Glossary
Neuropathic pain (or neuropathy) is a form of pain that is caused by illness or damage to the nervous system.
Erythromelalgia is a form of neuropathy which is characterised by severe burning pain and high skin temperatures.
Small fibre neuropathy is a disorder of the small nerves in the skin where severe pain and numbness can occur.
Non-freezing cold injury is a condition that can be found in ex-soldiers. People with non-freezing cold injury can often feel pain or numbness in their feet, and it is linked to “trench foot”.
Genetic variants refers to small changes in genes that can (sometimes) cause changes in how the gene works. These variants can be caused in a number of ways, but are often caused by mutations
Background
Neuropathic pain is very difficult for doctors and patients to deal with. It is often a sudden or severe form of pain and is very unpleasant for the people affected. Neuropathic pain might affect up to 10% of the general population and will often have a big impact on quality of life.
Understanding the genetic variants that could influence neuropathic pain should help us to design new drugs and find new targets for treatments. However, careful analysis is required for this type of research, as different mutations within the same gene can affect pain in very different ways. If a gene loses its function, it might lead to less pain; but becoming more active could easily cause higher levels of pain.
Some very rare genetic variants are associated with extreme levels of neuropathic pain. Finding the specific genetic changes associated with extreme pain disorders could be extremely useful for patient diagnosis and also for the development of new targeted medicines.
Study aims and objectives
This study was designed to discover new genetic variants that are likely to be causes of extreme pain disorders. People with high pain and also people with a lack of pain sensations were studied.
- Genetic variants were analysed and were reported to the patients’ medical teams if they were likely to give useful information for diagnosis or treatment.
- Laboratory tests of the new genetic variants were used to see how they function and how they might affect pain. Computer-based analysis was also used to look at how pain might be affected by each genetic change.
Study results and conclusions
A total of 205 people were recruited into the study. Although there were many genetics variants in the people studied, the researchers maintained a focus on the genes that are known to be important for neuropathy. A total of 26 genetic changes were found that were associated with neuropathic pain. A list of the most important changes is below.
- Two sisters were part of the study and both had erythromelalgia. A genetic variant that controls the activity of nerve signalling (called SCN9A p.Ile848Thr) was found in both sisters; and lab analyses showed that it caused an increase in nerve activity.
- A variant was found in a gene that helps to build nerve cells. This variant (SPTLC1 p.Cys133Trp) was found in 1 person and is a common mutation causing an inherited form of sensory neuropathy type-1. This person had neuropathic pain, although sensory neuropathy type-1 is often linked to loss of sensation.
- Two genetic variants associated with small fibre neuropathy were found in SCN10A and SCN11A genes (called SCN10A p.Gly1662Ser and SCN11A p.Cys1543Tyr).
- 40 participants in the study had non-freezing cold injury. Of these people, six had a genetic variant which is associated with small fibre neuropathy (the SCN9A p.Arg185His variant). All 6 people were of African descent, where non-freezing cold injury is more common. Their genetic variant was tested in the lab and found to increase the activity of nerve cells, implicating it in pain-related signalling. The researchers tested how this genetic variant responded to temperature and found that pain-related functions were gained when it was colder.
- One participant experienced widespread pain that came and went unpredictably. Extra analysis of other genetic changes showed a possible role for the TRPA1 gene, which is another gene that controls the signalling of nerve cells. A genetic variant (TRPA1 p.Ala172Val) was found in this person. Lab studies of this genetic variant showed that a gain of function was found in TRPA1 channel.
Recommendations to healthcare professionals and researchers
In the future, healthcare professionals might consider using genetic tests to help diagnose people with neuropathic pain. Researchers could endeavour to replicate the findings from this study in other populations.