BAR HARBOR MAINE, U.S.A. ROOSTERGNN recently explained the genetic condition called congenital analgesia, or congenital insensitivity to pain.
Here, we gain a further inside look into the world without pain through an interview with Jill Recla, PhD.
Dr. Recla is the Bioinformatics Analyst at The Jackson Laboratory based in Bar Harbor, Maine, U.S.A. Her graduate work focused on chronic pain in individuals.
When did the scientific community first learn about congenital analgesia?
Congenital insensitivity to pain is a rare condition; only ~20 cases have been reported in the scientific literature. The first case is said to have been reported by GV Dearborn in 1932 . The patient made a living as a human pincushion act. A crucifixion had to be called off when a woman in the audience fainted after a spike was driven through one of the patient’s hands.
The SCN9A gene is important to coding for sodium channels that aid pain communication in the body. How exactly does it do this?
The SCN9A gene provides instructions for making one part (the alpha subunit) of a sodium ion channel called NaV1.7. Sodium channels play a key role in a cell’s ability to generate and transmit electrical signals by transporting positively charged sodium ions into cells. NaV1.7 sodium ion channels are found in peripheral nerve cells called nociceptors that transmit pain signals to the spinal cord and brain. The peripheral nervous system connects the brain and spinal cord to muscles and cells that detect sensations such as touch, smell, and pain. Thus, congenital insensitivity to pain is considered a form of peripheral neuropathy.
The SCN9A gene mutations that cause congenital insensitivity to pain result in the production of nonfunctional alpha subunits that cannot be incorporated into NaV1.7 channels. As a result, the channels cannot be formed. The absence of NaV1.7 channels impairs the transmission of pain signals from the peripheral nervous system to the brain, causing those affected to be insensitive to pain.
How does SCN9A also impact individuals’ abilities to smell and sweat?
The NaV1.7 channel is also found in olfactory sensory neurons, which are nerve cells in the nasal cavity that transmit smell-related signals to the brain. Many people with congenital insensitivity to pain also have a complete loss of the sense of smell (anosmia). Loss of the NaV1.7 channel, potentially through mutations in SCN9A, likely leads to anosmia by impairing the transmission of smell-related signals to the brain.
Does SCN9A have any other roles and pathologies associated with it?
Mutations in the SCN9A gene account for approximately 30 percent of cases of small fiber neuropathy (SFN), a condition characterized by severe pain attacks and a reduced ability to differentiate between hot and cold. Unlike the mutations associated with congenital analgesia, which render the alpha subunit unusable by the Nav1.7 ion channel, the SCN9A mutations associated with SFN cause the alpha subunit of the Nav1.7 channels to not close completely, increasing the flow of sodium ions into nociceptor cells and leading to an increase in pain signals. The small fibers that extend from the nociceptors and transmit pain signals (axons) degenerate over time. Although the cause of this degeneration is unknown, it likely accounts for signs and symptoms related to the loss of temperature differentiation.
Recent research suggests that SCN9A may play a role in regulation of the vasomotor system, the part of the nervous system that controls the constriction and dilation of the blood vessels. When a blood vessel dilates, it allows more blood to reach the surface of the skin thus allowing heat to radiate from the body. Although it is unclear how SCN9A directly affects sweat production, there are clear possible avenues.
Mutations in SCN9A have also been associated with the onset of febrile seizures in humans and mice, although it is unknown how a change in the NaV1.7 sodium channel leads to the disorder.
While congenital analgesia gives individuals “superhuman” qualities, why is this dangerous?
Pain is an indication to our brain that our body needs something. The ability to sense and respond to acute pain is an evolutionary survival mechanism, alerting us to harmful stimuli and allowing us to take action before physiological damage ensues. Individuals with congenital analgesia are unable to sense or perceive pain, preventing them from becoming aware when their bodies are being damaged.
For example, people with congenital analgesia often do not realize their bodies have incurred damage or injury such as broken bones or skin burns until someone else brings it to their attention. This lack of pain awareness often leads to an accumulation of wounds, bruises, broken bones, and other health issues that may go undetected. Young children with congenital insensitivity to pain may have mouth or finger wounds due to repeated self-biting and may also experience multiple burn-related injuries. These repeated injuries often lead to a reduced life expectancy in people with congenital insensitivity to pain. Pain is also one of our primary gauges of internal health; without the ability to sense it, we lose one of our earliest detectors of internal disease and dysfunction, leaving us blind to the condition until it is possibly too late.
There is also a significant psychological component congenital analgesia. The inability to sense pain does not render a person immune to ailment or disease, but the lack of perception of the physiological damage can make patients appear to be physically healthy when they are not. This paradox can make it difficult for someone with, for example, congenital analgesia and severe arthritis to receive disability benefits, as they are able to work due to their inability to sense pain, even though physical labor may not be in the best interest of their health.
What does researching this condition mean for future developments in pain therapy?
SCN9A is an essential and non-redundant requirement for nociception, or the neural processes of encoding and processing noxious stimuli. Researching congenital analgesia is providing further insight into the role of SCN9A in healthy as well as disease states, the benefits of which are two-fold.
First, by studying the genetic components of congenital analgesia we are improving our understanding of the innate pain response in humans and potentially other animals, furthering our biological knowledge of innate pain-related physiology. An improved understanding of the innate workings of the human pain system will ultimately benefit our ability to understand and treat other types of pain-related conditions.
Second, by pin-pointing a genetic cause of congenital insensitivity to pain, we can stimulate the search for novel therapeutic compounds that target the alpha subunit of the Nav1.7 sodium ion channel selectively. The selective targeting of genes involved in a particular disease often increases effectiveness of the treatment while decreasing unwanted side effects. The role of NaV1.7 in other physiological abnormalities related to the ability to sweat and smell suggests a potential compound benefit if therapeutic treatments related to SCN9A and ultimately Nav1.7 are realized.