Living With CIPA
What is CIPA?
CIPA stands for Congenital Insensitivity to Pain with Anhidrosis. As the name implies, CIPA disease is the inability to feel physical pain. It is a rare congenital and genetic disease that affects the nervous system. It is an extremely rare disorder which may also cause a person to produce very little sweat, or none at all, and makes them incapable of feeling temperature. These symptoms appear early in childhood, typically at birth or during infancy.
Breaking it down: Congenital means a disease or physical abnormality present from birth (from the Cambridge English Corpus).
NCI dictionary of cancer terms defines anhidrosis, which is also called hypohidrosis, as “a rare condition in which the sweat glands make little or no sweat. It can affect the whole body or a small part of the body. Could be caused by severe burns, radiation, infection, inflammation, or other injuries to the skin. It may also be caused by certain medicines and some conditions that affect the skin, nerves, connective tissue, or sweat glands.”
CIPA is a genetic disease caused by a mutation in the NTRK1 gene. Mutations in this gene lead to a loss of the sensory neurons, as well as the ability to feel pain.
To properly explain CIPA, pain has to be explained and why it is necessary to feel pain.
CIPA, as explained above, is a disease that causes a person not to feel any form of pain. The body does not indicate when its temperature is high or low. Heart attacks go unnoticed in a condition called Silent Myocardial Infractions, also known as silent heart attack. It is called “silent” because it has no symptoms.
A heart attack means the heart isn't getting oxygen. This injures the heart, and in cases where the body is not responsive to any form of alteration in the full functioning of the body, it is likely going to cause more damage than just heart injury.
The Concept of Pain and Its Importance
Pain, in general, is a term that describes the feeling of discomfort. A general term that describes uncomfortable sensations in the body by activating the nervous system. An unpleasant experience that is primarily associated with tissue damage or described in that term, or both. Pain can range from annoying to debilitating. It may feel like a sharp stab or dull ache, or a feeling of uneasiness. It may also be described as pinching, throbbing, stinging, aching, burning, or sore.
Pain are perceptions created by the brain. But the brain is not where the pain is initiated. Experts established the classes of pain according to its mechanism:
Nociceptive
Peripheral
Neuropathic and
Central
CIPA has to do with the nociceptive mechanism of pain, where the nociceptors, a special pain receptors located around the skin, joints, muscles and internal organs, detect mechanical, chemical, or thermal (having to do with temperature) injuries.
Nociceptors have a specialized sodium channel, NaV1.7, that allows sodium ions to enter and activate the cell. If this channel stops working, the nociceptors automatically stop working. The activated nociceptors send signals along nerves and spinal cord to the part of the brain called the thalamus.
The thalamus is responsible for creating pain, but it cannot localize the area of the pain, so it sends signals to the somatosensory cortex (this is in charge of processing all the sensory information received and It is responsible for the transitioning and processing of information) of the brain to help detect where the pain is localized.
It is important to feel pain because pain, for starters, is like the whistleblower of the body. When something is not right with the body, pain helps the body detect what's wrong by causing the body to feel a form of discomfort. That sensation of pain is needed to know when it needs extra care. It's an important signal which causes you to pay more attention to your body and find ways to fix what hurts. Pain also prevents you from injuring a body part even more.
This concept is very different for CIPA patients. In fact, they do not feel any form of pain. There is a rare mutation in the gene called SCN9A (Sodium Voltage-gated Channel Alpha Subunit9), which results in the abnormal NaV1.7 sodium channels in the nociceptors. Without the influx of sodium ions, nociceptors are not activated, hence, no signal is sent to the brain by the nociceptors when there is any form of injury or alteration in the body.
Causes of CIPA
CIPA is caused by a mutation in the NTRK1- neurotrophic receptor tyrosine kinase 1 gene. The NTRK1 is the gene that provides instructions for making a protein (receptor protein that attaches or binds to another protein called NGFβ) that is essential for the development, survival, and functioning of the nerve cells (neurons), especially those that transmit information about sensations such as pain, temperature, and touch (sensory neurons). The NTRK1 gene is also called High Affinity Nerve Growth Factor Receptor, Neurotrophic Tyrosine Kinase, r, Type 1, and Ntrk1_Human.
Mutations in the NTRK1 gene lead to the formation of a protein that cannot transmit signals. Without the proper signaling, neurons die by a process of self-destruction called apoptosis. Loss of sensory neurons leads to the inability to feel pain in people with CIPA. CIPA patients also lose the nerves leading to their sweat gland which causes the anhidrosis seen in affected individuals.
In other words, CIPA patients do not feel pain due to the lack of neurons. When the neurons are not signaled, nothing is activated, that is why CIPA patients do not feel pain- absence of sensory neurons to alert the body when there is any damage or alteration.
Mode of Inheritance of CIPA
CIPA is a condition inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have the mutation. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition. However, if there is only one copy of the gene, that individual will only act as a carrier and will not express the disease phenotypically. In essence, there will be no visible signs and symptoms of the condition.
Diagnosis and Management
Patients with CIPA present in unusual ways. Some bite off the tip of their tongue, tear off their cornea while scratching their eyes when its itching. They can hardly tell when a foreign object is in the eye until it causes cornea object damage and vision problems. Burns, wounds, deep cuts, sores, even bone fractures go unnoticed. Symptoms, often times, appear early in childhood, typically at birth or during infancy.
CIPA is usually diagnosed after a complete evaluation of infants with recurrent fevers, who frequently bite their tongue, fingers, lips, other parts of the body. In older individuals, an evaluation is required if they continue to have traumatic injuries. Assessments of the sensory and autonomic functions are used to form a complete, clinical diagnosis.
Individuals with CIPA are advised to have a clinical history of complete assessment of the body, encompassing both physical and sensory functions. Regular physical examination is also advised. Genetic testing can also be used to test carriers of the disease.
There is no cure for CIPA but the condition can be managed with the help of a team of medical professionals that typically include specialists in orthopedics, pediatrics, dermatology, ophthalmology and dentistry. Parents or guardians of people with this condition are strongly advised to keep keen, watchful eyes on them at all times for any abnormality or signs of injury, and remove objects that can likely cause accidents.
Frequently Asked Questions
Is There Any Known Cure for CIPA?
At the moment, no. There is no cure for CIPA. No treatment is available to replace the missing sensation of pain or the function of sweating.
However, with gene therapy there is hope for the future. With the use of gene therapy, the mutated gene can be replaced with a functioning gene that can produce proteins responsible for the proper functioning of the nerve cells.
Individuals with the disease have to try to prevent injuries and monitor injuries carefully in order to avoid infection. Constant medical checkups are advised. Also, clinical history should be recorded and kept track of.
Do CIPA patients die early?
If diagnosed early and properly managed, individuals with CIPA tend to live a long healthy life. This is a genetic disease, not a life sentence. With good medical care and lifestyle adjustments, CIPA patients tend to live a normal, regular, productive life, just like everyone else.
Citations
Greco A, Miranda C, Pierotti MA. Rearrangements of NTRK1 gene in papillary thyroid carcinoma. Mol Cell Endocrinol. 2010 May 28;321(1):44-9. doi: 10.1016/j.mce.2009.10.009. Epub 2009 Oct 31. Review. Citation on PubMed
I Cox JJ, Reimann F, Nicholas AK, Thornton G, Roberts E, Springell K, Karbani G, Jafri H, Mannan J, Raashid Y, Al-Gazali L, Hamamy H, Valente EM, Gorman S, Williams R, McHale DP, Wood JN, Gribble FM, Woods CG. An SCN9A channelopathy causes congenital inability to experience pain. Nature. 2006 Dec 14;444(7121):894-8. Citation on PubMed
Indo Y. Molecular basis of congenital insensitivity to pain with anhidrosis (CIPA): mutations and polymorphisms in TRKA (NTRK1) gene encoding the receptor tyrosine kinase for nerve growth factor. Hum Mutat. 2001 Dec;18(6):462-71. Review. Citation on PubMed
