Causes of LEMS

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Lambert-Eaton myasthenic syndrome (LEMS) is a rare disease caused by the immune system erroneously attacking certain molecules found on nerve cells that control muscle movement. As a result, muscles do not receive normal signals from nerves instructing them to contract, ultimately causing muscle weakness.

In many cases, LEMS occurs in people with cancer. Certain genetic mutations may also increase the risk of LEMS.

How do nerve cells communicate with muscle cells?

Nerve cells come into contact with muscle cells in a region known as the neuromuscular junction. When a nerve cell is activated (usually by signals from the brain), an electrical impulse called action potential travels down its length until the neuromuscular junction.

Once this electrical signal reaches the neuromuscular junction, it activates proteins called voltage-gated calcium channels (VGCCs). As their name implies, these proteins act as channels that allow calcium ions to flow into nerve cells.

The influx of calcium, in turn, triggers nerve cells to release a chemical messenger called acetylcholine into the neuromuscular junction. Acetylcholine then activates protein receptors on muscle cells, ultimately triggering contraction.

What causes LEMS?

LEMS is caused by self-targeting antibodies, or autoantibodies, that target and damage VGCCs. As a consequence, nerve cells release less acetylcholine into the neuromuscular junction. This causes muscle cells to cease receiving normal signals alerting them to contract, resulting in muscle weakness. This weakness tends to worsen over time, as muscle cells tend to lose strength when they are not regularly contracting.

What’s the link between LEMS and cancer?

In roughly half of the cases, LEMS is associated with an underlying cancer. A particular type of lung cancer, called small cell lung cancer (SCLC), accounts for most of these cases, though other cancer types have been reported to be associated with LEMS. Typically in these cases, treating the underlying cancer can also effectively treat LEMS.

It is thought that LEMS may develop in cancer patients due to a phenomenon known as “cross reactivity.” This happens because VGCCs are found on the surface of certain cancer cells. The immune system, recognizing cancer cells as a threat, generates antibodies targeting VGCCs in an attempt to eliminate them. But these antibodies also end up attacking VGCCs on nerve cells, causing LEMS.

How do genes affect LEMS?

LEMS is not hereditary, meaning that it cannot be passed from parents to their biological children. However, some inherited genetic variations may influence the development of LEMS, particularly when the disease develops outside the context of cancer.

Specifically, genetic variations that affect human leukocyte antigen (HLA) proteins have been tied to LEMS. Simply put, HLA proteins act sort of like a display case on the surface of a cell. Immune cells can inspect these proteins to look for suspicious activity. For example, pieces of a virus being displayed by a cell’s HLA proteins could indicate that the cell has been infected with a virus, which would trigger an immune response to fight off the infection.

Variations in the genes that code for HLA proteins have been linked to LEMS and other autoimmune diseases like myasthenia gravis, although the exact mechanisms underlying these associations are still poorly understood. Specific HLA variants tied to an increased risk of LEMS include HLA-B8, HLA-DR3 and HLA-DQ2.

Last updated: Oct. 19, 2021

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