Congenital Analgesia- Random Notes

Congenital analgesia is a very rare condition (probably less than thirty individuals in the world) characterized by the affected individual’s inability to perceive pain despite being normal in all other respects. By ‘normal’ I mean that these individuals have normal cognition and intact and histologically normal peripheral and central nervous systems. All other sensory modalities are intact including proprioception, temperature perception and the ability to distinguish sharp and dull stimuli. This distinguishes congenital analgesia from a host of other conditions that share

the inability to experience pain. Notable amongst these other conditions are the Hereditary Sensory and Autonomic Neuropathies (HSAN) of which there are five types described. Leprosy is another condition that has pain insensitivity as a feature. But Leprosy and the HSANs involve other sensory modalities and have

histologically and physiologically abnormal peripheral nerves on biopsy.

Alternative names and terminology that have been applied to congenital analgesia are numerous and confusing. These include congenital indifference to pain, congenital insensitivity to pain and congenital universal insensitivity to pain. The first case described in the medical literature was by George Dearborn in 1932 in the Journal of Nervous and Mental disease. The four page article entitled “A Case of Congenital General Pure Analgesia” describes the

clinical features of a man with congenital analgesia. Several astounding episodes are recounted relating largely to traumatic injuries which would otherwise have been associated with considerable pain- “When seven years old, running behind a big labourer wielding a flat-edged pick, he was lifted two feet from the ground in the upswing, the dull pick-edge catching him under the right malar bone. His physician poured in tincture of iodine. He felt no pain at any time...” The man earned a living for a time as a vaudeville act, “The Human Pin-cushion”, his most spectacular feat being a re-enactment of a crucifixion complete with gold-plated spikes which were driven into his hands and feet with a sledge hammer.

Since then, numerous case reports have been published. There is only one published report in the anaesthetic literature. This was by Layman in 1986’s Anaesthesia, a case report relating the anaesthetic management of a man with congenital analgesia who underwent bilateral amputations for gross ulceration and destructive erosive arthritis of his Charcot’s joints. They decided to do the case with sedation using a total of 700mg thiopentone and 20mg midazolam over the three hour long procedure. No analgesics were given or necessary.

Congenital analgesia is a genetic disorder with the inheritance pattern being autosomal recessive. It has helped us understand the neurophysiology of pain better, especially demonstrating the distinction between the sensory and affective components of pain. It has reinforced the teleological advantage of pain as a protective sense in that subjects with congenital analgesia commonly present with significant injuries that have resulted purely from the fact that they are unaware of the injury- eg. burns, lacerations, ulcers, bitten tongue in infants.

A documentary film called “A Life Without Pain” has been made, detailing the lives of three children with congenital analgesia. Congenital analgesia has also featured in popular entertainment. Episodes of Grey’s Anatomy and House have featured characters with the condition. Most notably and recently, Swedish novelist Stieg Larsson’s Millennium series of books feature a character with congenital analgesia. Ronald Niedermann, the character, is a giant of a man who also happens to be a murderer and psychopath and hard to kill!

It is only in very recent years that scientists have managed to elucidate and describe the molecular biological basis of the disorder and this is perhaps the most interesting aspect of the condition, even more so than the ‘freak show’ acts attributed to people with congenital analgesia. James Cox et al published a paper in nature in December 2006 titled “An SCN9A channelopathy causes congenital inability to experience pain”. This blandly titled article describes an extraordinary and fascinating bit of molecular biological detective work. SCN9A is a gene that encodes a voltage-gated sodium channel known as Nav1.7. This channel is found predominantly in two types of neuron, nociceptive dorsal root ganglion neurons and sympathetic ganglion neurons. Both these neurons are intimately associated with pain nociception. Animal models of inflammatory pain express high levels of Nav1.7 and genetically engineered mice lacking the sodium channel display markedly reduced responses to pain. Cox and

colleagues performed gene mapping in three consanguineous families in Pakistan who had six members with congenital analgesia. The index case died at the age of fourteen after jumping off a roof. He liked to walk on hot coals and stick knives through his arms! They mapped the condition to an autosomal recessive trait on a part of a chromosome that contains SCN9A. Further analysis showed affected individuals had nonsense mutations causing loss of function of Nav1.7. They showed the mutations caused loss of function by performing patch clamp experiments on human embryonic kidney cells made to express the mutant channels. The article’s discussion and the accompanying editorial both highlight the theoretical huge potential therapeutic value of a specific blocker of Nav1.7 channels as an analgesic with minimal adverse effects.

As if this was not enough, a similarly impressive study of the genetics of congenital analgesia was published the following year in Clinical Genetics. Goldberg et al (Jews always interested in research into genetic disorders, especially Ashkenazi Jews) assembled the largest collection of individuals with the condition- 17 people from nine families in seven different countries (didn’t include Pakistan group studied by Cox). Gene mapping again lead to the SCN9A gene and they identified 10 mutations in the gene, nine of which resulted in loss of function of the Nav1.7 channel. The research was supported by Xenon Pharmaceuticals, a leader in developing genetically tailored drugs for neuropathic pain.

Selected References

Cox, J et al. An SCN9A channelopathy causes congenital inability to experience pain. Nature 444:894-8, 2006.

Goldberg, Y et al. Loss-of-function mutations in the Na(v)1,7 gene underlie congenital indifference to pain in multiple human populations. Clin. Genet. 71:311-19, 2007.

Nagasako, E et al. Congenital insensitivity to pain: an update. Pain 101: 213-19, 2003.