Geoff Woods (Image copyright: Geoff Woods)
How can studying rare diseases help those with more common conditions? To mark Rare Disease Day, Ellen Charman speaks to Professor Geoff Woods about how his discovery in Pakistan of a disease in which people don’t feel pain could lead to treatments for those who experience too much.
Can you tell me about this condition, congenital analgesia?
I first came across the condition when I was in Pakistan researching encephalopathy (diseases of the brain) and I was asked to see a boy who reportedly did not feel any pain. He was doing street theatre to earn money — walking across hot coals and putting daggers in his arms, and then going to the local children’s hospital to get patched up. Sadly, before I got the chance to see him, he’d jumped from a roof to amuse friends and walked away from it, but later died from a bleed in the brain.
When I came back to the UK, I asked around and found two families also affected by the condition. At first, due to the common inclination towards risky and dangerous activities, I assumed that those with the condition had a degree of intellectual disability; however, I later found their development to be normal, but without the sense of pain to modulate their behaviour.
How rare is the condition?
It’s hard to put a precise figure on it, but I would estimate that between one in 100,000 and one in one million people have the condition. It affects both males and females, however, it is the males who are less likely to modify their behaviour and so this is sadly why men with the condition often don’t live beyond their late teens or early twenties.
In 2006 your team identified a genetic cause for the disease — a mutation in a gene called SCN9A which encodes a sodium channel found in sensory nerve cells. How does this mutation affect a person’s ability to sense pain?
This sodium channel (a protein in a cell membrane that lets sodium into cells) acts as an amplifier of the pain signal. The sensory nerve cells respond to a potentially damaging stimulus by leaking a small sodium charge. The sodium channel amplifies this charge, sending a signal to the spinal cord and brain to perceive the stimulus as pain. The mutation in the gene means that the sodium channel does not function, so the pain signal does not reach the brain. Patients with the condition can feel touch, pressure and temperature, but not when those sensations reach a painful level.
The importance of this gene was actually almost missed. Professor John Wood at UCL had bred mice with mutations in this gene, but they kept dying soon after birth. We later discovered that this was because they had no sense of smell, and so couldn’t smell their mother’s milk and did not feed. It turned out that people with the mutation also don’t have any sense of smell.
What does the identification of this mutation mean for patients?
We’ve since set up an NHS genetics diagnostics centre so that those with the condition can get a proper diagnosis, genetic counselling on what it might mean for them and their families, and better treatment.
Mutations causing the condition have since been identified in genes for two other sodium channels — SCN10A and SCN11A. However, only half of those who come to the clinic have a genetic mutation, so there are likely to be more genes out there that influence pain detection.
How will these discoveries help people at the other end of the spectrum — those who feel too much pain?
Pain affects one in six people, and so if we can use this knowledge to develop new treatments, it will have an enormous impact. We know that once pain has become chronic — lasting longer than three to six months, it’s probably due to secondary changes in the spinal cord or brain. Current pain treatments, such as morphine, may relieve the symptoms, but do not treat the underlying cause, and often have side effects.
A treatment that works by inhibiting SCN9A is an exciting prospect because the sodium channel is not present in heart muscles or nerve cells in the central nervous system and so it will not cause side effects by acting on these parts of the body.
There has been a lot of interest from the pharmaceutical industry and there are currently clinical trials of SCN9A inhibitors taking place. So hopefully, one day soon, there will be a therapy that treats pain not only by tackling the symptoms, but perhaps resetting the whole pain circuitry system.
Ellen Charman
Professor Geoff Woods is a clinical geneticist at the Cambridge Institute of Medical Research. He has been awarded a MICA grant to discover new ion channel targets for human pain treatment.
Rare Disease Day is an annual event to raise awareness amongst the public and policy-makers about rare diseases and their impact on patients’ lives. Read a piece on our website about how MRC-funded research into rare diseases can often lead to a better understanding of more common diseases.
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