Inherited Pain Disorder: Origin Pinpointed

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Inherited Pain Disorder: Origin Pinpointed

http://www.medicalnewstoday.com/medicalnews.php?newsid=58398

The genetic basis for a rare inherited disorder that causes severe

burning pain with no warning has been pinpointed by researchers.

They found that paroxysmal extreme pain disorder (PEPD) is caused by

specific mutations in porelike sodium channels in peripheral nerve

cells-a discovery that they said emphasizes the role of such channel

disorders in inflammatory pain. Such findings of abnormal function

in disease also provide insights into the normal function of such

channels, they said.

R. Mark Gardiner, of University College London, and his colleagues

published their findings in the December 7, 2006, issue of the

journal Neuron, published by Cell Press.

So-called " voltage-gated sodium channels " are central to the

neuron's ability to propagate a nerve impulse. In response to

voltage changes in a nerve cell caused by a nerve impulse, these

channels snap open, allowing sodium to flow across the cell

membrane, further propagating the nerve impulse. Rapid, precise

activation and inactivation is key to their normal operation.

In their studies, the researchers sought to understand the basis of

PEPD, which is characterized by abrupt paroxysms of pain in the

rectum, eye, and jaw. They first performed a detailed genetic

comparison of affected and unaffected members of one large family

that showed inheritance of the disease. That analysis revealed that

mutations that compromise the gene for a component of one particular

sodium channel, called SCN9A, were the likely culprit. Further

analysis of the gene in 11 affected families and two sporadic cases,

indeed, revealed that mutations in SCN9A are responsible for the

disease in at least two-thirds of PEPD cases.

Analysis of these mutations revealed that they all disrupted the

ability of the sodium channel to rapidly snap shut, prolonging

activation of the peripheral nerves in which the channels

functioned. What's more, the researchers found, the drug

carbamazepine-known to be effective in PEPD-acts to correct this

abnormality in cultures of neurons.

The researchers also compared PEPD with another inherited pain

disorder, primary erythermalgia (PE) that is not alleviated by

carbamazepine. PE is also caused by mutations in SCN9A and is

characterized by pain in the extremities triggered by exercise or

temperature change. In contrast to PEPD, which is caused by

mutations that disrupt inactivation the sodium channel, PE arises

from mutations that lower its activation threshold.

The researchers concluded that their findings " further emphasize the

critical role of [this sodium channel] in human inflammatory pain

and explain the differential drug sensitivity of PEPD and PE. "

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The researchers include Caroline R. Fertleman, A. ,

Moffatt, Frances V. Elmslie, R. Mark Gardiner, and Michele

Rees of Royal Free and University College Medical School, University

College London in London, UK; Mark D. Baker, Bjarke Abrahamsen, and

N. Wood of University College London in London, UK; Johan

Ostman of Queen 's School of Medicine and Dentistry in London,

UK; Norbert Klugbauer of Albert-Ludwigs-Universitat Freiburg in

Freiburg, Germany.

This work was funded by The Wellcome Trust (Research Training

Fellowship, C.R.F.) and MRC (UK).

Fertleman et al.: " SCN9A Mutations in Paroxysmal Extreme Pain

Disorder: Allelic Variants Underlie Distinct Channel Defects and

Phenotypes. " Publishing in Neuron 52, 767-774, December 7, 2006 DOI

10.1016/j.neuron.2006.10.006. http://www.neuron.org/