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 Na v1.7 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.