Erythromelalgia – A dramatic pain of genetic origin, revealing pain mechanisms with implications for neuropathic pain in general

1 What is erythromelalgia

For readers who have not seen a case, or maybe even have not heard of patients suffering from attacks of painful red feet (and hands), here is a brief description of a patient with an attack of this rare (1:100 000) erythromelalgia – derived from three Greek words erythros (“red”), melos (“limb”), and algos (“pain”):

A young adult woman (as always more women with pain than men), in the middle of the winter, sits with her feet and hands in a bucket of ice-water, complaining that her red feet and hands are burning painfully.

The name erythromelalgia was coined by Silas Weird Mitchell (who also described causalgia) in 1878. In 2004 erythromelalgia became the first human neuropathic pain disorder known to be caused by an ion channel mutation, in the gene SCN9A encoding the voltage-gated sodium channel α-subunit of Na_V1.7. This voltage gated sodium channel is expressed in C-fibres of peripheral nerves and in nerves of the sympathetic autonomic nervous system. Vaso-dilatation causes the red skin of erythromelalagia. A similar painful disease, secondary eythromelalgia, can be caused by side-effects of medication, e.g. verapamil and nifedipin.The attacks of erythromelalgia pain, lasting from hours to months, arise from hyperexcitability of nociceptive C-fibres and their neurons in the dorsal root ganglia and autonomic ganglia, and can be precipitated by exertion, heating of the affected extremities, or pressure to the feet. Many avoid wearing shoes or socks because the warmth this generates can be enough to start pain attacks.

There are now 10 known mutations in this gene. It is fascinating that another mutation of the SCN9A-gene causes an inborn genetic error with inability to feel pain [2]. It is also interesting the Na_V1.7 channel is where our local anaesthetic drugs have their blocking effect.

2 New pieces of knowledge about genetics and clinic of erythromelalgia

The highly qualified scientists behind this paper investigated clinically and neurophysiologically 350 patients suspected of ery-thromelalgia in Oslo. Only 48 patients were confirmed to have erythromelalgia, still asignificant number considering how rare this pain condition is (1 in 100 000).

These 48 patients were screened for mutation in the Na_V1.7 channel and 29 other known pain-related genes (e.g. genes that express other voltage gated sodium channels, sodium channel subunits, transient receptor potential channels, and neurotrophic factors), using next generation sequencing and classical Sanger sequencing.

They found the expected mutations of Na_V1.7 in 5 patients and two patients with new mutations in Na_V1.7. They also found new, rare variants of other sodium channel alpha-subunits and beta-subunits.In 20 patients, they found new mutations in several of the other 10 known voltage gated sodium channels. In Na_V1.8 (found in peripheral nervous system), Na_V1.9 (also found in peripheral nervous system), Na_V1.6 (found in central nervous system, it is the most abundant sodium channel), Na_V1.5 (found in the heart), Na_V2.1, and the genes SCN1B and SCN3B. They found mutations in transient receptor potential channels (TRPA1 and TRPV1), and in other pain-related targets (NGFR and WNK1). Thus, they found more than 20 new mutations that have not been reported before [1].

They identified clinically important aspects of four patients with the I848T mutation in the Na_V1.7 gene: they typically had early onset of erythromelalgia with sever symptoms and signs. Noclinical characteristics differentiated the other patients with other Na_V1.7 mutations from the patients without such mutations.

3 Important implications of these new research findings

The authors conclude that functionally characterized mutations of Na_V1.7 are present only in a minority of patients with erythrome-lalgia. However, they found rare protein-modifying mutations in a majority (27) of their 48 patients with neuropathic pain. They emphasize that possible roles of rare variants of sodium channels, that provoke neuropathic chronic pain, are important fields of future pain research.

But already I am convinced that functioning abnormal mutations in channels and receptors must be part of, or possibly even the most significant, explanation for why some unlucky patients develop severe chronic pain after trauma (e.g. neck trauma), after surgery (e.g. persistent post-thoracotomy pain), or after infection (e.g. post-herpes zoster neuralgia), while most patients do not.

This paper is an excellent mini-review of the highly complex science of genetics of pain. The pieces of new knowledge they have added to the existing body of knowledge of erythromelalgia, will eventually help clarify the conundrums of this dramatic disease, but I am hopeful that our present meagre understanding of neuropathic pain in general, will benefit from this research in Martin Schmelz’s and Ellen Jørum’s research teams, and from research that will have to follow in their path.