Congenital insensitivity to pain

Last updated
Congenital insensitivity to pain
Specialty Neurology

Congenital insensitivity to pain (CIP), also known as congenital analgesia, is one or more extraordinarily rare conditions in which a person cannot feel (and has never felt) physical pain. [1] The conditions described here are separate from the HSAN group of disorders, which have more specific signs and cause. Because feeling physical pain is vital for survival, CIP is an extremely dangerous condition. [1] It is common for people with the condition to die in childhood due to injuries or illnesses going unnoticed. [1] [2] Burn injuries are among the more common injuries. [2]

Contents

Signs and symptoms

A patient and doctor discuss congenital insensitivity to pain

For people with this disorder, cognition and sensation are otherwise normal; for instance, patients can still feel discriminative touch (though not always temperature [3] ), and there are generally no detectable physical abnormalities.

Because children and adults with the disorder cannot feel pain, they may not respond to problems, thus being at a higher risk of more severe diseases. Children with this condition often sustain oral cavity damage both in and around the oral cavity (such as having bitten off the tip of their tongue) or fractures to bones. [2] Unnoticed infections and corneal damage due to foreign objects in the eye are also seen. [2] [4]

There are generally two types of non-response exhibited: [1] [4]

Causes

It may be that the condition is caused by increased production of endorphins in the brain.[ citation needed ] In this case, naloxone may be a treatment, but it does not always work. [5] In all cases, this disorder can be in the voltage-gated sodium channel SCN9A (Nav1.7). [6] Patients with such mutations are congenitally insensitive to pain and lack other neuropathies. There are three mutations in SCN9A: W897X, located in the P-loop of domain 2; I767X, located in the S2 segment of domain 2; and S459X, located in the linker region between domains 1 and 2. This results in a truncated non-functional protein. Nav1.7 channels are expressed at high levels in nociceptive neurons of the dorsal root ganglia. As these channels are likely involved in the formation and propagation of action potentials in such neurons, it is expected that a loss of function mutation in SCN9A leads to abolished nociceptive pain propagation. [7] [8]

PRDM12 gene is normally switched on during the development of pain-sensing nerve cells. People with homozygous mutations of the PRDM12 gene experience congenital insensitivity to pain (CIP). [9] [10]

Homozygous microdeletion in the FAAH-OUT pseudogene of the fatty acid amide hydrolase chromosomal region that is expressed in the brain and dorsal root ganglia was identified as the cause of congenital analgesia in a single individual (as of 2019). The individual experienced lifelong insensitivity to pain and was oblivious to cuts and burns, did not experience pain during childbirth, did not experience pain from degeneration of a hip that required hip replacement surgery, and did not require analgesics for postoperative pain. Furthermore, the individual exhibited expedited wound healing and reduced scarring, could not sense heat from chili peppers, did not experience depression, fear, and anxiety and lacked a normal fear response to erratic and aggressive behaviour. However, the individual also experienced slight memory impairment (was prone to losing the trail of thought while speaking, and experienced some forgetfulness), and could not experience thrill ("adrenaline rush"). [11] [12]

Another gene implicated in human pain insensitivity is ZFHX2, which encodes zinc finger homeobox 2. A 2018 study analysed six members of a family with inherited pain insensitivity and identified a "novel point mutation in ZFHX2, encoding a putative transcription factor expressed in small diameter sensory neurons", as the cause. As a therapeutic application, the study further discuses how "the ZFHX2 variant and downstream regulated genes associated with a human pain-insensitive phenotype are ... potential novel targets for the development of new analgesic drugs". [13]

Developmental disabilities such as autism can include varying degrees of pain insensitivity as a sign. [14] However, since these disorders are characterized by dysfunction of the sensory system in general, autism is not in itself an indicator of congenital insensitivity to pain.

Treatment

The opioid antagonist naloxone allowed a woman with congenital insensitivity to pain to experience it for the first time. [15] Similar effects were observed in Nav1.7 null mice treated with naloxone. [15] As such, opioid antagonists like naloxone and naltrexone may be effective in treating the condition. [15]

Epidemiology

It has been estimated to have a worldwide incidence of approximately 1 in every 125 million births. [16]

Congenital insensitivity to pain is found at an abnormally high frequency in Vittangi, a village in Kiruna Municipality in northern Sweden, where nearly 40 cases have been reported. [17]

See also

Related Research Articles

<span class="mw-page-title-main">Spinal muscular atrophies</span> Group of disorders

Spinal muscular atrophies (SMAs) are a genetically and clinically heterogeneous group of rare debilitating disorders characterised by the degeneration of lower motor neurons and subsequent atrophy (wasting) of various muscle groups in the body. While some SMAs lead to early infant death, other diseases of this group permit normal adult life with only mild weakness.

<span class="mw-page-title-main">Opioid use disorder</span> Medical condition

Opioid use disorder (OUD) is a substance use disorder characterized by cravings for opioids, continued use despite physical and/or psychological deterioration, increased tolerance with use, and withdrawal symptoms after discontinuing opioids. Opioid withdrawal symptoms include nausea, muscle aches, diarrhea, trouble sleeping, agitation, and a low mood. Addiction and dependence are important components of opioid use disorder.

<span class="mw-page-title-main">Buprenorphine</span> Opioid used to treat pain & opioid use disorder

Buprenorphine, sold under the brand name Subutex among others, is an opioid used to treat opioid use disorder, acute pain, and chronic pain. It can be used under the tongue (sublingual), in the cheek (buccal), by injection, as a skin patch (transdermal), or as an implant. For opioid use disorder, the patient must have moderate opioid withdrawal symptoms before buprenorphine can be administered under direct observation of a health-care provider.

<span class="mw-page-title-main">Erythromelalgia</span> Inflammation due to periodic blood vessel blockage

Erythromelalgia or Mitchell's disease is a rare vascular peripheral pain disorder in which blood vessels, usually in the lower extremities or hands, are episodically blocked, then become hyperemic and inflamed. There is severe burning pain and skin redness. The attacks are periodic and are commonly triggered by heat, pressure, mild activity, exertion, insomnia or stress. Erythromelalgia may occur either as a primary or secondary disorder. Secondary erythromelalgia can result from small fiber peripheral neuropathy of any cause, polycythemia vera, essential thrombocythemia, hypercholesterolemia, mushroom or mercury poisoning, and some autoimmune disorders. Primary erythromelalgia is caused by mutation of the voltage-gated sodium channel α-subunit gene SCN9A.

<span class="mw-page-title-main">Congenital insensitivity to pain with anhidrosis</span> Medical condition

Congenital insensitivity to pain with anhidrosis (CIPA) is a rare autosomal recessive disorder of the nervous system which prevents the feeling of pain or temperature, and prevents a person from sweating. Cognitive disorders are commonly coincident. CIPA is the fourth type of hereditary sensory and autonomic neuropathy (HSAN), and is also known as HSAN IV.

<span class="mw-page-title-main">Periaqueductal gray</span> Nucleus surrounding the cerebral aqueduct

The periaqueductal gray is a brain region that plays a critical role in autonomic function, motivated behavior and behavioural responses to threatening stimuli. PAG is also the primary control center for descending pain modulation. It has enkephalin-producing cells that suppress pain.

<span class="mw-page-title-main">Fatty-acid amide hydrolase 1</span> Mammalian protein found in Homo sapiens

Fatty-acid amide hydrolase 1 (FAAH) is a member of the serine hydrolase family of enzymes. It was first shown to break down anandamide (AEA), an N-acylethanolamine (NAE) in 1993. In humans, it is encoded by the gene FAAH.

Small fiber peripheral neuropathy is a type of peripheral neuropathy that occurs from damage to the small unmyelinated and myelinated peripheral nerve fibers. These fibers, categorized as C fibers and small Aδ fibers, are present in skin, peripheral nerves, and organs. The role of these nerves is to innervate some skin sensations and help control autonomic function. It is estimated that 15–20 million people in the United States have some form of peripheral neuropathy.

Na<sub>v</sub>1.7 Protein-coding gene in the species Homo sapiens

Nav1.7 is a sodium ion channel that in humans is encoded by the SCN9A gene. It is usually expressed at high levels in two types of neurons: the nociceptive (pain) neurons at the dorsal root ganglion (DRG) and trigeminal ganglion; and sympathetic ganglion neurons, which are part of the autonomic (involuntary) nervous system.

Na<sub>v</sub>1.9 Protein-coding gene in the species Homo sapiens

Sodium channel, voltage-gated, type XI, alpha subunit also known as SCN11A or Nav1.9 is a voltage-gated sodium ion channel protein which is encoded by the SCN11A gene on chromosome 3 in humans. Like Nav1.7 and Nav1.8, Nav1.9 plays a role in pain perception. This channel is largely expressed in small-diameter nociceptors of the dorsal root ganglion and trigeminal ganglion neurons, but is also found in intrinsic myenteric neurons.

Paroxysmal extreme pain disorder originally named familial rectal pain syndrome, is a rare disorder whose most notable features are pain in the mandibular, ocular and rectal areas as well as flushing. PEPD often first manifests at the beginning of life, perhaps even in utero, with symptoms persisting throughout life. PEPD symptoms are reminiscent of primary erythromelalgia, as both result in flushing and episodic pain, though pain is typically present in the extremities for primary erythromelalgia. Both of these disorders have recently been shown to be allelic, both caused by mutations in the voltage-gated sodium channel NaV1.7 encoded by the gene SCN9A. A different mutation in the SCN9A ion channel causes congenital insensitivity to pain.

Hereditary sensory and autonomic neuropathy (HSAN) or hereditary sensory neuropathy (HSN) is a condition used to describe any of the types of this disease which inhibit sensation.

Hereditary sensory neuropathy, type II also known as HSN2 is a region of a parent protein which in humans is encoded by the WNK1 gene. It is a transcript variant of the WNK1 gene that is selectively expressed in nervous system tissues, and during development. Mutations in this exon of the WNK1 gene have been identified as causative in genetic neuropathy syndromes, and in inherited pain insensitivity.

Na<sub>v</sub>1.8 Protein-coding gene in the species Homo sapiens

Nav1.8 is a sodium ion channel subtype that in humans is encoded by the SCN10A gene.

Hereditary sensory and autonomic neuropathy type I or hereditary sensory neuropathy type I is a group of autosomal dominant inherited neurological diseases that affect the peripheral nervous system particularly on the sensory and autonomic functions. The hallmark of the disease is the marked loss of pain and temperature sensation in the distal parts of the lower limbs. The autonomic disturbances, if present, manifest as sweating abnormalities.

<span class="mw-page-title-main">PRDM12</span> Protein-coding gene in the species Homo sapiens

PR domain zinc finger protein 12 is a protein that in humans is encoded by the PRDM12 gene. This gene is normally switched on during the development of pain-sensing nerve cells. People with homozygous mutations of the PRDM12 gene experience congenital insensitivity to pain (CIP). PRMD12 is a part of a larger domain that mediate histone methyltransferases. Enzymes target gene promoters in order to control gene expression.

<span class="mw-page-title-main">Zinc finger homeobox 2</span> Protein-coding gene in the species Homo sapiens

Zinc finger homeobox 2 is a protein that in humans is encoded by the ZFHX2 gene. It has been implicated in pain insensitivity.

The eradication or abolition of suffering is the concept of using biotechnology to create a permanent absence of involuntary pain and suffering in all sentient beings.

<span class="mw-page-title-main">17q12 microdeletion syndrome</span> Rare genetic anomaly in humans

17q12 microdeletion syndrome, also known as 17q12 deletion syndrome, is a rare chromosomal anomaly caused by the deletion of a small amount of material from a region in the long arm of chromosome 17. It is typified by deletion of the HNF1B gene, resulting in kidney abnormalities and renal cysts and diabetes syndrome. It also has neurocognitive effects, and has been implicated as a genetic factor for autism and schizophrenia.

<span class="mw-page-title-main">Marsili syndrome</span> Medical condition

Marsili syndrome is an extremely rare genetic disorder which is characterized by symptoms similar to those reported on individuals with congenital insensitivity to pain with anhidrosis. It can be fatal if it goes unnoticed/undiagnosed.

References

  1. 1 2 3 4 Linton S (2005). Understanding Pain for Better Clinical Practice: A Psychological Perspective. Elsevier Health Sciences. p. 14. ISBN   978-0444515919 . Retrieved April 13, 2017.
  2. 1 2 3 4 Hellier JL (2016). The Five Senses and Beyond: The Encyclopedia of Perception. ABC-CLIO. pp. 118–119. ISBN   978-1440834172 . Retrieved April 13, 2017.
  3. ↑ Online Mendelian Inheritance in Man (OMIM): Insensitivity to Pain, Congenital, with Anhidrosis; CIPA - 256800
  4. 1 2 Brodsky MC (2016). Pediatric Neuro-Ophthalmology. Springer. p. 741. ISBN   978-1493933846 . Retrieved April 13, 2017.
  5. ↑ Manfredi M, Bini G, Cruccu G, Accornero N, Berardelli A, Medolago L (August 1981). "Congenital absence of pain". Archives of Neurology. 38 (8): 507–11. doi:10.1001/archneur.1981.00510080069010. PMID   6166287.
  6. ↑ Bennett DL, Clark AJ, Huang J, Waxman SG, Dib-Hajj SD (April 2019). "The Role of Voltage-Gated Sodium Channels in Pain Signaling". Physiological Reviews. 99 (2): 1079–1151. doi: 10.1152/physrev.00052.2017 . PMID   30672368.
  7. ↑ Cox JJ, Reimann F, Nicholas AK, Thornton G, Roberts E, Springell K, et al. (December 2006). "An SCN9A channelopathy causes congenital inability to experience pain". Nature. 444 (7121): 894–8. Bibcode:2006Natur.444..894C. doi:10.1038/nature05413. PMC   7212082 . PMID   17167479.
  8. ↑ McDermott LA, Weir GA, Themistocleous AC, Segerdahl AR, Blesneac I, Baskozos G, Clark AJ, Millar V, Peck LJ, Ebner D, Tracey I, Serra J, Bennett DL (March 2019). "V1.7 in Human Nociception". Neuron. 101 (5): 905–919.e8. doi:10.1016/j.neuron.2019.01.047. PMC   6424805 . PMID   30795902.
  9. ↑ Chen YC, Auer-Grumbach M, Matsukawa S, Zitzelsberger M, Themistocleous AC, Strom TM, et al. (July 2015). "Transcriptional regulator PRDM12 is essential for human pain perception". Nature Genetics. 47 (7): 803–8. doi:10.1038/ng.3308. hdl: 2262/75983 . PMC   7212047 . PMID   26005867.
  10. ↑ Costandi M (2015-05-25). "Uncomfortably numb: The people who feel no pain". the guardian. Retrieved 31 July 2015.
  11. ↑ Murphy H (2019-03-28). "At 71, She's Never Felt Pain or Anxiety. Now Scientists Know Why". The New York Times. ISSN   0362-4331 . Retrieved 2019-03-30.
  12. ↑ Habib AM, Okorokov AL, Hill MN, Bras JT, Lee MC, Li S, Gossage SJ, van Drimmelen M, Morena M, Houlden H, Ramirez JD, Bennett DL, Srivastava D, Cox JJ (22 February 2019). "Microdeletion in a FAAH pseudogene identified in a patient with high anandamide concentrations and pain insensitivity". British Journal of Anaesthesia. 123 (2): e249–e253. doi:10.1016/j.bja.2019.02.019. PMC   6676009 . PMID   30929760.
  13. ↑ Habib, Abdella M.; Matsuyama, Ayako; Okorokov, Andrei L.; Santana-Varela, Sonia; Bras, Jose T.; Aloisi, Anna Maria; Emery, Edward C.; Bogdanov, Yury D.; Follenfant, Maryne; Gossage, Sam J.; Gras, Mathilde (2018-02-01). "A novel human pain insensitivity disorder caused by a point mutation in ZFHX2". Brain: A Journal of Neurology. 141 (2): 365–376. doi:10.1093/brain/awx326. ISSN   1460-2156. PMC   5837393 . PMID   29253101.
  14. ↑ Wolraich M (2008). Developmental-behavioral Pediatrics: Evidence and Practice. Elsevier Health Sciences. p. 399. ISBN   9780323040259.
  15. 1 2 3 Minett MS, Pereira V, Sikandar S, Matsuyama A, Lolignier S, Kanellopoulos AH, Mancini F, Iannetti GD, Bogdanov YD, Santana-Varela S, Millet Q, Baskozos G, MacAllister R, Cox JJ, Zhao J, Wood JN (December 2015). "Endogenous opioids contribute to insensitivity to pain in humans and mice lacking sodium channel Nav1.7". Nature Communications. 6 (1): 8967. Bibcode:2015NatCo...6.8967M. doi:10.1038/ncomms9967. PMC   4686868 . PMID   26634308.
  16. ↑ KARIMI, Mehran; LLAH, Razieh FA (Summer 2012). "A Case Report of Congenital Insensitivity to Pain and Anhidrosis (CIPA)". Iranian Journal of Child Neurology. 6 (3): 45–48. PMC   3943025 . PMID   24665272.
  17. ↑ Minde JK (April 2006). "Norrbottnian congenital insensitivity to pain". Acta Orthopaedica. Supplementum. 77 (321): 2–32. PMID   16768023.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.