researchers know that autoimmune responses drive MG, but don’t entirely understand how this aberrant immune activity originates. For many people, it may be related to changes in the thymus gland, an immune organ in the chest that helps train immune cells to fight off infections.
There are two main types of thymus gland abnormalities linked to MG:
- thymic hyperplasia: an enlarged thymus, observed in around 70% of people with MG
- thymoma: a thymus tumor, observed in about 10%-20% of people with MG
Thymic hyperplasia is a noncancerous condition that arises when there are too many immune cells in the organ, while thymoma is usually considered a slow-growing type of cancer. It’s thought that both of these conditions lead to abnormal immune activity that triggers the production of autoantibodies.
Thymus abnormalities are mainly associated with the production of AChR antibodies. Other MG antibody types don’t appear to be as strongly related to the thymus.
Other causes
About 10%-15% of babies born to mothers with MG develop a temporary form of the disease called transient neonatal MG. This occurs when autoantibodies transfer to the developing fetus through the placenta during pregnancy. Usually, babies with transient neonatal MG naturally recover as their immune systems develop.
Sometimes, symptoms similar to those seen in MG can develop due to mutations in genes involved in nerve-muscle communication, rather than from autoimmune attacks. This leads to a distinct group of disorders known as congenital myasthenic syndromes (CMS). CMS typically requires different types of treatment than MG.
Common triggers and risk factors
While scientists don’t know exactly why MG occurs, there are a few risk factors that can influence the likelihood that someone will have MG, although not everyone with these risk factors will develop the disease:
- a personal or family history of MG or other autoimmune diseases
- thymus problems
- demographic factors, with adult women under 40 and men over 60 being more susceptible
Most people living with MG have no family history of the disorder, and it isn’t considered an inherited disease. However, having a relative with MG may increase the likelihood of developing the disease, suggesting that some people may have a genetic predisposition that makes them more susceptible to MG.
Some triggers can cause MG symptoms to emerge or worsen, but they are not the root cause of the disease. These may lead to a diagnosis for some people because they make subtle symptoms more noticeable. MG triggers can vary between individuals and may include:
- fatigue or lack of sleep
- stress
- infection or illness
- surgery
- pregnancy
- menstruation
- heat
- use of certain medications or alcohol
A combination of risk factors and environmental triggers might be needed for MG symptoms to develop, although these interactions aren’t entirely understood.
Some medications can worsen MG symptoms or trigger myasthenic crisis, a potentially life-threatening MG complication that affects breathing muscles. These include:
- certain antibiotics
- Procainamide, a treatment for some heart rhythm problems
- beta blockers, which can help treat high blood pressure, heart disease, or migraines
- statins, a class of cholesterol-lowering medications
- quinine-based medications, used to treat malaria and some heart rhythm problems
- magnesium
These or other medications may need to be used with caution or avoided in people with MG. Patients should talk to their doctors about what is safe in their particular case.
Myasthenia Gravis News is strictly a news and information website about the disease. It does not provide medical advice, diagnosis, or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website.
