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There are a few diseases that cause an insensitivity to pain. This question asks about the relationship between the cold and pain, which got me thinking:
Is shivering a response driven by the sensation of cold, or a response to the pain associated caused by the cold? This is easy to work out by considering people that do not experience pain.
The key here is if people with congenital analgesia (AKA CIPA, CIP) shiver then we may assume that it is the sensation of the cold, not the pain and the cold, that causes the shivering.
Do CIPA patients shiver in the cold?
Does this mean that the shivering is caused by sensation pathways or pain pathways?
Disclaimer: I am not an anatomist and do not claim to have a working knowledge of the nervous system. Please point out any and all obvious errors in this question that might explain why this wouldn't be the case in the comments or as an answer if its a big error.
Interesting question. Here what I think (I am not an expert in congenital analgesia so take it with a grain of salt).
The pain provoked by an high temperature is mainly transmitted via the receptor TRPV1 (a Ca2+-channel nocireceptor) while cold sensation is driven by TRPM8 and possibly, for noxious cold, via TRPA1 (two similar types of Ca2+-channels). Those receptors are known as the temperature sensors. As an anecdote, TRPV1 is what give you a pungency sensation when eating spices while TRPM8/TRPA1 give you the cooling sensation from mint.
Mechanical pain is transmitted via other receptors, including TRP channels, but this is not fully understood at the molecular level.
As far as I know, the encoding of pain, and more generally physiological sensations, in the brain are also not yet fully understood but it is very likely that the pathways taken by TRPV1 differs from the one taken by TRPM8/A1 which would suggest that it is possible that CIPA individuals experience high-temperature pain and cold differently at the molecular level and therefore might respond, to some degree, to one but not the other. This also probably applies to mechanical pain vs temperature-driven pain.
I would actually not be too surprised if CIVA people shiver even if not feeling any temperature sensations. Would be interesting to have the opinion or even better the observations of experts in this field.
P.S. I know this is not a definitive answer but I have not enough reputation to comment.
Peripheral Nerve Disorders
Pierre Landrieu , Jonathan Baets , in Handbook of Clinical Neurology , 2013
HSAN IV (NTRK1, 1q21-22)
Congenital Insensitivity to Pain with Anhidrosis (CIPA) or HSAN IV is an AR disorder caused by mutations in NTRK1 (neurotrophic tyrosine kinase, receptor type) ( Indo et al., 1996 ). The CIPA phenotype has characteristic features: recurrent episodic fevers due to anhidrosis, absence of reaction to painful stimuli, self-mutilating behavior and mental retardation ( Axelrod and Gold-von Simson, 2007 ). Nerve conduction studies are usually within normal range ( Shatzky et al., 2000 Auer-Grumbach et al., 2003 Axelrod and Gold-von Simson, 2007 ). Nerve biopsy findings are dominated by almost complete disappearance of unmyelinated fibers.
Evidence so far suggests that CIPA is a genetically homogeneous disorder making diagnostic screening worthwhile in selected patients. Mutations in NTRK1 are found in up to 7% of cases in large HSAN cohorts ( Indo, 2001 Rotthier et al., 2009 ).
Congenital analgesia: The agony of feeling no pain
Steven Pete and his brother were born with the rare genetic disorder congenital analgesia. They grew up - in Washington state, US - with a sense of touch but, as he explains in his own words, without ever feeling pain.
It first became apparent to my parents that something was wrong when I was four or five months old.
I began chewing on my tongue while teething. They took me to a paediatrician where I underwent a series of tests.
At first they put a cigarette lighter underneath my foot and waited for my skin to blister. Once they saw that I had no response to that then they began running needles up and down my spine. And since I had no response to either of those tests they came to the conclusion that I had what I have - congenital analgesia.
By which point, I had chewed off about a quarter of my tongue through teething.
We grew up on a farm. My mum and dad tried to be protective without stifling my brother and me. But when you're out in the country, especially if you're a boy, you're going to go out and explore and get in a little mischief.
So during my early childhood I was absent from school a lot due to injury and illness.
There was one time, at the roller-skating rink. I can't recall all of the details, but I know that I broke my leg. People were pointing at me because my pants were just covered in blood from where the bone came out. After that, I wasn't allowed to roller skate until I was much older.
When I was five or six years old, I was taken away from my home by child protective services. Someone had reported my parents for child abuse.
I was in the state's care for, I believe, two months. And during that time I broke my leg before they finally realised that my parents and the paediatrician were telling the truth about my condition.
At school, a lot of children would have questions about my condition. They would ask: "Why do you have a cast on?" Most of the time I was in a cast, until I was around 11 or 12.
I was involved in fights quite frequently. Whenever a new kid came to school, the children would try to get that person to come and pick a fight with me, as a kind of introduction to the school. They would say: "If you can't feel pain, you will once I'm done with you."
Nowadays, I am not a particularly reckless person. I believe I'm actually more vigilant than most people because I know that if I were to injure myself I wouldn't know how severe it would be.
Internal injuries are the ones I fear the most. Appendicitis is what really scares me. Usually whenever I have any type of stomach issues or a fever I go to the hospital just to get it checked out.
The last time I had a broken bone, my wife actually noticed before I did. My foot was swollen, black and blue, so I went to the doctor and had an X-ray and they told me that I had broken two of my toes and they wanted to put a cast on it.
I had to go to work the next day. If had a cast on I wasn't going to be able to work for quite some time so I just told them Iɽ take care of myself. I went home and took some duct tape, taped it up, put my boots on and went to work that next morning.
One of the things I'm going to have to face soon is the fact that I won't have my left leg anymore. I've had quite a bit of surgery on my left knee in the past and it's got to the point where my doctors have told me to wait until it gives out completely. Once that occurs they're just going to have to amputate.
I really try not to think about it. I try not to let it get to me.
But I can't help thinking congenital analgesia was partly why my brother chose to take his own life.
His back was getting progressively worse. He was pretty close to graduating from a local college and the doctors told him that probably in the next year, year-and-a-half, he would be in a wheelchair.
He was an "outdoors man" - he liked to be outside, to fish and to hunt. But he tried to see about getting some sort of financial disability assistance once this would all happen. And pretty much what the judge told him was: "If you're not in pain then you have no reason to be on any type of assistance."
The thing is, with our condition, a lot of people see us and they might assume that we're healthy.
But they have no idea that my body could give out at any time, that I ache all over. I have severe arthritis in my joints. It's not painful - I don't feel pain - but it's hard to move around sometimes.
It feels like a compression, a throbbing compressed feeling in my joints. On a bad day it makes me very cranky when I have that feeling all day, because it's just a nuisance. It limits your mobility and your joint isn't able to move as much as it should.
As for doctors, I think they understand the condition. They just don't understand the human component of it - the psychology of what can happen when you grow up not being able to experience pain.
Steven Pete spoke to Outlook for the BBC World Service.
Here is a selection of your comments.
Twenty-five years ago when working at a children's hospital, I was the social worker for two little Pakistani boys who suffered from it. The parents were first cousins and there had been much close relationship marriage in their histories. The paediatricians thought this was probably a contributing factor. As in this article, the injuries to the boys' tongues and limbs were horrendous. Both boys were fearless and the very young parents quite unable to control them, as the boys leapt from the top of wardrobes, held their hands over flames and chewed through their tongues. These children were only four and six when I knew them and I always wondered how long they would survive as I left the hospital to work elsewhere and never knew what happened to them. Susan King, Farnham, UK
My four-year-old son suffers from this condition. It's ironic you have done this article today as it's his birthday. He was diagnosed at nine months after fracturing his skull. We and my partner were also investigated for child abuse and he was put under social services care whilst on the hospital ward for three weeks. The investigation was just after the Baby P case, so tension was high and we felt very let down by the hospital staff, police and social services as we were guilty in all their eyes and they certainly let us know. They suddenly changed their views after it was confirmed he had this condition. Life with him is a daily struggle. Richard, UK
I do not suffer from this particular condition but do have fibromyalgia, Raynaud's and erythromelalgia. All these conditions are the polar opposite of the condition mentioned above yet I can relate to the comments regarding medical professionals. I am in constant pain, cannot control my body temperature and have to use a wheelchair to get around. I am fortunate to have found a sympathetic doctor who has experience treating this condition but there are many health professionals who treat it like a joke. They think you are making things up and are reluctant to give you the medication you need to just get through the day. Medical professionals need to realise that there are conditions out there that are essentially invisible but can still be extremely distressing and painful. Boris, Somerset, UK
I have always had a hign pain threshold and did not experience childbirth as painful at all. In recent years, though, I have a mysterious condition that means I did not react when a freshly made hot water bottle split over my feet and when doctors stick needles all over my legs. I am aware that they are doing it but feel no pain. I am learning to be careful and they have no idea what it might be. I am getting in touch to make sure you are aware of the spectrum of the ɺnalgesia' phenomenon. Caroline Davies, Welshpool, Wales
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“Congenital Insensitivity to Pain” (CIPA, or congenital analgesia: CIPA hereafter) is an autosomal recessive disease (Indo, 2002) and was first observed in 1932 (Daneshjou, Jafarieh, and Raeeskarami, 2012). It is called a “congenital disorder” since it is present from birth. Since the disease is autosomal recessive, the closer the two parents are in relatedness, the more likely it is they will pass on a recessive disorder since they are more likely to have and pass on autosomal recessive mutations (Hamamy, 2012). First cousins, for example, 1.7-2.8% higher risk of having a child with an autosomal recessive disease (Teeuw et al, 2013). Consanguinity is common in North Africa (Anwar, Khyatti, and Hemminki, 2014) and the Bedouin have a high rate of this disease (Schulman et al, 2001 Lopez-Cortez et al, 2020 Singer et al, 2020). Three mutations in the TrkA (AKA NTRK1) have been shown to induce protein mis-folding which affect the function of the protein. Different mutations in the TrkA gene have been shown to have be associated with different disease outcomes (Franco et al, 2016). Since the mutated gene in question is needed for nerve growth factors, the pain signals cannot be transferred to the brain since there are hardly any of them there (Shin et al, 2016).
Individuals unfortunate enough to be inflicted with CIPA cannot feel pain. Whether it’s biting their tongues, feeling pain from extreme temperatures. People with CIPA have said that while they can feel the difference between extreme temperatures—hot and cold—they cannot feel the pain that is actually associated with the temperatures on their skin see (Schon et al, 2018). When they bump into things, they may not be aware of what happened and injuries may occur which heal incorrectly due to no medical attention and only noticing the fractures and other things that occur due to CIPA years later after they see doctors for what is possibly factors due to having the disease. People with CIPA are thought to be “dumb” because they constantly bump into things. But what is really happening is that, since they cannot feel pain, they have not learned that bumping into things could be damaging to their bodies, as pain is obviously an experience-dependent event. So these people learn, throughout their lives, to fake being in pain as to not draw suspicion to people who may not be aware of the condition. Children with the disease are thought, most of the time, to be victims of child abuse, but when it is discovered that the child who is thought to be a victim of abuse is inflicted with CIPA (van den Bosch et al, 2014 Amroh et al, 2020), treatments shift toward managing the disease.
About twenty percent of people with CIPA live until three years of age (Lear, 2011), while 20 percent of those who die at age 3 die from complications due to hyperpexia (an elevated body temperature over 106. degrees Fahrenheit) (Rosemberg, Marie, and Kliemann, 1994 Schulmann et al, 2001 Indo, 2002 Nabyev et al, 2018). Since they cannot feel the heat and get themselves to cool down, Due to a low life expectancy (many more live until about 25 years of age), this disease is really hard to study (Inoyue, 2007 Daneshjou, Jafarieh, and Raeeskarami, 2012). People hardly make it past that age since they either don’t feel the pain and do things that normal people, through experience, know not to do since we can feel pain and know to not do things that cause us pain and discomfort or they commit suicide since they have no quality of life due to damaged joints. Furthermore, since they cannot feel pain, people with this disease are more likely to self-mutilate since they cannot learn that self-mutilation causes pain (since pain is a deterrent for future action that may in fact cause pain to an individual). They also cannot sweat, meaning that control of the body temperature of one afflicted with CIPA is of utmost precedence (since they could overheat and die). Thus, these cases of deaths of individuals with CIPA do not occur due to CIPA per se, they occur due to, say, not feeling heat and then sweating while not attempting to regulate their body temperature and cool down (whether by naturally sweating due to being too hot or getting out of the extreme hot temperature causing the elevated body temperature). This is known as “hyperpyrexia” and this cause of death affects around 20 percent of CIPA patients (Sasnur, Sasnur, and Ghaus-ul, 2011). Furthermore, they are more likely to have thick, leathery skin and also show little muscular definition.
Not sweating is associated with CIPA and if one cannot sweat, one cannot have their body temperature regulated when they get too hot. So if they get too hot they cannot feel it and they will die of heat stroke. The disease, though, is rare, as only 17-60 people in America currently have it, while there are about 600 cases of the disease worldwide (Inoyue, 2007 Lear, 2011). This disease is quite hard to identify, but clinicians may be able to detect the presence of the disease through the following ways: Infants biting their lips, fingers, cheeks and not crying or showing any instance of being in pain after the event repeated fractures in older children a history of burns with no medical attention observing that a child has many healed joint injuries and bone fractures without the child’s parents seeking medical care observing that the patient does not react to hot or cold events (though they can say they can feel a difference between the two) they make errors in distinguishing in whether something is hot or cold (Indo, 2008).
Children who have this disease are at a higher risk of having certain kinds of bodily deformations, since they cannot feel the pain that would make them be hesitant to perform a certain action in the future. Due to this, people with this disease must constantly check themselves for cuts, abrasions, broken bones, etc to ensure that they cannot feel when they actually occur to them. They don’t cry, or show any discomfort, when experiencing what should be an event that would cause someone without CIPA to cry. CIPA-afflicted individuals are more likely to have bodily deformations since their joints and bones do not heal correctly after injury. This then leads to their walking and appearance to be affected. This is one of many reasons why the parents of people with CIPA must constantly check their children for signs of bodily harm or unintentional injuries. One thing that needs to be looked out for is what is termed Charcot joint—which is a degenerative joint disorder (Gucev et al, 2020).
A specific form of CIPA—called HSAN-IV—was discovered in a village in southern Finland called Vittangi, where it was traced to the founder of the village itself in the 1600s. Since the village was remote with such a small population, this meant that the only people around to marry and have children with were people who were closely related to each other. This, then, is the reason why this village in Finland has a high rate of people afflicted with this disease (Norberg, 2006 Minde, 2006). This, again, goes back to the above on consanguinity and autosomal recessive diseases—since CIPA is an autosomal recessive disease, one would reason that we would find it in populations that marry close relatives, either due to custom or population density.
Many features have been noted as showing that an individual is afflicted with CIPA: absent pain sensation from birth, the inability to sweat and mental retardation, lower height and weight for their age (Safari, Khaledi, and Vojdani, 2011 Perez-Lopez et al, 2015). Children with CIPA have lower IQs than children without CIPA, so there is an inverse relationship between IQ and age the older the age of the child with CIPA, the lower their IQ, while the reverse is true for individuals who are younger (Erez et al, 2010). One girl, for example. had a WISC-III IQ of 49, and she self-mutilated herself by picking at her nails until they were no longer there (Zafeirou et al, 2004). Another girl with CIPA was seen to have an IQ of 52, be afflicted with mental retardation, have a low birth weight, and was microcephalic (Nolano et al, 2000). Others were noted to have IQs in the normal range (Daneshjou, Jafarieh, and Raaeskarami, 2012). People with a specific form of this disease (HSN type II) were observed to have IQs in the normal range (though it is “caused by” a different set of genes than CIPA, HSN type IV Kouvelas and Terzoglou, 1989). However, it has been noted that the cut-off of 70 for mental retardation is arbitrary (see Arvidsson and Granlund, 2016). While running a full gamut of tests on an individual thought to have CIPA, we can better attempt to ensure a higher quality of life in individuals afflicted with the disease. In sum, IQ scores of CIPA individuals do not reflect that the mutations in TrkA “cause” IQ scores it is an outcome of a disrupted system (in this case, mutations on the TrkA gene).
There is currently no cure for this disease, and so, the only way to manage complications stemming from CIPA is to work on the injuries that occur to the joints that occur as they happen, to ensure that the individual has a good quality of life. Treatment for CIPA, therefore, is not actually curing the disease, but it is curing what occurs due to the disease (bone breaks, joint destruction), which would then heighten the quality of life of the person with CIPA (Nabiyev, Kara, and Aksoy, 2016). Naloxone may temporarily relieve CIPA (Rose et al, 2018), while others suggest treatments such as remifentanil (Takeuchi et al, 2018). We can treat outcomes that arise from the disease (like self-mutilation), but we cannot outright cure the disease itself (Daneshjou, Jafarieh, and Raaeskarami, 2012). The current best way to manage the disease is to identify the disease early in children and to do full-body scans of afflicted individuals to attempt to cure the by-products of the disease (such as limb/joint damage and other injuries). Maybe one day we can use gene therapy to help the afflicted, but for now, the best way forward is early identification along with frequent check-ups. By managing body temperature, having frequent check-ups, modifying the behavior of the child as to avoid injuries, wearing a mouth guard so they do not grind their teeth or bite their tongue, avoiding hot or cold environments or food, (Indo, 2008 Rose et al, 2018).
CIPA is a very rare—and very interesting—disease. By better understanding its aetiology, we can better help the extremely low number of people in the world who suffer from this disease.
What is Congenital Insensitivity to Pain? (with pictures)
The purpose of pain is to protect us from harming ourselves. When a person puts his hand on a hot stove, usually his first response is to yank that hand away. People with congenital insensitivity to pain do not feel pain. This means that a person with the disorder may not remove his hand from a hot stove because he does not feel the pain of his hand burning. This can lead to severe problems.
Although it is thoroughly unpleasant, pain is meant to teach us to stay away from dangerous items or situations. Pain can also be an indicator of a bigger problem in our bodies, such as cancer or a broken bone. A person with congenital insensitivity to pain has never felt pain and he never will. He can go through his whole life hurting himself and may never even know it. Medical treatment for people with congenital insensitivity to pain can be difficult as many times doctors make diagnoses partially depending on the location and severity of pain.
Congenital insensitivity to pain is a disorder that affects the part of the body that controls the reception of pain. The nerves that sense pain cannot translate that information to the brain, and so the person does not feel even the slightest bit of discomfort. This condition is congenital, meaning it is present at birth. Thus, a baby with congenital insensitivity to pain may be severely hurt, but will seem like a happy child.
A child with this conditione is in extreme danger. If we bite our tongue, for instance, we stop biting it because it hurts. A child with congenital insensitivity to pain will not stop because he does not know he is hurting himself. Such a child may play with the stove, pull out his hair, electrocute himself or play too roughly and harm himself because there is no negative stimuli telling him to stop. This can lead to severe problems and devastating injuries.
Another form of congenital insensitivity to pain is called congenital insensitivity to pain with anhidrosis. It is characterized by a person not being able to feel pain or extreme temperatures, and by being unable to sweat. Such a person may not know that he is too hot or too cold. In addition, without being able to sweat, a person cannot properly regulate his body temperature. No sweat means that the body is not able to properly cool itself, and the person could overheat.
Although congenital insensitivity to pain is rare, it is serious. Usually, people with the disorder do not live past age 25. Without the ability to experience pain, people can break their bones, burn themselves or contract serious illnesses without ever knowing that something is wrong with their body. Thus, they may develop serious infections or diseases that could have been avoided had they sought medical help earlier.
The people who can't feel pain: Scientists discover cause of rare inherited condition that turns off pain sensors
A genetic cause of a rare inherited condition that leaves people with an inability to feel physical pain has been discovered by scientists.
About one in a million people are thought to be born without a sense of pain, which results in severe self-inflicted injuries from an early age and can lead to premature death.
Scientists studying the condition, known as congenital insensitivity to pain, in 11 affected families in Europe and Asia have now identified mutations in a gene called PRDM12 that was already known to be involved in activating genetic switches.
The researchers found that mutations in both copies of the gene that a person inherits from their mother and father – who are unaffected carriers of the defective gene – results in all the pain sensors of the body being turned off from birth.
Teenager Ashlyn Blocker, who lives with her parents in the US town of Patterson, Georgia, feels no pain and is one of a small number of people in the world who have been diagnosed with congenital insensitivity to pain.
“Everyone in my class asks me about it, and I say, ‘I can feel pressure, but I can’t feel pain’,” Ashlyn explained.
She cannot feel hot objects, or cuts and scratches on her skin, or insect bites. She can, and has, put her hand in boiling water without feeling any painful sensation – which has led to a lifetime of anxiety for her parents Tara and John.
“John and I had never heard of this condition. It was mind-boggling. It was so frightening,” Ms Blocker told the New York Times in 2012 after Ashlyn had undergone genetic tests to determine the cause of her condition.
The tests revealed that Ashlyn had inherited two defective copies of the SCN9A gene, which is known to be involved in the transmission of nerve impulses in pain-sensing neurones.
Congenital insensitivity to pain is such a rare condition that only about 20 cases have been reported in the scientific literature. Many of these are the result of mutations in other genes, including one called SCN9A, which is involved in the transmission of electrical signals in the nerves.
The PRDM12 gene, however, plays a key role in modifying a protein called chromatin which becomes attached to the DNA of the chromosomes and acts as a control switch to activate or deactivate other genes on the chromosome.
Researchers showed in a study published in the journal Nature Genetics that all the different PRDM12 mutations that they found in the 11 unrelated families resulted in the complete blocking of the gene.
As chromatin plays a particularly significant role in the formation of nerve cells, the findings could explain why pain-sensing neurons do not form properly in patients suffering from congenital insensitivity to pain, they said.
“The ability to sense pain is essential to our self-preservation, yet we understand far more about excessive pain that we do about lack of pain perception,” said Professor Geoffrey Woods from the Cambridge Institute for Medical Research at Cambridge University.
“Both are equally important to the development of new pain treatments. If we know the mechanisms that underlie pain sensation, we can then potentially control and reduce unnecessary pain,” Professor Woods said.
Babies who are born with CIP often damage themselves unintentionally by chewing their tongues, cheeks or hands. In later life, sufferers have to take precautions against bruising and being burned by hot objects – although sufferers can often distinguish between warm and cold they do not feel the painful stimulus of heat.
A handful of genes have been implicated in contributing to the risk of inheriting the condition. The SCN9A gene, for instance, provides the genetic instructions to make one part of the “sodium channel” protein involved in transmitting nerve impulses to the brain and spinal cord via pain neurons called nociceptors.
By understanding the causes of the lack of sensitivity to pain in such patients, scientists hope to better understand the nature of pain and how to combat it in patients who suffer from long-term, chronic pain.
“We are very hopeful that this new gene could be an excellent candidate for drug development, particularly given recent successes with drugs targeting chromatin regulators in human disease,” said Ya-Chun Chen from Cambridge University, the first author of the study.
“This could potentially benefit those who are at danger from lack of pain perception and help in the development of new treatments for pain relief,” Dr Chen said.
Are people with Congenital Insensitivity to Pain (CIP) unable to feel emotional pain in the same way they are unable to feel physical pain?
People with congenital insensitivity to pain (or congenital analgesia) can’t feel physical pain. According to a study by Eisenberger, the same part of the brain controls both physical and emotional pain. So, does this mean that people with this condition also cannot feel emotional pain?
Congenital analgesia is a disorder of the peripheral nervous system where the sodium channels in nociceptor cells have a mutation. So it’s an issue with the sensory input, not with the brain’s ability to process pain.
Also, can you link the Eisenberger study? I’m curious how emotional pain was operationally defined and what exactly they determined about its neurological similarity to physical pain.
I actually wrote my dissertation on the role of voltage-gated sodium channels in pain back in my undergraduate degree! Loss of function mutations in NaV1.7 cause CIP and these are in peripheral sensory neurones, which prevents the pain signals from being transmitted to the brain. These neurones have no role in emotional pain and thus the 2 are not related. I used to play rugby with a guy who had this, he once noticed he had broken 2 fingers. after the game.
Gain of function mutations make people incredibly sensitive to pain in conditions such as paroxymal extreme pain disorder and erythromelalgia, which sounds awful.
Areas timely for developing research
PRDM12 as an analgesic target
Although PRDM12 clearly acts in early human development, it is also expressed at significant levels in adult nociceptors. This suggests that it may have a post-natal role in pain, just as the developmental CIP genes NTRK1 and NGF do. It may ensure that a nociceptive phenotype continues to be imposed on neurons, if it maintains its prenatal role as a transcription factor. In this case, antagonists may have a role in chronic pain treatment by changing neuronal identity.
Discovery of the function and analgesic potential of new CIP genes
There are only nine voltage-gated sodium channel proteins—three of which cause Mendelian pain syndromes, but there are 27 calcium and 36 potassium voltage-gated channels—none of which are known to be involved in monogenic pain disorders. It would seem likely that there are undiscovered membrane ion channels that cause significant pain phenotypes that would be ‘druggable’. And also defining the function(s) of the rare causes of CIP may suggest further new analgesics, e.g. ZFHX2 to modulate nociceptor identity, MPV17 as a topical treatment for shingles and trigeminal neuralgia, and FAAH inhibition where pain and anxiety co-exist.
Can NGF-TRKA be used in the treatment of S. aureus?
S. aureus infection and asymptomatic carriage continue to be a significant medical problem, especially for hospitals, because of the emergence of multi-resistant strains. New treatments against S. aureus that bolstering the body’s own responses may be possible if molecular distinctions can be found between the functional pathways of NGF pain sensing and NGF intracellular bacterial killing. 6
Signs of CIPA are present from infancy. Infants may present with seizures related to hyperthermia. Because people with this condition are unable to sweat, they are unable to regulate their body temperature.  Those affected are unable to feel pain and temperature. [ citation needed ]
Lack of pain puts those with CIPA at a high risk for accidental self-mutilation. Corneal ulceration occurs due to lack of protective impulses.  Joint and bone problems are common due to repeated injuries, and wounds heal poorly. 
CIPA is caused by a genetic mutation which prevents the formation of nerve cells which are responsible for transmitting signals of pain, heat, and cold to the brain. The disorder is autosomal recessive. [ citation needed ]
It is caused by a mutation in NTRK1, a gene encoding the neurotrophic tyrosine kinase receptor.  NTRK1 is a receptor for nerve growth factor (NGF). This protein induces outgrowth of axons and dendrites and promotes the survival of embryonic sensory and sympathetic neurons. The mutation in NTRK1 does not allow NGF to bind properly, causing defects in the development and function of nociceptive reception. 
Mitochondrial abnormalities in muscle cells have been found in people with CIPA. Skin biopsies show a lack of innervation of the eccrine glands  and nerve biopsies show a lack of small myelinated and unmyelinated fibers.  
Diagnosis is made based on clinical criteria and can be confirmed with genetic testing. 
There is no treatment for CIPA. Attention to injuries to prevent infection and worsening is necessary. 
The condition is inherited and is most common among Negev Arabs aka Negev Bedouins.  Approximately 20% of people with CIPA die of hyperthermia by age 3. 
For CIP sufferers themselves, the prospect of a future life with pain and all its advantages remains slim
In the meantime, new pathways behind pain continue to emerge from studying CIP. One of the most exciting is a gene called PRDM12 which appears to work as a master switch, turning on and off a series of genes relating to pain neurons.
“It could be that in chronic pain states, your PRDM12 isn’t working properly and it’s overactive,” Woods says. “If we could rewire that, you could potentially switch the pain neurons back to a normal acquiescent state. The other interesting thing about PRDM12 is that it’s only expressed in pain neurons, so if you had a drug which modulated it you might have an analgesic with very few side effects as it wouldn’t affect any other cells in the body.”
But while the world of painkiller research is benefiting from the uniqueness of those with this extraordinary disorder, for CIP sufferers themselves, the prospect of a future life with pain and all its advantages remains slim.
Further study of CIP could yield painkillers that target only the genes that cause pain itself (Credit: iStock)
Pimstone points out that by taking part in studies, these individuals are seen by medical professionals, and in many cases for the first time, begin to receive specialist advice. “Without their contributions we wouldn’t be able to move the field forward in the way we can, so we’re enormously grateful,” he says. “And being part of the medical system benefits them as strategies can be implemented within these families so that kids with this disorder do less harm to themselves growing up. Through these studies, a diagnostic could also become available which can detect CIP early on.”
Gene therapy is not yet at a stage where scientists could contemplate restoring a missing channel and perhaps giving back pain to someone who’s never had it, and for such a small percentage of individuals the financial motives of finding a way simply aren’t there.
But Betz says he lives in hope. “I want to contribute and be able to help the world understand more about pain. Perhaps one day they could use the understanding we gave them, to help us too.”